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n2:pmcid: PMC0
bibo:doi: 10.1007%2Fs00018-013-1514-y
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Subject Item: _:vb26774195
rdf:type: n5:Section
dc:title: introduction
n5:contains: _:vb26774200 _:vb26774201 _:vb26774202 _:vb26774203 _:vb26774204 _:vb26774205 _:vb26774206 _:vb26774207 _:vb26774196 _:vb26774197 _:vb26774198 _:vb26774199 _:vb26774208 _:vb26774209 _:vb26774210 _:vb26774211 _:vb26774212 _:vb26774213

Subject Item: _:vb26774196
rdf:type: n2:Context
rdf:value: Although different receptor families utilize common intracellular signaling-proteins and activate common signaling pathways, each cell surface receptor family leads to specific biological outcomes in the cell [>>1<<].
n2:mentions: n3:20602996

Subject Item: _:vb26774197
rdf:type: n2:Context
rdf:value: The receptor tyrosine kinases (RTKs) represent one major cell surface receptor family, containing around 60 members, subdivided into at least 13 receptor families [>>2<<, 3]. The RTKs are defined by the presence of an intracellular tyrosine kinase domain and typically a large glycosylated extracellular ligand binding domain, separated by a single transmembrane pass [4].
n2:mentions: n3:1659742

Subject Item: _:vb26774198
rdf:type: n2:Context
rdf:value: The receptor tyrosine kinases (RTKs) represent one major cell surface receptor family, containing around 60 members, subdivided into at least 13 receptor families [2, >>3<<]. The RTKs are defined by the presence of an intracellular tyrosine kinase domain and typically a large glycosylated extracellular ligand binding domain, separated by a single transmembrane pass [4].
n2:mentions: n3:17002595

Subject Item: _:vb26774199
rdf:type: n2:Context
rdf:value: The RTKs are defined by the presence of an intracellular tyrosine kinase domain and typically a large glycosylated extracellular ligand binding domain, separated by a single transmembrane pass [>>4<<]. Traditionally defined by their ligands and hence ligand binding domains, the cytoplasmic kinase regions, juxtamembrane domain and carboxyl (C)-terminal tail also differ significantly among the individual receptors.
n2:mentions: n3:2158859

Subject Item: _:vb26774200
rdf:type: n2:Context
rdf:value: The agonist stabilizes the “ON” state through autophosphorylation of tyrosine residues within the kinase domain, followed by exponential increase in its kinase activity and subsequent activation of the intra-cellular signaling pathways [>>1<<]. In most cases, the ligand-induced activation of the kinase domain is mediated by receptor oligomerization (for reviews, see [4–6]).
n2:mentions: n3:20602996

Subject Item: _:vb26774201
rdf:type: n2:Context
rdf:value: In most cases, the ligand-induced activation of the kinase domain is mediated by receptor oligomerization (for reviews, see [>>4<<–6]). This event favors interactions between cytoplasmic kinase-partners and induces kinase transactivation. Dimerization can take place between two identical receptors (homodimerization), between different members of the same receptor
n2:mentions: n3:2158859 n3:7834741 n3:9708728

Subject Item: _:vb26774202
rdf:type: n2:Context
rdf:value: Dimerization can take place between two identical receptors (homodimerization), between different members of the same receptor family, or, in some cases, between a receptor and an accessory protein (heterodimerization) [>>6<<–9]. How ligands bind to receptors and induce oligomerization seems specific for each class of RTK [7, 10].
n2:mentions: n3:7855887 n3:8864349 n3:7834741 n3:8033211

Subject Item: _:vb26774203
rdf:type: n2:Context
rdf:value: How ligands bind to receptors and induce oligomerization seems specific for each class of RTK [>>7<<, 10].
n2:mentions: n3:8864349

Subject Item: _:vb26774204
rdf:type: n2:Context
rdf:value: How ligands bind to receptors and induce oligomerization seems specific for each class of RTK [7, >>10<<].
n2:mentions: n3:9428509

Subject Item: _:vb26774205
rdf:type: n2:Context
rdf:value: From the first discovery of a mutated RTK in cancer in 1984 [>>11<<], a huge amount of information about aberrant RTK signaling in cancer has built up, leading to incontestable recognition of various forms of RTK hyper-activation in cancer:
n2:mentions: n3:6328312

Subject Item: _:vb26774206
rdf:type: n2:Context
rdf:value: up, leading to incontestable recognition of various forms of RTK hyper-activation in cancer: gene amplification, overexpression, mutation, or autocrine growth factor loops that are responsible for the cancer-promoting potential of RTKs [>>12<<].
n2:mentions: n3:17496923

Subject Item: _:vb26774207
rdf:type: n2:Context
rdf:value: The fundamental evidence for this is the demonstration that IGF-1R knock-out mouse embryonic cells are refractory to transformation by several oncogenes, viruses, or over-expression of other RTKs [>>13<<]. Subsequently, IGF-1R and its natural ligands were demonstrated to regulate multiple cellular functions essential for the malignant phenotype including cellular proliferation, survival, anchorage-independent growth, tumor
n2:mentions: n3:8196606

Subject Item: _:vb26774208
rdf:type: n2:Context
rdf:value: were demonstrated to regulate multiple cellular functions essential for the malignant phenotype including cellular proliferation, survival, anchorage-independent growth, tumor neovascularization, migration, invasion, and metastasis [>>14<<–17]. Confirming this critical role, in preclinical settings, a large amount of experimental data clearly demonstrates that inhibition of IGF-1R would be beneficial for cancer treatment [18–24].
n2:mentions: n3:18515591 n3:14601044 n3:11773005 n3:16489097

Subject Item: _:vb26774209
rdf:type: n2:Context
rdf:value: Confirming this critical role, in preclinical settings, a large amount of experimental data clearly demonstrates that inhibition of IGF-1R would be beneficial for cancer treatment [>>18<<–24]. In vivo and in vitro studies using IGF-1R antibodies, small molecule inhibitors, and antisense technology have shown that IGF-1R is functionally essential for tumor cell growth and proliferation in most if not all forms of cancer
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Subject Item: _:vb26774210
rdf:type: n2:Context
rdf:value: In vivo and in vitro studies using IGF-1R antibodies, small molecule inhibitors, and antisense technology have shown that IGF-1R is functionally essential for tumor cell growth and proliferation in most if not all forms of cancer [>>23<<, 25–28]. On the other hand, in clinical settings, no clear mechanism of aberrant IGF-1R could be recognized:
n2:mentions: n3:16083341

Subject Item: _:vb26774211
rdf:type: n2:Context
rdf:value: In vivo and in vitro studies using IGF-1R antibodies, small molecule inhibitors, and antisense technology have shown that IGF-1R is functionally essential for tumor cell growth and proliferation in most if not all forms of cancer [23, >>25<<–28]. On the other hand, in clinical settings, no clear mechanism of aberrant IGF-1R could be recognized:
n2:mentions: n3:19663769 n3:18267106 n3:19581933 n3:19790231

Subject Item: _:vb26774212
rdf:type: n2:Context
rdf:value: On the other hand, in clinical settings, no clear mechanism of aberrant IGF-1R could be recognized: IGF-1 or IGF-1R over-expression is not a general rule [>>17<<, 29], the receptor does not show intrinsic receptor abnormalities [30], and therefore other regulatory pathways and quantitative changes are likely to be involved and have to be considered.
n2:mentions: n3:11773005

Subject Item: _:vb26774213
rdf:type: n2:Context
rdf:value: On the other hand, in clinical settings, no clear mechanism of aberrant IGF-1R could be recognized: IGF-1 or IGF-1R over-expression is not a general rule [17, >>29<<], the receptor does not show intrinsic receptor abnormalities [30], and therefore other regulatory pathways and quantitative changes are likely to be involved and have to be considered.
n2:mentions: n3:11016658

Subject Item: _:vb26774214
rdf:type: n5:Section
dc:title: implications for treatment
n5:contains: _:vb26774292 _:vb26774288 _:vb26774289 _:vb26774290 _:vb26774291 _:vb26774284 _:vb26774285 _:vb26774286 _:vb26774287 _:vb26774280 _:vb26774281 _:vb26774282 _:vb26774283 _:vb26774276 _:vb26774277 _:vb26774278 _:vb26774279 _:vb26774272 _:vb26774273 _:vb26774274 _:vb26774275 _:vb26774268 _:vb26774269 _:vb26774270 _:vb26774271 _:vb26774264 _:vb26774265 _:vb26774266 _:vb26774267 _:vb26774260 _:vb26774261 _:vb26774262 _:vb26774263 _:vb26774256 _:vb26774257 _:vb26774258 _:vb26774259 _:vb26774252 _:vb26774253 _:vb26774254 _:vb26774255 _:vb26774248 _:vb26774249 _:vb26774250 _:vb26774251 _:vb26774244 _:vb26774245 _:vb26774246 _:vb26774247 _:vb26774240 _:vb26774241 _:vb26774242 _:vb26774243 _:vb26774236 _:vb26774237 _:vb26774238 _:vb26774239 _:vb26774232 _:vb26774233 _:vb26774234 _:vb26774235 _:vb26774228 _:vb26774229 _:vb26774230 _:vb26774231 _:vb26774224 _:vb26774225 _:vb26774226 _:vb26774227 _:vb26774220 _:vb26774221 _:vb26774222 _:vb26774223 _:vb26774216 _:vb26774217 _:vb26774218 _:vb26774219 _:vb26774215

Subject Item: _:vb26774215
rdf:type: n2:Context
rdf:value: Owing to its essential role in maintaining the malignant phenotype, IGF-1R-targeted therapy was considered a very promising strategy for cancer treatment [>>205<<–214]. Although several approaches targeting the IGF-1R were employed to prove the concept, the common aim for all these strategies is the inhibition of the classical kinase signaling cascade (for reviews, see [26, 27, 91, 215]).
n2:mentions: n3:7866982 n3:10940491 n3:9829727 n3:1594587 n3:8083365 n3:9699666 n3:1421419 n3:8174129 n3:8069850 n3:7923191

Subject Item: _:vb26774216
rdf:type: n2:Context
rdf:value: Although several approaches targeting the IGF-1R were employed to prove the concept, the common aim for all these strategies is the inhibition of the classical kinase signaling cascade (for reviews, see [>>26<<, 27, 91, 215]).
n2:mentions: n3:19663769

Subject Item: _:vb26774217
rdf:type: n2:Context
rdf:value: Although several approaches targeting the IGF-1R were employed to prove the concept, the common aim for all these strategies is the inhibition of the classical kinase signaling cascade (for reviews, see [26, >>27<<, 91, 215]).
n2:mentions: n3:19581933

Subject Item: _:vb26774218
rdf:type: n2:Context
rdf:value: Although several approaches targeting the IGF-1R were employed to prove the concept, the common aim for all these strategies is the inhibition of the classical kinase signaling cascade (for reviews, see [26, 27, >>91<<, 215]). This can be accomplished either by preventing ligand–receptor interaction (e.g., using blocking antibodies) or silencing the effects of this interaction (e.g., tyrosine kinase inhibitors, TKIs).
n2:mentions: n3:22761272

Subject Item: _:vb26774219
rdf:type: n2:Context
rdf:value: Although several approaches targeting the IGF-1R were employed to prove the concept, the common aim for all these strategies is the inhibition of the classical kinase signaling cascade (for reviews, see [26, 27, 91, >>215<<]). This can be accomplished either by preventing ligand–receptor interaction (e.g., using blocking antibodies) or silencing the effects of this interaction (e.g., tyrosine kinase inhibitors, TKIs).
n2:mentions: n3:21356169

Subject Item: _:vb26774220
rdf:type: n2:Context
rdf:value: Receptor downregulation was among the first approaches used to prevent ligand–receptor interaction and to validate IGF-1R as a therapeutic target [>>216<<]. This was achieved by antisense oligonucleotides, plasmids expressing IGF-1R antisense cDNA or triple helix-forming oligodeoxynucleotides [23].
n2:mentions: n3:11114737

Subject Item: _:vb26774221
rdf:type: n2:Context
rdf:value: This was achieved by antisense oligonucleotides, plasmids expressing IGF-1R antisense cDNA or triple helix-forming oligodeoxynucleotides [>>23<<]. The same outcome was obtained with drugs interfering with IGF-1R glycosylation, folding and expression at the cell surface (tunicamycin or lovastatin) [17–19, 217] or by directly increasing receptor degradation [114, 218]. The majority
n2:mentions: n3:16083341

Subject Item: _:vb26774222
rdf:type: n2:Context
rdf:value: The same outcome was obtained with drugs interfering with IGF-1R glycosylation, folding and expression at the cell surface (tunicamycin or lovastatin) [>>17<<–19, 217] or by directly increasing receptor degradation [114, 218].
n2:mentions: n3:9882513 n3:10888037 n3:11773005

Subject Item: _:vb26774223
rdf:type: n2:Context
rdf:value: The same outcome was obtained with drugs interfering with IGF-1R glycosylation, folding and expression at the cell surface (tunicamycin or lovastatin) [17–19, >>217<<] or by directly increasing receptor degradation [114, 218].
n2:mentions: n3:10705577

Subject Item: _:vb26774224
rdf:type: n2:Context
rdf:value: The same outcome was obtained with drugs interfering with IGF-1R glycosylation, folding and expression at the cell surface (tunicamycin or lovastatin) [17–19, 217] or by directly increasing receptor degradation [>>114<<, 218]. The majority of these systems were unsuitable for transfer to the clinic, either because they were unable to be delivered or because they were too unspecific, so the next work in this area focused on clinically suitable methods for
n2:mentions: n3:7622464

Subject Item: _:vb26774225
rdf:type: n2:Context
rdf:value: The same outcome was obtained with drugs interfering with IGF-1R glycosylation, folding and expression at the cell surface (tunicamycin or lovastatin) [17–19, 217] or by directly increasing receptor degradation [114, >>218<<]. The majority of these systems were unsuitable for transfer to the clinic, either because they were unable to be delivered or because they were too unspecific, so the next work in this area focused on clinically suitable methods for
n2:mentions: n3:11278993

Subject Item: _:vb26774226
rdf:type: n2:Context
rdf:value: In this category are included strategies that involve upregulation of the IGFBPs, the natural IGF inhibitors [>>219<<], IGFs peptide analogues [219, 220], or ligand or receptor neutralizing antibodies [206, 221].
n2:mentions: n3:1385103

Subject Item: _:vb26774227
rdf:type: n2:Context
rdf:value: In this category are included strategies that involve upregulation of the IGFBPs, the natural IGF inhibitors [219], IGFs peptide analogues [>>219<<, 220], or ligand or receptor neutralizing antibodies [206, 221]. There are seven different IGFBPs, most of them have been shown to inhibit the actions of IGFs.
n2:mentions: n3:1385103

Subject Item: _:vb26774228
rdf:type: n2:Context
rdf:value: In this category are included strategies that involve upregulation of the IGFBPs, the natural IGF inhibitors [219], IGFs peptide analogues [219, >>220<<], or ligand or receptor neutralizing antibodies [206, 221]. There are seven different IGFBPs, most of them have been shown to inhibit the actions of IGFs.
n2:mentions: n3:8439954

Subject Item: _:vb26774229
rdf:type: n2:Context
rdf:value: In this category are included strategies that involve upregulation of the IGFBPs, the natural IGF inhibitors [219], IGFs peptide analogues [219, 220], or ligand or receptor neutralizing antibodies [>>206<<, 221]. There are seven different IGFBPs, most of them have been shown to inhibit the actions of IGFs.
n2:mentions: n3:7923191

Subject Item: _:vb26774230
rdf:type: n2:Context
rdf:value: In this category are included strategies that involve upregulation of the IGFBPs, the natural IGF inhibitors [219], IGFs peptide analogues [219, 220], or ligand or receptor neutralizing antibodies [206, >>221<<]. There are seven different IGFBPs, most of them have been shown to inhibit the actions of IGFs.
n2:mentions: n3:2961338

Subject Item: _:vb26774231
rdf:type: n2:Context
rdf:value: In vitro and in vivo experiments indicate that increasing IGFBPs could be an alternative to IGF-1R targeting, particularly due to the lack of interference with insulin signaling [>>222<<]. There is also evidence that free IGFBPs have anti-tumor activity independent of their IGF-binding capacity [223]. Anti-ligand antibodies, developed to mimic IGFBP action, have a high affinity against both IGF-1 and IGF-2, and do not
n2:mentions: n3:20599789

Subject Item: _:vb26774232
rdf:type: n2:Context
rdf:value: There is also evidence that free IGFBPs have anti-tumor activity independent of their IGF-binding capacity [>>223<<]. Anti-ligand antibodies, developed to mimic IGFBP action, have a high affinity against both IGF-1 and IGF-2, and do not cross-react with insulin [224–226]. Several antibodies targeting IGF-1 or IGF-2 have been reported, with one reaching
n2:mentions: n3:12466191

Subject Item: _:vb26774233
rdf:type: n2:Context
rdf:value: Anti-ligand antibodies, developed to mimic IGFBP action, have a high affinity against both IGF-1 and IGF-2, and do not cross-react with insulin [>>224<<–226]. Several antibodies targeting IGF-1 or IGF-2 have been reported, with one reaching clinical trial [225]. They prevent signaling through the IGF-1R and the hybrid receptors, but, importantly, they do not affect insulin-stimulated
n2:mentions: n3:20515953 n3:21750218 n3:21245093

Subject Item: _:vb26774234
rdf:type: n2:Context
rdf:value: Several antibodies targeting IGF-1 or IGF-2 have been reported, with one reaching clinical trial [>>225<<]. They prevent signaling through the IGF-1R and the hybrid receptors, but, importantly, they do not affect insulin-stimulated phosphorylation of the insulin receptor (IR) and its downstream signaling. While most of the ligand-targeting
n2:mentions: n3:21245093

Subject Item: _:vb26774235
rdf:type: n2:Context
rdf:value: While most of the ligand-targeting antibodies bind to both IGFs, a few have higher affinity for IGF-2 [>>224<<, 226, 227].
n2:mentions: n3:20515953

Subject Item: _:vb26774236
rdf:type: n2:Context
rdf:value: While most of the ligand-targeting antibodies bind to both IGFs, a few have higher affinity for IGF-2 [224, >>226<<, 227]. Notably, antibody sequestration of ligand can lead to high levels of free IGFBPs, a consequence that might improve their intended effect [93].
n2:mentions: n3:21750218

Subject Item: _:vb26774237
rdf:type: n2:Context
rdf:value: While most of the ligand-targeting antibodies bind to both IGFs, a few have higher affinity for IGF-2 [224, 226, >>227<<]. Notably, antibody sequestration of ligand can lead to high levels of free IGFBPs, a consequence that might improve their intended effect [93].
n2:mentions: n3:16432169

Subject Item: _:vb26774238
rdf:type: n2:Context
rdf:value: Notably, antibody sequestration of ligand can lead to high levels of free IGFBPs, a consequence that might improve their intended effect [>>93<<].
n2:mentions: n3:22337149

Subject Item: _:vb26774239
rdf:type: n2:Context
rdf:value: Antibodies against the extracellular ligand binding domain of the IGF-1R were designed to block ligand–receptor interaction [>>27<<, 93]. This strategy was considered to be very promising, and therefore most of the large pharmaceutical companies developed anti-IGF-1R antibodies and those demonstrating significant activity in preclinical settings were taken forward for
n2:mentions: n3:19581933

Subject Item: _:vb26774240
rdf:type: n2:Context
rdf:value: Antibodies against the extracellular ligand binding domain of the IGF-1R were designed to block ligand–receptor interaction [27, >>93<<]. This strategy was considered to be very promising, and therefore most of the large pharmaceutical companies developed anti-IGF-1R antibodies and those demonstrating significant activity in preclinical settings were taken forward for
n2:mentions: n3:22337149

Subject Item: _:vb26774241
rdf:type: n2:Context
rdf:value: considered to be very promising, and therefore most of the large pharmaceutical companies developed anti-IGF-1R antibodies and those demonstrating significant activity in preclinical settings were taken forward for clinical evaluation [>>27<<, 93]. However, in clinical settings, treatment with anti-IGF-1R antibodies induced clinical responses only in some cases of Ewing’s sarcoma (ES) [228–230] and selected cases of lung carcinoma [93, 231, 232].
n2:mentions: n3:19581933

Subject Item: _:vb26774242
rdf:type: n2:Context
rdf:value: to be very promising, and therefore most of the large pharmaceutical companies developed anti-IGF-1R antibodies and those demonstrating significant activity in preclinical settings were taken forward for clinical evaluation [27, >>93<<]. However, in clinical settings, treatment with anti-IGF-1R antibodies induced clinical responses only in some cases of Ewing’s sarcoma (ES) [228–230] and selected cases of lung carcinoma [93, 231, 232].
n2:mentions: n3:22337149

Subject Item: _:vb26774243
rdf:type: n2:Context
rdf:value: However, in clinical settings, treatment with anti-IGF-1R antibodies induced clinical responses only in some cases of Ewing’s sarcoma (ES) [>>228<<–230] and selected cases of lung carcinoma [93, 231, 232].
n2:mentions: n3:20036194 n3:21647361 n3:22025154

Subject Item: _:vb26774244
rdf:type: n2:Context
rdf:value: However, in clinical settings, treatment with anti-IGF-1R antibodies induced clinical responses only in some cases of Ewing’s sarcoma (ES) [228–230] and selected cases of lung carcinoma [>>93<<, 231, 232].
n2:mentions: n3:22337149

Subject Item: _:vb26774245
rdf:type: n2:Context
rdf:value: However, in clinical settings, treatment with anti-IGF-1R antibodies induced clinical responses only in some cases of Ewing’s sarcoma (ES) [228–230] and selected cases of lung carcinoma [93, >>231<<, 232]. Although not chosen by design, all anti-IGF-1R antibodies used in clinical trials, besides inhibiting IGF-1-induced receptor phosphorylation, also trigger receptor downregulation ([140] and below).
n2:mentions: n3:20670944

Subject Item: _:vb26774246
rdf:type: n2:Context
rdf:value: However, in clinical settings, treatment with anti-IGF-1R antibodies induced clinical responses only in some cases of Ewing’s sarcoma (ES) [228–230] and selected cases of lung carcinoma [93, 231, >>232<<]. Although not chosen by design, all anti-IGF-1R antibodies used in clinical trials, besides inhibiting IGF-1-induced receptor phosphorylation, also trigger receptor downregulation ([140] and below).
n2:mentions: n3:21149666

Subject Item: _:vb26774247
rdf:type: n2:Context
rdf:value: Although not chosen by design, all anti-IGF-1R antibodies used in clinical trials, besides inhibiting IGF-1-induced receptor phosphorylation, also trigger receptor downregulation ([>>140<<] and below).
n2:mentions: n3:23188799

Subject Item: _:vb26774248
rdf:type: n2:Context
rdf:value: The proof of mechanism for this approach is represented by IGF-1R kinase-dominant negative mutants, successfully tested in preclinical settings by several laboratories [>>211<<, 233]. Cells transfected to express IGF-1R cDNA with kinase-inactivating [234] or kinase-limiting mutations [235, 236], lose their malignant phenotype as well as their invasive and metastatic potential [237].
n2:mentions: n3:9829727

Subject Item: _:vb26774249
rdf:type: n2:Context
rdf:value: The proof of mechanism for this approach is represented by IGF-1R kinase-dominant negative mutants, successfully tested in preclinical settings by several laboratories [211, >>233<<]. Cells transfected to express IGF-1R cDNA with kinase-inactivating [234] or kinase-limiting mutations [235, 236], lose their malignant phenotype as well as their invasive and metastatic potential [237].
n2:mentions: n3:7677754

Subject Item: _:vb26774250
rdf:type: n2:Context
rdf:value: Cells transfected to express IGF-1R cDNA with kinase-inactivating [>>234<<] or kinase-limiting mutations [235, 236], lose their malignant phenotype as well as their invasive and metastatic potential [237].
n2:mentions: n3:7798258

Subject Item: _:vb26774251
rdf:type: n2:Context
rdf:value: Cells transfected to express IGF-1R cDNA with kinase-inactivating [234] or kinase-limiting mutations [>>235<<, 236], lose their malignant phenotype as well as their invasive and metastatic potential [237].
n2:mentions: n3:9537584

Subject Item: _:vb26774252
rdf:type: n2:Context
rdf:value: Cells transfected to express IGF-1R cDNA with kinase-inactivating [234] or kinase-limiting mutations [235, >>236<<], lose their malignant phenotype as well as their invasive and metastatic potential [237].
n2:mentions: n3:12209582

Subject Item: _:vb26774253
rdf:type: n2:Context
rdf:value: Cells transfected to express IGF-1R cDNA with kinase-inactivating [234] or kinase-limiting mutations [235, 236], lose their malignant phenotype as well as their invasive and metastatic potential [>>237<<]. The promising strategy of inhibiting IGF-1R kinase activity is complicated by IR cross-reactivity issues, as the kinase domain of the IGF-1R shares 85 % homology with that of the IR, with the ATP binding cleft 100 % conserved [40].
n2:mentions: n3:11007947

Subject Item: _:vb26774254
rdf:type: n2:Context
rdf:value: The promising strategy of inhibiting IGF-1R kinase activity is complicated by IR cross-reactivity issues, as the kinase domain of the IGF-1R shares 85 % homology with that of the IR, with the ATP binding cleft 100 % conserved [>>40<<]. Nevertheless, several small inhibitors have been developed (for review [238, 239]) and despite some of them having shown signs of cross-reactivity with the IR, they are still considered for use in clinical settings. Additionally, there
n2:mentions: n3:2877871

Subject Item: _:vb26774255
rdf:type: n2:Context
rdf:value: Nevertheless, several small inhibitors have been developed (for review [238, >>239<<]) and despite some of them having shown signs of cross-reactivity with the IR, they are still considered for use in clinical settings.
n2:mentions: n3:22393939

Subject Item: _:vb26774256
rdf:type: n2:Context
rdf:value: Additionally, there is recent evidence and debate in the literature as to whether co-inhibition of the IR is beneficial for anti-IGF-1R therapy [>>240<<, 241]. While all small molecules targeting IGF-1R prevent kinase activation, they can be further divided in two subgroups, based on their mechanism of action: inhibitors of the ATP binding cleft or inhibitors of the kinase–substrate
n2:mentions: n3:20924128

Subject Item: _:vb26774257
rdf:type: n2:Context
rdf:value: Additionally, there is recent evidence and debate in the literature as to whether co-inhibition of the IR is beneficial for anti-IGF-1R therapy [240, >>241<<]. While all small molecules targeting IGF-1R prevent kinase activation, they can be further divided in two subgroups, based on their mechanism of action: inhibitors of the ATP binding cleft or inhibitors of the kinase–substrate
n2:mentions: n3:20457905

Subject Item: _:vb26774258
rdf:type: n2:Context
rdf:value: The two drugs were tested in various models such as fibrosarcoma, myeloma, and ES [>>242<<, 243]. Another small molecule, OSI-906 is a dual IGF-1R/IR kinase inhibitor with a strong anti-tumoral efficiency in an IGF-IR-driven xenograft model [244]. There have been several such inhibitors tested in clinical trials [27], and what
n2:mentions: n3:15050914

Subject Item: _:vb26774259
rdf:type: n2:Context
rdf:value: The two drugs were tested in various models such as fibrosarcoma, myeloma, and ES [242, >>243<<]. Another small molecule, OSI-906 is a dual IGF-1R/IR kinase inhibitor with a strong anti-tumoral efficiency in an IGF-IR-driven xenograft model [244]. There have been several such inhibitors tested in clinical trials [27], and what they
n2:mentions: n3:15867386

Subject Item: _:vb26774260
rdf:type: n2:Context
rdf:value: Another small molecule, OSI-906 is a dual IGF-1R/IR kinase inhibitor with a strong anti-tumoral efficiency in an IGF-IR-driven xenograft model [>>244<<]. There have been several such inhibitors tested in clinical trials [27], and what they have in common is that inhibition of the ATP-binding also prevents IGF-1R downregulation. This is not surprising as in vitro experiments clearly
n2:mentions: n3:21425998

Subject Item: _:vb26774261
rdf:type: n2:Context
rdf:value: There have been several such inhibitors tested in clinical trials [>>27<<], and what they have in common is that inhibition of the ATP-binding also prevents IGF-1R downregulation.
n2:mentions: n3:19581933

Subject Item: _:vb26774262
rdf:type: n2:Context
rdf:value: This is not surprising as in vitro experiments clearly demonstrated that IGF-1R ATP-defective mutants are not ubiquitinated [>>121<<].
n2:mentions: n3:17406664

Subject Item: _:vb26774263
rdf:type: n2:Context
rdf:value: PPP was originally described to inhibit the IGF-1R without altering the IR, reducing Akt phosphorylation [>>20<<] and inducing tumor regression in xenografted mice.
n2:mentions: n3:14729630

Subject Item: _:vb26774264
rdf:type: n2:Context
rdf:value: PPP specifically blocked phosphorylation of the tyrosine (Y) 1136 residue, while sparing the two others (Y1131 and Y1135), suggesting that it might act as a substrate inhibitor [>>245<<]. Since its discovery [20], PPP has been proven to inhibit IGF-1R biological activities in a very large number of experimental models as well as in clinical settings [14, 16, 24, 90, 246–258], has been demonstrated to produce very limited
n2:mentions: n3:15334055

Subject Item: _:vb26774265
rdf:type: n2:Context
rdf:value: PPP specifically blocked phosphorylation of the tyrosine (Y) 1136 residue, while sparing the two others (Y1131 and Y1135), suggesting that it might act as a substrate inhibitor [245]. Since its discovery [>>20<<], PPP has been proven to inhibit IGF-1R biological activities in a very large number of experimental models as well as in clinical settings [14, 16, 24, 90, 246–258], has been demonstrated to produce very limited resistance [22, 259, 260]
n2:mentions: n3:14729630

Subject Item: _:vb26774266
rdf:type: n2:Context
rdf:value: Since its discovery [20], PPP has been proven to inhibit IGF-1R biological activities in a very large number of experimental models as well as in clinical settings [>>14<<, 16, 24, 90, 246–258], has been demonstrated to produce very limited resistance [22, 259, 260] to anti-IGF-1R therapy, and has proven efficacy in clinical trials [261].
n2:mentions: n3:16489097

Subject Item: _:vb26774267
rdf:type: n2:Context
rdf:value: Since its discovery [20], PPP has been proven to inhibit IGF-1R biological activities in a very large number of experimental models as well as in clinical settings [14, >>16<<, 24, 90, 246–258], has been demonstrated to produce very limited resistance [22, 259, 260] to anti-IGF-1R therapy, and has proven efficacy in clinical trials [261].
n2:mentions: n3:18515591

Subject Item: _:vb26774268
rdf:type: n2:Context
rdf:value: Since its discovery [20], PPP has been proven to inhibit IGF-1R biological activities in a very large number of experimental models as well as in clinical settings [14, 16, >>24<<, 90, 246–258], has been demonstrated to produce very limited resistance [22, 259, 260] to anti-IGF-1R therapy, and has proven efficacy in clinical trials [261].
n2:mentions: n3:20150364

Subject Item: _:vb26774269
rdf:type: n2:Context
rdf:value: Since its discovery [20], PPP has been proven to inhibit IGF-1R biological activities in a very large number of experimental models as well as in clinical settings [14, 16, 24, 90, >>246<<–258], has been demonstrated to produce very limited resistance [22, 259, 260] to anti-IGF-1R therapy, and has proven efficacy in clinical trials [261].
n2:mentions: n3:16166596 n3:16046527 n3:17148586 n3:18576606 n3:17419944 n3:17546599 n3:18537183 n3:16303922 n3:18515579 n3:15671548 n3:19174523 n3:19302825 n3:17606126

Subject Item: _:vb26774270
rdf:type: n2:Context
rdf:value: [20], PPP has been proven to inhibit IGF-1R biological activities in a very large number of experimental models as well as in clinical settings [14, 16, 24, 90, 246–258], has been demonstrated to produce very limited resistance [>>22<<, 259, 260] to anti-IGF-1R therapy, and has proven efficacy in clinical trials [261].
n2:mentions: n3:16407828

Subject Item: _:vb26774271
rdf:type: n2:Context
rdf:value: [20], PPP has been proven to inhibit IGF-1R biological activities in a very large number of experimental models as well as in clinical settings [14, 16, 24, 90, 246–258], has been demonstrated to produce very limited resistance [22, >>259<<, 260] to anti-IGF-1R therapy, and has proven efficacy in clinical trials [261].
n2:mentions: n3:21423728

Subject Item: _:vb26774272
rdf:type: n2:Context
rdf:value: PPP has been proven to inhibit IGF-1R biological activities in a very large number of experimental models as well as in clinical settings [14, 16, 24, 90, 246–258], has been demonstrated to produce very limited resistance [22, 259, >>260<<] to anti-IGF-1R therapy, and has proven efficacy in clinical trials [261]. The remarkable feature of PPP that differentiates it from ATP-inhibitors is that, similar to anti-IGF-1R antibodies, PPP also triggers IGF-1R downregulation [143].
n2:mentions: n3:16857168

Subject Item: _:vb26774273
rdf:type: n2:Context
rdf:value: large number of experimental models as well as in clinical settings [14, 16, 24, 90, 246–258], has been demonstrated to produce very limited resistance [22, 259, 260] to anti-IGF-1R therapy, and has proven efficacy in clinical trials [>>261<<]. The remarkable feature of PPP that differentiates it from ATP-inhibitors is that, similar to anti-IGF-1R antibodies, PPP also triggers IGF-1R downregulation [143].
n2:mentions: n3:20698809

Subject Item: _:vb26774274
rdf:type: n2:Context
rdf:value: The remarkable feature of PPP that differentiates it from ATP-inhibitors is that, similar to anti-IGF-1R antibodies, PPP also triggers IGF-1R downregulation [>>143<<]. This feature deserves special attention because it supports the logical but still contentious [90] assumption that receptor downregulation is desirable in addition to inhibition of its TK activity [15, 95].
n2:mentions: n3:18070930

Subject Item: _:vb26774275
rdf:type: n2:Context
rdf:value: This feature deserves special attention because it supports the logical but still contentious [90] assumption that receptor downregulation is desirable in addition to inhibition of its TK activity [>>15<<, 95].
n2:mentions: n3:14601044

Subject Item: _:vb26774276
rdf:type: n2:Context
rdf:value: This feature deserves special attention because it supports the logical but still contentious [90] assumption that receptor downregulation is desirable in addition to inhibition of its TK activity [15, >>95<<].
n2:mentions: n3:15956962

Subject Item: _:vb26774277
rdf:type: n2:Context
rdf:value: This contradiction was recently investigated for the case of anti-IGF-1R antibody (Figitumumab)-induced receptor degradation [>>140<<]. Although the antibodies were primarily designed to block the ligand–receptor interaction thus preventing kinase activity, it has been demonstrated that targeting antibodies act as “biased” IGF-1R agonists, activating β-arrestin
n2:mentions: n3:23188799

Subject Item: _:vb26774278
rdf:type: n2:Context
rdf:value: been demonstrated that targeting antibodies act as “biased” IGF-1R agonists, activating β-arrestin recruitment to the receptor, with subsequent receptor ubiquitination, internalization, ERK signaling activation, and IGF-1R degradation [>>140<<]. In agreement with this, anti-IGF-1R therapy efficacy was proven to be highly dependent on β-arrestin 1 expression and modulated by co-targeting β-arrestin 1-mediated signaling [140].
n2:mentions: n3:23188799

Subject Item: _:vb26774279
rdf:type: n2:Context
rdf:value: In agreement with this, anti-IGF-1R therapy efficacy was proven to be highly dependent on β-arrestin 1 expression and modulated by co-targeting β-arrestin 1-mediated signaling [>>140<<]. Notably, a similar mechanism of β-arrestin 1-mediated receptor ubiquitination and downregulation with activation of the β-arrestin 1/ERK second signaling wave has also been demonstrated in the case of the PPP paradox [143].
n2:mentions: n3:23188799

Subject Item: _:vb26774280
rdf:type: n2:Context
rdf:value: Notably, a similar mechanism of β-arrestin 1-mediated receptor ubiquitination and downregulation with activation of the β-arrestin 1/ERK second signaling wave has also been demonstrated in the case of the PPP paradox [>>143<<].
n2:mentions: n3:18070930

Subject Item: _:vb26774281
rdf:type: n2:Context
rdf:value: data, demonstrating that IGF-1R signaling is not exclusively dependent on its kinase activity and can be activated and downregulated in a “biased” manner via β-arrestin 1 by IGF-1R inhibitors or by natural “biased” agonists [>>143<<, 253] (Table 2). In the emerging model of IGF-1R signaling, the question of “how important receptor is downregulation in relation to kinase inhibition?
n2:mentions: n3:18070930

Subject Item: _:vb26774282
rdf:type: n2:Context
rdf:value: data, demonstrating that IGF-1R signaling is not exclusively dependent on its kinase activity and can be activated and downregulated in a “biased” manner via β-arrestin 1 by IGF-1R inhibitors or by natural “biased” agonists [143, >>253<<] (Table 2). In the emerging model of IGF-1R signaling, the question of “how important receptor is downregulation in relation to kinase inhibition?
n2:mentions: n3:18576606

Subject Item: _:vb26774283
rdf:type: n2:Context
rdf:value: ” As downregulation without signaling has never been recognized, a simpler solution would be to identify the biased signaling pathways and target them separately [>>140<<].
n2:mentions: n3:23188799

Subject Item: _:vb26774284
rdf:type: n2:Context
rdf:value: The best example is the case of anti-IGF-1R antibody: during their development, antibodies were designed to achieve the maximum binding to IGF-1R, to compete with the natural agonists [>>140<<]. In the subsequent drug screening for clonal selection, the assays were limited to confirmation of their inhibitory effects on IGF-1-induced receptor signaling [142, 262–265]. As long as the canonical IGF-1R model does not acknowledge
n2:mentions: n3:23188799

Subject Item: _:vb26774285
rdf:type: n2:Context
rdf:value: In the subsequent drug screening for clonal selection, the assays were limited to confirmation of their inhibitory effects on IGF-1-induced receptor signaling [>>142<<, 262–265].
n2:mentions: n3:19165858

Subject Item: _:vb26774286
rdf:type: n2:Context
rdf:value: In the subsequent drug screening for clonal selection, the assays were limited to confirmation of their inhibitory effects on IGF-1-induced receptor signaling [142, >>262<<–265]. As long as the canonical IGF-1R model does not acknowledge kinase-independent signaling, it is not surprising that targeting antibodies were rarely evaluated in IGF-1-independent conditions to estimate their intrinsic agonistic
n2:mentions: n3:20574692 n3:21393993 n3:16093437 n3:17875788

Subject Item: _:vb26774287
rdf:type: n2:Context
rdf:value: Despite big expectations regarding the use of anti-IGF-1R for cancer treatment, almost all clinical trials were stopped due to futility, whereas some pharmaceutical companies closed their programs for developing IGF-1R inhibitors [>>93<<]. Furthermore, the value of IGF-1R as a target for cancer therapy has been questioned [90, 93].
n2:mentions: n3:22337149

Subject Item: _:vb26774288
rdf:type: n2:Context
rdf:value: Furthermore, the value of IGF-1R as a target for cancer therapy has been questioned [90, >>93<<]. While several reasons for the failure of the anti-IGF-1R have already been discussed in detail [90, 93], the new paradigm we propose for the IGF-1R signaling highlights another potential cause for these unsatisfactory results:
n2:mentions: n3:22337149

Subject Item: _:vb26774289
rdf:type: n2:Context
rdf:value: While several reasons for the failure of the anti-IGF-1R have already been discussed in detail [90, >>93<<], the new paradigm we propose for the IGF-1R signaling highlights another potential cause for these unsatisfactory results:
n2:mentions: n3:22337149

Subject Item: _:vb26774290
rdf:type: n2:Context
rdf:value: In Ewing sarcoma, at least two resistance mechanisms have been reported, developed after Figitumumab treatment: formation of the IGF-1R/IR hybrid receptors [>>266<<] and biased IGF-1R signaling activation [140].
n2:mentions: n3:22798295

Subject Item: _:vb26774291
rdf:type: n2:Context
rdf:value: In Ewing sarcoma, at least two resistance mechanisms have been reported, developed after Figitumumab treatment: formation of the IGF-1R/IR hybrid receptors [266] and biased IGF-1R signaling activation [>>140<<]. As described before, the IGF-1R/IR hybrid formation could be appreciated as a form of receptor bias. Challenging the classical two-state model in which the antibodies were designed, the new paradigm in which a biased-receptor (IGF-1R/IR
n2:mentions: n3:23188799

Subject Item: _:vb26774292
rdf:type: n2:Context
rdf:value: (Figitumumab) provides an explanation as to why such a strategy did not work in clinical settings and advocates recognition of IGF-1R as a key target for cancer therapy and a clear choice for the baby rather than the bathwater [>>91<<].
n2:mentions: n3:22761272

Subject Item: _:vb26774293
rdf:type: n5:Section
dc:title: something old: classical signaling pathways through igf-1r phosphorylation
n5:contains: _:vb26774416 _:vb26774417 _:vb26774418 _:vb26774419 _:vb26774420 _:vb26774421 _:vb26774422 _:vb26774423 _:vb26774424 _:vb26774425 _:vb26774400 _:vb26774401 _:vb26774402 _:vb26774403 _:vb26774404 _:vb26774405 _:vb26774406 _:vb26774407 _:vb26774408 _:vb26774409 _:vb26774410 _:vb26774411 _:vb26774412 _:vb26774413 _:vb26774414 _:vb26774415 _:vb26774320 _:vb26774321 _:vb26774322 _:vb26774323 _:vb26774324 _:vb26774325 _:vb26774326 _:vb26774327 _:vb26774328 _:vb26774329 _:vb26774330 _:vb26774331 _:vb26774332 _:vb26774333 _:vb26774334 _:vb26774335 _:vb26774304 _:vb26774305 _:vb26774306 _:vb26774307 _:vb26774308 _:vb26774309 _:vb26774310 _:vb26774311 _:vb26774312 _:vb26774313 _:vb26774314 _:vb26774315 _:vb26774316 _:vb26774317 _:vb26774318 _:vb26774319 _:vb26774294 _:vb26774295 _:vb26774296 _:vb26774297 _:vb26774298 _:vb26774299 _:vb26774300 _:vb26774301 _:vb26774302 _:vb26774303 _:vb26774384 _:vb26774385 _:vb26774386 _:vb26774387 _:vb26774388 _:vb26774389 _:vb26774390 _:vb26774391 _:vb26774392 _:vb26774393 _:vb26774394 _:vb26774395 _:vb26774396 _:vb26774397 _:vb26774398 _:vb26774399 _:vb26774368 _:vb26774369 _:vb26774370 _:vb26774371 _:vb26774372 _:vb26774373 _:vb26774374 _:vb26774375 _:vb26774376 _:vb26774377 _:vb26774378 _:vb26774379 _:vb26774380 _:vb26774381 _:vb26774382 _:vb26774383 _:vb26774352 _:vb26774353 _:vb26774354 _:vb26774355 _:vb26774356 _:vb26774357 _:vb26774358 _:vb26774359 _:vb26774360 _:vb26774361 _:vb26774362 _:vb26774363 _:vb26774364 _:vb26774365 _:vb26774366 _:vb26774367 _:vb26774336 _:vb26774337 _:vb26774338 _:vb26774339 _:vb26774340 _:vb26774341 _:vb26774342 _:vb26774343 _:vb26774344 _:vb26774345 _:vb26774346 _:vb26774347 _:vb26774348 _:vb26774349 _:vb26774350 _:vb26774351

Subject Item: _:vb26774294
rdf:type: n2:Context
rdf:value: Classically, there are three ligands (insulin, IGF-1, and IGF-2), three cell surface receptors [insulin receptor (IR), IGF-1R, and IGF-2R] and at least seven IGFBPs modulating the biological activity of the growth factors [>>31<<–33].
n2:mentions: n3:11739335 n3:7758431 n3:10961344

Subject Item: _:vb26774295
rdf:type: n2:Context
rdf:value: Besides these archetypal members, more recent work has identified other proteins as potential members of the IGF family: the antimicrobial peptide LL-37 as ligand [>>34<<], the orphan insulin-receptor-related receptor (IRR) [35], the insulin-IGF-1R hybrid receptor [36, 37], and a growing number of IGFBPs [38].
n2:mentions: n3:21685939

Subject Item: _:vb26774296
rdf:type: n2:Context
rdf:value: members, more recent work has identified other proteins as potential members of the IGF family: the antimicrobial peptide LL-37 as ligand [34], the orphan insulin-receptor-related receptor (IRR) [35], the insulin-IGF-1R hybrid receptor [>>36<<, 37], and a growing number of IGFBPs [38].
n2:mentions: n3:9355755

Subject Item: _:vb26774297
rdf:type: n2:Context
rdf:value: more recent work has identified other proteins as potential members of the IGF family: the antimicrobial peptide LL-37 as ligand [34], the orphan insulin-receptor-related receptor (IRR) [35], the insulin-IGF-1R hybrid receptor [36, >>37<<], and a growing number of IGFBPs [38].
n2:mentions: n3:19752219

Subject Item: _:vb26774298
rdf:type: n2:Context
rdf:value: other proteins as potential members of the IGF family: the antimicrobial peptide LL-37 as ligand [34], the orphan insulin-receptor-related receptor (IRR) [35], the insulin-IGF-1R hybrid receptor [36, 37], and a growing number of IGFBPs [>>38<<].
n2:mentions: n3:23250396

Subject Item: _:vb26774299
rdf:type: n2:Context
rdf:value: It is synthesized as a single chain α-β pro-receptor which is processed by proteolysis and glycosylation [>>33<<, 39]. In mature, functional form, it consists of two identical extra cellular α-subunits and two identical β-subunits, all linked by disulfide bridges. The β-chain contains an extra cellular domain, a transmembrane domain, and a
n2:mentions: n3:10961344

Subject Item: _:vb26774300
rdf:type: n2:Context
rdf:value: It is synthesized as a single chain α-β pro-receptor which is processed by proteolysis and glycosylation [33, >>39<<]. In mature, functional form, it consists of two identical extra cellular α-subunits and two identical β-subunits, all linked by disulfide bridges. The β-chain contains an extra cellular domain, a transmembrane domain, and a
n2:mentions: n3:9516079

Subject Item: _:vb26774301
rdf:type: n2:Context
rdf:value: The β-chain contains an extra cellular domain, a transmembrane domain, and a kinase-containing intracellular domain [>>39<<, 40] (Fig.
n2:mentions: n3:9516079

Subject Item: _:vb26774302
rdf:type: n2:Context
rdf:value: The β-chain contains an extra cellular domain, a transmembrane domain, and a kinase-containing intracellular domain [39, >>40<<] (Fig. 1). On the whole, there is high homology (70 %) between the IGF-1R and the IR amino acid sequences [40, 41].Fig.
n2:mentions: n3:2877871

Subject Item: _:vb26774303
rdf:type: n2:Context
rdf:value: On the whole, there is high homology (70 %) between the IGF-1R and the IR amino acid sequences [>>40<<, 41].Fig.
n2:mentions: n3:2877871

Subject Item: _:vb26774304
rdf:type: n2:Context
rdf:value: On the whole, there is high homology (70 %) between the IGF-1R and the IR amino acid sequences [40, >>41<<].Fig.
n2:mentions: n3:7540132

Subject Item: _:vb26774305
rdf:type: n2:Context
rdf:value: The α-subunit contains 710 amino acids (aa 1–710) and has in its structure two homologous domains (L1 and L2) separated by a cysteine-rich domain (48 %) containing 25 or 27 cysteines, in three repeating units [>>33<<]. The cysteine-rich domain (aa 148–302) is responsible for the ligand binding and is also conserved in the IR [42–46].
n2:mentions: n3:10961344

Subject Item: _:vb26774306
rdf:type: n2:Context
rdf:value: The cysteine-rich domain (aa 148–302) is responsible for the ligand binding and is also conserved in the IR [>>42<<–46]. The spanning plasma membrane β-subunit contains 627 amino acid residues (aa 711–1337), distributed among the extra cellular domain (196 aa), the transmembrane domain (aa 906–929), and the intracellular portion of the β-subunit, which
n2:mentions: n3:2223767 n3:1852007 n3:1645190 n3:2170418 n3:1655782

Subject Item: _:vb26774307
rdf:type: n2:Context
rdf:value: The juxtamembrane domain contains an NPXY motif, which may be important for receptor internalization [>>47<<–50]. The catalytic region of IGF-1R contains the ATP binding motif (GXGXXG) at positions 976–981, and a catalytic lysine in position 1003, which is critical for the Mg-ATP binding [51]. Within the TK domain, a cluster of three tyrosines,
n2:mentions: n3:8163493 n3:3513311 n3:2204623 n3:8299569

Subject Item: _:vb26774308
rdf:type: n2:Context
rdf:value: The catalytic region of IGF-1R contains the ATP binding motif (GXGXXG) at positions 976–981, and a catalytic lysine in position 1003, which is critical for the Mg-ATP binding [>>51<<]. Within the TK domain, a cluster of three tyrosines, located at positions 1131, 1135, and 1136, is critical for receptor autophosphorylation [41]. The C-terminus of the IGF-1R (roughly the last 100 amino acids) contains several
n2:mentions: n3:3291115

Subject Item: _:vb26774309
rdf:type: n2:Context
rdf:value: Within the TK domain, a cluster of three tyrosines, located at positions 1131, 1135, and 1136, is critical for receptor autophosphorylation [>>41<<]. The C-terminus of the IGF-1R (roughly the last 100 amino acids) contains several regulatory elements essential for IGF-1R function [52] (Table 1; Fig. 1).Table
n2:mentions: n3:7540132

Subject Item: _:vb26774310
rdf:type: n2:Context
rdf:value: The C-terminus of the IGF-1R (roughly the last 100 amino acids) contains several regulatory elements essential for IGF-1R function [>>52<<] (Table 1; Fig.
n2:mentions: n3:10816097

Subject Item: _:vb26774311
rdf:type: n2:Context
rdf:value: ResiduesBinding partnersFunctionsV922M [>>267<<]Y943I [50]Y950IRS-1/2/3/4 [268–271], Shc [268, 269, 272], CrkII, CrkL [82, 273, 274]I [49, 50], M, T [89, 275–278], pYY957I [50]Kinase domain 969–1236RACK1 [87], Vav [80], Vav3 [81], p125FAK [83]976–981ATP binding site, A [89]K1003A, M,
n2:mentions: n3:7642566

Subject Item: _:vb26774312
rdf:type: n2:Context
rdf:value: ResiduesBinding partnersFunctionsV922M [267]Y943I [>>50<<]Y950IRS-1/2/3/4 [268–271], Shc [268, 269, 272], CrkII, CrkL [82, 273, 274]I [49, 50], M, T [89, 275–278], pYY957I [50]Kinase domain 969–1236RACK1 [87], Vav [80], Vav3 [81], p125FAK [83]976–981ATP binding site, A [89]K1003A, M, T, K [89,
n2:mentions: n3:8163493

Subject Item: _:vb26774313
rdf:type: n2:Context
rdf:value: ResiduesBinding partnersFunctionsV922M [267]Y943I [50]Y950IRS-1/2/3/4 [>>268<<–271], Shc [268, 269, 272], CrkII, CrkL [82, 273, 274]I [49, 50], M, T [89, 275–278], pYY957I [50]Kinase domain 969–1236RACK1 [87], Vav [80], Vav3 [81], p125FAK [83]976–981ATP binding site, A [89]K1003A, M, T, K [89, 279]K1025, K1100,
n2:mentions: n3:7541045 n3:8662806 n3:10329736 n3:7559507

Subject Item: _:vb26774314
rdf:type: n2:Context
rdf:value: ResiduesBinding partnersFunctionsV922M [267]Y943I [50]Y950IRS-1/2/3/4 [268–271], Shc [>>268<<, 269, 272], CrkII, CrkL [82, 273, 274]I [49, 50], M, T [89, 275–278], pYY957I [50]Kinase domain 969–1236RACK1 [87], Vav [80], Vav3 [81], p125FAK [83]976–981ATP binding site, A [89]K1003A, M, T, K [89, 279]K1025, K1100, K1120Su
n2:mentions: n3:7541045

Subject Item: _:vb26774315
rdf:type: n2:Context
rdf:value: ResiduesBinding partnersFunctionsV922M [267]Y943I [50]Y950IRS-1/2/3/4 [268–271], Shc [268, >>269<<, 272], CrkII, CrkL [82, 273, 274]I [49, 50], M, T [89, 275–278], pYY957I [50]Kinase domain 969–1236RACK1 [87], Vav [80], Vav3 [81], p125FAK [83]976–981ATP binding site, A [89]K1003A, M, T, K [89, 279]K1025, K1100, K1120Su
n2:mentions: n3:7559507

Subject Item: _:vb26774316
rdf:type: n2:Context
rdf:value: ResiduesBinding partnersFunctionsV922M [267]Y943I [50]Y950IRS-1/2/3/4 [268–271], Shc [268, 269, >>272<<], CrkII, CrkL [82, 273, 274]I [49, 50], M, T [89, 275–278], pYY957I [50]Kinase domain 969–1236RACK1 [87], Vav [80], Vav3 [81], p125FAK [83]976–981ATP binding site, A [89]K1003A, M, T, K [89, 279]K1025, K1100, K1120Su [151]K1081[280]G1125K
n2:mentions: n3:8776723

Subject Item: _:vb26774317
rdf:type: n2:Context
rdf:value: ResiduesBinding partnersFunctionsV922M [267]Y943I [50]Y950IRS-1/2/3/4 [268–271], Shc [268, 269, 272], CrkII, CrkL [>>82<<, 273, 274]I [49, 50], M, T [89, 275–278], pYY957I [50]Kinase domain 969–1236RACK1 [87], Vav [80], Vav3 [81], p125FAK [83]976–981ATP binding site, A [89]K1003A, M, T, K [89, 279]K1025, K1100, K1120Su [151]K1081[280]G1125K [281]K1138,
n2:mentions: n3:7534289

Subject Item: _:vb26774318
rdf:type: n2:Context
rdf:value: ResiduesBinding partnersFunctionsV922M [267]Y943I [50]Y950IRS-1/2/3/4 [268–271], Shc [268, 269, 272], CrkII, CrkL [82, >>273<<, 274]I [49, 50], M, T [89, 275–278], pYY957I [50]Kinase domain 969–1236RACK1 [87], Vav [80], Vav3 [81], p125FAK [83]976–981ATP binding site, A [89]K1003A, M, T, K [89, 279]K1025, K1100, K1120Su [151]K1081[280]G1125K [281]K1138, K1141Ub
n2:mentions: n3:7491107

Subject Item: _:vb26774319
rdf:type: n2:Context
rdf:value: ResiduesBinding partnersFunctionsV922M [267]Y943I [50]Y950IRS-1/2/3/4 [268–271], Shc [268, 269, 272], CrkII, CrkL [82, 273, >>274<<]I [49, 50], M, T [89, 275–278], pYY957I [50]Kinase domain 969–1236RACK1 [87], Vav [80], Vav3 [81], p125FAK [83]976–981ATP binding site, A [89]K1003A, M, T, K [89, 279]K1025, K1100, K1120Su [151]K1081[280]G1125K [281]K1138, K1141Ub
n2:mentions: n3:9480911

Subject Item: _:vb26774320
rdf:type: n2:Context
rdf:value: ResiduesBinding partnersFunctionsV922M [267]Y943I [50]Y950IRS-1/2/3/4 [268–271], Shc [268, 269, 272], CrkII, CrkL [82, 273, 274]I [>>49<<, 50], M, T [89, 275–278], pYY957I [50]Kinase domain 969–1236RACK1 [87], Vav [80], Vav3 [81], p125FAK [83]976–981ATP binding site, A [89]K1003A, M, T, K [89, 279]K1025, K1100, K1120Su [151]K1081[280]G1125K [281]K1138, K1141Ub [141]Y1131,
n2:mentions: n3:8299569

Subject Item: _:vb26774321
rdf:type: n2:Context
rdf:value: ResiduesBinding partnersFunctionsV922M [267]Y943I [50]Y950IRS-1/2/3/4 [268–271], Shc [268, 269, 272], CrkII, CrkL [82, 273, 274]I [49, >>50<<], M, T [89, 275–278], pYY957I [50]Kinase domain 969–1236RACK1 [87], Vav [80], Vav3 [81], p125FAK [83]976–981ATP binding site, A [89]K1003A, M, T, K [89, 279]K1025, K1100, K1120Su [151]K1081[280]G1125K [281]K1138, K1141Ub [141]Y1131,
n2:mentions: n3:8163493

Subject Item: _:vb26774322
rdf:type: n2:Context
rdf:value: ResiduesBinding partnersFunctionsV922M [267]Y943I [50]Y950IRS-1/2/3/4 [268–271], Shc [268, 269, 272], CrkII, CrkL [82, 273, 274]I [49, 50], M, T [>>89<<, 275–278], pYY957I [50]Kinase domain 969–1236RACK1 [87], Vav [80], Vav3 [81], p125FAK [83]976–981ATP binding site, A [89]K1003A, M, T, K [89, 279]K1025, K1100, K1120Su [151]K1081[280]G1125K [281]K1138, K1141Ub [141]Y1131, Y1135,
n2:mentions: n3:8972223

Subject Item: _:vb26774323
rdf:type: n2:Context
rdf:value: ResiduesBinding partnersFunctionsV922M [267]Y943I [50]Y950IRS-1/2/3/4 [268–271], Shc [268, 269, 272], CrkII, CrkL [82, 273, 274]I [49, 50], M, T [89, >>275<<–278], pYY957I [50]Kinase domain 969–1236RACK1 [87], Vav [80], Vav3 [81], p125FAK [83]976–981ATP binding site, A [89]K1003A, M, T, K [89, 279]K1025, K1100, K1120Su [151]K1081[280]G1125K [281]K1138, K1141Ub [141]Y1131, Y1135,
n2:mentions: n3:9202243 n3:7834637 n3:1400411 n3:8550552

Subject Item: _:vb26774324
rdf:type: n2:Context
rdf:value: ResiduesBinding partnersFunctionsV922M [267]Y943I [50]Y950IRS-1/2/3/4 [268–271], Shc [268, 269, 272], CrkII, CrkL [82, 273, 274]I [49, 50], M, T [89, 275–278], pYY957I [>>50<<]Kinase domain 969–1236RACK1 [87], Vav [80], Vav3 [81], p125FAK [83]976–981ATP binding site, A [89]K1003A, M, T, K [89, 279]K1025, K1100, K1120Su [151]K1081[280]G1125K [281]K1138, K1141Ub [141]Y1131, Y1135, Y1136Auto-phosphorylation, M, T,
n2:mentions: n3:8163493

Subject Item: _:vb26774325
rdf:type: n2:Context
rdf:value: ResiduesBinding partnersFunctionsV922M [267]Y943I [50]Y950IRS-1/2/3/4 [268–271], Shc [268, 269, 272], CrkII, CrkL [82, 273, 274]I [49, 50], M, T [89, 275–278], pYY957I [50]Kinase domain 969–1236RACK1 [>>87<<], Vav [80], Vav3 [81], p125FAK [83]976–981ATP binding site, A [89]K1003A, M, T, K [89, 279]K1025, K1100, K1120Su [151]K1081[280]G1125K [281]K1138, K1141Ub [141]Y1131, Y1135, Y1136Auto-phosphorylation, M, T, K [89, 234, 276, 282, 283],
n2:mentions: n3:11884618

Subject Item: _:vb26774326
rdf:type: n2:Context
rdf:value: ResiduesBinding partnersFunctionsV922M [267]Y943I [50]Y950IRS-1/2/3/4 [268–271], Shc [268, 269, 272], CrkII, CrkL [82, 273, 274]I [49, 50], M, T [89, 275–278], pYY957I [50]Kinase domain 969–1236RACK1 [87], Vav [>>80<<], Vav3 [81], p125FAK [83]976–981ATP binding site, A [89]K1003A, M, T, K [89, 279]K1025, K1100, K1120Su [151]K1081[280]G1125K [281]K1138, K1141Ub [141]Y1131, Y1135, Y1136Auto-phosphorylation, M, T, K [89, 234, 276, 282, 283], pYW1173A, T
n2:mentions: n3:8605967

Subject Item: _:vb26774327
rdf:type: n2:Context
rdf:value: ResiduesBinding partnersFunctionsV922M [267]Y943I [50]Y950IRS-1/2/3/4 [268–271], Shc [268, 269, 272], CrkII, CrkL [82, 273, 274]I [49, 50], M, T [89, 275–278], pYY957I [50]Kinase domain 969–1236RACK1 [87], Vav [80], Vav3 [>>81<<], p125FAK [83]976–981ATP binding site, A [89]K1003A, M, T, K [89, 279]K1025, K1100, K1120Su [151]K1081[280]G1125K [281]K1138, K1141Ub [141]Y1131, Y1135, Y1136Auto-phosphorylation, M, T, K [89, 234, 276, 282, 283], pYW1173A, T [284]Y1221K
n2:mentions: n3:11094073

Subject Item: _:vb26774328
rdf:type: n2:Context
rdf:value: ResiduesBinding partnersFunctionsV922M [267]Y943I [50]Y950IRS-1/2/3/4 [268–271], Shc [268, 269, 272], CrkII, CrkL [82, 273, 274]I [49, 50], M, T [89, 275–278], pYY957I [50]Kinase domain 969–1236RACK1 [87], Vav [80], Vav3 [81], p125FAK [>>83<<]976–981ATP binding site, A [89]K1003A, M, T, K [89, 279]K1025, K1100, K1120Su [151]K1081[280]G1125K [281]K1138, K1141Ub [141]Y1131, Y1135, Y1136Auto-phosphorylation, M, T, K [89, 234, 276, 282, 283], pYW1173A, T [284]Y1221K
n2:mentions: n3:9507031

Subject Item: _:vb26774329
rdf:type: n2:Context
rdf:value: [267]Y943I [50]Y950IRS-1/2/3/4 [268–271], Shc [268, 269, 272], CrkII, CrkL [82, 273, 274]I [49, 50], M, T [89, 275–278], pYY957I [50]Kinase domain 969–1236RACK1 [87], Vav [80], Vav3 [81], p125FAK [83]976–981ATP binding site, A [>>89<<]K1003A, M, T, K [89, 279]K1025, K1100, K1120Su [151]K1081[280]G1125K [281]K1138, K1141Ub [141]Y1131, Y1135, Y1136Auto-phosphorylation, M, T, K [89, 234, 276, 282, 283], pYW1173A, T [284]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [88],
n2:mentions: n3:8972223

Subject Item: _:vb26774330
rdf:type: n2:Context
rdf:value: [50]Y950IRS-1/2/3/4 [268–271], Shc [268, 269, 272], CrkII, CrkL [82, 273, 274]I [49, 50], M, T [89, 275–278], pYY957I [50]Kinase domain 969–1236RACK1 [87], Vav [80], Vav3 [81], p125FAK [83]976–981ATP binding site, A [89]K1003A, M, T, K [>>89<<, 279]K1025, K1100, K1120Su [151]K1081[280]G1125K [281]K1138, K1141Ub [141]Y1131, Y1135, Y1136Auto-phosphorylation, M, T, K [89, 234, 276, 282, 283], pYW1173A, T [284]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [88], βarr1 [124, 134]pSY1250T
n2:mentions: n3:8972223

Subject Item: _:vb26774331
rdf:type: n2:Context
rdf:value: [268–271], Shc [268, 269, 272], CrkII, CrkL [82, 273, 274]I [49, 50], M, T [89, 275–278], pYY957I [50]Kinase domain 969–1236RACK1 [87], Vav [80], Vav3 [81], p125FAK [83]976–981ATP binding site, A [89]K1003A, M, T, K [89, >>279<<]K1025, K1100, K1120Su [151]K1081[280]G1125K [281]K1138, K1141Ub [141]Y1131, Y1135, Y1136Auto-phosphorylation, M, T, K [89, 234, 276, 282, 283], pYW1173A, T [284]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [88], βarr1 [124, 134]pSY1250T
n2:mentions: n3:7679099

Subject Item: _:vb26774332
rdf:type: n2:Context
rdf:value: [268, 269, 272], CrkII, CrkL [82, 273, 274]I [49, 50], M, T [89, 275–278], pYY957I [50]Kinase domain 969–1236RACK1 [87], Vav [80], Vav3 [81], p125FAK [83]976–981ATP binding site, A [89]K1003A, M, T, K [89, 279]K1025, K1100, K1120Su [>>151<<]K1081[280]G1125K [281]K1138, K1141Ub [141]Y1131, Y1135, Y1136Auto-phosphorylation, M, T, K [89, 234, 276, 282, 283], pYW1173A, T [284]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [88], βarr1 [124, 134]pSY1250T [128], M/I, A [89, 276,
n2:mentions: n3:20145208

Subject Item: _:vb26774333
rdf:type: n2:Context
rdf:value: 272], CrkII, CrkL [82, 273, 274]I [49, 50], M, T [89, 275–278], pYY957I [50]Kinase domain 969–1236RACK1 [87], Vav [80], Vav3 [81], p125FAK [83]976–981ATP binding site, A [89]K1003A, M, T, K [89, 279]K1025, K1100, K1120Su [151]K1081[>>280<<]G1125K [281]K1138, K1141Ub [141]Y1131, Y1135, Y1136Auto-phosphorylation, M, T, K [89, 234, 276, 282, 283], pYW1173A, T [284]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [88], βarr1 [124, 134]pSY1250T [128], M/I, A [89, 276, 285]Y1251I [286],
n2:mentions: n3:22685298

Subject Item: _:vb26774334
rdf:type: n2:Context
rdf:value: CrkL [82, 273, 274]I [49, 50], M, T [89, 275–278], pYY957I [50]Kinase domain 969–1236RACK1 [87], Vav [80], Vav3 [81], p125FAK [83]976–981ATP binding site, A [89]K1003A, M, T, K [89, 279]K1025, K1100, K1120Su [151]K1081[280]G1125K [>>281<<]K1138, K1141Ub [141]Y1131, Y1135, Y1136Auto-phosphorylation, M, T, K [89, 234, 276, 282, 283], pYW1173A, T [284]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [88], βarr1 [124, 134]pSY1250T [128], M/I, A [89, 276, 285]Y1251I [286], K [276], A,
n2:mentions: n3:20103656

Subject Item: _:vb26774335
rdf:type: n2:Context
rdf:value: 274]I [49, 50], M, T [89, 275–278], pYY957I [50]Kinase domain 969–1236RACK1 [87], Vav [80], Vav3 [81], p125FAK [83]976–981ATP binding site, A [89]K1003A, M, T, K [89, 279]K1025, K1100, K1120Su [151]K1081[280]G1125K [281]K1138, K1141Ub [>>141<<]Y1131, Y1135, Y1136Auto-phosphorylation, M, T, K [89, 234, 276, 282, 283], pYW1173A, T [284]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [88], βarr1 [124, 134]pSY1250T [128], M/I, A [89, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I
n2:mentions: n3:21994939

Subject Item: _:vb26774336
rdf:type: n2:Context
rdf:value: domain 969–1236RACK1 [87], Vav [80], Vav3 [81], p125FAK [83]976–981ATP binding site, A [89]K1003A, M, T, K [89, 279]K1025, K1100, K1120Su [151]K1081[280]G1125K [281]K1138, K1141Ub [141]Y1131, Y1135, Y1136Auto-phosphorylation, M, T, K [>>89<<, 234, 276, 282, 283], pYW1173A, T [284]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [88], βarr1 [124, 134]pSY1250T [128], M/I, A [89, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288,
n2:mentions: n3:8972223

Subject Item: _:vb26774337
rdf:type: n2:Context
rdf:value: 969–1236RACK1 [87], Vav [80], Vav3 [81], p125FAK [83]976–981ATP binding site, A [89]K1003A, M, T, K [89, 279]K1025, K1100, K1120Su [151]K1081[280]G1125K [281]K1138, K1141Ub [141]Y1131, Y1135, Y1136Auto-phosphorylation, M, T, K [89, >>234<<, 276, 282, 283], pYW1173A, T [284]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [88], βarr1 [124, 134]pSY1250T [128], M/I, A [89, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T
n2:mentions: n3:7798258

Subject Item: _:vb26774338
rdf:type: n2:Context
rdf:value: [87], Vav [80], Vav3 [81], p125FAK [83]976–981ATP binding site, A [89]K1003A, M, T, K [89, 279]K1025, K1100, K1120Su [151]K1081[280]G1125K [281]K1138, K1141Ub [141]Y1131, Y1135, Y1136Auto-phosphorylation, M, T, K [89, 234, >>276<<, 282, 283], pYW1173A, T [284]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [88], βarr1 [124, 134]pSY1250T [128], M/I, A [89, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290,
n2:mentions: n3:8550552

Subject Item: _:vb26774339
rdf:type: n2:Context
rdf:value: [87], Vav [80], Vav3 [81], p125FAK [83]976–981ATP binding site, A [89]K1003A, M, T, K [89, 279]K1025, K1100, K1120Su [151]K1081[280]G1125K [281]K1138, K1141Ub [141]Y1131, Y1135, Y1136Auto-phosphorylation, M, T, K [89, 234, 276, >>282<<, 283], pYW1173A, T [284]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [88], βarr1 [124, 134]pSY1250T [128], M/I, A [89, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290,
n2:mentions: n3:7588225

Subject Item: _:vb26774340
rdf:type: n2:Context
rdf:value: [87], Vav [80], Vav3 [81], p125FAK [83]976–981ATP binding site, A [89]K1003A, M, T, K [89, 279]K1025, K1100, K1120Su [151]K1081[280]G1125K [281]K1138, K1141Ub [141]Y1131, Y1135, Y1136Auto-phosphorylation, M, T, K [89, 234, 276, 282, >>283<<], pYW1173A, T [284]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [88], βarr1 [124, 134]pSY1250T [128], M/I, A [89, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290,
n2:mentions: n3:7493944

Subject Item: _:vb26774341
rdf:type: n2:Context
rdf:value: Vav3 [81], p125FAK [83]976–981ATP binding site, A [89]K1003A, M, T, K [89, 279]K1025, K1100, K1120Su [151]K1081[280]G1125K [281]K1138, K1141Ub [141]Y1131, Y1135, Y1136Auto-phosphorylation, M, T, K [89, 234, 276, 282, 283], pYW1173A, T [>>284<<]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [88], βarr1 [124, 134]pSY1250T [128], M/I, A [89, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290, 291]S1291βarr1 [124,
n2:mentions: n3:7852347

Subject Item: _:vb26774342
rdf:type: n2:Context
rdf:value: [83]976–981ATP binding site, A [89]K1003A, M, T, K [89, 279]K1025, K1100, K1120Su [151]K1081[280]G1125K [281]K1138, K1141Ub [141]Y1131, Y1135, Y1136Auto-phosphorylation, M, T, K [89, 234, 276, 282, 283], pYW1173A, T [284]Y1221K [>>276<<]1229–1245Grb10 [78]S1248RACK1 [88], βarr1 [124, 134]pSY1250T [128], M/I, A [89, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A
n2:mentions: n3:8550552

Subject Item: _:vb26774343
rdf:type: n2:Context
rdf:value: binding site, A [89]K1003A, M, T, K [89, 279]K1025, K1100, K1120Su [151]K1081[280]G1125K [281]K1138, K1141Ub [141]Y1131, Y1135, Y1136Auto-phosphorylation, M, T, K [89, 234, 276, 282, 283], pYW1173A, T [284]Y1221K [276]1229–1245Grb10 [>>78<<]S1248RACK1 [88], βarr1 [124, 134]pSY1250T [128], M/I, A [89, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A
n2:mentions: n3:8764099

Subject Item: _:vb26774344
rdf:type: n2:Context
rdf:value: A [89]K1003A, M, T, K [89, 279]K1025, K1100, K1120Su [151]K1081[280]G1125K [281]K1138, K1141Ub [141]Y1131, Y1135, Y1136Auto-phosphorylation, M, T, K [89, 234, 276, 282, 283], pYW1173A, T [284]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [>>88<<], βarr1 [124, 134]pSY1250T [128], M/I, A [89, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [79],
n2:mentions: n3:11964397

Subject Item: _:vb26774345
rdf:type: n2:Context
rdf:value: M, T, K [89, 279]K1025, K1100, K1120Su [151]K1081[280]G1125K [281]K1138, K1141Ub [141]Y1131, Y1135, Y1136Auto-phosphorylation, M, T, K [89, 234, 276, 282, 283], pYW1173A, T [284]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [88], βarr1 [>>124<<, 134]pSY1250T [128], M/I, A [89, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [79], p85 [293],
n2:mentions: n3:22509025

Subject Item: _:vb26774346
rdf:type: n2:Context
rdf:value: T, K [89, 279]K1025, K1100, K1120Su [151]K1081[280]G1125K [281]K1138, K1141Ub [141]Y1131, Y1135, Y1136Auto-phosphorylation, M, T, K [89, 234, 276, 282, 283], pYW1173A, T [284]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [88], βarr1 [124, >>134<<]pSY1250T [128], M/I, A [89, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [79], p85 [293], SHP2
n2:mentions: n3:17303558

Subject Item: _:vb26774347
rdf:type: n2:Context
rdf:value: K1100, K1120Su [151]K1081[280]G1125K [281]K1138, K1141Ub [141]Y1131, Y1135, Y1136Auto-phosphorylation, M, T, K [89, 234, 276, 282, 283], pYW1173A, T [284]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [88], βarr1 [124, 134]pSY1250T [>>128<<], M/I, A [89, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [79], p85 [293], SHP2 [84, 145], PI3K
n2:mentions: n3:9345292

Subject Item: _:vb26774348
rdf:type: n2:Context
rdf:value: K1120Su [151]K1081[280]G1125K [281]K1138, K1141Ub [141]Y1131, Y1135, Y1136Auto-phosphorylation, M, T, K [89, 234, 276, 282, 283], pYW1173A, T [284]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [88], βarr1 [124, 134]pSY1250T [128], M/I, A [>>89<<, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [79], p85 [293], SHP2 [84, 145], PI3K [63][89,
n2:mentions: n3:8972223

Subject Item: _:vb26774349
rdf:type: n2:Context
rdf:value: [151]K1081[280]G1125K [281]K1138, K1141Ub [141]Y1131, Y1135, Y1136Auto-phosphorylation, M, T, K [89, 234, 276, 282, 283], pYW1173A, T [284]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [88], βarr1 [124, 134]pSY1250T [128], M/I, A [89, >>276<<, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [79], p85 [293], SHP2 [84, 145], PI3K [63][89,
n2:mentions: n3:8550552

Subject Item: _:vb26774350
rdf:type: n2:Context
rdf:value: [151]K1081[280]G1125K [281]K1138, K1141Ub [141]Y1131, Y1135, Y1136Auto-phosphorylation, M, T, K [89, 234, 276, 282, 283], pYW1173A, T [284]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [88], βarr1 [124, 134]pSY1250T [128], M/I, A [89, 276, >>285<<]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [79], p85 [293], SHP2 [84, 145], PI3K [63][89,
n2:mentions: n3:11445567

Subject Item: _:vb26774351
rdf:type: n2:Context
rdf:value: [281]K1138, K1141Ub [141]Y1131, Y1135, Y1136Auto-phosphorylation, M, T, K [89, 234, 276, 282, 283], pYW1173A, T [284]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [88], βarr1 [124, 134]pSY1250T [128], M/I, A [89, 276, 285]Y1251I [>>286<<], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [79], p85 [293], SHP2 [84, 145], PI3K [63][89, 292]Undeterminedp38, JNK
n2:mentions: n3:7673254

Subject Item: _:vb26774352
rdf:type: n2:Context
rdf:value: [281]K1138, K1141Ub [141]Y1131, Y1135, Y1136Auto-phosphorylation, M, T, K [89, 234, 276, 282, 283], pYW1173A, T [284]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [88], βarr1 [124, 134]pSY1250T [128], M/I, A [89, 276, 285]Y1251I [286], K [>>276<<], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [79], p85 [293], SHP2 [84, 145], PI3K [63][89, 292]Undeterminedp38, JNK [294],
n2:mentions: n3:8550552

Subject Item: _:vb26774353
rdf:type: n2:Context
rdf:value: K1141Ub [141]Y1131, Y1135, Y1136Auto-phosphorylation, M, T, K [89, 234, 276, 282, 283], pYW1173A, T [284]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [88], βarr1 [124, 134]pSY1250T [128], M/I, A [89, 276, 285]Y1251I [286], K [276], A, T [>>89<<]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [79], p85 [293], SHP2 [84, 145], PI3K [63][89, 292]Undeterminedp38, JNK [294], TIMP2 [295],
n2:mentions: n3:8972223

Subject Item: _:vb26774354
rdf:type: n2:Context
rdf:value: Y1135, Y1136Auto-phosphorylation, M, T, K [89, 234, 276, 282, 283], pYW1173A, T [284]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [88], βarr1 [124, 134]pSY1250T [128], M/I, A [89, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [>>280<<]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [79], p85 [293], SHP2 [84, 145], PI3K [63][89, 292]Undeterminedp38, JNK [294], TIMP2 [295], SOCS1/2 [86],
n2:mentions: n3:22685298

Subject Item: _:vb26774355
rdf:type: n2:Context
rdf:value: M, T, K [89, 234, 276, 282, 283], pYW1173A, T [284]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [88], βarr1 [124, 134]pSY1250T [128], M/I, A [89, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [>>287<<]S1280–S128314.3.3 [268, 288, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [79], p85 [293], SHP2 [84, 145], PI3K [63][89, 292]Undeterminedp38, JNK [294], TIMP2 [295], SOCS1/2 [86], SOCS3 [296], p55γ
n2:mentions: n3:9111084

Subject Item: _:vb26774356
rdf:type: n2:Context
rdf:value: M, T, K [89, 234, 276, 282, 283], pYW1173A, T [284]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [88], βarr1 [124, 134]pSY1250T [128], M/I, A [89, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [>>268<<, 288, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [79], p85 [293], SHP2 [84, 145], PI3K [63][89, 292]Undeterminedp38, JNK [294], TIMP2 [295], SOCS1/2 [86], SOCS3 [296], p55γ [297], JAK1/2
n2:mentions: n3:7541045

Subject Item: _:vb26774357
rdf:type: n2:Context
rdf:value: K [89, 234, 276, 282, 283], pYW1173A, T [284]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [88], βarr1 [124, 134]pSY1250T [128], M/I, A [89, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, >>288<<, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [79], p85 [293], SHP2 [84, 145], PI3K [63][89, 292]Undeterminedp38, JNK [294], TIMP2 [295], SOCS1/2 [86], SOCS3 [296], p55γ [297], JAK1/2
n2:mentions: n3:9581554

Subject Item: _:vb26774358
rdf:type: n2:Context
rdf:value: 234, 276, 282, 283], pYW1173A, T [284]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [88], βarr1 [124, 134]pSY1250T [128], M/I, A [89, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, >>289<<]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [79], p85 [293], SHP2 [84, 145], PI3K [63][89, 292]Undeterminedp38, JNK [294], TIMP2 [295], SOCS1/2 [86], SOCS3 [296], p55γ [297], JAK1/2
n2:mentions: n3:11352919

Subject Item: _:vb26774359
rdf:type: n2:Context
rdf:value: 276, 282, 283], pYW1173A, T [284]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [88], βarr1 [124, 134]pSY1250T [128], M/I, A [89, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [>>290<<, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [79], p85 [293], SHP2 [84, 145], PI3K [63][89, 292]Undeterminedp38, JNK [294], TIMP2 [295], SOCS1/2 [86], SOCS3 [296], p55γ [297], JAK1/2
n2:mentions: n3:8647823

Subject Item: _:vb26774360
rdf:type: n2:Context
rdf:value: 282, 283], pYW1173A, T [284]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [88], βarr1 [124, 134]pSY1250T [128], M/I, A [89, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290, >>291<<]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [79], p85 [293], SHP2 [84, 145], PI3K [63][89, 292]Undeterminedp38, JNK [294], TIMP2 [295], SOCS1/2 [86], SOCS3 [296], p55γ [297], JAK1/2
n2:mentions: n3:10746631

Subject Item: _:vb26774361
rdf:type: n2:Context
rdf:value: T [284]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [88], βarr1 [124, 134]pSY1250T [128], M/I, A [89, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290, 291]S1291βarr1 [>>124<<, 134]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [79], p85 [293], SHP2 [84, 145], PI3K [63][89, 292]Undeterminedp38, JNK [294], TIMP2 [295], SOCS1/2 [86], SOCS3 [296], p55γ [297], JAK1/2
n2:mentions: n3:22509025

Subject Item: _:vb26774362
rdf:type: n2:Context
rdf:value: T [284]Y1221K [276]1229–1245Grb10 [78]S1248RACK1 [88], βarr1 [124, 134]pSY1250T [128], M/I, A [89, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290, 291]S1291βarr1 [124, >>134<<]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [79], p85 [293], SHP2 [84, 145], PI3K [63][89, 292]Undeterminedp38, JNK [294], TIMP2 [295], SOCS1/2 [86], SOCS3 [296], p55γ [297], JAK1/2
n2:mentions: n3:17303558

Subject Item: _:vb26774363
rdf:type: n2:Context
rdf:value: [78]S1248RACK1 [88], βarr1 [124, 134]pSY1250T [128], M/I, A [89, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [>>89<<, 292]F1310A [277]Y1316Grb10 [79], p85 [293], SHP2 [84, 145], PI3K [63][89, 292]Undeterminedp38, JNK [294], TIMP2 [295], SOCS1/2 [86], SOCS3 [296], p55γ [297], JAK1/2
n2:mentions: n3:8972223

Subject Item: _:vb26774364
rdf:type: n2:Context
rdf:value: [78]S1248RACK1 [88], βarr1 [124, 134]pSY1250T [128], M/I, A [89, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, >>292<<]F1310A [277]Y1316Grb10 [79], p85 [293], SHP2 [84, 145], PI3K [63][89, 292]Undeterminedp38, JNK [294], TIMP2 [295], SOCS1/2 [86], SOCS3 [296], p55γ [297], JAK1/2
n2:mentions: n3:8649825

Subject Item: _:vb26774365
rdf:type: n2:Context
rdf:value: [88], βarr1 [124, 134]pSY1250T [128], M/I, A [89, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A [>>277<<]Y1316Grb10 [79], p85 [293], SHP2 [84, 145], PI3K [63][89, 292]Undeterminedp38, JNK [294], TIMP2 [295], SOCS1/2 [86], SOCS3 [296], p55γ [297], JAK1/2
n2:mentions: n3:9202243

Subject Item: _:vb26774366
rdf:type: n2:Context
rdf:value: βarr1 [124, 134]pSY1250T [128], M/I, A [89, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [>>79<<], p85 [293], SHP2 [84, 145], PI3K [63][89, 292]Undeterminedp38, JNK [294], TIMP2 [295], SOCS1/2 [86], SOCS3 [296], p55γ [297], JAK1/2
n2:mentions: n3:10454568

Subject Item: _:vb26774367
rdf:type: n2:Context
rdf:value: [124, 134]pSY1250T [128], M/I, A [89, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [79], p85 [>>293<<], SHP2 [84, 145], PI3K [63][89, 292]Undeterminedp38, JNK [294], TIMP2 [295], SOCS1/2 [86], SOCS3 [296], p55γ [297], JAK1/2
n2:mentions: n3:7589433

Subject Item: _:vb26774368
rdf:type: n2:Context
rdf:value: [128], M/I, A [89, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [79], p85 [293], SHP2 [>>84<<, 145], PI3K [63][89, 292]Undeterminedp38, JNK [294], TIMP2 [295], SOCS1/2 [86], SOCS3 [296], p55γ [297], JAK1/2
n2:mentions: n3:7642582

Subject Item: _:vb26774369
rdf:type: n2:Context
rdf:value: [128], M/I, A [89, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [79], p85 [293], SHP2 [84, >>145<<], PI3K [63][89, 292]Undeterminedp38, JNK [294], TIMP2 [295], SOCS1/2 [86], SOCS3 [296], p55γ [297], JAK1/2
n2:mentions: n3:8895367

Subject Item: _:vb26774370
rdf:type: n2:Context
rdf:value: A [89, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [79], p85 [293], SHP2 [84, 145], PI3K [>>63<<][89, 292]Undeterminedp38, JNK [294], TIMP2 [295], SOCS1/2 [86], SOCS3 [296], p55γ [297], JAK1/2
n2:mentions: n3:22767591

Subject Item: _:vb26774371
rdf:type: n2:Context
rdf:value: A [89, 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [79], p85 [293], SHP2 [84, 145], PI3K [63][>>89<<, 292]Undeterminedp38, JNK [294], TIMP2 [295], SOCS1/2 [86], SOCS3 [296], p55γ [297], JAK1/2
n2:mentions: n3:8972223

Subject Item: _:vb26774372
rdf:type: n2:Context
rdf:value: 276, 285]Y1251I [286], K [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [79], p85 [293], SHP2 [84, 145], PI3K [63][89, >>292<<]Undeterminedp38, JNK [294], TIMP2 [295], SOCS1/2 [86], SOCS3 [296], p55γ [297], JAK1/2
n2:mentions: n3:8649825

Subject Item: _:vb26774373
rdf:type: n2:Context
rdf:value: [276], A, T [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [79], p85 [293], SHP2 [84, 145], PI3K [63][89, 292]Undeterminedp38, JNK [>>294<<], TIMP2 [295], SOCS1/2 [86], SOCS3 [296], p55γ [297], JAK1/2
n2:mentions: n3:14710357

Subject Item: _:vb26774374
rdf:type: n2:Context
rdf:value: [89]S1252pS, I [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [79], p85 [293], SHP2 [84, 145], PI3K [63][89, 292]Undeterminedp38, JNK [294], TIMP2 [>>295<<], SOCS1/2 [86], SOCS3 [296], p55γ [297], JAK1/2
n2:mentions: n3:20940305

Subject Item: _:vb26774375
rdf:type: n2:Context
rdf:value: [280]S127214.3.3 [287]S1280–S128314.3.3 [268, 288, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [79], p85 [293], SHP2 [84, 145], PI3K [63][89, 292]Undeterminedp38, JNK [294], TIMP2 [295], SOCS1/2 [>>86<<], SOCS3 [296], p55γ [297], JAK1/2
n2:mentions: n3:9727029

Subject Item: _:vb26774376
rdf:type: n2:Context
rdf:value: [287]S1280–S128314.3.3 [268, 288, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [79], p85 [293], SHP2 [84, 145], PI3K [63][89, 292]Undeterminedp38, JNK [294], TIMP2 [295], SOCS1/2 [86], SOCS3 [>>296<<], p55γ [297], JAK1/2
n2:mentions: n3:11071852

Subject Item: _:vb26774377
rdf:type: n2:Context
rdf:value: [268, 288, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [79], p85 [293], SHP2 [84, 145], PI3K [63][89, 292]Undeterminedp38, JNK [294], TIMP2 [295], SOCS1/2 [86], SOCS3 [296], p55γ [>>297<<], JAK1/2
n2:mentions: n3:9524259

Subject Item: _:vb26774378
rdf:type: n2:Context
rdf:value: [268, 288, 289]T [290, 291]S1291βarr1 [124, 134]pSH1293–K1294A [89, 292]F1310A [277]Y1316Grb10 [79], p85 [293], SHP2 [84, 145], PI3K [63][89, 292]Undeterminedp38, JNK [294], TIMP2 [295], SOCS1/2 [86], SOCS3 [296], p55γ [297], JAK1/2 [>>298<<
n2:mentions: n3:9492017

Subject Item: _:vb26774379
rdf:type: n2:Context
rdf:value: The TK domain is highly homologous to that of the IR (84 %), the juxtamembrane domain shares 61 % of homology with the IR, whereas the C-terminal domain shares only 44 % [>>40<<]. Despite this high degree of homology, it is largely accepted that the two receptors have distinct biological roles.
n2:mentions: n3:2877871

Subject Item: _:vb26774380
rdf:type: n2:Context
rdf:value: The IR is known to be a key regulator of physiological processes such as glucose transport and biosynthesis of glycogen and fat [>>53<<], whereas the IGF-1R is a potent regulator of cell growth, proliferation, and differentiation [54, 55].
n2:mentions: n3:10212828

Subject Item: _:vb26774381
rdf:type: n2:Context
rdf:value: The IR is known to be a key regulator of physiological processes such as glucose transport and biosynthesis of glycogen and fat [53], whereas the IGF-1R is a potent regulator of cell growth, proliferation, and differentiation [>>54<<, 55]. The structure–function relationship of the IGF-1R has been extensively investigated, with mutational analysis revealing residues crucial for the binding of signaling or adaptor proteins (Table 1; Fig. 1) or particular downstream
n2:mentions: n3:8899293

Subject Item: _:vb26774382
rdf:type: n2:Context
rdf:value: The IR is known to be a key regulator of physiological processes such as glucose transport and biosynthesis of glycogen and fat [53], whereas the IGF-1R is a potent regulator of cell growth, proliferation, and differentiation [54, >>55<<]. The structure–function relationship of the IGF-1R has been extensively investigated, with mutational analysis revealing residues crucial for the binding of signaling or adaptor proteins (Table 1; Fig.
n2:mentions: n3:2548842

Subject Item: _:vb26774383
rdf:type: n2:Context
rdf:value: According to the classical model, IGF-1/2 binding induces a conformational change in the preformed dimeric receptor, leading to activation of the RTK [>>6<<]. In the unphosphorylated state, the receptor catalytic activity is very low due to the inhibitory conformation of a specific domain in the kinase region, which interferes with ATP-binding and tyrosine phosphorylation.
n2:mentions: n3:7834741

Subject Item: _:vb26774384
rdf:type: n2:Context
rdf:value: This domain, known as the activation loop (A-loop), behaves as a pseudosubstrate that blocks the active site [>>56<<]. The A-loop contains the critical tyrosine (Tyr) residues 1131, 1135, and 1136 and the activation of intrinsic protein kinase activity results in the autophosphorylation of them [56] (Fig. 1). Tyr 1135 (being the first tyrosine to be
n2:mentions: n3:11694888

Subject Item: _:vb26774385
rdf:type: n2:Context
rdf:value: The A-loop contains the critical tyrosine (Tyr) residues 1131, 1135, and 1136 and the activation of intrinsic protein kinase activity results in the autophosphorylation of them [>>56<<] (Fig. 1). Tyr 1135 (being the first tyrosine to be phosphorylated) in the A-loop is bound in cis position in the active site, thus preventing substrate access while simultaneously occluding the ATP binding site. The kinase activity is at
n2:mentions: n3:11694888

Subject Item: _:vb26774386
rdf:type: n2:Context
rdf:value: Phosphorylation of Tyr 1135 and Tyr 1131 destabilizes the auto-inhibitory conformation of the A-loop, whereas phosphorylation of Tyr 1136 and, to a lesser extent, Tyr 1135 stabilizes the catalytically optimized conformation of it [>>56<<]. Autophosphorylation of Tyr 1135 is necessary but not sufficient to destabilize the autoinhibitory A-loop conformation; full destabilization also requires autophosphorylation of Tyr 1131.
n2:mentions: n3:11694888

Subject Item: _:vb26774387
rdf:type: n2:Context
rdf:value: C-terminal domain with multiple potential phosphorylation sites (more than 20 in IRS1/2/4) that interact with high affinity to SH2 domain-containing-proteins in a manner dependent on the specific phospho-tyrosine motif (YXXX) involved [>>57<<]. The SH2 domain-containing-proteins include a p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K) class I, growth-factor-receptor-bound protein 2 (Grb2), SH-PTP2 (a tyrosine phosphatase), and other adaptor proteins like Crk
n2:mentions: n3:8372354

Subject Item: _:vb26774388
rdf:type: n2:Context
rdf:value: IRS1, as a docking-protein, has been involved in interactions with multiple molecules secondary to IGF-1R activation, and among them β1 integrins seem to have an important role in cell adhesion to laminin after IGF-1 stimulation [>>58<<]. In addition, a recent study described that IRSs form high-molecular-mass complexes with a variety of proteins in a phospho-tyrosine-independent manner and modulate their availability to the IGF-1R [59, 60].
n2:mentions: n3:15289498

Subject Item: _:vb26774389
rdf:type: n2:Context
rdf:value: In addition, a recent study described that IRSs form high-molecular-mass complexes with a variety of proteins in a phospho-tyrosine-independent manner and modulate their availability to the IGF-1R [>>59<<, 60].
n2:mentions: n3:21168390

Subject Item: _:vb26774390
rdf:type: n2:Context
rdf:value: In addition, a recent study described that IRSs form high-molecular-mass complexes with a variety of proteins in a phospho-tyrosine-independent manner and modulate their availability to the IGF-1R [59, >>60<<].
n2:mentions: n3:22634009

Subject Item: _:vb26774391
rdf:type: n2:Context
rdf:value: Shc has been shown to consist of four unique members, ShcA, B, C, and D, and multiple splicing isoforms [>>61<<]. In general, Shc proteins possess a PTB domain at the N-terminal region and a SH2 domain at the C-terminal region. Between the PTB domain and SH2 domain, there are three tyrosine residues, possibly phosphorylated by IGF-1R, involved in
n2:mentions: n3:22970934

Subject Item: _:vb26774392
rdf:type: n2:Context
rdf:value: activated by the IGF-1R involves IRS interaction with a p85 regulatory subunit of PI3K class I, leading to activation of the catalytic subunit p110 of PI3K and inducing phospholipid products activating the downstream signaling pathway [>>62<<].
n2:mentions: n3:10950308

Subject Item: _:vb26774393
rdf:type: n2:Context
rdf:value: It has also been shown that tyrosine phosphorylation of the IGF-1R (Y1316XXM) can also induce direct binding of PI3K to the cytoplasmic region of the receptor [>>63<<] (Figs. 1, 2).
n2:mentions: n3:22767591

Subject Item: _:vb26774394
rdf:type: n2:Context
rdf:value: These phospholipids function as ligands for recruiting PH domain-containing-proteins to the inner surface of the cell membrane [>>39<<]. The Akt/PKB serine threonine kinase interacts with these phospholipids causing its translocation to the inner membrane and activation by the 3-phosphoinositide-dependent protein kinases (PDKs) located around the membrane. IGFs-mediated
n2:mentions: n3:9516079

Subject Item: _:vb26774395
rdf:type: n2:Context
rdf:value: IGFs-mediated activation of the PI3K pathway induces phosphorylation of the Thr308 and Ser473 residues on Akt and activates this kinase [>>64<<, 65]. Active Akt in turn phosphorylates and inhibits several pro-apoptotic proteins such as Bad [66] and caspase 9 [67], plus at least three other Akt effectors: the survival transcription factor cyclic AMP response element
n2:mentions: n3:8978681

Subject Item: _:vb26774396
rdf:type: n2:Context
rdf:value: IGFs-mediated activation of the PI3K pathway induces phosphorylation of the Thr308 and Ser473 residues on Akt and activates this kinase [64, >>65<<]. Active Akt in turn phosphorylates and inhibits several pro-apoptotic proteins such as Bad [66] and caspase 9 [67], plus at least three other Akt effectors: the survival transcription factor cyclic AMP response element binding-protein
n2:mentions: n3:10601311

Subject Item: _:vb26774397
rdf:type: n2:Context
rdf:value: Active Akt in turn phosphorylates and inhibits several pro-apoptotic proteins such as Bad [>>66<<] and caspase 9 [67], plus at least three other Akt effectors:
n2:mentions: n3:9381178

Subject Item: _:vb26774398
rdf:type: n2:Context
rdf:value: Active Akt in turn phosphorylates and inhibits several pro-apoptotic proteins such as Bad [66] and caspase 9 [>>67<<], plus at least three other Akt effectors:
n2:mentions: n3:9812896

Subject Item: _:vb26774399
rdf:type: n2:Context
rdf:value: Akt activation can also induce stimulation of mTOR that will lead to phosphorylation of the 40S ribosomal S6 protein by the p70S6 kinase, thereby enabling efficient translation of 5′ terminal oligopyrimidine tract (5′TOP) mRNA [>>68<<]. This class of mRNA is critically involved in the control of the protein synthesis machinery regulating the transition from G0 to G1 of the cell cycle. Activated mTOR can also induce phosphorylation of eukaryotic initiation factor 4E
n2:mentions: n3:14710353

Subject Item: _:vb26774400
rdf:type: n2:Context
rdf:value: Activated mTOR can also induce phosphorylation of eukaryotic initiation factor 4E (eIF-4E) binding-protein (4E-BP), thus regulating cell cycle proteins like cyclin D1 [>>69<<]. mTOR is also involved in activation of matrix metallo proteinase (MMP)2 with effects on cell migration and metastasis potential [70]. Another effect of Akt activation is phosphorylation of Mdm2 on serine 166 and serine 186.
n2:mentions: n3:11357143

Subject Item: _:vb26774401
rdf:type: n2:Context
rdf:value: mTOR is also involved in activation of matrix metallo proteinase (MMP)2 with effects on cell migration and metastasis potential [>>70<<]. Another effect of Akt activation is phosphorylation of Mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of Mdm2 from the cytoplasm into the nucleus, where Mdm2 decreases p53
n2:mentions: n3:14993222

Subject Item: _:vb26774402
rdf:type: n2:Context
rdf:value: Phosphorylation on these sites is necessary for translocation of Mdm2 from the cytoplasm into the nucleus, where Mdm2 decreases p53 transcriptional activity and hence diminishes cellular levels of p53 [>>71<<].
n2:mentions: n3:11504915

Subject Item: _:vb26774403
rdf:type: n2:Context
rdf:value: ERK also mediates transcriptional induction of the cyclin D1 gene, stimulating phosphorylation of the pRb protein and release of the E2F-1 transcription factor [>>72<<]. The free E2F-1 can activate in its turn the transcription of p14ARF [73]. ARF was shown to inhibit the p53-Mdm2 association that maintains p53 in its inactive form [74]. In its turn, p53 can directly interfere with the Ras/MAPK cascade
n2:mentions: n3:9062190

Subject Item: _:vb26774404
rdf:type: n2:Context
rdf:value: The free E2F-1 can activate in its turn the transcription of p14ARF [>>73<<]. ARF was shown to inhibit the p53-Mdm2 association that maintains p53 in its inactive form [74].
n2:mentions: n3:9744267

Subject Item: _:vb26774405
rdf:type: n2:Context
rdf:value: ARF was shown to inhibit the p53-Mdm2 association that maintains p53 in its inactive form [>>74<<]. In its turn, p53 can directly interfere with the Ras/MAPK cascade by inactivating ERK2/MAPK via caspase-mediated cleavage [75]. One of the other substrates of MAPK is p90Rsk. Both MAPK and p90Rsk translocate to the nucleus after
n2:mentions: n3:10679383

Subject Item: _:vb26774406
rdf:type: n2:Context
rdf:value: In its turn, p53 can directly interfere with the Ras/MAPK cascade by inactivating ERK2/MAPK via caspase-mediated cleavage [>>75<<]. One of the other substrates of MAPK is p90Rsk. Both MAPK and p90Rsk translocate to the nucleus after phosphorylation, where they phosphorylate and activate transcription factors such as serum-responsive factor (SRF), T cell-specific
n2:mentions: n3:15150542

Subject Item: _:vb26774407
rdf:type: n2:Context
rdf:value: By regulating microtubule networks, MAPK regulates the CyclinB/Cdc2 complex: Cyclin B phosphorylation by MAPK is important for the translocation of the complex to the nucleus where it is activated by CDC 25C [>>76<<, 77].
n2:mentions: n3:12612056

Subject Item: _:vb26774408
rdf:type: n2:Context
rdf:value: By regulating microtubule networks, MAPK regulates the CyclinB/Cdc2 complex: Cyclin B phosphorylation by MAPK is important for the translocation of the complex to the nucleus where it is activated by CDC 25C [76, >>77<<].
n2:mentions: n3:1828290

Subject Item: _:vb26774409
rdf:type: n2:Context
rdf:value: Ligand activation of the IGF-1R involves the Grb10 adaptor protein, which probably binds to autophosphorylated tyrosine residues located between amino acids 1229 and 1245 of IGF-1R [>>78<<] or tyrosine 1316 [79].
n2:mentions: n3:8764099

Subject Item: _:vb26774410
rdf:type: n2:Context
rdf:value: Ligand activation of the IGF-1R involves the Grb10 adaptor protein, which probably binds to autophosphorylated tyrosine residues located between amino acids 1229 and 1245 of IGF-1R [78] or tyrosine 1316 [>>79<<]. Activated Grb10 interacts with neuronal precursor cell-expressed developmentally downregulated 4 (Nedd4), and by doing this it has an important role in ubiquitination of the IGF-1R. Other substrates of the IGF-1R tyrosine kinase include
n2:mentions: n3:10454568

Subject Item: _:vb26774411
rdf:type: n2:Context
rdf:value: Other substrates of the IGF-1R tyrosine kinase include the guanine nucleotide exchange factors Vav [>>80<<] and Vav3 [81], the adapters CrkII and CrkL [82], and focal adhesion kinase (FAK) [83].
n2:mentions: n3:8605967

Subject Item: _:vb26774412
rdf:type: n2:Context
rdf:value: Other substrates of the IGF-1R tyrosine kinase include the guanine nucleotide exchange factors Vav [80] and Vav3 [>>81<<], the adapters CrkII and CrkL [82], and focal adhesion kinase (FAK) [83].
n2:mentions: n3:11094073

Subject Item: _:vb26774413
rdf:type: n2:Context
rdf:value: Other substrates of the IGF-1R tyrosine kinase include the guanine nucleotide exchange factors Vav [80] and Vav3 [81], the adapters CrkII and CrkL [>>82<<], and focal adhesion kinase (FAK) [83].
n2:mentions: n3:7534289

Subject Item: _:vb26774414
rdf:type: n2:Context
rdf:value: Other substrates of the IGF-1R tyrosine kinase include the guanine nucleotide exchange factors Vav [80] and Vav3 [81], the adapters CrkII and CrkL [82], and focal adhesion kinase (FAK) [>>83<<]. Aside from IRS proteins, IGF-1R has been reported to interact in vitro and/or in vivo with numerous molecules, including Syp [39], GTPase-activating-protein [84], C-terminal Src kinase [85], and suppressor of cytokine signaling (SOCS)2
n2:mentions: n3:9507031

Subject Item: _:vb26774415
rdf:type: n2:Context
rdf:value: Aside from IRS proteins, IGF-1R has been reported to interact in vitro and/or in vivo with numerous molecules, including Syp [>>39<<], GTPase-activating-protein [84], C-terminal Src kinase [85], and suppressor of cytokine signaling (SOCS)2 [86].
n2:mentions: n3:9516079

Subject Item: _:vb26774416
rdf:type: n2:Context
rdf:value: Aside from IRS proteins, IGF-1R has been reported to interact in vitro and/or in vivo with numerous molecules, including Syp [39], GTPase-activating-protein [>>84<<], C-terminal Src kinase [85], and suppressor of cytokine signaling (SOCS)2 [86].
n2:mentions: n3:7642582

Subject Item: _:vb26774417
rdf:type: n2:Context
rdf:value: Aside from IRS proteins, IGF-1R has been reported to interact in vitro and/or in vivo with numerous molecules, including Syp [39], GTPase-activating-protein [84], C-terminal Src kinase [>>85<<], and suppressor of cytokine signaling (SOCS)2 [86].
n2:mentions: n3:10026153

Subject Item: _:vb26774418
rdf:type: n2:Context
rdf:value: Aside from IRS proteins, IGF-1R has been reported to interact in vitro and/or in vivo with numerous molecules, including Syp [39], GTPase-activating-protein [84], C-terminal Src kinase [85], and suppressor of cytokine signaling (SOCS)2 [>>86<<]. The IGF-1R can also activate the stress-activated protein kinases (SAPKs) including p38 and Jun N terminal kinase (JNK), a pathway associated with regulation of DNA damage responses and cell survival.
n2:mentions: n3:9727029

Subject Item: _:vb26774419
rdf:type: n2:Context
rdf:value: It has been shown that RACK1, a small molecule that was identified as an IGF-1R interacting protein using a yeast two-hybrid interaction trap, regulates IGF-1R signaling and interaction of the IGF-1R with integrin signaling [>>87<<–89]. However, information regarding the roles of many of these molecules in IGF-1R signaling and biological functions is currently limited.
n2:mentions: n3:8972223 n3:11884618 n3:11964397

Subject Item: _:vb26774420
rdf:type: n2:Context
rdf:value: The classical IGF-1R signaling cascades are more complex, and they have been described in great detail in some dedicated reviews [>>1<<, 23, 33, 37, 41, 90–94].
n2:mentions: n3:20602996

Subject Item: _:vb26774421
rdf:type: n2:Context
rdf:value: The classical IGF-1R signaling cascades are more complex, and they have been described in great detail in some dedicated reviews [1, >>23<<, 33, 37, 41, 90–94].
n2:mentions: n3:16083341

Subject Item: _:vb26774422
rdf:type: n2:Context
rdf:value: The classical IGF-1R signaling cascades are more complex, and they have been described in great detail in some dedicated reviews [1, 23, >>33<<, 37, 41, 90–94].
n2:mentions: n3:10961344

Subject Item: _:vb26774423
rdf:type: n2:Context
rdf:value: The classical IGF-1R signaling cascades are more complex, and they have been described in great detail in some dedicated reviews [1, 23, 33, >>37<<, 41, 90–94].
n2:mentions: n3:19752219

Subject Item: _:vb26774424
rdf:type: n2:Context
rdf:value: The classical IGF-1R signaling cascades are more complex, and they have been described in great detail in some dedicated reviews [1, 23, 33, 37, >>41<<, 90–94].
n2:mentions: n3:7540132

Subject Item: _:vb26774425
rdf:type: n2:Context
rdf:value: The classical IGF-1R signaling cascades are more complex, and they have been described in great detail in some dedicated reviews [1, 23, 33, 37, 41, >>90<<–94].
n2:mentions: n3:21963847 n3:22337149 n3:12767520 n3:22761272

Subject Item: _:vb26774426
rdf:type: n5:Section
dc:title: something new: posttranslational modification of igf-1r controlling igf-1r expression and function
n5:contains: _:vb26774428 _:vb26774429 _:vb26774430 _:vb26774431 _:vb26774427 _:vb26774444 _:vb26774445 _:vb26774446 _:vb26774447 _:vb26774440 _:vb26774441 _:vb26774442 _:vb26774443 _:vb26774436 _:vb26774437 _:vb26774438 _:vb26774439 _:vb26774432 _:vb26774433 _:vb26774434 _:vb26774435 _:vb26774460 _:vb26774461 _:vb26774462 _:vb26774463 _:vb26774456 _:vb26774457 _:vb26774458 _:vb26774459 _:vb26774452 _:vb26774453 _:vb26774454 _:vb26774455 _:vb26774448 _:vb26774449 _:vb26774450 _:vb26774451 _:vb26774476 _:vb26774477 _:vb26774478 _:vb26774479 _:vb26774472 _:vb26774473 _:vb26774474 _:vb26774475 _:vb26774468 _:vb26774469 _:vb26774470 _:vb26774471 _:vb26774464 _:vb26774465 _:vb26774466 _:vb26774467 _:vb26774492 _:vb26774493 _:vb26774494 _:vb26774495 _:vb26774488 _:vb26774489 _:vb26774490 _:vb26774491 _:vb26774484 _:vb26774485 _:vb26774486 _:vb26774487 _:vb26774480 _:vb26774481 _:vb26774482 _:vb26774483 _:vb26774508 _:vb26774509 _:vb26774510 _:vb26774511 _:vb26774504 _:vb26774505 _:vb26774506 _:vb26774507 _:vb26774500 _:vb26774501 _:vb26774502 _:vb26774503 _:vb26774496 _:vb26774497 _:vb26774498 _:vb26774499 _:vb26774524 _:vb26774525 _:vb26774526 _:vb26774527 _:vb26774520 _:vb26774521 _:vb26774522 _:vb26774523 _:vb26774516 _:vb26774517 _:vb26774518 _:vb26774519 _:vb26774512 _:vb26774513 _:vb26774514 _:vb26774515 _:vb26774536 _:vb26774532 _:vb26774533 _:vb26774534 _:vb26774535 _:vb26774528 _:vb26774529 _:vb26774530 _:vb26774531

Subject Item: _:vb26774427
rdf:type: n2:Context
rdf:value: Owing to the presence of an intracellular tyrosine kinase domain, IGF-1R is classified as an RTK, and accordingly phosphorylation was considered to be the central process governing IGF-1R signaling [>>94<<, 95]. However, during the last decade, several laboratories have been investigating the mechanisms controlling the subsequent receptor downregulation and signaling desensitization.
n2:mentions: n3:12767520

Subject Item: _:vb26774428
rdf:type: n2:Context
rdf:value: Owing to the presence of an intracellular tyrosine kinase domain, IGF-1R is classified as an RTK, and accordingly phosphorylation was considered to be the central process governing IGF-1R signaling [94, >>95<<]. However, during the last decade, several laboratories have been investigating the mechanisms controlling the subsequent receptor downregulation and signaling desensitization.
n2:mentions: n3:15956962

Subject Item: _:vb26774429
rdf:type: n2:Context
rdf:value: Many cell surface receptors undergo endocytosis, being incorporated into clathrin- [>>96<<] or caveolin-coated vesicles.
n2:mentions: n3:2177341

Subject Item: _:vb26774430
rdf:type: n2:Context
rdf:value: Some receptors are internalized constitutively and recycled (e.g., the transferrin receptor); however, with most RTKs and G-protein-coupled receptors (GPCRs), internalization is triggered by ligand binding [>>97<<, 98]. Ligand-activated receptors are normally downregulated by internalization [99–101], allowing the cells to return to an unstimulated, basal state. This internalization is considered to occur only for phosphorylated receptors [99–101],
n2:mentions: n3:2564002

Subject Item: _:vb26774431
rdf:type: n2:Context
rdf:value: Some receptors are internalized constitutively and recycled (e.g., the transferrin receptor); however, with most RTKs and G-protein-coupled receptors (GPCRs), internalization is triggered by ligand binding [97, >>98<<]. Ligand-activated receptors are normally downregulated by internalization [99–101], allowing the cells to return to an unstimulated, basal state. This internalization is considered to occur only for phosphorylated receptors [99–101], and
n2:mentions: n3:9277131

Subject Item: _:vb26774432
rdf:type: n2:Context
rdf:value: Ligand-activated receptors are normally downregulated by internalization [>>99<<–101], allowing the cells to return to an unstimulated, basal state.
n2:mentions: n3:11265249 n3:9409540 n3:10201076

Subject Item: _:vb26774433
rdf:type: n2:Context
rdf:value: This internalization is considered to occur only for phosphorylated receptors [>>99<<–101], and is thus ligand-dependent.
n2:mentions: n3:11265249 n3:9409540 n3:10201076

Subject Item: _:vb26774434
rdf:type: n2:Context
rdf:value: Early endosomes are mildly acidic, allowing detachment of the ligand and hence attenuation of the signal [>>102<<, 103]. If the receptor is to be degraded, it will progress to the highly acidic, hydrolase-containing lysosomal compartments. Internalization of a receptor does not necessarily mean immediate cessation of the signal followed by receptor
n2:mentions: n3:22357968

Subject Item: _:vb26774435
rdf:type: n2:Context
rdf:value: Early endosomes are mildly acidic, allowing detachment of the ligand and hence attenuation of the signal [102, >>103<<]. If the receptor is to be degraded, it will progress to the highly acidic, hydrolase-containing lysosomal compartments. Internalization of a receptor does not necessarily mean immediate cessation of the signal followed by receptor
n2:mentions: n3:22113372

Subject Item: _:vb26774436
rdf:type: n2:Context
rdf:value: endocytosis appears to have a double function: although subsequently attenuating the signal from activated receptors, it is also facilitating the interaction between the internalized receptor and the downstream signaling molecules [>>103<<]. For example, signaling through the EGFR is maintained in endosomal compartments and determines the longevity of the signaling [104, 105].
n2:mentions: n3:22113372

Subject Item: _:vb26774437
rdf:type: n2:Context
rdf:value: For example, signaling through the EGFR is maintained in endosomal compartments and determines the longevity of the signaling [>>104<<, 105].
n2:mentions: n3:21172338

Subject Item: _:vb26774438
rdf:type: n2:Context
rdf:value: For example, signaling through the EGFR is maintained in endosomal compartments and determines the longevity of the signaling [104, >>105<<].
n2:mentions: n3:22575736

Subject Item: _:vb26774439
rdf:type: n2:Context
rdf:value: The ubiquitin pathway is a regulatory system for endocytosis [>>99<<–101, 106], and RTKs are well recognized as targets of ubiquitination [107].
n2:mentions: n3:11265249 n3:9409540 n3:10201076

Subject Item: _:vb26774440
rdf:type: n2:Context
rdf:value: The ubiquitin pathway is a regulatory system for endocytosis [99–101, >>106<<], and RTKs are well recognized as targets of ubiquitination [107].
n2:mentions: n3:10637223

Subject Item: _:vb26774441
rdf:type: n2:Context
rdf:value: The ubiquitin pathway is a regulatory system for endocytosis [99–101, 106], and RTKs are well recognized as targets of ubiquitination [>>107<<]. Ubiquitination is the covalent attachment of the 7-kDa ubiquitin polypeptide to lysine residues on target proteins through the sequential actions of E1, E2, and E3 ligase enzymes [108, 109].
n2:mentions: n3:19007773

Subject Item: _:vb26774442
rdf:type: n2:Context
rdf:value: Ubiquitination is the covalent attachment of the 7-kDa ubiquitin polypeptide to lysine residues on target proteins through the sequential actions of E1, E2, and E3 ligase enzymes [>>108<<, 109]. E1 and E2 work to load the E3 ligase with the ubiquitin, while E3 transfers the ubiquitin to the target protein. The E3 provides the specificity for the substrate, binding directly or through adaptor proteins. Ubiquitination can
n2:mentions: n3:11395416

Subject Item: _:vb26774443
rdf:type: n2:Context
rdf:value: Ubiquitination is the covalent attachment of the 7-kDa ubiquitin polypeptide to lysine residues on target proteins through the sequential actions of E1, E2, and E3 ligase enzymes [108, >>109<<]. E1 and E2 work to load the E3 ligase with the ubiquitin, while E3 transfers the ubiquitin to the target protein. The E3 provides the specificity for the substrate, binding directly or through adaptor proteins. Ubiquitination can either
n2:mentions: n3:11265246

Subject Item: _:vb26774444
rdf:type: n2:Context
rdf:value: Proteins can be multi-ubiquitinated (at multiple lysine residues) and polyubiquitination can be straight or branched type, depending on which of the lysine residues within ubiquitin the subsequent ubiquitin is attached [>>101<<, 110–112].
n2:mentions: n3:11265249

Subject Item: _:vb26774445
rdf:type: n2:Context
rdf:value: Proteins can be multi-ubiquitinated (at multiple lysine residues) and polyubiquitination can be straight or branched type, depending on which of the lysine residues within ubiquitin the subsequent ubiquitin is attached [101, >>110<<–112]. The type of ubiquitination is increasingly being recognized as determining the fate of the substrate protein [113]. Old or damaged cytosolic proteins are labeled with a polyubiquitin chain, which is recognized by the proteasome,
n2:mentions: n3:21641804 n3:22820888 n3:22036065

Subject Item: _:vb26774446
rdf:type: n2:Context
rdf:value: In mammalian cells, a number of membrane proteins which are ubiquitinated are degraded through both the proteasome and lysosomal pathways [>>100<<], including the IGF-1R [114–117] and other RTKs [118, 119].
n2:mentions: n3:10201076

Subject Item: _:vb26774447
rdf:type: n2:Context
rdf:value: In mammalian cells, a number of membrane proteins which are ubiquitinated are degraded through both the proteasome and lysosomal pathways [100], including the IGF-1R [>>114<<–117] and other RTKs [118, 119].
n2:mentions: n3:7622464 n3:12821780 n3:18632619 n3:16619240

Subject Item: _:vb26774448
rdf:type: n2:Context
rdf:value: In mammalian cells, a number of membrane proteins which are ubiquitinated are degraded through both the proteasome and lysosomal pathways [100], including the IGF-1R [114–117] and other RTKs [>>118<<, 119]. In some cases (e.g., the RTK Met), cytoplasmic fragments are cleaved from the receptor and degraded by the proteasome, in a complementary mechanism to lysosomal degradation [119].
n2:mentions: n3:22745586

Subject Item: _:vb26774449
rdf:type: n2:Context
rdf:value: In mammalian cells, a number of membrane proteins which are ubiquitinated are degraded through both the proteasome and lysosomal pathways [100], including the IGF-1R [114–117] and other RTKs [118, >>119<<]. In some cases (e.g., the RTK Met), cytoplasmic fragments are cleaved from the receptor and degraded by the proteasome, in a complementary mechanism to lysosomal degradation [119].
n2:mentions: n3:22672335

Subject Item: _:vb26774450
rdf:type: n2:Context
rdf:value: In some cases (e.g., the RTK Met), cytoplasmic fragments are cleaved from the receptor and degraded by the proteasome, in a complementary mechanism to lysosomal degradation [>>119<<].
n2:mentions: n3:22672335

Subject Item: _:vb26774451
rdf:type: n2:Context
rdf:value: The IGF-1R has been shown to be ubiquitinated [>>116<<, 117, 120] and internalized, through both clathrin and caveolin routes, in a ligand-dependent manner [116, 117, 120, 121].
n2:mentions: n3:12821780

Subject Item: _:vb26774452
rdf:type: n2:Context
rdf:value: The IGF-1R has been shown to be ubiquitinated [116, >>117<<, 120] and internalized, through both clathrin and caveolin routes, in a ligand-dependent manner [116, 117, 120, 121].
n2:mentions: n3:18632619

Subject Item: _:vb26774453
rdf:type: n2:Context
rdf:value: The IGF-1R has been shown to be ubiquitinated [116, 117, >>120<<] and internalized, through both clathrin and caveolin routes, in a ligand-dependent manner [116, 117, 120, 121].
n2:mentions: n3:12697834

Subject Item: _:vb26774454
rdf:type: n2:Context
rdf:value: The IGF-1R has been shown to be ubiquitinated [116, 117, 120] and internalized, through both clathrin and caveolin routes, in a ligand-dependent manner [>>116<<, 117, 120, 121]. Ubiquitination of the IGF-1R occurs prior to entry into endocytotic vesicles [120].
n2:mentions: n3:12821780

Subject Item: _:vb26774455
rdf:type: n2:Context
rdf:value: The IGF-1R has been shown to be ubiquitinated [116, 117, 120] and internalized, through both clathrin and caveolin routes, in a ligand-dependent manner [116, >>117<<, 120, 121]. Ubiquitination of the IGF-1R occurs prior to entry into endocytotic vesicles [120].
n2:mentions: n3:18632619

Subject Item: _:vb26774456
rdf:type: n2:Context
rdf:value: The IGF-1R has been shown to be ubiquitinated [116, 117, 120] and internalized, through both clathrin and caveolin routes, in a ligand-dependent manner [116, 117, >>120<<, 121]. Ubiquitination of the IGF-1R occurs prior to entry into endocytotic vesicles [120].
n2:mentions: n3:12697834

Subject Item: _:vb26774457
rdf:type: n2:Context
rdf:value: The IGF-1R has been shown to be ubiquitinated [116, 117, 120] and internalized, through both clathrin and caveolin routes, in a ligand-dependent manner [116, 117, 120, >>121<<]. Ubiquitination of the IGF-1R occurs prior to entry into endocytotic vesicles [120].
n2:mentions: n3:17406664

Subject Item: _:vb26774458
rdf:type: n2:Context
rdf:value: Ubiquitination of the IGF-1R occurs prior to entry into endocytotic vesicles [>>120<<]. IGF-1R internalization reaches an apparent plateau after 20 min at 37 °C in cultured hippocampal neurons, while half-maximal IGF-1R internalization was obtained after 5 min at 37 °C in NIH-3T3 fibroblasts [122]. After internalization,
n2:mentions: n3:12697834

Subject Item: _:vb26774459
rdf:type: n2:Context
rdf:value: IGF-1R internalization reaches an apparent plateau after 20 min at 37 °C in cultured hippocampal neurons, while half-maximal IGF-1R internalization was obtained after 5 min at 37 °C in NIH-3T3 fibroblasts [>>122<<]. After internalization, some receptors are sorted for recycling to the cell surface. In activated T lymphocytes, internalization of the IGF-1R from the cell membrane was accompanied by a reduction in its mRNA. This was followed by
n2:mentions: n3:9145794

Subject Item: _:vb26774460
rdf:type: n2:Context
rdf:value: However, a slower increase in the mRNA levels indicated that the earlier recovery of IGF-1R results from receptor recycling, followed by de novo synthesis [>>123<<]. There are certainly internal routes where the IGF-1R is recycled back to the cell surface and where this balance between recycling and degradation can be manipulated [124]. After internalization, IGF-1R degradation is mediated by both
n2:mentions: n3:12784091

Subject Item: _:vb26774461
rdf:type: n2:Context
rdf:value: There are certainly internal routes where the IGF-1R is recycled back to the cell surface and where this balance between recycling and degradation can be manipulated [>>124<<]. After internalization, IGF-1R degradation is mediated by both the proteasome and lysosomal pathways or recycled to the plasma membrane [100, 114, 116, 117, 120], although the relative roles of each are not clear.
n2:mentions: n3:22509025

Subject Item: _:vb26774462
rdf:type: n2:Context
rdf:value: After internalization, IGF-1R degradation is mediated by both the proteasome and lysosomal pathways or recycled to the plasma membrane [>>100<<, 114, 116, 117, 120], although the relative roles of each are not clear.
n2:mentions: n3:10201076

Subject Item: _:vb26774463
rdf:type: n2:Context
rdf:value: After internalization, IGF-1R degradation is mediated by both the proteasome and lysosomal pathways or recycled to the plasma membrane [100, >>114<<, 116, 117, 120], although the relative roles of each are not clear.
n2:mentions: n3:7622464

Subject Item: _:vb26774464
rdf:type: n2:Context
rdf:value: After internalization, IGF-1R degradation is mediated by both the proteasome and lysosomal pathways or recycled to the plasma membrane [100, 114, >>116<<, 117, 120], although the relative roles of each are not clear.
n2:mentions: n3:12821780

Subject Item: _:vb26774465
rdf:type: n2:Context
rdf:value: After internalization, IGF-1R degradation is mediated by both the proteasome and lysosomal pathways or recycled to the plasma membrane [100, 114, 116, >>117<<, 120], although the relative roles of each are not clear.
n2:mentions: n3:18632619

Subject Item: _:vb26774466
rdf:type: n2:Context
rdf:value: After internalization, IGF-1R degradation is mediated by both the proteasome and lysosomal pathways or recycled to the plasma membrane [100, 114, 116, 117, >>120<<], although the relative roles of each are not clear.
n2:mentions: n3:12697834

Subject Item: _:vb26774467
rdf:type: n2:Context
rdf:value: The ligand-activated receptors are targeted to clathrin-coated membrane invaginations [>>125<<], a process mediated by a specific internalization signal situated within cytoplasmic domain of the receptor [100].
n2:mentions: n3:10712919

Subject Item: _:vb26774468
rdf:type: n2:Context
rdf:value: The ligand-activated receptors are targeted to clathrin-coated membrane invaginations [125], a process mediated by a specific internalization signal situated within cytoplasmic domain of the receptor [>>100<<]. There is evidence that internalization signals have a tyrosine-based motif usually located within the juxtamembrane region of the receptor [126, 127].
n2:mentions: n3:10201076

Subject Item: _:vb26774469
rdf:type: n2:Context
rdf:value: There is evidence that internalization signals have a tyrosine-based motif usually located within the juxtamembrane region of the receptor [>>126<<, 127]. The human IGF-1R contains three tyrosine residues in the juxtamembrane region [50] that may be involved in internalization. However, contradictory results have been reported regarding the role of these tyrosine-based motifs as
n2:mentions: n3:1400571

Subject Item: _:vb26774470
rdf:type: n2:Context
rdf:value: There is evidence that internalization signals have a tyrosine-based motif usually located within the juxtamembrane region of the receptor [126, >>127<<]. The human IGF-1R contains three tyrosine residues in the juxtamembrane region [50] that may be involved in internalization. However, contradictory results have been reported regarding the role of these tyrosine-based motifs as
n2:mentions: n3:7983165

Subject Item: _:vb26774471
rdf:type: n2:Context
rdf:value: The human IGF-1R contains three tyrosine residues in the juxtamembrane region [>>50<<] that may be involved in internalization.
n2:mentions: n3:8163493

Subject Item: _:vb26774472
rdf:type: n2:Context
rdf:value: Prager et al. [>>50<<] demonstrated that the NPXY motif in IGF-1R is important for receptor internalization, whereas Miura et al. [128] demonstrated that tyrosine 1250 within the IGF-1R tail is the functional tyrosine-based internalization signal (Fig.
n2:mentions: n3:8163493

Subject Item: _:vb26774473
rdf:type: n2:Context
rdf:value: Prager et al. [50] demonstrated that the NPXY motif in IGF-1R is important for receptor internalization, whereas Miura et al. [>>128<<] demonstrated that tyrosine 1250 within the IGF-1R tail is the functional tyrosine-based internalization signal (Fig.
n2:mentions: n3:9345292

Subject Item: _:vb26774474
rdf:type: n2:Context
rdf:value: Degradation of the IGF-1R by a proteasome mediated route was originally described by Sepp-Lorenzino et al. [>>114<<] to explain the mechanism of Herbymicin A-induced IGF-1R downregulation.
n2:mentions: n3:7622464

Subject Item: _:vb26774475
rdf:type: n2:Context
rdf:value: Since then, the IGF-1R has been demonstrated to be a substrate of three E3 ubiquitin ligases: Mdm2 [>>116<<], Nedd4 [120], and c-Cbl [117].
n2:mentions: n3:12821780

Subject Item: _:vb26774476
rdf:type: n2:Context
rdf:value: Since then, the IGF-1R has been demonstrated to be a substrate of three E3 ubiquitin ligases: Mdm2 [116], Nedd4 [>>120<<], and c-Cbl [117].
n2:mentions: n3:12697834

Subject Item: _:vb26774477
rdf:type: n2:Context
rdf:value: Since then, the IGF-1R has been demonstrated to be a substrate of three E3 ubiquitin ligases: Mdm2 [116], Nedd4 [120], and c-Cbl [>>117<<].
n2:mentions: n3:18632619

Subject Item: _:vb26774478
rdf:type: n2:Context
rdf:value: After Grb10 recognition as an IGF-1R interacting partner and negative regulator of IGF-1 signaling [>>78<<, 129], a yeast two-hybrid screen subsequently identified Grb10 as a binding partner of the Nedd4 E3 ligase [130].
n2:mentions: n3:8764099

Subject Item: _:vb26774479
rdf:type: n2:Context
rdf:value: After Grb10 recognition as an IGF-1R interacting partner and negative regulator of IGF-1 signaling [78, >>129<<], a yeast two-hybrid screen subsequently identified Grb10 as a binding partner of the Nedd4 E3 ligase [130].
n2:mentions: n3:9334212

Subject Item: _:vb26774480
rdf:type: n2:Context
rdf:value: After Grb10 recognition as an IGF-1R interacting partner and negative regulator of IGF-1 signaling [78, 129], a yeast two-hybrid screen subsequently identified Grb10 as a binding partner of the Nedd4 E3 ligase [>>130<<]. Grb10 overexpression increased ligand-dependent IGF-1R ubiquitination, receptor internalization, and degradation.
n2:mentions: n3:10446181

Subject Item: _:vb26774481
rdf:type: n2:Context
rdf:value: This ubiquitination did not occur with a catalytically inactive Nedd4 or with mutant Grb10 unable to bind Nedd4 [>>120<<]. This work identified Nedd4 as an ubiquitin E3 ligase and Grb10 as the key adaptor protein to recruit Nedd4 to the IGF-1R. Further work from the Morrione laboratory described Nedd4 ubiquitination of the IGF-1R as predominantly of
n2:mentions: n3:12697834

Subject Item: _:vb26774482
rdf:type: n2:Context
rdf:value: Further work from the Morrione laboratory described Nedd4 ubiquitination of the IGF-1R as predominantly of multi-monoubiquitination type [>>131<<]. In addition, the internalization mediated by Nedd4 was both clathrin- and caveolin-dependent as demonstrated by co-localization studies [131].
n2:mentions: n3:18286479

Subject Item: _:vb26774483
rdf:type: n2:Context
rdf:value: In addition, the internalization mediated by Nedd4 was both clathrin- and caveolin-dependent as demonstrated by co-localization studies [>>131<<].
n2:mentions: n3:18286479

Subject Item: _:vb26774484
rdf:type: n2:Context
rdf:value: Following original research demonstrating a feedback mechanism of wild-type p53 negatively regulating IGF-1R at the transcriptional level [>>132<<], it was revealed that overexpressed mutant or wild-type p53 mitigate ligand-induced IGF-1R downregulation [29].
n2:mentions: n3:8710868

Subject Item: _:vb26774485
rdf:type: n2:Context
rdf:value: research demonstrating a feedback mechanism of wild-type p53 negatively regulating IGF-1R at the transcriptional level [132], it was revealed that overexpressed mutant or wild-type p53 mitigate ligand-induced IGF-1R downregulation [>>29<<]. Analysis of IGF-1R mRNA levels discard an exclusively transcriptional mechanism, indicating a posttranslational p53-IGF-1R control mechanism [29].
n2:mentions: n3:11016658

Subject Item: _:vb26774486
rdf:type: n2:Context
rdf:value: Analysis of IGF-1R mRNA levels discard an exclusively transcriptional mechanism, indicating a posttranslational p53-IGF-1R control mechanism [>>29<<]. Further work demonstrated that an inhibition of p53 caused ubiquitination and degradation of the IGF-1R, suggesting that p53 and IGF-1R might compete for the same ubiquitin ligase [116]. This possibility was validated in experiments in
n2:mentions: n3:11016658

Subject Item: _:vb26774487
rdf:type: n2:Context
rdf:value: Further work demonstrated that an inhibition of p53 caused ubiquitination and degradation of the IGF-1R, suggesting that p53 and IGF-1R might compete for the same ubiquitin ligase [>>116<<]. This possibility was validated in experiments in which inhibition of Mdm2 (the well-known p53 ubiquitin ligase) resulted in accumulation of IGF-1R [116]. This work confirmed the direct IGF-1R/Mdm2 interaction, identified Mdm2 as an
n2:mentions: n3:12821780

Subject Item: _:vb26774488
rdf:type: n2:Context
rdf:value: This possibility was validated in experiments in which inhibition of Mdm2 (the well-known p53 ubiquitin ligase) resulted in accumulation of IGF-1R [>>116<<]. This work confirmed the direct IGF-1R/Mdm2 interaction, identified Mdm2 as an ubiquitin ligase for the IGF-1R, promoting proteasome-inhibitor-sensitive IGF-1R degradation, and highlighted a positive posttranslational control mechanism
n2:mentions: n3:12821780

Subject Item: _:vb26774489
rdf:type: n2:Context
rdf:value: direct IGF-1R/Mdm2 interaction, identified Mdm2 as an ubiquitin ligase for the IGF-1R, promoting proteasome-inhibitor-sensitive IGF-1R degradation, and highlighted a positive posttranslational control mechanism between p53 and IGF-1R [>>116<<]. Subsequent research revealed the mechanism of Mdm2 binding to the IGF-1R by identifying that β-arrestins, otherwise known as master regulators of GPCR biology, serve as adaptors to bring the E3 ligase Mdm2 to the IGF-1R [133].
n2:mentions: n3:12821780

Subject Item: _:vb26774490
rdf:type: n2:Context
rdf:value: Subsequent research revealed the mechanism of Mdm2 binding to the IGF-1R by identifying that β-arrestins, otherwise known as master regulators of GPCR biology, serve as adaptors to bring the E3 ligase Mdm2 to the IGF-1R [>>133<<]. Both Mdm2 and β-arrestin co-immunoprecipitated with the IGF-1R and in an in vitro reaction β-arrestins enhanced Mdm2-mediated IGF-1R ubiquitination [133]. In a cell system, overexpression or depletion of β-arrestin 1 enhanced and
n2:mentions: n3:15878855

Subject Item: _:vb26774491
rdf:type: n2:Context
rdf:value: Both Mdm2 and β-arrestin co-immunoprecipitated with the IGF-1R and in an in vitro reaction β-arrestins enhanced Mdm2-mediated IGF-1R ubiquitination [>>133<<]. In a cell system, overexpression or depletion of β-arrestin 1 enhanced and decreased IGF-1R ubiquitination and degradation, respectively. Thus, β-arrestin 1 was proved to act as an essential component in the ubiquitination and
n2:mentions: n3:15878855

Subject Item: _:vb26774492
rdf:type: n2:Context
rdf:value: Thus, β-arrestin 1 was proved to act as an essential component in the ubiquitination and downregulation of the IGF-1R [>>133<<]. Most recently, β-arrestin 1 was recognized not only as an aid to IGF-1R internalization and signal cessation but to initiate its own second wave of signaling through the MAPK/ERK pathway [134], with IGF-1R stimulation also leading to
n2:mentions: n3:15878855

Subject Item: _:vb26774493
rdf:type: n2:Context
rdf:value: Most recently, β-arrestin 1 was recognized not only as an aid to IGF-1R internalization and signal cessation but to initiate its own second wave of signaling through the MAPK/ERK pathway [>>134<<], with IGF-1R stimulation also leading to ubiquitination of β arrestin 1 [134].
n2:mentions: n3:17303558

Subject Item: _:vb26774494
rdf:type: n2:Context
rdf:value: recognized not only as an aid to IGF-1R internalization and signal cessation but to initiate its own second wave of signaling through the MAPK/ERK pathway [134], with IGF-1R stimulation also leading to ubiquitination of β arrestin 1 [>>134<<]. Intriguingly, this β-arrestin 1-mediated ERK activation occurs even when the classical IGF-1R kinase signaling is impaired (see below) [134].
n2:mentions: n3:17303558

Subject Item: _:vb26774495
rdf:type: n2:Context
rdf:value: Intriguingly, this β-arrestin 1-mediated ERK activation occurs even when the classical IGF-1R kinase signaling is impaired (see below) [>>134<<]. Taken together, these studies demonstrated that β-arrestin 1 serves as an adaptor to bring the E3 ubiquitin-ligase Mdm2 to the IGF-1R, with a dual outcome on the IGF-1R: ubiquitination and receptor downregulation as well as
n2:mentions: n3:17303558

Subject Item: _:vb26774496
rdf:type: n2:Context
rdf:value: The identification of c-Cbl as an ubiquitin-ligase for IGF-1R [>>117<<] was based on the observation that suppression of Mdm2 did not completely abolish ligand-induced IGF-1R ubiquitination, suggesting that there are other ligases contributing to this process.
n2:mentions: n3:18632619

Subject Item: _:vb26774497
rdf:type: n2:Context
rdf:value: Previously recognized as an E3 ligase of other RTKs, including EGFR and PDGFR [>>135<<], c-Cbl was demonstrated to associate with and to ubiquitinate the IGF-1R [117], especially at higher doses of IGF-1, indicating complementary roles for the different E3 ligases [117].
n2:mentions: n3:19183301

Subject Item: _:vb26774498
rdf:type: n2:Context
rdf:value: Previously recognized as an E3 ligase of other RTKs, including EGFR and PDGFR [135], c-Cbl was demonstrated to associate with and to ubiquitinate the IGF-1R [>>117<<], especially at higher doses of IGF-1, indicating complementary roles for the different E3 ligases [117].
n2:mentions: n3:18632619

Subject Item: _:vb26774499
rdf:type: n2:Context
rdf:value: E3 ligase of other RTKs, including EGFR and PDGFR [135], c-Cbl was demonstrated to associate with and to ubiquitinate the IGF-1R [117], especially at higher doses of IGF-1, indicating complementary roles for the different E3 ligases [>>117<<]. In vitro experiments using ubiquitin with mutated lysine residues suggested that Mdm2 polyubiquitinates IGF-1R with K63 type chains, whereas c-Cbl polyubiquitinates IGF-1R with K48 type chains.
n2:mentions: n3:18632619

Subject Item: _:vb26774500
rdf:type: n2:Context
rdf:value: The E3 ligases Mdm2 and Nedd4 have been demonstrated to bind to the IGF-1R through the adaptor proteins β-arrestin 1 [>>133<<] and Grb10 [131], respectively, suggesting that adaptor proteins determine substrate specificity.
n2:mentions: n3:15878855

Subject Item: _:vb26774501
rdf:type: n2:Context
rdf:value: The E3 ligases Mdm2 and Nedd4 have been demonstrated to bind to the IGF-1R through the adaptor proteins β-arrestin 1 [133] and Grb10 [>>131<<], respectively, suggesting that adaptor proteins determine substrate specificity.
n2:mentions: n3:18286479

Subject Item: _:vb26774502
rdf:type: n2:Context
rdf:value: For Nedd4, there is evidence of the ligase determining appropriate localization of the receptor [>>136<<], and that it directs towards a proteasome-independent pathway of degradation [137].
n2:mentions: n3:18812566

Subject Item: _:vb26774503
rdf:type: n2:Context
rdf:value: For Nedd4, there is evidence of the ligase determining appropriate localization of the receptor [136], and that it directs towards a proteasome-independent pathway of degradation [>>137<<]. The ligases c-Cbl and Mdm2 appear to have complementary roles, with c-Cbl recruited following high dose IGF-1 and initiating caveolin-dependent endocytosis and Mdm2 recruited at low dose IGF-1 and initiating clathrin-dependent
n2:mentions: n3:18723765

Subject Item: _:vb26774504
rdf:type: n2:Context
rdf:value: ligases c-Cbl and Mdm2 appear to have complementary roles, with c-Cbl recruited following high dose IGF-1 and initiating caveolin-dependent endocytosis and Mdm2 recruited at low dose IGF-1 and initiating clathrin-dependent endocytosis [>>117<<]. It is clear, however, that different ligases associated with the IGF-1R as well as their adaptor proteins have redundant as well as complementary roles:
n2:mentions: n3:18632619

Subject Item: _:vb26774505
rdf:type: n2:Context
rdf:value: ligases associated with the IGF-1R as well as their adaptor proteins have redundant as well as complementary roles: they keep the balance between recycling, relocalization, and proteasome/lysosomal degradation of the receptor [>>117<<, 120, 121, 131, 133, 134]. The complexity is further increased by the fact that receptor signaling relies on its localization:
n2:mentions: n3:18632619

Subject Item: _:vb26774506
rdf:type: n2:Context
rdf:value: ligases associated with the IGF-1R as well as their adaptor proteins have redundant as well as complementary roles: they keep the balance between recycling, relocalization, and proteasome/lysosomal degradation of the receptor [117, >>120<<, 121, 131, 133, 134]. The complexity is further increased by the fact that receptor signaling relies on its localization:
n2:mentions: n3:12697834

Subject Item: _:vb26774507
rdf:type: n2:Context
rdf:value: associated with the IGF-1R as well as their adaptor proteins have redundant as well as complementary roles: they keep the balance between recycling, relocalization, and proteasome/lysosomal degradation of the receptor [117, 120, >>121<<, 131, 133, 134]. The complexity is further increased by the fact that receptor signaling relies on its localization:
n2:mentions: n3:17406664

Subject Item: _:vb26774508
rdf:type: n2:Context
rdf:value: associated with the IGF-1R as well as their adaptor proteins have redundant as well as complementary roles: they keep the balance between recycling, relocalization, and proteasome/lysosomal degradation of the receptor [117, 120, 121, >>131<<, 133, 134]. The complexity is further increased by the fact that receptor signaling relies on its localization:
n2:mentions: n3:18286479

Subject Item: _:vb26774509
rdf:type: n2:Context
rdf:value: with the IGF-1R as well as their adaptor proteins have redundant as well as complementary roles: they keep the balance between recycling, relocalization, and proteasome/lysosomal degradation of the receptor [117, 120, 121, 131, >>133<<, 134]. The complexity is further increased by the fact that receptor signaling relies on its localization:
n2:mentions: n3:15878855

Subject Item: _:vb26774510
rdf:type: n2:Context
rdf:value: with the IGF-1R as well as their adaptor proteins have redundant as well as complementary roles: they keep the balance between recycling, relocalization, and proteasome/lysosomal degradation of the receptor [117, 120, 121, 131, 133, >>134<<]. The complexity is further increased by the fact that receptor signaling relies on its localization:
n2:mentions: n3:17303558

Subject Item: _:vb26774511
rdf:type: n2:Context
rdf:value: The complexity is further increased by the fact that receptor signaling relies on its localization: signaling still occurs from endosomes and prevention of endocytosis is even inhibitory to signaling [>>84<<, 124, 134, 138].
n2:mentions: n3:7642582

Subject Item: _:vb26774512
rdf:type: n2:Context
rdf:value: The complexity is further increased by the fact that receptor signaling relies on its localization: signaling still occurs from endosomes and prevention of endocytosis is even inhibitory to signaling [84, >>124<<, 134, 138].
n2:mentions: n3:22509025

Subject Item: _:vb26774513
rdf:type: n2:Context
rdf:value: The complexity is further increased by the fact that receptor signaling relies on its localization: signaling still occurs from endosomes and prevention of endocytosis is even inhibitory to signaling [84, 124, >>134<<, 138].
n2:mentions: n3:17303558

Subject Item: _:vb26774514
rdf:type: n2:Context
rdf:value: The complexity is further increased by the fact that receptor signaling relies on its localization: signaling still occurs from endosomes and prevention of endocytosis is even inhibitory to signaling [84, 124, 134, >>138<<].
n2:mentions: n3:17545147

Subject Item: _:vb26774515
rdf:type: n2:Context
rdf:value: Through IGF-1R mutation analysis, the interplay between phosphorylation and ubiquitination has been demonstrated [>>121<<]. According to this study, a completely kinase-dead IGF-1R (with mutation of the ATP pocket) cannot be ubiquitinated after ligand stimulation, while a kinase impaired IGF-1R (Y1136A) is ubiquitinated, activates ERK signaling, but fails to
n2:mentions: n3:17406664

Subject Item: _:vb26774516
rdf:type: n2:Context
rdf:value: Deletion of the C-terminal tail (Δ1245) had no effect on IGF-1R phosphorylation but completely abolished its ubiquitination [>>121<<], confirming the previous findings that IGF-1R ubiquitination is essentially dependent on its β-arrestin binding domain [133, 134].
n2:mentions: n3:17406664

Subject Item: _:vb26774517
rdf:type: n2:Context
rdf:value: C-terminal tail (Δ1245) had no effect on IGF-1R phosphorylation but completely abolished its ubiquitination [121], confirming the previous findings that IGF-1R ubiquitination is essentially dependent on its β-arrestin binding domain [>>133<<, 134].
n2:mentions: n3:15878855

Subject Item: _:vb26774518
rdf:type: n2:Context
rdf:value: tail (Δ1245) had no effect on IGF-1R phosphorylation but completely abolished its ubiquitination [121], confirming the previous findings that IGF-1R ubiquitination is essentially dependent on its β-arrestin binding domain [133, >>134<<].
n2:mentions: n3:17303558

Subject Item: _:vb26774519
rdf:type: n2:Context
rdf:value: a modification initiated by the natural ligand binding to the receptor, recent studies suggest that IGF-1R ubiquitination is a more complex process that can also be activated kinase-dependent (activation-loop phosphorylation) by IGF-2 [>>139<<], insulin [139], LL-37 [140], or kinase-independent by anti-IGF-1R antibodies [140–142].
n2:mentions: n3:22318726

Subject Item: _:vb26774520
rdf:type: n2:Context
rdf:value: initiated by the natural ligand binding to the receptor, recent studies suggest that IGF-1R ubiquitination is a more complex process that can also be activated kinase-dependent (activation-loop phosphorylation) by IGF-2 [139], insulin [>>139<<], LL-37 [140], or kinase-independent by anti-IGF-1R antibodies [140–142].
n2:mentions: n3:22318726

Subject Item: _:vb26774521
rdf:type: n2:Context
rdf:value: the natural ligand binding to the receptor, recent studies suggest that IGF-1R ubiquitination is a more complex process that can also be activated kinase-dependent (activation-loop phosphorylation) by IGF-2 [139], insulin [139], LL-37 [>>140<<], or kinase-independent by anti-IGF-1R antibodies [140–142].
n2:mentions: n3:23188799

Subject Item: _:vb26774522
rdf:type: n2:Context
rdf:value: suggest that IGF-1R ubiquitination is a more complex process that can also be activated kinase-dependent (activation-loop phosphorylation) by IGF-2 [139], insulin [139], LL-37 [140], or kinase-independent by anti-IGF-1R antibodies [>>140<<–142]. In addition, IGF-1R ubiquitination can be activated in a ligand and kinase-independent manner, from inside the cell, by adaptor proteins recruited to the intracellular domain of the IGF-1R [124, 143, 144].
n2:mentions: n3:21994939 n3:23188799 n3:19165858

Subject Item: _:vb26774523
rdf:type: n2:Context
rdf:value: In addition, IGF-1R ubiquitination can be activated in a ligand and kinase-independent manner, from inside the cell, by adaptor proteins recruited to the intracellular domain of the IGF-1R [>>124<<, 143, 144].
n2:mentions: n3:22509025

Subject Item: _:vb26774524
rdf:type: n2:Context
rdf:value: In addition, IGF-1R ubiquitination can be activated in a ligand and kinase-independent manner, from inside the cell, by adaptor proteins recruited to the intracellular domain of the IGF-1R [124, >>143<<, 144]. The mechanism of IGF-1R ubiquitination is different depending on the ligand, adaptor protein, or ubiquitin-ligase employed; however, the common theme is that a specific receptor conformation may trigger ubiquitination with
n2:mentions: n3:18070930

Subject Item: _:vb26774525
rdf:type: n2:Context
rdf:value: In addition, IGF-1R ubiquitination can be activated in a ligand and kinase-independent manner, from inside the cell, by adaptor proteins recruited to the intracellular domain of the IGF-1R [124, 143, >>144<<]. The mechanism of IGF-1R ubiquitination is different depending on the ligand, adaptor protein, or ubiquitin-ligase employed; however, the common theme is that a specific receptor conformation may trigger ubiquitination with divergent
n2:mentions: n3:11278773

Subject Item: _:vb26774526
rdf:type: n2:Context
rdf:value: Rocchi et al. [>>145<<] described the association of activated IGF-1R with the phosphatase SHP2, with binding between phospho-tyrosines on IGF-1R and SH2 domains in SHP2 being critical.
n2:mentions: n3:8895367

Subject Item: _:vb26774527
rdf:type: n2:Context
rdf:value: Subsequently, it was demonstrated that SHPS2 is critical for recruitment of SHP2 to the plasma membrane for this purpose [>>146<<]. Cross-talk with the αVβ3 integrin, through SHP2, was later described, with blockage of this integrin reducing IGF-1-induced IGF-1R phosphorylation [146, 147]. The phosphatase PTP1B also negatively regulates the IGF-1R [148], associating
n2:mentions: n3:12399420

Subject Item: _:vb26774528
rdf:type: n2:Context
rdf:value: Cross-talk with the αVβ3 integrin, through SHP2, was later described, with blockage of this integrin reducing IGF-1-induced IGF-1R phosphorylation [>>146<<, 147]. The phosphatase PTP1B also negatively regulates the IGF-1R [148], associating with it in a ligand-dependent manner [149].
n2:mentions: n3:12399420

Subject Item: _:vb26774529
rdf:type: n2:Context
rdf:value: Cross-talk with the αVβ3 integrin, through SHP2, was later described, with blockage of this integrin reducing IGF-1-induced IGF-1R phosphorylation [146, >>147<<]. The phosphatase PTP1B also negatively regulates the IGF-1R [148], associating with it in a ligand-dependent manner [149].
n2:mentions: n3:16195423

Subject Item: _:vb26774530
rdf:type: n2:Context
rdf:value: The phosphatase PTP1B also negatively regulates the IGF-1R [>>148<<], associating with it in a ligand-dependent manner [149].
n2:mentions: n3:11884589

Subject Item: _:vb26774531
rdf:type: n2:Context
rdf:value: The phosphatase PTP1B also negatively regulates the IGF-1R [148], associating with it in a ligand-dependent manner [>>149<<].
n2:mentions: n3:15976035

Subject Item: _:vb26774532
rdf:type: n2:Context
rdf:value: Nuclear localization has been demonstrated for the IGF-1R and shown to be mediated by sumoylation, the addition of a small protein similar to ubiquitin [>>150<<, 151]. The direction to the nuclear compartment and the role of nuclear IGF-1R is currently little investigated, but studies suggesting that IGF-1R nuclear localization can alter transcription [152], and that nuclear localization of
n2:mentions: n3:21147068

Subject Item: _:vb26774533
rdf:type: n2:Context
rdf:value: Nuclear localization has been demonstrated for the IGF-1R and shown to be mediated by sumoylation, the addition of a small protein similar to ubiquitin [150, >>151<<]. The direction to the nuclear compartment and the role of nuclear IGF-1R is currently little investigated, but studies suggesting that IGF-1R nuclear localization can alter transcription [152], and that nuclear localization of IGF-1R
n2:mentions: n3:20145208

Subject Item: _:vb26774534
rdf:type: n2:Context
rdf:value: The direction to the nuclear compartment and the role of nuclear IGF-1R is currently little investigated, but studies suggesting that IGF-1R nuclear localization can alter transcription [>>152<<], and that nuclear localization of IGF-1R predicts better outcome in patients treated with IGF-1R antibody [153], suggest that further research would have therapeutic relevance.
n2:mentions: n3:22128190

Subject Item: _:vb26774535
rdf:type: n2:Context
rdf:value: IGF-1R is currently little investigated, but studies suggesting that IGF-1R nuclear localization can alter transcription [152], and that nuclear localization of IGF-1R predicts better outcome in patients treated with IGF-1R antibody [>>153<<], suggest that further research would have therapeutic relevance.
n2:mentions: n3:22682017

Subject Item: _:vb26774536
rdf:type: n2:Context
rdf:value: One study has demonstrated that transfer to the nucleus is mediated at least in part by clathrin, and confirmed that both the α- and β-chains of IGF-1R translocate to the nucleus [>>154<<], suggesting a more complex function to IGF-1R internalization than solely degradation versus recycling.
n2:mentions: n3:20710042

Subject Item: _:vb26774537
rdf:type: n5:Section
dc:title: something borrowed: igf-1r transactivation by other plasma-membrane receptors
n5:contains: _:vb26774538 _:vb26774539 _:vb26774540 _:vb26774541 _:vb26774542 _:vb26774543 _:vb26774544 _:vb26774545 _:vb26774546 _:vb26774547 _:vb26774548 _:vb26774549 _:vb26774550 _:vb26774551 _:vb26774552 _:vb26774553 _:vb26774554 _:vb26774555 _:vb26774556 _:vb26774557 _:vb26774558 _:vb26774559 _:vb26774560 _:vb26774561 _:vb26774562 _:vb26774563 _:vb26774564 _:vb26774565 _:vb26774566 _:vb26774567 _:vb26774568

Subject Item: _:vb26774538
rdf:type: n2:Context
rdf:value: Among the RTKs, probably the best studied is the IGF-1R interaction with the IR, resulting in formation of hybrid receptors [>>187<<, 188] which are able to respond to insulin, IGF-1, and IGF-2 but with different affinities.
n2:mentions: n3:18001849

Subject Item: _:vb26774539
rdf:type: n2:Context
rdf:value: Among the RTKs, probably the best studied is the IGF-1R interaction with the IR, resulting in formation of hybrid receptors [187, >>188<<] which are able to respond to insulin, IGF-1, and IGF-2 but with different affinities.
n2:mentions: n3:3017298

Subject Item: _:vb26774540
rdf:type: n2:Context
rdf:value: The mechanism of hybrid receptor activation, signaling, as well as their biological effects, have been extensively investigated [>>37<<, 139, 156–158]; however, it should be highlighted here that simple interaction of the IGF-1R with IR modified IGF-1R signaling and trafficking to various ligands [139] and anti-IGF-1R antibodies [156].
n2:mentions: n3:19752219

Subject Item: _:vb26774541
rdf:type: n2:Context
rdf:value: The mechanism of hybrid receptor activation, signaling, as well as their biological effects, have been extensively investigated [37, >>139<<, 156–158]; however, it should be highlighted here that simple interaction of the IGF-1R with IR modified IGF-1R signaling and trafficking to various ligands [139] and anti-IGF-1R antibodies [156].
n2:mentions: n3:22318726

Subject Item: _:vb26774542
rdf:type: n2:Context
rdf:value: The mechanism of hybrid receptor activation, signaling, as well as their biological effects, have been extensively investigated [37, 139, >>156<<–158]; however, it should be highlighted here that simple interaction of the IGF-1R with IR modified IGF-1R signaling and trafficking to various ligands [139] and anti-IGF-1R antibodies [156].
n2:mentions: n3:17346183 n3:17451939 n3:10401676

Subject Item: _:vb26774543
rdf:type: n2:Context
rdf:value: well as their biological effects, have been extensively investigated [37, 139, 156–158]; however, it should be highlighted here that simple interaction of the IGF-1R with IR modified IGF-1R signaling and trafficking to various ligands [>>139<<] and anti-IGF-1R antibodies [156].
n2:mentions: n3:22318726

Subject Item: _:vb26774544
rdf:type: n2:Context
rdf:value: have been extensively investigated [37, 139, 156–158]; however, it should be highlighted here that simple interaction of the IGF-1R with IR modified IGF-1R signaling and trafficking to various ligands [139] and anti-IGF-1R antibodies [>>156<<]. The IR is not the only RTK associated with the IGF-1R; for example, a direct interaction between the IGF-1R and EGFR was identified in cancer cells, with EGFR depletion affecting IGF-1R ubiquitination, degradation, and signaling [159].
n2:mentions: n3:17451939

Subject Item: _:vb26774545
rdf:type: n2:Context
rdf:value: The IR is not the only RTK associated with the IGF-1R; for example, a direct interaction between the IGF-1R and EGFR was identified in cancer cells, with EGFR depletion affecting IGF-1R ubiquitination, degradation, and signaling [>>159<<]. In a similar manner, another group of plasma-membrane molecules were demonstrated to modify the IGF-1R response to IGF-1.
n2:mentions: n3:17307140

Subject Item: _:vb26774546
rdf:type: n2:Context
rdf:value: Integrins, as transmembrane receptors, transfer information from the extracellular matrix (ECM) to signaling pathways inside cells (outside–in signaling) or from within the cell (inside–out signaling) [>>160<<]. They form part of cell surface signaling complexes known as focal adhesions which link the cytoskeleton to the ECM and are intimately linked with cell adhesion and migration [160]. There has been increasing recognition of the
n2:mentions: n3:19240129

Subject Item: _:vb26774547
rdf:type: n2:Context
rdf:value: They form part of cell surface signaling complexes known as focal adhesions which link the cytoskeleton to the ECM and are intimately linked with cell adhesion and migration [>>160<<]. There has been increasing recognition of the bi-directional cross-talk between integrins and the IGF-1R signaling pathway [161]: integrin activation modulating the IGF-1R signaling and vice versa. Studies identifying the overlap between
n2:mentions: n3:19240129

Subject Item: _:vb26774548
rdf:type: n2:Context
rdf:value: There has been increasing recognition of the bi-directional cross-talk between integrins and the IGF-1R signaling pathway [>>161<<]: integrin activation modulating the IGF-1R signaling and vice versa. Studies identifying the overlap between IGF-1R and integrin signaling pathways from the Clemmons group demonstrated IGF-1R-dependent “transactivation” of αvβ3 integrin
n2:mentions: n3:19722108

Subject Item: _:vb26774549
rdf:type: n2:Context
rdf:value: Studies identifying the overlap between IGF-1R and integrin signaling pathways from the Clemmons group demonstrated IGF-1R-dependent “transactivation” of αvβ3 integrin [>>162<<]. The mechanism was described as due to the recruitment and phosphorylation/dephosphorylation of adaptor proteins. IGF-1 stimulation causes phosphorylation of the transmembrane adaptor protein SHPS1 and subsequent SHP2 recruitment [146].
n2:mentions: n3:11707450

Subject Item: _:vb26774550
rdf:type: n2:Context
rdf:value: IGF-1 stimulation causes phosphorylation of the transmembrane adaptor protein SHPS1 and subsequent SHP2 recruitment [>>146<<]. Along with SHP2, IGF-1R through IRS1 recruits the focal contact adaptor protein paxillin and FAK, which are involved in the turnover of focal contacts. IGF-1 stimulation leads to SHP2 dephosphorylation of paxillin and FAK, as part of an
n2:mentions: n3:12399420

Subject Item: _:vb26774551
rdf:type: n2:Context
rdf:value: IGF-1 stimulation leads to SHP2 dephosphorylation of paxillin and FAK, as part of an integrin deactivation mechanism crucial for migration [>>163<<]. In further evidence, the DOK1 protein, itself an IRS protein, brings SHP2 to the αvβ5 integrin [164]. IGF-1 is well known to initiate cell migration, IGF-1 triggers integrin activation and binding to ECM [165], and evidence showed that
n2:mentions: n3:10082579

Subject Item: _:vb26774552
rdf:type: n2:Context
rdf:value: In further evidence, the DOK1 protein, itself an IRS protein, brings SHP2 to the αvβ5 integrin [>>164<<]. IGF-1 is well known to initiate cell migration, IGF-1 triggers integrin activation and binding to ECM [165], and evidence showed that αvβ3 and αvβ5 are involved in the migratory/invasive IGF-1 response [165, 166].
n2:mentions: n3:15546884

Subject Item: _:vb26774553
rdf:type: n2:Context
rdf:value: IGF-1 is well known to initiate cell migration, IGF-1 triggers integrin activation and binding to ECM [>>165<<], and evidence showed that αvβ3 and αvβ5 are involved in the migratory/invasive IGF-1 response [165, 166].
n2:mentions: n3:8637900

Subject Item: _:vb26774554
rdf:type: n2:Context
rdf:value: IGF-1 is well known to initiate cell migration, IGF-1 triggers integrin activation and binding to ECM [165], and evidence showed that αvβ3 and αvβ5 are involved in the migratory/invasive IGF-1 response [>>165<<, 166].
n2:mentions: n3:8637900

Subject Item: _:vb26774555
rdf:type: n2:Context
rdf:value: IGF-1 is well known to initiate cell migration, IGF-1 triggers integrin activation and binding to ECM [165], and evidence showed that αvβ3 and αvβ5 are involved in the migratory/invasive IGF-1 response [165, >>166<<].
n2:mentions: n3:9077549

Subject Item: _:vb26774556
rdf:type: n2:Context
rdf:value: The SHP2 protein is not only recruited to integrins and dephosphorylates paxillin and FAK but regulates IGF-1R dephosphorylation, curtailing the IGF-1R signaling response [>>146<<], identifying it as a common molecule between the integrin and IGF-1R signaling pathways.
n2:mentions: n3:12399420

Subject Item: _:vb26774557
rdf:type: n2:Context
rdf:value: group also describe integrin modulation of the SHPS1-IGF-1R association, with activation and tyrosine phosphorylation of αvβ3 integrin determining the recruitment to the IGF-1R of SHPS1 and subsequently SHP2, and involving IAP [>>167<<, 168]. Overall, ligand occupancy of at least some integrins is required for a sustained IGF-1 response [169], and transmembrane integrin complexes including SHPS1 and IAP modulate IGF-1R signaling through determining SHP2 recruitment
n2:mentions: n3:12791772

Subject Item: _:vb26774558
rdf:type: n2:Context
rdf:value: group also describe integrin modulation of the SHPS1-IGF-1R association, with activation and tyrosine phosphorylation of αvβ3 integrin determining the recruitment to the IGF-1R of SHPS1 and subsequently SHP2, and involving IAP [167, >>168<<]. Overall, ligand occupancy of at least some integrins is required for a sustained IGF-1 response [169], and transmembrane integrin complexes including SHPS1 and IAP modulate IGF-1R signaling through determining SHP2 recruitment (reviewed
n2:mentions: n3:12972543

Subject Item: _:vb26774559
rdf:type: n2:Context
rdf:value: Overall, ligand occupancy of at least some integrins is required for a sustained IGF-1 response [>>169<<], and transmembrane integrin complexes including SHPS1 and IAP modulate IGF-1R signaling through determining SHP2 recruitment (reviewed in [170]), with subsequent effects on cell behavior [171].
n2:mentions: n3:15528274

Subject Item: _:vb26774560
rdf:type: n2:Context
rdf:value: ligand occupancy of at least some integrins is required for a sustained IGF-1 response [169], and transmembrane integrin complexes including SHPS1 and IAP modulate IGF-1R signaling through determining SHP2 recruitment (reviewed in [>>170<<]), with subsequent effects on cell behavior [171].
n2:mentions: n3:12697669

Subject Item: _:vb26774561
rdf:type: n2:Context
rdf:value: required for a sustained IGF-1 response [169], and transmembrane integrin complexes including SHPS1 and IAP modulate IGF-1R signaling through determining SHP2 recruitment (reviewed in [170]), with subsequent effects on cell behavior [>>171<<].
n2:mentions: n3:17627944

Subject Item: _:vb26774562
rdf:type: n2:Context
rdf:value: The RACK1 scaffolding-protein, known to interact with β1 integrin, was identified as also binding IGF-1R affecting Shc/Grb2 downstream signaling [>>87<<, 172]. Further, the O’Conner group demonstrated that RACK1 associated mutually exclusively with phosphatase PP2A or β1 integrin, controlled by IGF-1 stimulation [173]. However, this complex differed between transformed and non-transformed
n2:mentions: n3:11884618

Subject Item: _:vb26774563
rdf:type: n2:Context
rdf:value: The RACK1 scaffolding-protein, known to interact with β1 integrin, was identified as also binding IGF-1R affecting Shc/Grb2 downstream signaling [87, >>172<<]. Further, the O’Conner group demonstrated that RACK1 associated mutually exclusively with phosphatase PP2A or β1 integrin, controlled by IGF-1 stimulation [173]. However, this complex differed between transformed and non-transformed
n2:mentions: n3:10477272

Subject Item: _:vb26774564
rdf:type: n2:Context
rdf:value: Further, the O’Conner group demonstrated that RACK1 associated mutually exclusively with phosphatase PP2A or β1 integrin, controlled by IGF-1 stimulation [>>173<<]. However, this complex differed between transformed and non-transformed cells, with only transformed cells showing direct RACK1–IGF-1R interaction [174].
n2:mentions: n3:16705158

Subject Item: _:vb26774565
rdf:type: n2:Context
rdf:value: However, this complex differed between transformed and non-transformed cells, with only transformed cells showing direct RACK1–IGF-1R interaction [>>174<<].
n2:mentions: n3:17900863

Subject Item: _:vb26774566
rdf:type: n2:Context
rdf:value: They demonstrated direct binding of IGF-1 ligand to αvβ3 integrin and α6β4 integrin and direct effects on IGF-1R signaling [>>175<<], including sustaining of cells during anchorage independence [176] [177].
n2:mentions: n3:19578119

Subject Item: _:vb26774567
rdf:type: n2:Context
rdf:value: They demonstrated direct binding of IGF-1 ligand to αvβ3 integrin and α6β4 integrin and direct effects on IGF-1R signaling [175], including sustaining of cells during anchorage independence [176] [>>177<<]. In their further work, an IGF-1 mutant unable to bind integrins but able to bind IGF-1R had a dominant negative effect on IGF-1R-mediated tumorigenesis in vivo [178], suggesting further functional effects of such ternary complexes.
n2:mentions: n3:22351760

Subject Item: _:vb26774568
rdf:type: n2:Context
rdf:value: In their further work, an IGF-1 mutant unable to bind integrins but able to bind IGF-1R had a dominant negative effect on IGF-1R-mediated tumorigenesis in vivo [>>178<<], suggesting further functional effects of such ternary complexes.
n2:mentions: n3:23696648

Subject Item: _:vb26774569
rdf:type: n5:Section
dc:title: something borrowed: igf-1r utilize components of gpcr signaling
n5:contains: _:vb26774592 _:vb26774593 _:vb26774594 _:vb26774595 _:vb26774596 _:vb26774597 _:vb26774598 _:vb26774599 _:vb26774600 _:vb26774601 _:vb26774602 _:vb26774603 _:vb26774604 _:vb26774605 _:vb26774606 _:vb26774607 _:vb26774608 _:vb26774609 _:vb26774610 _:vb26774611 _:vb26774612 _:vb26774613 _:vb26774614 _:vb26774615 _:vb26774616 _:vb26774617 _:vb26774618 _:vb26774619 _:vb26774620 _:vb26774621 _:vb26774622 _:vb26774623 _:vb26774624 _:vb26774625 _:vb26774626 _:vb26774627 _:vb26774628 _:vb26774570 _:vb26774571 _:vb26774572 _:vb26774573 _:vb26774574 _:vb26774575 _:vb26774576 _:vb26774577 _:vb26774578 _:vb26774579 _:vb26774580 _:vb26774581 _:vb26774582 _:vb26774583 _:vb26774584 _:vb26774585 _:vb26774586 _:vb26774587 _:vb26774588 _:vb26774589 _:vb26774590 _:vb26774591

Subject Item: _:vb26774570
rdf:type: n2:Context
rdf:value: It is generally accepted that RTKs share signaling pathways with the larger class of the GPCRs [>>3<<, 179]. Over the last decades, at least two mechanisms of receptor cross-talk between RTKs and GPCRs have been described:
n2:mentions: n3:17002595

Subject Item: _:vb26774571
rdf:type: n2:Context
rdf:value: It is generally accepted that RTKs share signaling pathways with the larger class of the GPCRs [3, >>179<<]. Over the last decades, at least two mechanisms of receptor cross-talk between RTKs and GPCRs have been described:
n2:mentions: n3:15125894

Subject Item: _:vb26774572
rdf:type: n2:Context
rdf:value: One example is represented by the lysophosphatidic acid (LPA) transactivation of the EGFR [>>180<<]: LPA, a classical GPCR agonist, triggers EGFR auto-phosphorylation and MAPK signaling activation, effects that are sensitive to EGFR-kinase inhibitors or expression of EGFR kinase-defective mutants [180]. Although not completely
n2:mentions: n3:9384582

Subject Item: _:vb26774573
rdf:type: n2:Context
rdf:value: transactivation of the EGFR [180]: LPA, a classical GPCR agonist, triggers EGFR auto-phosphorylation and MAPK signaling activation, effects that are sensitive to EGFR-kinase inhibitors or expression of EGFR kinase-defective mutants [>>180<<]. Although not completely understood, the mechanism of LPA-induced transactivation of EGF receptors is likely to involve the release of an EGFR ligand by a GPCR-activated metalloproteinase.
n2:mentions: n3:9384582

Subject Item: _:vb26774574
rdf:type: n2:Context
rdf:value: Several other RTKs, including the ones for PDGF, VEGF, and NGF, were reported to be transactivated by GPCR agonists such as LPA, angiotensin, endothelin, and bradykinin (for review, see [>>179<<]). It is noteworthy that RTK transactivation by GPCRs required tyrosine phosphorylation and kinase activity of the growth factor receptor and is sensitive to inhibitors of receptor kinases [179, 181]. The IGF-1R is not an exception from
n2:mentions: n3:15125894

Subject Item: _:vb26774575
rdf:type: n2:Context
rdf:value: It is noteworthy that RTK transactivation by GPCRs required tyrosine phosphorylation and kinase activity of the growth factor receptor and is sensitive to inhibitors of receptor kinases [>>179<<, 181]. The IGF-1R is not an exception from this rule: transactivation and phosphorylation of the IGF-1R with subsequent MAPK activation was reported following thrombin stimulation of aortic smooth muscle cells [182]. Several other
n2:mentions: n3:15125894

Subject Item: _:vb26774576
rdf:type: n2:Context
rdf:value: It is noteworthy that RTK transactivation by GPCRs required tyrosine phosphorylation and kinase activity of the growth factor receptor and is sensitive to inhibitors of receptor kinases [179, >>181<<]. The IGF-1R is not an exception from this rule: transactivation and phosphorylation of the IGF-1R with subsequent MAPK activation was reported following thrombin stimulation of aortic smooth muscle cells [182]. Several other
n2:mentions: n3:21612832

Subject Item: _:vb26774577
rdf:type: n2:Context
rdf:value: The IGF-1R is not an exception from this rule: transactivation and phosphorylation of the IGF-1R with subsequent MAPK activation was reported following thrombin stimulation of aortic smooth muscle cells [>>182<<]. Several other GPCR-agonists were described as IGF-1R transactivators, including neurotensin [183] and vasopressin [184].
n2:mentions: n3:7499260

Subject Item: _:vb26774578
rdf:type: n2:Context
rdf:value: Several other GPCR-agonists were described as IGF-1R transactivators, including neurotensin [>>183<<] and vasopressin [184].
n2:mentions: n3:21212273

Subject Item: _:vb26774579
rdf:type: n2:Context
rdf:value: Several other GPCR-agonists were described as IGF-1R transactivators, including neurotensin [183] and vasopressin [>>184<<].
n2:mentions: n3:22493236

Subject Item: _:vb26774580
rdf:type: n2:Context
rdf:value: Characteristic of this type of signaling is the response to G-protein signaling inhibitors (e.g., pertussis toxin which uncouples Gαi from an activated receptor), G-protein sequestration [>>185<<], or β-arrestin downregulation [144, 186].
n2:mentions: n3:7622449

Subject Item: _:vb26774581
rdf:type: n2:Context
rdf:value: Characteristic of this type of signaling is the response to G-protein signaling inhibitors (e.g., pertussis toxin which uncouples Gαi from an activated receptor), G-protein sequestration [185], or β-arrestin downregulation [>>144<<, 186]. Most if not all RTKs, including PDGFR, EGFR, and VEGFR, utilize G-proteins as signaling mediators (for in depth reviews, see [3, 179, 181, 187]). In this context, it is worth mentioning that the members of the IR family were the
n2:mentions: n3:11278773

Subject Item: _:vb26774582
rdf:type: n2:Context
rdf:value: Characteristic of this type of signaling is the response to G-protein signaling inhibitors (e.g., pertussis toxin which uncouples Gαi from an activated receptor), G-protein sequestration [185], or β-arrestin downregulation [144, >>186<<]. Most if not all RTKs, including PDGFR, EGFR, and VEGFR, utilize G-proteins as signaling mediators (for in depth reviews, see [3, 179, 181, 187]).
n2:mentions: n3:1698770

Subject Item: _:vb26774583
rdf:type: n2:Context
rdf:value: Most if not all RTKs, including PDGFR, EGFR, and VEGFR, utilize G-proteins as signaling mediators (for in depth reviews, see [>>3<<, 179, 181, 187]).
n2:mentions: n3:17002595

Subject Item: _:vb26774584
rdf:type: n2:Context
rdf:value: Most if not all RTKs, including PDGFR, EGFR, and VEGFR, utilize G-proteins as signaling mediators (for in depth reviews, see [3, >>179<<, 181, 187]).
n2:mentions: n3:15125894

Subject Item: _:vb26774585
rdf:type: n2:Context
rdf:value: Most if not all RTKs, including PDGFR, EGFR, and VEGFR, utilize G-proteins as signaling mediators (for in depth reviews, see [3, 179, >>181<<, 187]). In this context, it is worth mentioning that the members of the IR family were the first described to engage the G-proteins signaling: the IR signaling was demonstrated to be sensitive to pertussis toxin treatment [186], with
n2:mentions: n3:21612832

Subject Item: _:vb26774586
rdf:type: n2:Context
rdf:value: Most if not all RTKs, including PDGFR, EGFR, and VEGFR, utilize G-proteins as signaling mediators (for in depth reviews, see [3, 179, 181, >>187<<]). In this context, it is worth mentioning that the members of the IR family were the first described to engage the G-proteins signaling: the IR signaling was demonstrated to be sensitive to pertussis toxin treatment [186], with
n2:mentions: n3:18001849

Subject Item: _:vb26774587
rdf:type: n2:Context
rdf:value: In this context, it is worth mentioning that the members of the IR family were the first described to engage the G-proteins signaling: the IR signaling was demonstrated to be sensitive to pertussis toxin treatment [>>186<<], with subsequent decrease of the insulin-induced inhibition of adenylyl cyclase in isolated hepatocytes [188].
n2:mentions: n3:1698770

Subject Item: _:vb26774588
rdf:type: n2:Context
rdf:value: described to engage the G-proteins signaling: the IR signaling was demonstrated to be sensitive to pertussis toxin treatment [186], with subsequent decrease of the insulin-induced inhibition of adenylyl cyclase in isolated hepatocytes [>>188<<]. Several other studies have demonstrated the Gαi involvement in IR signaling and their effects on insulin signaling biological outcomes [186, 189].
n2:mentions: n3:3017298

Subject Item: _:vb26774589
rdf:type: n2:Context
rdf:value: Several other studies have demonstrated the Gαi involvement in IR signaling and their effects on insulin signaling biological outcomes [>>186<<, 189]. Given the high structural similarities between IR and IGF-1R, it is not surprising that some G-proteins have also been identified to physically associate and mediate IGF-1R signaling. Almost 20 years ago, a study from Robert
n2:mentions: n3:1698770

Subject Item: _:vb26774590
rdf:type: n2:Context
rdf:value: Several other studies have demonstrated the Gαi involvement in IR signaling and their effects on insulin signaling biological outcomes [186, >>189<<]. Given the high structural similarities between IR and IGF-1R, it is not surprising that some G-proteins have also been identified to physically associate and mediate IGF-1R signaling. Almost 20 years ago, a study from Robert Lefkowitz’s
n2:mentions: n3:3139671

Subject Item: _:vb26774591
rdf:type: n2:Context
rdf:value: from Robert Lefkowitz’s laboratory reported that IGF-1R-dependent activation of the MAPK signaling pathway was inhibited by the Gαi-inhibitor pertussis toxin or by sequestration of G-protein βγ subunits by a peptide derived from GRK2 [>>185<<]. This study clearly demonstrated that IGF-1R signaling depends on heterotrimeric G-proteins containing the Gαi and Gβγ subunits.
n2:mentions: n3:7622449

Subject Item: _:vb26774592
rdf:type: n2:Context
rdf:value: More importantly, this study demonstrated the IGF-1 induced release of the Gβ subunits from the IGF-1R with no effect on IGF-1R/Gαi association, indicating a discrete pool of Gβγ subunits available for IGF-1R downstream signaling [>>190<<]. The IGF-1R/Gαi association was also reported in a separate study investigating the roles of heterotrimeric G-protein signaling components in insulin and IGF-1 signaling.
n2:mentions: n3:10644671

Subject Item: _:vb26774593
rdf:type: n2:Context
rdf:value: In 3T3L1 adipocytes, in basal state, Gαi and Gβ were associated with the IGF-1R, while IGF-1 stimulation increased the IGF-1R/Gαi association, releasing the Gβ subunits [>>144<<].
n2:mentions: n3:11278773

Subject Item: _:vb26774594
rdf:type: n2:Context
rdf:value: and is today considered a “classical” signaling pathway, the complexity of the RTK/GPCR cross-talk was further demonstrated by recent findings of bidirectional cross-communication between RTKs and GPCRs (for in depth reviews, see [>>181<<, 187]). In these processes, the GPCR signaling is activated by RTKs by the same two mechanisms described above:
n2:mentions: n3:21612832

Subject Item: _:vb26774595
rdf:type: n2:Context
rdf:value: and is today considered a “classical” signaling pathway, the complexity of the RTK/GPCR cross-talk was further demonstrated by recent findings of bidirectional cross-communication between RTKs and GPCRs (for in depth reviews, see [181, >>187<<]). In these processes, the GPCR signaling is activated by RTKs by the same two mechanisms described above:
n2:mentions: n3:18001849

Subject Item: _:vb26774596
rdf:type: n2:Context
rdf:value: In these processes, the GPCR signaling is activated by RTKs by the same two mechanisms described above: production of a GPCR ligand stimulated by RTK activation or a ligand-independent cross-activation of the signaling network [>>181<<, 187]. In the case of the IGF-1R, such GPCR-transactivation has been demonstrated to be essential for migratory and pro-survival functions controlled by IGF-1 [181, 187]. Taken together, these studies indicate a common signaling platform
n2:mentions: n3:21612832

Subject Item: _:vb26774597
rdf:type: n2:Context
rdf:value: In these processes, the GPCR signaling is activated by RTKs by the same two mechanisms described above: production of a GPCR ligand stimulated by RTK activation or a ligand-independent cross-activation of the signaling network [181, >>187<<]. In the case of the IGF-1R, such GPCR-transactivation has been demonstrated to be essential for migratory and pro-survival functions controlled by IGF-1 [181, 187].
n2:mentions: n3:18001849

Subject Item: _:vb26774598
rdf:type: n2:Context
rdf:value: In the case of the IGF-1R, such GPCR-transactivation has been demonstrated to be essential for migratory and pro-survival functions controlled by IGF-1 [>>181<<, 187]. Taken together, these studies indicate a common signaling platform between IGF-1R and GPCRs to differentiate between the responses upon combined growth factor/GPCR agonist stimulation from single stimulation by either ligand.
n2:mentions: n3:21612832

Subject Item: _:vb26774599
rdf:type: n2:Context
rdf:value: In the case of the IGF-1R, such GPCR-transactivation has been demonstrated to be essential for migratory and pro-survival functions controlled by IGF-1 [181, >>187<<]. Taken together, these studies indicate a common signaling platform between IGF-1R and GPCRs to differentiate between the responses upon combined growth factor/GPCR agonist stimulation from single stimulation by either ligand.
n2:mentions: n3:18001849

Subject Item: _:vb26774600
rdf:type: n2:Context
rdf:value: The Gαi subunit is constitutively associated with the IGF-1R while IGF-1 treatment leads to GTP loading of Gαi2 [>>144<<] and Gβγ dissociation.
n2:mentions: n3:11278773

Subject Item: _:vb26774601
rdf:type: n2:Context
rdf:value: in IGF-1R signaling and trafficking: a dominant negative mutant of β-arrestin 1 was demonstrated to impair IGF-1R internalization, whereas overexpression of wild-type β-arrestin 1 or β-arrestin 2 increases IGF-1R internalization [>>191<<]. Moreover, G-protein signaling activated by IGF-1R was demonstrated to be sensitive to β-arrestin inhibition [144].
n2:mentions: n3:9822622

Subject Item: _:vb26774602
rdf:type: n2:Context
rdf:value: Moreover, G-protein signaling activated by IGF-1R was demonstrated to be sensitive to β-arrestin inhibition [>>144<<].
n2:mentions: n3:11278773

Subject Item: _:vb26774603
rdf:type: n2:Context
rdf:value: The discovery of the dual regulatory role of β-arrestin 1 in the case of IGF-1R, downregulation [>>133<<], and signaling activation [134], pointed towards a remarkable parallel with the role of β-arrestins in the case of the larger GPCR family.
n2:mentions: n3:15878855

Subject Item: _:vb26774604
rdf:type: n2:Context
rdf:value: The discovery of the dual regulatory role of β-arrestin 1 in the case of IGF-1R, downregulation [133], and signaling activation [>>134<<], pointed towards a remarkable parallel with the role of β-arrestins in the case of the larger GPCR family.
n2:mentions: n3:17303558

Subject Item: _:vb26774605
rdf:type: n2:Context
rdf:value: While internalizing the GPCR and ending G-protein signaling, β-arrestins activate the MAPK pathway [>>192<<–194].
n2:mentions: n3:15276710 n3:15845844 n3:16280323

Subject Item: _:vb26774606
rdf:type: n2:Context
rdf:value: Recognized as a universal mechanism of GPCR regulation, β-arrestin 1 binds to the receptor and desensitizes G-protein signaling only after phosphorylation of specific serine residues by the G-protein–coupled receptor kinases (GRKs) [>>193<<, 195, 196]. Therefore, a legitimate question was whether the same mechanism is in place for the IGF-1R.
n2:mentions: n3:15845844

Subject Item: _:vb26774607
rdf:type: n2:Context
rdf:value: as a universal mechanism of GPCR regulation, β-arrestin 1 binds to the receptor and desensitizes G-protein signaling only after phosphorylation of specific serine residues by the G-protein–coupled receptor kinases (GRKs) [193, >>195<<, 196]. Therefore, a legitimate question was whether the same mechanism is in place for the IGF-1R.
n2:mentions: n3:12959637

Subject Item: _:vb26774608
rdf:type: n2:Context
rdf:value: as a universal mechanism of GPCR regulation, β-arrestin 1 binds to the receptor and desensitizes G-protein signaling only after phosphorylation of specific serine residues by the G-protein–coupled receptor kinases (GRKs) [193, 195, >>196<<]. Therefore, a legitimate question was whether the same mechanism is in place for the IGF-1R.
n2:mentions: n3:17305471

Subject Item: _:vb26774609
rdf:type: n2:Context
rdf:value: Investigating this scenario, we found that activated IGF-1R allows recruitment of the GRK proteins, specifically with contrasting effects between GRK2 and GRK6 [>>124<<]. Subsequent GRK2- or GRK6-dependent phosphorylation of IGF-1R C-terminal serine residues 1248 or 1291, respectively, allows β-arrestin 1 recruitment, with the residue that is phosphorylated controlling the duration and strength of the
n2:mentions: n3:22509025

Subject Item: _:vb26774610
rdf:type: n2:Context
rdf:value: This paradigm shift is founded on the accepted universal model of GPCR activation and desensitization delineated by six distinct processes [>>195<<, 197], all of which have been identified to occur for the IGF-1R (Fig.
n2:mentions: n3:12959637

Subject Item: _:vb26774611
rdf:type: n2:Context
rdf:value: This paradigm shift is founded on the accepted universal model of GPCR activation and desensitization delineated by six distinct processes [195, >>197<<], all of which have been identified to occur for the IGF-1R (Fig.
n2:mentions: n3:16595179

Subject Item: _:vb26774612
rdf:type: n2:Context
rdf:value: 3): (1) ligand binding to the IGF-1R, in addition to the classical kinase signaling cascade triggers signaling through heterotrimeric G-proteins [>>144<<, 185], (2) subsequent GRK2- or GRK6-dependent phosphorylation of IGF-1R C-terminal serine residues 1248 or 1291, allowing β-arrestin binding to these specific phosphorylated serine residues [124], with (3) β-arrestin recruitment [124,
n2:mentions: n3:11278773

Subject Item: _:vb26774613
rdf:type: n2:Context
rdf:value: 3): (1) ligand binding to the IGF-1R, in addition to the classical kinase signaling cascade triggers signaling through heterotrimeric G-proteins [144, >>185<<], (2) subsequent GRK2- or GRK6-dependent phosphorylation of IGF-1R C-terminal serine residues 1248 or 1291, allowing β-arrestin binding to these specific phosphorylated serine residues [124], with (3) β-arrestin recruitment [124, 133,
n2:mentions: n3:7622449

Subject Item: _:vb26774614
rdf:type: n2:Context
rdf:value: through heterotrimeric G-proteins [144, 185], (2) subsequent GRK2- or GRK6-dependent phosphorylation of IGF-1R C-terminal serine residues 1248 or 1291, allowing β-arrestin binding to these specific phosphorylated serine residues [>>124<<], with (3) β-arrestin recruitment [124, 133, 134], (4) subsequent kinase/G-protein signaling desensitization, (5) activation of a β-arrestin-dependent second signaling wave through MAPK [124, 134], and (6) receptor endocytosis with the
n2:mentions: n3:22509025

Subject Item: _:vb26774615
rdf:type: n2:Context
rdf:value: [144, 185], (2) subsequent GRK2- or GRK6-dependent phosphorylation of IGF-1R C-terminal serine residues 1248 or 1291, allowing β-arrestin binding to these specific phosphorylated serine residues [124], with (3) β-arrestin recruitment [>>124<<, 133, 134], (4) subsequent kinase/G-protein signaling desensitization, (5) activation of a β-arrestin-dependent second signaling wave through MAPK [124, 134], and (6) receptor endocytosis with the GRK isoform determining receptor
n2:mentions: n3:22509025

Subject Item: _:vb26774616
rdf:type: n2:Context
rdf:value: 185], (2) subsequent GRK2- or GRK6-dependent phosphorylation of IGF-1R C-terminal serine residues 1248 or 1291, allowing β-arrestin binding to these specific phosphorylated serine residues [124], with (3) β-arrestin recruitment [124, >>133<<, 134], (4) subsequent kinase/G-protein signaling desensitization, (5) activation of a β-arrestin-dependent second signaling wave through MAPK [124, 134], and (6) receptor endocytosis with the GRK isoform determining receptor degradation
n2:mentions: n3:15878855

Subject Item: _:vb26774617
rdf:type: n2:Context
rdf:value: (2) subsequent GRK2- or GRK6-dependent phosphorylation of IGF-1R C-terminal serine residues 1248 or 1291, allowing β-arrestin binding to these specific phosphorylated serine residues [124], with (3) β-arrestin recruitment [124, 133, >>134<<], (4) subsequent kinase/G-protein signaling desensitization, (5) activation of a β-arrestin-dependent second signaling wave through MAPK [124, 134], and (6) receptor endocytosis with the GRK isoform determining receptor degradation [124,
n2:mentions: n3:17303558

Subject Item: _:vb26774618
rdf:type: n2:Context
rdf:value: specific phosphorylated serine residues [124], with (3) β-arrestin recruitment [124, 133, 134], (4) subsequent kinase/G-protein signaling desensitization, (5) activation of a β-arrestin-dependent second signaling wave through MAPK [>>124<<, 134], and (6) receptor endocytosis with the GRK isoform determining receptor degradation [124, 133] or recycling [124].
n2:mentions: n3:22509025

Subject Item: _:vb26774619
rdf:type: n2:Context
rdf:value: phosphorylated serine residues [124], with (3) β-arrestin recruitment [124, 133, 134], (4) subsequent kinase/G-protein signaling desensitization, (5) activation of a β-arrestin-dependent second signaling wave through MAPK [124, >>134<<], and (6) receptor endocytosis with the GRK isoform determining receptor degradation [124, 133] or recycling [124].
n2:mentions: n3:17303558

Subject Item: _:vb26774620
rdf:type: n2:Context
rdf:value: (4) subsequent kinase/G-protein signaling desensitization, (5) activation of a β-arrestin-dependent second signaling wave through MAPK [124, 134], and (6) receptor endocytosis with the GRK isoform determining receptor degradation [>>124<<, 133] or recycling [124]. In this model, one uncertainty is whether, for the IGF-1R, GRK-mediated β-arrestin binding initiates a desensitization process (Fig.
n2:mentions: n3:22509025

Subject Item: _:vb26774621
rdf:type: n2:Context
rdf:value: (4) subsequent kinase/G-protein signaling desensitization, (5) activation of a β-arrestin-dependent second signaling wave through MAPK [124, 134], and (6) receptor endocytosis with the GRK isoform determining receptor degradation [124, >>133<<] or recycling [124]. In this model, one uncertainty is whether, for the IGF-1R, GRK-mediated β-arrestin binding initiates a desensitization process (Fig.
n2:mentions: n3:15878855

Subject Item: _:vb26774622
rdf:type: n2:Context
rdf:value: signaling desensitization, (5) activation of a β-arrestin-dependent second signaling wave through MAPK [124, 134], and (6) receptor endocytosis with the GRK isoform determining receptor degradation [124, 133] or recycling [>>124<<]. In this model, one uncertainty is whether, for the IGF-1R, GRK-mediated β-arrestin binding initiates a desensitization process (Fig.
n2:mentions: n3:22509025

Subject Item: _:vb26774623
rdf:type: n2:Context
rdf:value: While for GPCRs the key role of GRKs in desensitization is well recognized, for RTKs few studies have investigated the contribution of GRKs [>>3<<]. In all published studies, GRK2 is reported to desensitize or modulate RTK signaling. For instance, GRK2 is recruited and co-localizes with the ligand-activated EGFR or PDGFR, leading to receptor serine phosphorylation and increased ERK
n2:mentions: n3:17002595

Subject Item: _:vb26774624
rdf:type: n2:Context
rdf:value: For instance, GRK2 is recruited and co-localizes with the ligand-activated EGFR or PDGFR, leading to receptor serine phosphorylation and increased ERK activation in the case of EGFR [>>198<<], or inhibiting the kinase activity in the case of PDGFR [199].
n2:mentions: n3:16077899

Subject Item: _:vb26774625
rdf:type: n2:Context
rdf:value: GRK2 is recruited and co-localizes with the ligand-activated EGFR or PDGFR, leading to receptor serine phosphorylation and increased ERK activation in the case of EGFR [198], or inhibiting the kinase activity in the case of PDGFR [>>199<<]. The insulin receptor (IR), closely related to the IGF-1R, is a special case:
n2:mentions: n3:12381737

Subject Item: _:vb26774626
rdf:type: n2:Context
rdf:value: is a special case: GRK2 was shown to have inhibitory effects on IR-mediated signaling and glucose uptake, though the observed effects were demonstrated to be mediated in a kinase-independent manner through GRK2 sequestration of Gαq/11 [>>200<<].Fig.
n2:mentions: n3:15241473

Subject Item: _:vb26774627
rdf:type: n2:Context
rdf:value: In a palmitoylated state, GRK6 has been found to be exclusively associated with the membrane; however, it is not yet clear whether this reversible posttranslational modification is induced by activated receptor [>>3<<]. On the other hand, a clear regulatory negative feedback, induced by activated receptor, was demonstrated for GRK2: Gβγ subunits, generated by the agonist-occupied receptor, interact with GRK2 and serve to target this enzyme into
n2:mentions: n3:17002595

Subject Item: _:vb26774628
rdf:type: n2:Context
rdf:value: feedback, induced by activated receptor, was demonstrated for GRK2: Gβγ subunits, generated by the agonist-occupied receptor, interact with GRK2 and serve to target this enzyme into proximity with its membrane receptor substrate [>>201<<]. Consequently, β-arrestin recruitment to GRK-phosphorylated receptors physically prevents the coupling of receptor to its cognate G-protein.
n2:mentions: n3:9759500

Subject Item: _:vb26774629
rdf:type: n5:Section
dc:title: the emerging paradigm for igf-1r signaling
n5:contains: _:vb26774640 _:vb26774641 _:vb26774642 _:vb26774643 _:vb26774644 _:vb26774645 _:vb26774646 _:vb26774647 _:vb26774648 _:vb26774649 _:vb26774650 _:vb26774651 _:vb26774652 _:vb26774653 _:vb26774654 _:vb26774630 _:vb26774631 _:vb26774632 _:vb26774633 _:vb26774634 _:vb26774635 _:vb26774636 _:vb26774637 _:vb26774638 _:vb26774639

Subject Item: _:vb26774630
rdf:type: n2:Context
rdf:value: Yet, there is experimental data that do not support this model, including some major contradictions (Table 2) such as kinase-independent signaling activation [>>124<<, 134, 202] or unbalanced signaling in the same cellular background [34, 124, 134], signaling-degradation dissociation, or receptor downregulation in the absence of the ligand or activation-loop phosphorylation [37, 124, 203].
n2:mentions: n3:22509025

Subject Item: _:vb26774631
rdf:type: n2:Context
rdf:value: Yet, there is experimental data that do not support this model, including some major contradictions (Table 2) such as kinase-independent signaling activation [124, >>134<<, 202] or unbalanced signaling in the same cellular background [34, 124, 134], signaling-degradation dissociation, or receptor downregulation in the absence of the ligand or activation-loop phosphorylation [37, 124, 203].
n2:mentions: n3:17303558

Subject Item: _:vb26774632
rdf:type: n2:Context
rdf:value: Yet, there is experimental data that do not support this model, including some major contradictions (Table 2) such as kinase-independent signaling activation [124, 134, >>202<<] or unbalanced signaling in the same cellular background [34, 124, 134], signaling-degradation dissociation, or receptor downregulation in the absence of the ligand or activation-loop phosphorylation [37, 124, 203].
n2:mentions: n3:21215800

Subject Item: _:vb26774633
rdf:type: n2:Context
rdf:value: Yet, there is experimental data that do not support this model, including some major contradictions (Table 2) such as kinase-independent signaling activation [124, 134, 202] or unbalanced signaling in the same cellular background [>>34<<, 124, 134], signaling-degradation dissociation, or receptor downregulation in the absence of the ligand or activation-loop phosphorylation [37, 124, 203].
n2:mentions: n3:21685939

Subject Item: _:vb26774634
rdf:type: n2:Context
rdf:value: Yet, there is experimental data that do not support this model, including some major contradictions (Table 2) such as kinase-independent signaling activation [124, 134, 202] or unbalanced signaling in the same cellular background [34, >>124<<, 134], signaling-degradation dissociation, or receptor downregulation in the absence of the ligand or activation-loop phosphorylation [37, 124, 203].
n2:mentions: n3:22509025

Subject Item: _:vb26774635
rdf:type: n2:Context
rdf:value: there is experimental data that do not support this model, including some major contradictions (Table 2) such as kinase-independent signaling activation [124, 134, 202] or unbalanced signaling in the same cellular background [34, 124, >>134<<], signaling-degradation dissociation, or receptor downregulation in the absence of the ligand or activation-loop phosphorylation [37, 124, 203].
n2:mentions: n3:17303558

Subject Item: _:vb26774636
rdf:type: n2:Context
rdf:value: signaling activation [124, 134, 202] or unbalanced signaling in the same cellular background [34, 124, 134], signaling-degradation dissociation, or receptor downregulation in the absence of the ligand or activation-loop phosphorylation [>>37<<, 124, 203].
n2:mentions: n3:19752219

Subject Item: _:vb26774637
rdf:type: n2:Context
rdf:value: activation [124, 134, 202] or unbalanced signaling in the same cellular background [34, 124, 134], signaling-degradation dissociation, or receptor downregulation in the absence of the ligand or activation-loop phosphorylation [37, >>124<<, 203]. Beyond this, there is the major paradox of the IGF-1R inhibitors (antibodies and small molecules inhibitors, see below), which are able to activate IGF-1R downregulation and signaling despite clear inhibitory effects on receptor
n2:mentions: n3:22509025

Subject Item: _:vb26774638
rdf:type: n2:Context
rdf:value: activation [124, 134, 202] or unbalanced signaling in the same cellular background [34, 124, 134], signaling-degradation dissociation, or receptor downregulation in the absence of the ligand or activation-loop phosphorylation [37, 124, >>203<<]. Beyond this, there is the major paradox of the IGF-1R inhibitors (antibodies and small molecules inhibitors, see below), which are able to activate IGF-1R downregulation and signaling despite clear inhibitory effects on receptor
n2:mentions: n3:1316361

Subject Item: _:vb26774639
rdf:type: n2:Context
rdf:value: Contradiction: kinase-independent signaling activation: IGF-1R can trigger MAPK signaling in the absence of the ligand or without kinase domain activation [>>124<<, 134,
n2:mentions: n3:22509025

Subject Item: _:vb26774640
rdf:type: n2:Context
rdf:value: Contradiction: kinase-independent signaling activation: IGF-1R can trigger MAPK signaling in the absence of the ligand or without kinase domain activation [124, >>134<<,
n2:mentions: n3:17303558

Subject Item: _:vb26774641
rdf:type: n2:Context
rdf:value: Contradiction: kinase-independent signaling activation: IGF-1R can trigger MAPK signaling in the absence of the ligand or without kinase domain activation [124, 134, >>202<<
n2:mentions: n3:21215800

Subject Item: _:vb26774642
rdf:type: n2:Context
rdf:value: Contradictions: signaling–downregulation dissociation-specific point-mutations outside the kinase domain can activate signaling or receptor downregulation in the absence of the ligand or activation-loop phosphorylation [>>124<<
n2:mentions: n3:22509025

Subject Item: _:vb26774643
rdf:type: n2:Context
rdf:value: Contradictions: unbalanced signaling: in the same cellular background, IGF-1R can preferentially activate either the MAPK or PI3K/AKT pathways [>>34<<, 124,
n2:mentions: n3:21685939

Subject Item: _:vb26774644
rdf:type: n2:Context
rdf:value: Contradictions: unbalanced signaling: in the same cellular background, IGF-1R can preferentially activate either the MAPK or PI3K/AKT pathways [34, >>124<<,
n2:mentions: n3:22509025

Subject Item: _:vb26774645
rdf:type: n2:Context
rdf:value: Contradictions: unbalanced signaling: in the same cellular background, IGF-1R can preferentially activate either the MAPK or PI3K/AKT pathways [34, 124, >>134<<
n2:mentions: n3:17303558

Subject Item: _:vb26774646
rdf:type: n2:Context
rdf:value: The appreciation of the dual functions of β-arrestin, as a mediator of IGF-1R signaling [>>124<<, 134, 191, 204] as well as mediator of receptor downregulation [124, 133], provide the basis for the emerging paradigm of IGF-1R signaling.
n2:mentions: n3:22509025

Subject Item: _:vb26774647
rdf:type: n2:Context
rdf:value: The appreciation of the dual functions of β-arrestin, as a mediator of IGF-1R signaling [124, >>134<<, 191, 204] as well as mediator of receptor downregulation [124, 133], provide the basis for the emerging paradigm of IGF-1R signaling.
n2:mentions: n3:17303558

Subject Item: _:vb26774648
rdf:type: n2:Context
rdf:value: The appreciation of the dual functions of β-arrestin, as a mediator of IGF-1R signaling [124, 134, >>191<<, 204] as well as mediator of receptor downregulation [124, 133], provide the basis for the emerging paradigm of IGF-1R signaling.
n2:mentions: n3:9822622

Subject Item: _:vb26774649
rdf:type: n2:Context
rdf:value: The appreciation of the dual functions of β-arrestin, as a mediator of IGF-1R signaling [124, 134, 191, >>204<<] as well as mediator of receptor downregulation [124, 133], provide the basis for the emerging paradigm of IGF-1R signaling.
n2:mentions: n3:14534298

Subject Item: _:vb26774650
rdf:type: n2:Context
rdf:value: The appreciation of the dual functions of β-arrestin, as a mediator of IGF-1R signaling [124, 134, 191, 204] as well as mediator of receptor downregulation [>>124<<, 133], provide the basis for the emerging paradigm of IGF-1R signaling.
n2:mentions: n3:22509025

Subject Item: _:vb26774651
rdf:type: n2:Context
rdf:value: The appreciation of the dual functions of β-arrestin, as a mediator of IGF-1R signaling [124, 134, 191, 204] as well as mediator of receptor downregulation [124, >>133<<], provide the basis for the emerging paradigm of IGF-1R signaling.
n2:mentions: n3:15878855

Subject Item: _:vb26774652
rdf:type: n2:Context
rdf:value: conformation activating the kinase signaling can be distinct from that which interacts with β-arrestins, as demonstrated by the IGF-1R mutants constitutively binding β-arrestin, that are degraded even in the absence of the ligand [>>124<<] (Fig. 4). This scenario can explain the dissociation between kinase activation and receptor degradation as well as kinase-independent signaling.
n2:mentions: n3:22509025

Subject Item: _:vb26774653
rdf:type: n2:Context
rdf:value: The same model would also accommodate the unbalanced IGF-1R signaling, activated in a “biased manner” via β-arrestin by IGF-1R inhibitors as well as by natural “biased” agonists [>>22<<, 143]. In this emerging model, not all receptors are equal and their activity can be modulated from inside the cell by particular posttranslational modifications (e.g., serine phosphorylation, ubiquitination, etc.) or by interacting
n2:mentions: n3:16407828

Subject Item: _:vb26774654
rdf:type: n2:Context
rdf:value: The same model would also accommodate the unbalanced IGF-1R signaling, activated in a “biased manner” via β-arrestin by IGF-1R inhibitors as well as by natural “biased” agonists [22, >>143<<]. In this emerging model, not all receptors are equal and their activity can be modulated from inside the cell by particular posttranslational modifications (e.g., serine phosphorylation, ubiquitination, etc.) or by interacting proteins
n2:mentions: n3:18070930

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rdf:type: n2:RelevantBibliographicResource
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rdf:type: n2:RelevantBibliographicResource
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rdf:type: n2:RelevantBibliographicResource
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