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10.1186%2F2045-3701-3-32
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introduction
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The Hippo tumour suppressor pathway regulates cell proliferation, cell death and cell differentiation in multicellular organisms to ensure normal tissue development [>>1<<,2]. The final output of Hippo signalling is the inhibition of the transcriptional co-activators Yorkie and YAP (yes-associated protein) / TAZ (transcriptional co-activator with PDZ-binding motif) in flies and mammals, respectively [3].
n3:mentions
n2:22575479
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The Hippo tumour suppressor pathway regulates cell proliferation, cell death and cell differentiation in multicellular organisms to ensure normal tissue development [1,>>2<<]. The final output of Hippo signalling is the inhibition of the transcriptional co-activators Yorkie and YAP (yes-associated protein) / TAZ (transcriptional co-activator with PDZ-binding motif) in flies and mammals, respectively [3].
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The final output of Hippo signalling is the inhibition of the transcriptional co-activators Yorkie and YAP (yes-associated protein) / TAZ (transcriptional co-activator with PDZ-binding motif) in flies and mammals, respectively [>>3<<]. Essentially, the core Hippo signalling module is composed of members of the Ste20-like kinase, the MOB (mps one binder) co-activator and the AGC (protein kinase A(PKA)/PKG/PKC-like) kinase families [4]. In Drosophila, the stimulated
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n2:22659496
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Essentially, the core Hippo signalling module is composed of members of the Ste20-like kinase, the MOB (mps one binder) co-activator and the AGC (protein kinase A(PKA)/PKG/PKC-like) kinase families [>>4<<]. In Drosophila, the stimulated Ste20-like Hippo kinase phosphorylates and thereby activates a complex composed of Mats (mob as tumour suppressor) and the AGC Warts kinase. The Mats/Warts complex then phosphorylates and inactivates the
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n2:16607288
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While all core Hippo components upstream of Yorkie have been defined as tumour suppressors in flies, Yorkie displays proto-oncogenic properties [>>5<<]. In mammals, genetic studies provided the same picture, namely that loss of MST1/2 [6], MOB1A/B [7], or LATS1 [8] results in tumour growth, while YAP overexpression is sufficient to induce tumours [9]. Therefore, mammalian Hippo
n3:mentions
n2:22174083
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In mammals, genetic studies provided the same picture, namely that loss of MST1/2 [>>6<<], MOB1A/B [7], or LATS1 [8] results in tumour growth, while YAP overexpression is sufficient to induce tumours [9].
n3:mentions
n2:19878874
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In mammals, genetic studies provided the same picture, namely that loss of MST1/2 [6], MOB1A/B [>>7<<], or LATS1 [8] results in tumour growth, while YAP overexpression is sufficient to induce tumours [9].
n3:mentions
n2:23143302
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In mammals, genetic studies provided the same picture, namely that loss of MST1/2 [6], MOB1A/B [7], or LATS1 [>>8<<] results in tumour growth, while YAP overexpression is sufficient to induce tumours [9].
n3:mentions
n2:9988269
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In mammals, genetic studies provided the same picture, namely that loss of MST1/2 [6], MOB1A/B [7], or LATS1 [8] results in tumour growth, while YAP overexpression is sufficient to induce tumours [>>9<<]. Therefore, mammalian Hippo signalling has been defined as a tumour suppressor pathway that is essential for the control of the proto-oncoproteins YAP/TAZ [10,11]. Since the functions and regulation of YAP/TAZ have been reviewed recently
n3:mentions
n2:17889654
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Therefore, mammalian Hippo signalling has been defined as a tumour suppressor pathway that is essential for the control of the proto-oncoproteins YAP/TAZ [>>10<<,11]. Since the functions and regulation of YAP/TAZ have been reviewed recently [3], we will focus in this review only on the LATS-mediated regulation of YAP/TAZ. Furthermore, for a discussion of the crosstalk between Hippo and Wnt/TGFβ
n3:mentions
n2:23467301
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n3:Context
rdf:value
Therefore, mammalian Hippo signalling has been defined as a tumour suppressor pathway that is essential for the control of the proto-oncoproteins YAP/TAZ [10,>>11<<]. Since the functions and regulation of YAP/TAZ have been reviewed recently [3], we will focus in this review only on the LATS-mediated regulation of YAP/TAZ. Furthermore, for a discussion of the crosstalk between Hippo and Wnt/TGFβ
n3:mentions
n2:20951342
Subject Item
_:vb24745234
rdf:type
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Since the functions and regulation of YAP/TAZ have been reviewed recently [>>3<<], we will focus in this review only on the LATS-mediated regulation of YAP/TAZ.
n3:mentions
n2:22659496
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_:vb24745235
rdf:type
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rdf:value
Furthermore, for a discussion of the crosstalk between Hippo and Wnt/TGFβ signalling we refer the reader to a recent overview provided by Varelas and Wrana [>>12<<].
n3:mentions
n2:22153608
Subject Item
_:vb24745236
rdf:type
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rdf:value
Drosophila Warts and mammalian LATS1/2 kinases are members of the serine/threonine AGC class of protein kinases [>>13<<]. More specifically, LATS1/2 have been classified as a subgroup of AGC kinases together with NDR1/2 (nuclear Dbf2 related kinases 1/2; also known as STK38/STK38L), based on two unique characteristics, a conserved N-terminal regulatory
n3:mentions
n2:20027184
Subject Item
_:vb24745237
rdf:type
n3:Context
rdf:value
with NDR1/2 (nuclear Dbf2 related kinases 1/2; also known as STK38/STK38L), based on two unique characteristics, a conserved N-terminal regulatory domain (NTR) and an insert between subdomains VII and VIII of the catalytic kinase domain [>>4<<]. Like other AGC kinases, LATS/NDR kinases are regulated by phosphorylation on the activation segment motif (AS; also referred to as T-loop) and a C-terminally located hydrophobic motif (HM), which will be discussed later in more detail.
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n2:16607288
Subject Item
_:vb24745238
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Initially, our understanding of LATS/NDR kinases was mainly based on genetic studies performed in yeast and flies [>>4<<]. Therefore, before focusing entirely on our current understanding of mammalian LATS/NDR kinases, we feel that it is appropriate to give a brief historic overview of key discoveries with respect to core Hippo signalling.
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n2:16607288
Subject Item
_:vb24745239
rdf:type
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In budding and fission yeast, the LATS/NDR kinases Dbf2p and Sid2p were described as central members of MEN/SIN signalling which is essential for proper mitotic exit [>>14<<], while the LATS/NDR kinases Cbk1 and Orb6 were attributed functions in the regulation of morphogenesis [4].
n3:mentions
n2:22525225
Subject Item
_:vb24745240
rdf:type
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rdf:value
kinases Dbf2p and Sid2p were described as central members of MEN/SIN signalling which is essential for proper mitotic exit [14], while the LATS/NDR kinases Cbk1 and Orb6 were attributed functions in the regulation of morphogenesis [>>4<<]. In Drosophila, Warts and Tricornered (the counterparts of mammalian LATS1/2 and NDR1/2, respectively) were discovered more than 10 years ago [15-17], and subsequent studies established Warts and Trc (Tricornered) as key players in Hippo
n3:mentions
n2:16607288
Subject Item
_:vb24745241
rdf:type
n3:Context
rdf:value
In Drosophila, Warts and Tricornered (the counterparts of mammalian LATS1/2 and NDR1/2, respectively) were discovered more than 10 years ago [>>15<<-17], and subsequent studies established Warts and Trc (Tricornered) as key players in Hippo signalling and dendritic tiling, respectively [5,18].
n3:mentions
n2:7743921 n2:11102376 n2:7698644
Subject Item
_:vb24745242
rdf:type
n3:Context
rdf:value
of mammalian LATS1/2 and NDR1/2, respectively) were discovered more than 10 years ago [15-17], and subsequent studies established Warts and Trc (Tricornered) as key players in Hippo signalling and dendritic tiling, respectively [>>5<<,18]. Significantly, human LATS1 and NDR1 were able to rescue the loss of Warts and Trc function, respectively [19,20], strongly suggesting that LATS/NDR functions are conserved between flies and mammals [4].
n3:mentions
n2:22174083
Subject Item
_:vb24745243
rdf:type
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rdf:value
of mammalian LATS1/2 and NDR1/2, respectively) were discovered more than 10 years ago [15-17], and subsequent studies established Warts and Trc (Tricornered) as key players in Hippo signalling and dendritic tiling, respectively [5,>>18<<]. Significantly, human LATS1 and NDR1 were able to rescue the loss of Warts and Trc function, respectively [19,20], strongly suggesting that LATS/NDR functions are conserved between flies and mammals [4].
n3:mentions
n2:21697237
Subject Item
_:vb24745244
rdf:type
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rdf:value
Significantly, human LATS1 and NDR1 were able to rescue the loss of Warts and Trc function, respectively [>>19<<,20], strongly suggesting that LATS/NDR functions are conserved between flies and mammals [4].
n3:mentions
n2:9988268
Subject Item
_:vb24745245
rdf:type
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rdf:value
Significantly, human LATS1 and NDR1 were able to rescue the loss of Warts and Trc function, respectively [19,>>20<<], strongly suggesting that LATS/NDR functions are conserved between flies and mammals [4].
n3:mentions
n2:15591127
Subject Item
_:vb24745246
rdf:type
n3:Context
rdf:value
Significantly, human LATS1 and NDR1 were able to rescue the loss of Warts and Trc function, respectively [19,20], strongly suggesting that LATS/NDR functions are conserved between flies and mammals [>>4<<]. In 2002, Tapon et al. reported the regulation of Warts by the scaffolding protein Salvador (also known as WW45 in mammals) [21]. However, the breakthrough for Hippo signalling were five publications in 2003 [22-26], demonstrating that
n3:mentions
n2:16607288
Subject Item
_:vb24745247
rdf:type
n3:Context
rdf:value
In 2002, Tapon et al. reported the regulation of Warts by the scaffolding protein Salvador (also known as WW45 in mammals) [>>21<<]. However, the breakthrough for Hippo signalling were five publications in 2003 [22-26], demonstrating that the Ste20-like kinase Hippo is functioning upstream of Warts in tissue growth control. Significantly, one study even showed that
n3:mentions
n2:12202036
Subject Item
_:vb24745248
rdf:type
n3:Context
rdf:value
However, the breakthrough for Hippo signalling were five publications in 2003 [>>22<<-26], demonstrating that the Ste20-like kinase Hippo is functioning upstream of Warts in tissue growth control.
n3:mentions
n2:14561774 n2:14502294 n2:14502295 n2:12941273 n2:12941274
Subject Item
_:vb24745249
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Significantly, one study even showed that human MST2 can compensate for Hippo loss of function [>>26<<]. Subsequently, Lai et al. described Mats (also known as dMOB1) as a key regulator of Warts downstream of Hippo [27]. The same study also showed that hMOB1A can rescue the lethality associated with loss of Mats function in flies [27].
n3:mentions
n2:12941273
Subject Item
_:vb24745250
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rdf:value
Subsequently, Lai et al. described Mats (also known as dMOB1) as a key regulator of Warts downstream of Hippo [>>27<<]. The same study also showed that hMOB1A can rescue the lethality associated with loss of Mats function in flies [27]. Next, the Pan laboratory discovered first that proto-oncogenic Yorkie was functioning downstream of Hippo/Warts/Mats
n3:mentions
n2:15766530
Subject Item
_:vb24745251
rdf:type
n3:Context
rdf:value
The same study also showed that hMOB1A can rescue the lethality associated with loss of Mats function in flies [>>27<<]. Next, the Pan laboratory discovered first that proto-oncogenic Yorkie was functioning downstream of Hippo/Warts/Mats signalling [28], and then also showed the phospho-regulation of Yorkie by Warts [9]. These studies enabled then the Pan
n3:mentions
n2:15766530
Subject Item
_:vb24745252
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rdf:value
Next, the Pan laboratory discovered first that proto-oncogenic Yorkie was functioning downstream of Hippo/Warts/Mats signalling [>>28<<], and then also showed the phospho-regulation of Yorkie by Warts [9].
n3:mentions
n2:16096061
Subject Item
_:vb24745253
rdf:type
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rdf:value
Next, the Pan laboratory discovered first that proto-oncogenic Yorkie was functioning downstream of Hippo/Warts/Mats signalling [28], and then also showed the phospho-regulation of Yorkie by Warts [>>9<<]. These studies enabled then the Pan and Guan laboratories to establish how YAP (one of two human counterparts of Yorkie) was regulated by LATS1/2 phosphorylation in mammalian cells [9,29], which will be discussed in more detail later.
n3:mentions
n2:17889654
Subject Item
_:vb24745254
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These studies enabled then the Pan and Guan laboratories to establish how YAP (one of two human counterparts of Yorkie) was regulated by LATS1/2 phosphorylation in mammalian cells [>>9<<,29], which will be discussed in more detail later.
n3:mentions
n2:17889654
Subject Item
_:vb24745255
rdf:type
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rdf:value
These studies enabled then the Pan and Guan laboratories to establish how YAP (one of two human counterparts of Yorkie) was regulated by LATS1/2 phosphorylation in mammalian cells [9,>>29<<], which will be discussed in more detail later.
n3:mentions
n2:17974916
Subject Item
_:vb24745256
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Since these discoveries were published nearly a decade ago, the Drosophila community has continued to discover positive and negative regulators of Hippo signalling, which has been reviewed in detail recently [>>5<<]. Based on our personal interest in kinase signalling in the Hippo pathway, we will only briefly mention how additional kinases influence Hippo signalling, besides Hippo/MST and Warts/LATS kinases.
n3:mentions
n2:22174083
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_:vb24745257
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Recently, the kinases Tao (thousand and one) and HIPKs (homeodomain-interacting protein kinases) were shown to regulate Hippo activity [>>30<<,31] and Yki function [32,33], respectively.
n3:mentions
n2:22075147
Subject Item
_:vb24745258
rdf:type
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rdf:value
Recently, the kinases Tao (thousand and one) and HIPKs (homeodomain-interacting protein kinases) were shown to regulate Hippo activity [30,>>31<<] and Yki function [32,33], respectively.
n3:mentions
n2:22075148
Subject Item
_:vb24745259
rdf:type
n3:Context
rdf:value
Recently, the kinases Tao (thousand and one) and HIPKs (homeodomain-interacting protein kinases) were shown to regulate Hippo activity [30,31] and Yki function [>>32<<,33], respectively.
n3:mentions
n2:22840522
Subject Item
_:vb24745260
rdf:type
n3:Context
rdf:value
Recently, the kinases Tao (thousand and one) and HIPKs (homeodomain-interacting protein kinases) were shown to regulate Hippo activity [30,31] and Yki function [32,>>33<<], respectively.
n3:mentions
n2:22840515
Subject Item
_:vb24745261
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Both regulatory mechanisms appear to be conserved from flies to humans, since human TAO1 can also activate MST2 [>>31<<], and HIPK2 promotes YAP activity in human cells [33].
n3:mentions
n2:22075148
Subject Item
_:vb24745262
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Both regulatory mechanisms appear to be conserved from flies to humans, since human TAO1 can also activate MST2 [31], and HIPK2 promotes YAP activity in human cells [>>33<<]. In addition, Sik (salt-inducible kinase) has recently been shown to be required for Hippo signalling by phosphorylating Salvador in flies [34]. However, while human SIK2 can also inhibit YAP activity in HEK293 cells, the molecular
n3:mentions
n2:22840515
Subject Item
_:vb24745263
rdf:type
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rdf:value
In addition, Sik (salt-inducible kinase) has recently been shown to be required for Hippo signalling by phosphorylating Salvador in flies [>>34<<]. However, while human SIK2 can also inhibit YAP activity in HEK293 cells, the molecular mechanism must be different between flies and mammals, since the phosphorylation site in Drosophila Salvador is not conserved in mammals [34]. This
n3:mentions
n2:23263283
Subject Item
_:vb24745264
rdf:type
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rdf:value
However, while human SIK2 can also inhibit YAP activity in HEK293 cells, the molecular mechanism must be different between flies and mammals, since the phosphorylation site in Drosophila Salvador is not conserved in mammals [>>34<<]. This molecular difference was not so surprising, since the transcriptional outputs of Hippo signalling are known to differ significantly between flies and mammalian cells [35], and Bossuyt et al. recently reported fundamental
n3:mentions
n2:23263283
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_:vb24745265
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This molecular difference was not so surprising, since the transcriptional outputs of Hippo signalling are known to differ significantly between flies and mammalian cells [>>35<<], and Bossuyt et al. recently reported fundamental differences in the upstream regulatory mechanisms of Hippo signalling between Drosophila and mammals [36].
n3:mentions
n2:19584286
Subject Item
_:vb24745266
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Nevertheless, in spite of this growing complexity upstream of Hippo, Drosophila genetics still supports a linear Mats/Warts/Yorkie cascade downstream of Hippo [>>5<<]. In light of this canonical Hippo signalling (Hippo signals to Mats/Warts, which then regulates Yorkie), we review here the regulation and functions of mammalian LATS1/2 kinases.
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n2:22174083
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_:vb24745267
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In spite of the fast progress with deciphering Warts and LATS1/2 functions in flies and mammals, the mechanism of NDR1/2 regulation by phosphorylation currently must serve as a model for LATS1/2 regulation [>>4<<,37]. Therefore, we will first describe how mammalian NDR1/2 kinases are regulated, before highlighting our limited understanding of the regulatory mechanism of mammalian LATS1/2 (see Table  1).
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n2:16607288
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_:vb24745268
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In spite of the fast progress with deciphering Warts and LATS1/2 functions in flies and mammals, the mechanism of NDR1/2 regulation by phosphorylation currently must serve as a model for LATS1/2 regulation [4,>>37<<]. Therefore, we will first describe how mammalian NDR1/2 kinases are regulated, before highlighting our limited understanding of the regulatory mechanism of mammalian LATS1/2 (see Table  1).
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n2:22898666
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_:vb24745269
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As already mentioned, NDR1/2 kinases are members of a subgroup of AGC kinases containing two key regulatory phosphorylation sites [>>38<<], the Ser281/282 AS and Thr444/Thr442 HM, respectively [4].
n3:mentions
n2:10567341
Subject Item
_:vb24745270
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As already mentioned, NDR1/2 kinases are members of a subgroup of AGC kinases containing two key regulatory phosphorylation sites [38], the Ser281/282 AS and Thr444/Thr442 HM, respectively [>>4<<]. Binding of hMOB1A/B (the human counterparts of Mats) to the NTR domain of NDR1/2, which is highly conserved from yeast to humans and located N-terminally of the catalytic domain [4,39], increases the auto-phosphorylation activity of
n3:mentions
n2:16607288
Subject Item
_:vb24745271
rdf:type
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rdf:value
Binding of hMOB1A/B (the human counterparts of Mats) to the NTR domain of NDR1/2, which is highly conserved from yeast to humans and located N-terminally of the catalytic domain [>>4<<,39], increases the auto-phosphorylation activity of NDR1/2, thereby elevating Ser281/282 phosphorylation on NDR1/2 [40].
n3:mentions
n2:16607288
Subject Item
_:vb24745272
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Binding of hMOB1A/B (the human counterparts of Mats) to the NTR domain of NDR1/2, which is highly conserved from yeast to humans and located N-terminally of the catalytic domain [4,>>39<<], increases the auto-phosphorylation activity of NDR1/2, thereby elevating Ser281/282 phosphorylation on NDR1/2 [40].
n3:mentions
n2:21539912
Subject Item
_:vb24745273
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NTR domain of NDR1/2, which is highly conserved from yeast to humans and located N-terminally of the catalytic domain [4,39], increases the auto-phosphorylation activity of NDR1/2, thereby elevating Ser281/282 phosphorylation on NDR1/2 [>>40<<]. In contrast, HM phosphorylation of NDR1/2 is performed independently of NDR1/2 kinase activity [41].
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n2:15197186
Subject Item
_:vb24745274
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In contrast, HM phosphorylation of NDR1/2 is performed independently of NDR1/2 kinase activity [>>41<<]. MST1/2 (the human counterparts of Hippo) and MST3, another member of the MST kinase family [42], can phosphorylate NDR1/2 on Thr444/442 [43-46]. These S281 and Thr444 phosphorylations occur independently of Insulin/IGF-1/PDK1 signalling
n3:mentions
n2:12493777
Subject Item
_:vb24745275
rdf:type
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rdf:value
MST1/2 (the human counterparts of Hippo) and MST3, another member of the MST kinase family [>>42<<], can phosphorylate NDR1/2 on Thr444/442 [43-46].
n3:mentions
n2:18255267
Subject Item
_:vb24745276
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rdf:value
MST1/2 (the human counterparts of Hippo) and MST3, another member of the MST kinase family [42], can phosphorylate NDR1/2 on Thr444/442 [>>43<<-46]. These S281 and Thr444 phosphorylations occur independently of Insulin/IGF-1/PDK1 signalling [38], but are counteracted by PP2A (protein phosphatase type 2A), since recombinant PP2A dephosphorylates NDR1 in vitro[38] and treatment of
n3:mentions
n2:19062280 n2:21262772 n2:19836237 n2:16314523
Subject Item
_:vb24745277
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These S281 and Thr444 phosphorylations occur independently of Insulin/IGF-1/PDK1 signalling [>>38<<], but are counteracted by PP2A (protein phosphatase type 2A), since recombinant PP2A dephosphorylates NDR1 in vitro[38] and treatment of cells with okadaic acid (OA), a potent PP2A inhibitor, increases NDR1/2 phosphorylation levels
n3:mentions
n2:10567341
Subject Item
_:vb24745278
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These S281 and Thr444 phosphorylations occur independently of Insulin/IGF-1/PDK1 signalling [38], but are counteracted by PP2A (protein phosphatase type 2A), since recombinant PP2A dephosphorylates NDR1 in vitro[>>38<<] and treatment of cells with okadaic acid (OA), a potent PP2A inhibitor, increases NDR1/2 phosphorylation levels [38,41,47].
n3:mentions
n2:10567341
Subject Item
_:vb24745279
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[38], but are counteracted by PP2A (protein phosphatase type 2A), since recombinant PP2A dephosphorylates NDR1 in vitro[38] and treatment of cells with okadaic acid (OA), a potent PP2A inhibitor, increases NDR1/2 phosphorylation levels [>>38<<,41,47]. NDR1/2 versions carrying S281/282A, S281D, S281E, T444/442A, T444D or T444E mutations have dramatically reduced kinase activities upon OA treatment [38,47], suggesting that both regulatory sites on NDR1/2 are essential for NDR1/2
n3:mentions
n2:10567341
Subject Item
_:vb24745280
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but are counteracted by PP2A (protein phosphatase type 2A), since recombinant PP2A dephosphorylates NDR1 in vitro[38] and treatment of cells with okadaic acid (OA), a potent PP2A inhibitor, increases NDR1/2 phosphorylation levels [38,>>41<<,47]. NDR1/2 versions carrying S281/282A, S281D, S281E, T444/442A, T444D or T444E mutations have dramatically reduced kinase activities upon OA treatment [38,47], suggesting that both regulatory sites on NDR1/2 are essential for NDR1/2
n3:mentions
n2:12493777
Subject Item
_:vb24745281
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but are counteracted by PP2A (protein phosphatase type 2A), since recombinant PP2A dephosphorylates NDR1 in vitro[38] and treatment of cells with okadaic acid (OA), a potent PP2A inhibitor, increases NDR1/2 phosphorylation levels [38,41,>>47<<]. NDR1/2 versions carrying S281/282A, S281D, S281E, T444/442A, T444D or T444E mutations have dramatically reduced kinase activities upon OA treatment [38,47], suggesting that both regulatory sites on NDR1/2 are essential for NDR1/2 kinase
n3:mentions
n2:15037617
Subject Item
_:vb24745282
rdf:type
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rdf:value
NDR1/2 versions carrying S281/282A, S281D, S281E, T444/442A, T444D or T444E mutations have dramatically reduced kinase activities upon OA treatment [>>38<<,47], suggesting that both regulatory sites on NDR1/2 are essential for NDR1/2 kinase activity, but cannot be mimicked by standard phospho-mimetic alterations.
n3:mentions
n2:10567341
Subject Item
_:vb24745283
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rdf:value
NDR1/2 versions carrying S281/282A, S281D, S281E, T444/442A, T444D or T444E mutations have dramatically reduced kinase activities upon OA treatment [38,>>47<<], suggesting that both regulatory sites on NDR1/2 are essential for NDR1/2 kinase activity, but cannot be mimicked by standard phospho-mimetic alterations.
n3:mentions
n2:15037617
Subject Item
_:vb24745284
rdf:type
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Kinase(s)Upstream kinaseSite(s)Role of phosphorylationNDR1/2Auto-phosphorylationSer281/Ser282Essential for kinase activity [>>38<<,41,47]NDR1/2MST1/2Thr444/Thr442Crucial for kinase activity [38,41,43,44]NDR1/2MST3Thr442Crucial for kinase activity [45,46]LATS1Unknown mechanism#Ser909Essential for kinase activity [48,49]#LATS1MST1/2#Thr1079Essential for kinase activity
n3:mentions
n2:10567341
Subject Item
_:vb24745285
rdf:type
n3:Context
rdf:value
Kinase(s)Upstream kinaseSite(s)Role of phosphorylationNDR1/2Auto-phosphorylationSer281/Ser282Essential for kinase activity [38,>>41<<,47]NDR1/2MST1/2Thr444/Thr442Crucial for kinase activity [38,41,43,44]NDR1/2MST3Thr442Crucial for kinase activity [45,46]LATS1Unknown mechanism#Ser909Essential for kinase activity [48,49]#LATS1MST1/2#Thr1079Essential for kinase activity
n3:mentions
n2:12493777
Subject Item
_:vb24745286
rdf:type
n3:Context
rdf:value
Kinase(s)Upstream kinaseSite(s)Role of phosphorylationNDR1/2Auto-phosphorylationSer281/Ser282Essential for kinase activity [38,41,>>47<<]NDR1/2MST1/2Thr444/Thr442Crucial for kinase activity [38,41,43,44]NDR1/2MST3Thr442Crucial for kinase activity [45,46]LATS1Unknown mechanism#Ser909Essential for kinase activity [48,49]#LATS1MST1/2#Thr1079Essential for kinase activity
n3:mentions
n2:15037617
Subject Item
_:vb24745287
rdf:type
n3:Context
rdf:value
Kinase(s)Upstream kinaseSite(s)Role of phosphorylationNDR1/2Auto-phosphorylationSer281/Ser282Essential for kinase activity [38,41,47]NDR1/2MST1/2Thr444/Thr442Crucial for kinase activity [>>38<<,41,43,44]NDR1/2MST3Thr442Crucial for kinase activity [45,46]LATS1Unknown mechanism#Ser909Essential for kinase activity [48,49]#LATS1MST1/2#Thr1079Essential for kinase activity [48,49]#LATS1Cdk1/cyclin BThr490Might play a role in mitosis
n3:mentions
n2:10567341
Subject Item
_:vb24745288
rdf:type
n3:Context
rdf:value
Kinase(s)Upstream kinaseSite(s)Role of phosphorylationNDR1/2Auto-phosphorylationSer281/Ser282Essential for kinase activity [38,41,47]NDR1/2MST1/2Thr444/Thr442Crucial for kinase activity [38,>>41<<,43,44]NDR1/2MST3Thr442Crucial for kinase activity [45,46]LATS1Unknown mechanism#Ser909Essential for kinase activity [48,49]#LATS1MST1/2#Thr1079Essential for kinase activity [48,49]#LATS1Cdk1/cyclin BThr490Might play a role in mitosis [50]
n3:mentions
n2:12493777
Subject Item
_:vb24745289
rdf:type
n3:Context
rdf:value
Kinase(s)Upstream kinaseSite(s)Role of phosphorylationNDR1/2Auto-phosphorylationSer281/Ser282Essential for kinase activity [38,41,47]NDR1/2MST1/2Thr444/Thr442Crucial for kinase activity [38,41,>>43<<,44]NDR1/2MST3Thr442Crucial for kinase activity [45,46]LATS1Unknown mechanism#Ser909Essential for kinase activity [48,49]#LATS1MST1/2#Thr1079Essential for kinase activity [48,49]#LATS1Cdk1/cyclin BThr490Might play a role in mitosis [50]
n3:mentions
n2:19836237
Subject Item
_:vb24745290
rdf:type
n3:Context
rdf:value
Kinase(s)Upstream kinaseSite(s)Role of phosphorylationNDR1/2Auto-phosphorylationSer281/Ser282Essential for kinase activity [38,41,47]NDR1/2MST1/2Thr444/Thr442Crucial for kinase activity [38,41,43,>>44<<]NDR1/2MST3Thr442Crucial for kinase activity [45,46]LATS1Unknown mechanism#Ser909Essential for kinase activity [48,49]#LATS1MST1/2#Thr1079Essential for kinase activity [48,49]#LATS1Cdk1/cyclin BThr490Might play a role in mitosis [50]
n3:mentions
n2:19062280
Subject Item
_:vb24745291
rdf:type
n3:Context
rdf:value
kinaseSite(s)Role of phosphorylationNDR1/2Auto-phosphorylationSer281/Ser282Essential for kinase activity [38,41,47]NDR1/2MST1/2Thr444/Thr442Crucial for kinase activity [38,41,43,44]NDR1/2MST3Thr442Crucial for kinase activity [>>45<<,46]LATS1Unknown mechanism#Ser909Essential for kinase activity [48,49]#LATS1MST1/2#Thr1079Essential for kinase activity [48,49]#LATS1Cdk1/cyclin BThr490Might play a role in mitosis [50]  Ser613 LATS1NUAK1Ser464Controls LATS1 protein
n3:mentions
n2:21262772
Subject Item
_:vb24745292
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n3:Context
rdf:value
kinaseSite(s)Role of phosphorylationNDR1/2Auto-phosphorylationSer281/Ser282Essential for kinase activity [38,41,47]NDR1/2MST1/2Thr444/Thr442Crucial for kinase activity [38,41,43,44]NDR1/2MST3Thr442Crucial for kinase activity [45,>>46<<]LATS1Unknown mechanism#Ser909Essential for kinase activity [48,49]#LATS1MST1/2#Thr1079Essential for kinase activity [48,49]#LATS1Cdk1/cyclin BThr490Might play a role in mitosis [50]  Ser613 LATS1NUAK1Ser464Controls LATS1 protein stability
n3:mentions
n2:16314523
Subject Item
_:vb24745293
rdf:type
n3:Context
rdf:value
for kinase activity [38,41,47]NDR1/2MST1/2Thr444/Thr442Crucial for kinase activity [38,41,43,44]NDR1/2MST3Thr442Crucial for kinase activity [45,46]LATS1Unknown mechanism#Ser909Essential for kinase activity [>>48<<,49]#LATS1MST1/2#Thr1079Essential for kinase activity [48,49]#LATS1Cdk1/cyclin BThr490Might play a role in mitosis [50]  Ser613 LATS1NUAK1Ser464Controls LATS1 protein stability [51]LATS2Aurora ASer83/Ser380plays a role in mitosis
n3:mentions
n2:15688006
Subject Item
_:vb24745294
rdf:type
n3:Context
rdf:value
for kinase activity [38,41,47]NDR1/2MST1/2Thr444/Thr442Crucial for kinase activity [38,41,43,44]NDR1/2MST3Thr442Crucial for kinase activity [45,46]LATS1Unknown mechanism#Ser909Essential for kinase activity [48,>>49<<]#LATS1MST1/2#Thr1079Essential for kinase activity [48,49]#LATS1Cdk1/cyclin BThr490Might play a role in mitosis [50]  Ser613 LATS1NUAK1Ser464Controls LATS1 protein stability [51]LATS2Aurora ASer83/Ser380plays a role in mitosis
n3:mentions
n2:16674920
Subject Item
_:vb24745295
rdf:type
n3:Context
rdf:value
for kinase activity [38,41,43,44]NDR1/2MST3Thr442Crucial for kinase activity [45,46]LATS1Unknown mechanism#Ser909Essential for kinase activity [48,49]#LATS1MST1/2#Thr1079Essential for kinase activity [>>48<<,49]#LATS1Cdk1/cyclin BThr490Might play a role in mitosis [50]  Ser613 LATS1NUAK1Ser464Controls LATS1 protein stability [51]LATS2Aurora ASer83/Ser380plays a role in mitosis [52-54]LATS2CHK1/2Ser408Plays a role in DNA damage signalling
n3:mentions
n2:15688006
Subject Item
_:vb24745296
rdf:type
n3:Context
rdf:value
for kinase activity [38,41,43,44]NDR1/2MST3Thr442Crucial for kinase activity [45,46]LATS1Unknown mechanism#Ser909Essential for kinase activity [48,49]#LATS1MST1/2#Thr1079Essential for kinase activity [48,>>49<<]#LATS1Cdk1/cyclin BThr490Might play a role in mitosis [50]  Ser613 LATS1NUAK1Ser464Controls LATS1 protein stability [51]LATS2Aurora ASer83/Ser380plays a role in mitosis [52-54]LATS2CHK1/2Ser408Plays a role in DNA damage signalling
n3:mentions
n2:16674920
Subject Item
_:vb24745297
rdf:type
n3:Context
rdf:value
for kinase activity [45,46]LATS1Unknown mechanism#Ser909Essential for kinase activity [48,49]#LATS1MST1/2#Thr1079Essential for kinase activity [48,49]#LATS1Cdk1/cyclin BThr490Might play a role in mitosis [>>50<<]  Ser613 LATS1NUAK1Ser464Controls LATS1 protein stability [51]LATS2Aurora ASer83/Ser380plays a role in mitosis [52-54]LATS2CHK1/2Ser408Plays a role in DNA damage signalling [55]LATS2PKASer172Regulate LATS2 activity towards YAP [56]
n3:mentions
n2:12372621
Subject Item
_:vb24745298
rdf:type
n3:Context
rdf:value
mechanism#Ser909Essential for kinase activity [48,49]#LATS1MST1/2#Thr1079Essential for kinase activity [48,49]#LATS1Cdk1/cyclin BThr490Might play a role in mitosis [50]  Ser613 LATS1NUAK1Ser464Controls LATS1 protein stability [>>51<<]LATS2Aurora ASer83/Ser380plays a role in mitosis [52-54]LATS2CHK1/2Ser408Plays a role in DNA damage signalling [55]LATS2PKASer172Regulate LATS2 activity towards YAP [56]  Ser380   Ser592   Ser598
n3:mentions
n2:19927127
Subject Item
_:vb24745299
rdf:type
n3:Context
rdf:value
[48,49]#LATS1MST1/2#Thr1079Essential for kinase activity [48,49]#LATS1Cdk1/cyclin BThr490Might play a role in mitosis [50]  Ser613 LATS1NUAK1Ser464Controls LATS1 protein stability [51]LATS2Aurora ASer83/Ser380plays a role in mitosis [>>52<<-54]LATS2CHK1/2Ser408Plays a role in DNA damage signalling [55]LATS2PKASer172Regulate LATS2 activity towards YAP [56]  Ser380   Ser592   Ser598
n3:mentions
n2:15147269 n2:22904328 n2:21822051
Subject Item
_:vb24745300
rdf:type
n3:Context
rdf:value
BThr490Might play a role in mitosis [50]  Ser613 LATS1NUAK1Ser464Controls LATS1 protein stability [51]LATS2Aurora ASer83/Ser380plays a role in mitosis [52-54]LATS2CHK1/2Ser408Plays a role in DNA damage signalling [>>55<<]LATS2PKASer172Regulate LATS2 activity towards YAP [56]  Ser380   Ser592   Ser598
n3:mentions
n2:21118956
Subject Item
_:vb24745301
rdf:type
n3:Context
rdf:value
[50]  Ser613 LATS1NUAK1Ser464Controls LATS1 protein stability [51]LATS2Aurora ASer83/Ser380plays a role in mitosis [52-54]LATS2CHK1/2Ser408Plays a role in DNA damage signalling [55]LATS2PKASer172Regulate LATS2 activity towards YAP [>>56<<]  Ser380   Ser592   Ser598
n3:mentions
n2:23644383
Subject Item
_:vb24745302
rdf:type
n3:Context
rdf:value
Therefore, we can only predict here that MST1/2 mainly phosphorylate Thr1079/Thr1041 on LATS1/2, based on the reported conserved regulatory mechanism between MST1/2 and NDR1/2 in human cells [>>43<<,44] and Hippo and Warts/Trc in fly cells [57].
n3:mentions
n2:19836237
Subject Item
_:vb24745303
rdf:type
n3:Context
rdf:value
Therefore, we can only predict here that MST1/2 mainly phosphorylate Thr1079/Thr1041 on LATS1/2, based on the reported conserved regulatory mechanism between MST1/2 and NDR1/2 in human cells [43,>>44<<] and Hippo and Warts/Trc in fly cells [57].
n3:mentions
n2:19062280
Subject Item
_:vb24745304
rdf:type
n3:Context
rdf:value
Therefore, we can only predict here that MST1/2 mainly phosphorylate Thr1079/Thr1041 on LATS1/2, based on the reported conserved regulatory mechanism between MST1/2 and NDR1/2 in human cells [43,44] and Hippo and Warts/Trc in fly cells [>>57<<].
n3:mentions
n2:16906135
Subject Item
_:vb24745305
rdf:type
n3:Context
rdf:value
MST1/2 kinases also phosphorylate hMOB1A/B on Thr12 and Thr35, thereby increasing the affinity of hMOB1A/B towards NDR1/2 [>>58<<]. Moreover, NDR1 deficient in hMOB1A/B binding cannot be phosphorylated by MST1 on Thr444 in S-phase arrested cells [43], suggesting that hMOB1A/B binding to NDR1/2 is required for the phosphorylation of both regulatory sites in human
n3:mentions
n2:18328708
Subject Item
_:vb24745306
rdf:type
n3:Context
rdf:value
Moreover, NDR1 deficient in hMOB1A/B binding cannot be phosphorylated by MST1 on Thr444 in S-phase arrested cells [>>43<<], suggesting that hMOB1A/B binding to NDR1/2 is required for the phosphorylation of both regulatory sites in human cells [39].
n3:mentions
n2:19836237
Subject Item
_:vb24745307
rdf:type
n3:Context
rdf:value
NDR1 deficient in hMOB1A/B binding cannot be phosphorylated by MST1 on Thr444 in S-phase arrested cells [43], suggesting that hMOB1A/B binding to NDR1/2 is required for the phosphorylation of both regulatory sites in human cells [>>39<<]. NDR1/2 are also regulated by binding to hMOB2, which is a level of regulation that does not exist with LATS1/2, since hMOB2 does not bind to LATS1/2 [39].
n3:mentions
n2:21539912
Subject Item
_:vb24745308
rdf:type
n3:Context
rdf:value
NDR1/2 are also regulated by binding to hMOB2, which is a level of regulation that does not exist with LATS1/2, since hMOB2 does not bind to LATS1/2 [>>39<<]. hMOB2 competes with hMOB1A/B for binding to the NTR of NDR1/2, where hMOB2 binding appears to be inhibitory, while hMOB1A/B binding is activating [59]. In addition, MICAL-1 (molecules interacting with CasL 1) competes with MST1 for
n3:mentions
n2:21539912
Subject Item
_:vb24745309
rdf:type
n3:Context
rdf:value
hMOB2 competes with hMOB1A/B for binding to the NTR of NDR1/2, where hMOB2 binding appears to be inhibitory, while hMOB1A/B binding is activating [>>59<<]. In addition, MICAL-1 (molecules interacting with CasL 1) competes with MST1 for binding to the HM of NDR1/2, thereby antagonizing MST1-induced NDR activation [60]. The TORC2 (target of rapamycin complex 2) can also interact with NDR1 in
n3:mentions
n2:20624913
Subject Item
_:vb24745310
rdf:type
n3:Context
rdf:value
In addition, MICAL-1 (molecules interacting with CasL 1) competes with MST1 for binding to the HM of NDR1/2, thereby antagonizing MST1-induced NDR activation [>>60<<]. The TORC2 (target of rapamycin complex 2) can also interact with NDR1 in HeLa cells [61], however, whether this interaction influences NDR1/2 activity is yet to be determined. The subcellular localisation of NDR1/2 seems to provide a
n3:mentions
n2:21730291
Subject Item
_:vb24745311
rdf:type
n3:Context
rdf:value
The TORC2 (target of rapamycin complex 2) can also interact with NDR1 in HeLa cells [>>61<<], however, whether this interaction influences NDR1/2 activity is yet to be determined.
n3:mentions
n2:19875983
Subject Item
_:vb24745312
rdf:type
n3:Context
rdf:value
The subcellular localisation of NDR1/2 seems to provide a further level of regulation, since membrane targeting of NDR1/2 is sufficient to trigger NDR1/2 phosphorylation and activation [>>62<<].
n3:mentions
n2:16135814
Subject Item
_:vb24745313
rdf:type
n3:Context
rdf:value
LATS1/2 also contain the two conserved key regulatory phosphorylation sites of AGC kinases, the Ser909/872 AS and Thr1079/Thr1041 HM, respectively [>>4<<]. Both sites are phosphorylated in cells and are essential for LATS1 kinase activity, since LATS1 S909A or T1079A mutants are inactive [48,49].
n3:mentions
n2:16607288
Subject Item
_:vb24745314
rdf:type
n3:Context
rdf:value
Both sites are phosphorylated in cells and are essential for LATS1 kinase activity, since LATS1 S909A or T1079A mutants are inactive [>>48<<,49]. Like with NDR1/2, LATS1 activity is counteracted by PP2A-mediated dephosphorylation of the AS and HM, since OA treatment of mammalian cells results in dramatically increased AS/HM phosphorylation and kinase activity of LATS1 [49,58].
n3:mentions
n2:15688006
Subject Item
_:vb24745315
rdf:type
n3:Context
rdf:value
Both sites are phosphorylated in cells and are essential for LATS1 kinase activity, since LATS1 S909A or T1079A mutants are inactive [48,>>49<<]. Like with NDR1/2, LATS1 activity is counteracted by PP2A-mediated dephosphorylation of the AS and HM, since OA treatment of mammalian cells results in dramatically increased AS/HM phosphorylation and kinase activity of LATS1 [49,58].
n3:mentions
n2:16674920
Subject Item
_:vb24745316
rdf:type
n3:Context
rdf:value
Like with NDR1/2, LATS1 activity is counteracted by PP2A-mediated dephosphorylation of the AS and HM, since OA treatment of mammalian cells results in dramatically increased AS/HM phosphorylation and kinase activity of LATS1 [>>49<<,58]. hMOB1A/B also bind to the conserved NTR domain of LATS1/2 [49,63,64], but whether this affects the auto-phosphorylation activity of LATS1/2 is still undefined. Moreover, LATS1 deficient in hMOB1A/B binding is inactive and does not
n3:mentions
n2:16674920
Subject Item
_:vb24745317
rdf:type
n3:Context
rdf:value
Like with NDR1/2, LATS1 activity is counteracted by PP2A-mediated dephosphorylation of the AS and HM, since OA treatment of mammalian cells results in dramatically increased AS/HM phosphorylation and kinase activity of LATS1 [49,>>58<<]. hMOB1A/B also bind to the conserved NTR domain of LATS1/2 [49,63,64], but whether this affects the auto-phosphorylation activity of LATS1/2 is still undefined.
n3:mentions
n2:18328708
Subject Item
_:vb24745318
rdf:type
n3:Context
rdf:value
hMOB1A/B also bind to the conserved NTR domain of LATS1/2 [>>49<<,63,64], but whether this affects the auto-phosphorylation activity of LATS1/2 is still undefined.
n3:mentions
n2:16674920
Subject Item
_:vb24745319
rdf:type
n3:Context
rdf:value
hMOB1A/B also bind to the conserved NTR domain of LATS1/2 [49,>>63<<,64], but whether this affects the auto-phosphorylation activity of LATS1/2 is still undefined.
n3:mentions
n2:16061636
Subject Item
_:vb24745320
rdf:type
n3:Context
rdf:value
hMOB1A/B also bind to the conserved NTR domain of LATS1/2 [49,63,>>64<<], but whether this affects the auto-phosphorylation activity of LATS1/2 is still undefined.
n3:mentions
n2:17478426
Subject Item
_:vb24745321
rdf:type
n3:Context
rdf:value
Moreover, LATS1 deficient in hMOB1A/B binding is inactive and does not phosphorylate YAP [>>49<<,56], and in MOB1A/B double knock out (DKO) keratinocytes LATS1/2 phosphorylation on the HM is decreased, while MST1/2 appears unaffected [7], indicating that LATS1/hMOB1 complex formation is required for LATS1 phosphorylation and kinase
n3:mentions
n2:16674920
Subject Item
_:vb24745322
rdf:type
n3:Context
rdf:value
Moreover, LATS1 deficient in hMOB1A/B binding is inactive and does not phosphorylate YAP [49,>>56<<], and in MOB1A/B double knock out (DKO) keratinocytes LATS1/2 phosphorylation on the HM is decreased, while MST1/2 appears unaffected [7], indicating that LATS1/hMOB1 complex formation is required for LATS1 phosphorylation and kinase
n3:mentions
n2:23644383
Subject Item
_:vb24745323
rdf:type
n3:Context
rdf:value
Moreover, LATS1 deficient in hMOB1A/B binding is inactive and does not phosphorylate YAP [49,56], and in MOB1A/B double knock out (DKO) keratinocytes LATS1/2 phosphorylation on the HM is decreased, while MST1/2 appears unaffected [>>7<<], indicating that LATS1/hMOB1 complex formation is required for LATS1 phosphorylation and kinase activity.
n3:mentions
n2:23143302
Subject Item
_:vb24745324
rdf:type
n3:Context
rdf:value
Phosphorylation of hMOB1A/B on Thr12 and Thr35 by MST1/2 further plays a role in regulating LATS1/hMOB1 complex formation, since T12A and T35A mutants of hMOB1A/B did not bind to LATS1 [>>58<<]. MST1/2 also phosphorylate LATS1/2 [48], but whether MST1/2 phosphorylate only the HM of LATS1/2 is currently unknown. However, in MST1/2-deficient liver cells, LATS1 S909 and T1079 phosphorylation was not impaired, although MOB1A/B
n3:mentions
n2:18328708
Subject Item
_:vb24745325
rdf:type
n3:Context
rdf:value
MST1/2 also phosphorylate LATS1/2 [>>48<<], but whether MST1/2 phosphorylate only the HM of LATS1/2 is currently unknown.
n3:mentions
n2:15688006
Subject Item
_:vb24745326
rdf:type
n3:Context
rdf:value
However, in MST1/2-deficient liver cells, LATS1 S909 and T1079 phosphorylation was not impaired, although MOB1A/B phosphorylation on Thr12/35 was absent [>>6<<]. In mouse thymocytes MST1/2 phosphorylation of MOB1A/B also functions independent of LATS1/2 [66], strongly suggesting that LATS/MOB1 complex formation is not always essential for LATS phosphorylation/activation. The subcellular
n3:mentions
n2:19878874
Subject Item
_:vb24745327
rdf:type
n3:Context
rdf:value
In mouse thymocytes MST1/2 phosphorylation of MOB1A/B also functions independent of LATS1/2 [>>66<<], strongly suggesting that LATS/MOB1 complex formation is not always essential for LATS phosphorylation/activation.
n3:mentions
n2:22412158
Subject Item
_:vb24745328
rdf:type
n3:Context
rdf:value
The subcellular localisation of LATS1 is also likely to play a role in the regulation of LATS1 activity, since membrane targeting of LATS1 increased LATS1 activity [>>49<<]. Significantly, membrane targeting of Warts together with Mats was sufficient to reduce tissue growth in Drosophila[67], suggesting that the membrane bound pool of LATS1/2 might be physiologically relevant as well. In contrast, in mouse
n3:mentions
n2:16674920
Subject Item
_:vb24745329
rdf:type
n3:Context
rdf:value
Significantly, membrane targeting of Warts together with Mats was sufficient to reduce tissue growth in Drosophila[>>67<<], suggesting that the membrane bound pool of LATS1/2 might be physiologically relevant as well.
n3:mentions
n2:19913529
Subject Item
_:vb24745330
rdf:type
n3:Context
rdf:value
In contrast, in mouse keratinocytes LATS1/2 seem to be activated by MST1/2 in the nucleus [>>68<<]. In summary, current evidence suggests that LATS1/2 are likely to be regulated in a similar fashion as already reported for NDR1/2 [4]. AS and HM phosphorylations of LATS1/2 are essential for kinase activation, but whether these specific
n3:mentions
n2:18369314
Subject Item
_:vb24745331
rdf:type
n3:Context
rdf:value
In summary, current evidence suggests that LATS1/2 are likely to be regulated in a similar fashion as already reported for NDR1/2 [>>4<<]. AS and HM phosphorylations of LATS1/2 are essential for kinase activation, but whether these specific phosphorylation events are regulated through hMOB1A/B-mediated auto-phosphorylation on Ser909/872 on one hand, and by MST1/2
n3:mentions
n2:16607288
Subject Item
_:vb24745332
rdf:type
n3:Context
rdf:value
LATS1 is phosphorylated on Thr490/Ser613 by Cdk1/cyclin B, which could play a role in mitosis [>>50<<]. LATS2 is phosphorylated on Ser83/380 and Ser408 by Aurora A and CHK1/2, respectively, which seems to play a role in mitotic progression and DNA damage signalling [52-55]. Phosphorylation of LATS2 by PKA on Ser172/380/592/598 further
n3:mentions
n2:12372621
Subject Item
_:vb24745333
rdf:type
n3:Context
rdf:value
LATS2 is phosphorylated on Ser83/380 and Ser408 by Aurora A and CHK1/2, respectively, which seems to play a role in mitotic progression and DNA damage signalling [>>52<<-55]. Phosphorylation of LATS2 by PKA on Ser172/380/592/598 further stimulates LATS2 activity towards YAP [56]. Loss of PKA phosphorylation on LATS2 neither affects the LATS2/hMOB1 interaction, nor alters the AS and HM phosphorylations of
n3:mentions
n2:15147269 n2:22904328 n2:21822051 n2:21118956
Subject Item
_:vb24745334
rdf:type
n3:Context
rdf:value
Phosphorylation of LATS2 by PKA on Ser172/380/592/598 further stimulates LATS2 activity towards YAP [>>56<<]. Loss of PKA phosphorylation on LATS2 neither affects the LATS2/hMOB1 interaction, nor alters the AS and HM phosphorylations of LATS2, although the LATS2 kinase activity towards YAP is impaired [56]. This suggests that other activating
n3:mentions
n2:23644383
Subject Item
_:vb24745335
rdf:type
n3:Context
rdf:value
Loss of PKA phosphorylation on LATS2 neither affects the LATS2/hMOB1 interaction, nor alters the AS and HM phosphorylations of LATS2, although the LATS2 kinase activity towards YAP is impaired [>>56<<]. This suggests that other activating factors such as changes in subcellular localisation and structural conformation might be dependent on PKA phosphorylation of LATS1/2. Moreover, phosphorylation of LATS1 by NUAK-1 (novel (nua) kinase
n3:mentions
n2:23644383
Subject Item
_:vb24745336
rdf:type
n3:Context
rdf:value
Moreover, phosphorylation of LATS1 by NUAK-1 (novel (nua) kinase family 1) on Ser464 controls LATS1 protein stability [>>51<<]. However, whether this phosphorylation event regulates the ubiquitin-mediated degradation of LATS1 by the Itch and WWP1 E3 ligases [69-71] is currently unknown. Furthermore, LATS1/2 protein stability can be controlled by HSP90 [72] and
n3:mentions
n2:19927127
Subject Item
_:vb24745337
rdf:type
n3:Context
rdf:value
However, whether this phosphorylation event regulates the ubiquitin-mediated degradation of LATS1 by the Itch and WWP1 E3 ligases [>>69<<-71] is currently unknown.
n3:mentions
n2:23573293 n2:21383157 n2:21212414
Subject Item
_:vb24745338
rdf:type
n3:Context
rdf:value
Furthermore, LATS1/2 protein stability can be controlled by HSP90 [>>72<<] and ROS-PKC delta signalling [73].
n3:mentions
n2:20841485
Subject Item
_:vb24745339
rdf:type
n3:Context
rdf:value
Furthermore, LATS1/2 protein stability can be controlled by HSP90 [72] and ROS-PKC delta signalling [>>73<<]. Significantly, LATS2 expression levels are further regulated on the transcriptional level by the transcription factors FOXP3 and p53 [74,75]. LATS2 expression is also regulated by TTP (tristetraprolin), an ARE (AU-rich element) binding
n3:mentions
n2:17028578
Subject Item
_:vb24745340
rdf:type
n3:Context
rdf:value
Significantly, LATS2 expression levels are further regulated on the transcriptional level by the transcription factors FOXP3 and p53 [>>74<<,75]. LATS2 expression is also regulated by TTP (tristetraprolin), an ARE (AU-rich element) binding protein that promotes the degradation of ARE-containing transcripts [76], and at least six different microRNAs have been shown to
n3:mentions
n2:21278236
Subject Item
_:vb24745341
rdf:type
n3:Context
rdf:value
Significantly, LATS2 expression levels are further regulated on the transcriptional level by the transcription factors FOXP3 and p53 [74,>>75<<]. LATS2 expression is also regulated by TTP (tristetraprolin), an ARE (AU-rich element) binding protein that promotes the degradation of ARE-containing transcripts [76], and at least six different microRNAs have been shown to negatively
n3:mentions
n2:17015431
Subject Item
_:vb24745342
rdf:type
n3:Context
rdf:value
LATS2 expression is also regulated by TTP (tristetraprolin), an ARE (AU-rich element) binding protein that promotes the degradation of ARE-containing transcripts [>>76<<], and at least six different microRNAs have been shown to negatively regulate LATS2 expression [77-81].
n3:mentions
n2:20335167
Subject Item
_:vb24745343
rdf:type
n3:Context
rdf:value
regulated by TTP (tristetraprolin), an ARE (AU-rich element) binding protein that promotes the degradation of ARE-containing transcripts [76], and at least six different microRNAs have been shown to negatively regulate LATS2 expression [>>77<<-81].
n3:mentions
n2:20237410 n2:22286172 n2:23111389 n2:16564011
Subject Item
_:vb24745344
rdf:type
n3:Context
rdf:value
Besides the regulatory protein-protein interaction (PPI) between hMOB1A/B and LATS1/2 kinases [>>39<<], mammalian Hippo signalling is regulated by additional PPIs which directly or indirectly affect LATS/NDR activity [2,82].
n3:mentions
n2:21539912
Subject Item
_:vb24745345
rdf:type
n3:Context
rdf:value
Besides the regulatory protein-protein interaction (PPI) between hMOB1A/B and LATS1/2 kinases [39], mammalian Hippo signalling is regulated by additional PPIs which directly or indirectly affect LATS/NDR activity [>>2<<,82]. Due to the emphasis of this review, we focus on discussing reported direct PPIs of LATS1/2 with scaffolding/adaptor proteins.
n3:mentions
n2:23431053
Subject Item
_:vb24745346
rdf:type
n3:Context
rdf:value
Besides the regulatory protein-protein interaction (PPI) between hMOB1A/B and LATS1/2 kinases [39], mammalian Hippo signalling is regulated by additional PPIs which directly or indirectly affect LATS/NDR activity [2,>>82<<]. Due to the emphasis of this review, we focus on discussing reported direct PPIs of LATS1/2 with scaffolding/adaptor proteins.
n3:mentions
n2:22260677
Subject Item
_:vb24745347
rdf:type
n3:Context
rdf:value
Scribble has been shown to link MST/LATS/YAP/TAZ complexes, thereby facilitating LATS phosphorylation of YAP/TAZ [>>83<<]. The Angiomotin proteins AMOT, AMOTL1 and AMOTL2 can bind to and activate LATS1/2 kinases [84], in addition to forming AMOT/YAP and AMOT/TAZ complexes [85-87]. The mammalian Ajuba LIM proteins, Ajuba, LIMD1 and WTIP, can interact with
n3:mentions
n2:22078877
Subject Item
_:vb24745348
rdf:type
n3:Context
rdf:value
The Angiomotin proteins AMOT, AMOTL1 and AMOTL2 can bind to and activate LATS1/2 kinases [>>84<<], in addition to forming AMOT/YAP and AMOT/TAZ complexes [85-87].
n3:mentions
n2:21832154
Subject Item
_:vb24745349
rdf:type
n3:Context
rdf:value
The Angiomotin proteins AMOT, AMOTL1 and AMOTL2 can bind to and activate LATS1/2 kinases [84], in addition to forming AMOT/YAP and AMOT/TAZ complexes [>>85<<-87]. The mammalian Ajuba LIM proteins, Ajuba, LIMD1 and WTIP, can interact with LATS1/2, which seems to decrease LATS1/2 phosphorylation of YAP [88,89], suggesting that Ajuba LIM proteins are negative regulators of LATS1/2 activity. Kibra
n3:mentions
n2:21205866 n2:21224387 n2:21187284
Subject Item
_:vb24745350
rdf:type
n3:Context
rdf:value
The mammalian Ajuba LIM proteins, Ajuba, LIMD1 and WTIP, can interact with LATS1/2, which seems to decrease LATS1/2 phosphorylation of YAP [>>88<<,89], suggesting that Ajuba LIM proteins are negative regulators of LATS1/2 activity.
n3:mentions
n2:20303269
Subject Item
_:vb24745351
rdf:type
n3:Context
rdf:value
The mammalian Ajuba LIM proteins, Ajuba, LIMD1 and WTIP, can interact with LATS1/2, which seems to decrease LATS1/2 phosphorylation of YAP [88,>>89<<], suggesting that Ajuba LIM proteins are negative regulators of LATS1/2 activity.
n3:mentions
n2:23484853
Subject Item
_:vb24745352
rdf:type
n3:Context
rdf:value
Kibra overexpression appears to stimulate Thr1079 phosphorylation by binding to LATS1 [>>90<<], while depletion of Kibra caused a decrease of LATS1 phosphorylation on Ser909 [91].
n3:mentions
n2:21233212
Subject Item
_:vb24745353
rdf:type
n3:Context
rdf:value
Kibra overexpression appears to stimulate Thr1079 phosphorylation by binding to LATS1 [90], while depletion of Kibra caused a decrease of LATS1 phosphorylation on Ser909 [>>91<<]. However, the involvement of endogenous MST1/2 and hMOB1A/B in these regulatory PPIs are yet unknown, therefore it is currently not possible to describe in more detail how these scaffolding/adaptor proteins regulate LATS1/2.
n3:mentions
n2:22614006
Subject Item
_:vb24745354
rdf:type
n3:Context
rdf:value
LATS1/2 phosphorylate YAP on Ser61/109/127/164/381 [>>29<<,92] and TAZ on Ser66/89/117/311 [93], which led to the definition of a HXRXXS/T consensus motif for LATS1/2 kinases.
n3:mentions
n2:17974916
Subject Item
_:vb24745355
rdf:type
n3:Context
rdf:value
LATS1/2 phosphorylate YAP on Ser61/109/127/164/381 [29,>>92<<] and TAZ on Ser66/89/117/311 [93], which led to the definition of a HXRXXS/T consensus motif for LATS1/2 kinases.
n3:mentions
n2:18158288
Subject Item
_:vb24745356
rdf:type
n3:Context
rdf:value
LATS1/2 phosphorylate YAP on Ser61/109/127/164/381 [29,92] and TAZ on Ser66/89/117/311 [>>93<<], which led to the definition of a HXRXXS/T consensus motif for LATS1/2 kinases.
n3:mentions
n2:18227151
Subject Item
_:vb24745357
rdf:type
n3:Context
rdf:value
YAP phosphorylation on Ser127 increases 14-3-3 binding to YAP, which results in the cytoplasmic retention of inactive Ser127-phosphorylated YAP [>>9<<,29,94]. In contrast, phosphorylation of YAP on Ser381 regulates YAP protein stability [95]. TAZ phosphorylation on Ser89 and Ser311 follows a very similar principle, with Ser89 phosphorylation facilitating 14-3-3 binding and cytoplasmic
n3:mentions
n2:17889654
Subject Item
_:vb24745358
rdf:type
n3:Context
rdf:value
YAP phosphorylation on Ser127 increases 14-3-3 binding to YAP, which results in the cytoplasmic retention of inactive Ser127-phosphorylated YAP [9,>>29<<,94]. In contrast, phosphorylation of YAP on Ser381 regulates YAP protein stability [95]. TAZ phosphorylation on Ser89 and Ser311 follows a very similar principle, with Ser89 phosphorylation facilitating 14-3-3 binding and cytoplasmic
n3:mentions
n2:17974916
Subject Item
_:vb24745359
rdf:type
n3:Context
rdf:value
YAP phosphorylation on Ser127 increases 14-3-3 binding to YAP, which results in the cytoplasmic retention of inactive Ser127-phosphorylated YAP [9,29,>>94<<]. In contrast, phosphorylation of YAP on Ser381 regulates YAP protein stability [95]. TAZ phosphorylation on Ser89 and Ser311 follows a very similar principle, with Ser89 phosphorylation facilitating 14-3-3 binding and cytoplasmic
n3:mentions
n2:18640976
Subject Item
_:vb24745360
rdf:type
n3:Context
rdf:value
In contrast, phosphorylation of YAP on Ser381 regulates YAP protein stability [>>95<<]. TAZ phosphorylation on Ser89 and Ser311 follows a very similar principle, with Ser89 phosphorylation facilitating 14-3-3 binding and cytoplasmic retention of TAZ [93,96,97] and Ser311 phosphorylation regulating TAZ protein stability
n3:mentions
n2:20048001
Subject Item
_:vb24745361
rdf:type
n3:Context
rdf:value
TAZ phosphorylation on Ser89 and Ser311 follows a very similar principle, with Ser89 phosphorylation facilitating 14-3-3 binding and cytoplasmic retention of TAZ [>>93<<,96,97] and Ser311 phosphorylation regulating TAZ protein stability [98].
n3:mentions
n2:18227151
Subject Item
_:vb24745362
rdf:type
n3:Context
rdf:value
TAZ phosphorylation on Ser89 and Ser311 follows a very similar principle, with Ser89 phosphorylation facilitating 14-3-3 binding and cytoplasmic retention of TAZ [93,>>96<<,97] and Ser311 phosphorylation regulating TAZ protein stability [98].
n3:mentions
n2:11118213
Subject Item
_:vb24745363
rdf:type
n3:Context
rdf:value
TAZ phosphorylation on Ser89 and Ser311 follows a very similar principle, with Ser89 phosphorylation facilitating 14-3-3 binding and cytoplasmic retention of TAZ [93,96,>>97<<] and Ser311 phosphorylation regulating TAZ protein stability [98].
n3:mentions
n2:18568018
Subject Item
_:vb24745364
rdf:type
n3:Context
rdf:value
TAZ phosphorylation on Ser89 and Ser311 follows a very similar principle, with Ser89 phosphorylation facilitating 14-3-3 binding and cytoplasmic retention of TAZ [93,96,97] and Ser311 phosphorylation regulating TAZ protein stability [>>98<<]. In summary, LATS1/2-mediated phosphorylation of YAP/TAZ trigger the inhibition of YAP/TAZ on at least two levels, namely (1) cytoplasmic retention/nuclear exclusion of YAP/TAZ, and (2) decreasing protein stability of YAP/TAZ [3].
n3:mentions
n2:20858893
Subject Item
_:vb24745365
rdf:type
n3:Context
rdf:value
In summary, LATS1/2-mediated phosphorylation of YAP/TAZ trigger the inhibition of YAP/TAZ on at least two levels, namely (1) cytoplasmic retention/nuclear exclusion of YAP/TAZ, and (2) decreasing protein stability of YAP/TAZ [>>3<<].
n3:mentions
n2:22659496
Subject Item
_:vb24745366
rdf:type
n3:Context
rdf:value
Targeting motifKinase(s)Target siteHVRGDpSLATS1/2YAP on Ser61 [>>29<<,92]HSRQApSLATS1/2YAP on Ser109 [29,92]HVRAHpSLATS1/2YAP on Ser127 [29,92]HLRQSpSLATS1/2YAP on Ser164 [29,92]HSRDEpSLATS1/2YAP on Ser381# [29,92]HSRQSpSLATS1/2TAZ on Ser66 [93]HVRSHpSLATS1/2TAZ on Ser89 [93]HLRQQpSLATS1/2TAZ on Ser117
n3:mentions
n2:17974916
Subject Item
_:vb24745367
rdf:type
n3:Context
rdf:value
Targeting motifKinase(s)Target siteHVRGDpSLATS1/2YAP on Ser61 [29,>>92<<]HSRQApSLATS1/2YAP on Ser109 [29,92]HVRAHpSLATS1/2YAP on Ser127 [29,92]HLRQSpSLATS1/2YAP on Ser164 [29,92]HSRDEpSLATS1/2YAP on Ser381# [29,92]HSRQSpSLATS1/2TAZ on Ser66 [93]HVRSHpSLATS1/2TAZ on Ser89 [93]HLRQQpSLATS1/2TAZ on Ser117
n3:mentions
n2:18158288
Subject Item
_:vb24745368
rdf:type
n3:Context
rdf:value
Targeting motifKinase(s)Target siteHVRGDpSLATS1/2YAP on Ser61 [29,92]HSRQApSLATS1/2YAP on Ser109 [>>29<<,92]HVRAHpSLATS1/2YAP on Ser127 [29,92]HLRQSpSLATS1/2YAP on Ser164 [29,92]HSRDEpSLATS1/2YAP on Ser381# [29,92]HSRQSpSLATS1/2TAZ on Ser66 [93]HVRSHpSLATS1/2TAZ on Ser89 [93]HLRQQpSLATS1/2TAZ on Ser117 [93]HSREQpSLATS1/2TAZ on Ser311
n3:mentions
n2:17974916
Subject Item
_:vb24745369
rdf:type
n3:Context
rdf:value
Targeting motifKinase(s)Target siteHVRGDpSLATS1/2YAP on Ser61 [29,92]HSRQApSLATS1/2YAP on Ser109 [29,>>92<<]HVRAHpSLATS1/2YAP on Ser127 [29,92]HLRQSpSLATS1/2YAP on Ser164 [29,92]HSRDEpSLATS1/2YAP on Ser381# [29,92]HSRQSpSLATS1/2TAZ on Ser66 [93]HVRSHpSLATS1/2TAZ on Ser89 [93]HLRQQpSLATS1/2TAZ on Ser117 [93]HSREQpSLATS1/2TAZ on Ser311
n3:mentions
n2:18158288
Subject Item
_:vb24745370
rdf:type
n3:Context
rdf:value
Targeting motifKinase(s)Target siteHVRGDpSLATS1/2YAP on Ser61 [29,92]HSRQApSLATS1/2YAP on Ser109 [29,92]HVRAHpSLATS1/2YAP on Ser127 [>>29<<,92]HLRQSpSLATS1/2YAP on Ser164 [29,92]HSRDEpSLATS1/2YAP on Ser381# [29,92]HSRQSpSLATS1/2TAZ on Ser66 [93]HVRSHpSLATS1/2TAZ on Ser89 [93]HLRQQpSLATS1/2TAZ on Ser117 [93]HSREQpSLATS1/2TAZ on Ser311 [93]LRKTGpSLATS1MYPT1 on Ser445
n3:mentions
n2:17974916
Subject Item
_:vb24745371
rdf:type
n3:Context
rdf:value
Targeting motifKinase(s)Target siteHVRGDpSLATS1/2YAP on Ser61 [29,92]HSRQApSLATS1/2YAP on Ser109 [29,92]HVRAHpSLATS1/2YAP on Ser127 [29,>>92<<]HLRQSpSLATS1/2YAP on Ser164 [29,92]HSRDEpSLATS1/2YAP on Ser381# [29,92]HSRQSpSLATS1/2TAZ on Ser66 [93]HVRSHpSLATS1/2TAZ on Ser89 [93]HLRQQpSLATS1/2TAZ on Ser117 [93]HSREQpSLATS1/2TAZ on Ser311 [93]LRKTGpSLATS1MYPT1 on Ser445
n3:mentions
n2:18158288
Subject Item
_:vb24745372
rdf:type
n3:Context
rdf:value
Targeting motifKinase(s)Target siteHVRGDpSLATS1/2YAP on Ser61 [29,92]HSRQApSLATS1/2YAP on Ser109 [29,92]HVRAHpSLATS1/2YAP on Ser127 [29,92]HLRQSpSLATS1/2YAP on Ser164 [>>29<<,92]HSRDEpSLATS1/2YAP on Ser381# [29,92]HSRQSpSLATS1/2TAZ on Ser66 [93]HVRSHpSLATS1/2TAZ on Ser89 [93]HLRQQpSLATS1/2TAZ on Ser117 [93]HSREQpSLATS1/2TAZ on Ser311 [93]LRKTGpSLATS1MYPT1 on Ser445 [99]GARRSpSLATS214-3-3γ on Ser59
n3:mentions
n2:17974916
Subject Item
_:vb24745373
rdf:type
n3:Context
rdf:value
Targeting motifKinase(s)Target siteHVRGDpSLATS1/2YAP on Ser61 [29,92]HSRQApSLATS1/2YAP on Ser109 [29,92]HVRAHpSLATS1/2YAP on Ser127 [29,92]HLRQSpSLATS1/2YAP on Ser164 [29,>>92<<]HSRDEpSLATS1/2YAP on Ser381# [29,92]HSRQSpSLATS1/2TAZ on Ser66 [93]HVRSHpSLATS1/2TAZ on Ser89 [93]HLRQQpSLATS1/2TAZ on Ser117 [93]HSREQpSLATS1/2TAZ on Ser311 [93]LRKTGpSLATS1MYPT1 on Ser445 [99]GARRSpSLATS214-3-3γ on Ser59
n3:mentions
n2:18158288
Subject Item
_:vb24745374
rdf:type
n3:Context
rdf:value
Targeting motifKinase(s)Target siteHVRGDpSLATS1/2YAP on Ser61 [29,92]HSRQApSLATS1/2YAP on Ser109 [29,92]HVRAHpSLATS1/2YAP on Ser127 [29,92]HLRQSpSLATS1/2YAP on Ser164 [29,92]HSRDEpSLATS1/2YAP on Ser381# [>>29<<,92]HSRQSpSLATS1/2TAZ on Ser66 [93]HVRSHpSLATS1/2TAZ on Ser89 [93]HLRQQpSLATS1/2TAZ on Ser117 [93]HSREQpSLATS1/2TAZ on Ser311 [93]LRKTGpSLATS1MYPT1 on Ser445 [99]GARRSpSLATS214-3-3γ on Ser59 [55]HVRTHpTLATS2Snail1 on Thr203
n3:mentions
n2:17974916
Subject Item
_:vb24745375
rdf:type
n3:Context
rdf:value
Targeting motifKinase(s)Target siteHVRGDpSLATS1/2YAP on Ser61 [29,92]HSRQApSLATS1/2YAP on Ser109 [29,92]HVRAHpSLATS1/2YAP on Ser127 [29,92]HLRQSpSLATS1/2YAP on Ser164 [29,92]HSRDEpSLATS1/2YAP on Ser381# [29,>>92<<]HSRQSpSLATS1/2TAZ on Ser66 [93]HVRSHpSLATS1/2TAZ on Ser89 [93]HLRQQpSLATS1/2TAZ on Ser117 [93]HSREQpSLATS1/2TAZ on Ser311 [93]LRKTGpSLATS1MYPT1 on Ser445 [99]GARRSpSLATS214-3-3γ on Ser59 [55]HVRTHpTLATS2Snail1 on Thr203
n3:mentions
n2:18158288
Subject Item
_:vb24745376
rdf:type
n3:Context
rdf:value
motifKinase(s)Target siteHVRGDpSLATS1/2YAP on Ser61 [29,92]HSRQApSLATS1/2YAP on Ser109 [29,92]HVRAHpSLATS1/2YAP on Ser127 [29,92]HLRQSpSLATS1/2YAP on Ser164 [29,92]HSRDEpSLATS1/2YAP on Ser381# [29,92]HSRQSpSLATS1/2TAZ on Ser66 [>>93<<]HVRSHpSLATS1/2TAZ on Ser89 [93]HLRQQpSLATS1/2TAZ on Ser117 [93]HSREQpSLATS1/2TAZ on Ser311 [93]LRKTGpSLATS1MYPT1 on Ser445 [99]GARRSpSLATS214-3-3γ on Ser59 [55]HVRTHpTLATS2Snail1 on Thr203 [100]KRRQTpSNDR1/2p21 on Ser146
n3:mentions
n2:18227151
Subject Item
_:vb24745377
rdf:type
n3:Context
rdf:value
on Ser61 [29,92]HSRQApSLATS1/2YAP on Ser109 [29,92]HVRAHpSLATS1/2YAP on Ser127 [29,92]HLRQSpSLATS1/2YAP on Ser164 [29,92]HSRDEpSLATS1/2YAP on Ser381# [29,92]HSRQSpSLATS1/2TAZ on Ser66 [93]HVRSHpSLATS1/2TAZ on Ser89 [>>93<<]HLRQQpSLATS1/2TAZ on Ser117 [93]HSREQpSLATS1/2TAZ on Ser311 [93]LRKTGpSLATS1MYPT1 on Ser445 [99]GARRSpSLATS214-3-3γ on Ser59 [55]HVRTHpTLATS2Snail1 on Thr203 [100]KRRQTpSNDR1/2p21 on Ser146 [45]HRRILpSNDR1/2AAK1 on Ser635
n3:mentions
n2:18227151
Subject Item
_:vb24745378
rdf:type
n3:Context
rdf:value
on Ser109 [29,92]HVRAHpSLATS1/2YAP on Ser127 [29,92]HLRQSpSLATS1/2YAP on Ser164 [29,92]HSRDEpSLATS1/2YAP on Ser381# [29,92]HSRQSpSLATS1/2TAZ on Ser66 [93]HVRSHpSLATS1/2TAZ on Ser89 [93]HLRQQpSLATS1/2TAZ on Ser117 [>>93<<]HSREQpSLATS1/2TAZ on Ser311 [93]LRKTGpSLATS1MYPT1 on Ser445 [99]GARRSpSLATS214-3-3γ on Ser59 [55]HVRTHpTLATS2Snail1 on Thr203 [100]KRRQTpSNDR1/2p21 on Ser146 [45]HRRILpSNDR1/2AAK1 on Ser635 [101]HTRNKpSNDR/2Rabin8(mouse) on Ser240
n3:mentions
n2:18227151
Subject Item
_:vb24745379
rdf:type
n3:Context
rdf:value
[29,92]HVRAHpSLATS1/2YAP on Ser127 [29,92]HLRQSpSLATS1/2YAP on Ser164 [29,92]HSRDEpSLATS1/2YAP on Ser381# [29,92]HSRQSpSLATS1/2TAZ on Ser66 [93]HVRSHpSLATS1/2TAZ on Ser89 [93]HLRQQpSLATS1/2TAZ on Ser117 [93]HSREQpSLATS1/2TAZ on Ser311 [>>93<<]LRKTGpSLATS1MYPT1 on Ser445 [99]GARRSpSLATS214-3-3γ on Ser59 [55]HVRTHpTLATS2Snail1 on Thr203 [100]KRRQTpSNDR1/2p21 on Ser146 [45]HRRILpSNDR1/2AAK1 on Ser635 [101]HTRNKpSNDR/2Rabin8(mouse) on Ser240 [101]HTRNKpSNDR2Rabin8(human) on Ser272
n3:mentions
n2:18227151
Subject Item
_:vb24745380
rdf:type
n3:Context
rdf:value
[29,92]HLRQSpSLATS1/2YAP on Ser164 [29,92]HSRDEpSLATS1/2YAP on Ser381# [29,92]HSRQSpSLATS1/2TAZ on Ser66 [93]HVRSHpSLATS1/2TAZ on Ser89 [93]HLRQQpSLATS1/2TAZ on Ser117 [93]HSREQpSLATS1/2TAZ on Ser311 [93]LRKTGpSLATS1MYPT1 on Ser445 [>>99<<]GARRSpSLATS214-3-3γ on Ser59 [55]HVRTHpTLATS2Snail1 on Thr203 [100]KRRQTpSNDR1/2p21 on Ser146 [45]HRRILpSNDR1/2AAK1 on Ser635 [101]HTRNKpSNDR/2Rabin8(mouse) on Ser240 [101]HTRNKpSNDR2Rabin8(human) on Ser272 [102]HXRXXpS/T
n3:mentions
n2:22641346
Subject Item
_:vb24745381
rdf:type
n3:Context
rdf:value
[29,92]HSRDEpSLATS1/2YAP on Ser381# [29,92]HSRQSpSLATS1/2TAZ on Ser66 [93]HVRSHpSLATS1/2TAZ on Ser89 [93]HLRQQpSLATS1/2TAZ on Ser117 [93]HSREQpSLATS1/2TAZ on Ser311 [93]LRKTGpSLATS1MYPT1 on Ser445 [99]GARRSpSLATS214-3-3γ on Ser59 [>>55<<]HVRTHpTLATS2Snail1 on Thr203 [100]KRRQTpSNDR1/2p21 on Ser146 [45]HRRILpSNDR1/2AAK1 on Ser635 [101]HTRNKpSNDR/2Rabin8(mouse) on Ser240 [101]HTRNKpSNDR2Rabin8(human) on Ser272 [102]HXRXXpS/T
n3:mentions
n2:21118956
Subject Item
_:vb24745382
rdf:type
n3:Context
rdf:value
Ser381# [29,92]HSRQSpSLATS1/2TAZ on Ser66 [93]HVRSHpSLATS1/2TAZ on Ser89 [93]HLRQQpSLATS1/2TAZ on Ser117 [93]HSREQpSLATS1/2TAZ on Ser311 [93]LRKTGpSLATS1MYPT1 on Ser445 [99]GARRSpSLATS214-3-3γ on Ser59 [55]HVRTHpTLATS2Snail1 on Thr203 [>>100<<]KRRQTpSNDR1/2p21 on Ser146 [45]HRRILpSNDR1/2AAK1 on Ser635 [101]HTRNKpSNDR/2Rabin8(mouse) on Ser240 [101]HTRNKpSNDR2Rabin8(human) on Ser272 [102]HXRXXpS/T
n3:mentions
n2:21952048
Subject Item
_:vb24745383
rdf:type
n3:Context
rdf:value
on Ser66 [93]HVRSHpSLATS1/2TAZ on Ser89 [93]HLRQQpSLATS1/2TAZ on Ser117 [93]HSREQpSLATS1/2TAZ on Ser311 [93]LRKTGpSLATS1MYPT1 on Ser445 [99]GARRSpSLATS214-3-3γ on Ser59 [55]HVRTHpTLATS2Snail1 on Thr203 [100]KRRQTpSNDR1/2p21 on Ser146 [>>45<<]HRRILpSNDR1/2AAK1 on Ser635 [101]HTRNKpSNDR/2Rabin8(mouse) on Ser240 [101]HTRNKpSNDR2Rabin8(human) on Ser272 [102]HXRXXpS/T
n3:mentions
n2:21262772
Subject Item
_:vb24745384
rdf:type
n3:Context
rdf:value
on Ser89 [93]HLRQQpSLATS1/2TAZ on Ser117 [93]HSREQpSLATS1/2TAZ on Ser311 [93]LRKTGpSLATS1MYPT1 on Ser445 [99]GARRSpSLATS214-3-3γ on Ser59 [55]HVRTHpTLATS2Snail1 on Thr203 [100]KRRQTpSNDR1/2p21 on Ser146 [45]HRRILpSNDR1/2AAK1 on Ser635 [>>101<<]HTRNKpSNDR/2Rabin8(mouse) on Ser240 [101]HTRNKpSNDR2Rabin8(human) on Ser272 [102]HXRXXpS/T
n3:mentions
n2:22445341
Subject Item
_:vb24745385
rdf:type
n3:Context
rdf:value
[93]HSREQpSLATS1/2TAZ on Ser311 [93]LRKTGpSLATS1MYPT1 on Ser445 [99]GARRSpSLATS214-3-3γ on Ser59 [55]HVRTHpTLATS2Snail1 on Thr203 [100]KRRQTpSNDR1/2p21 on Ser146 [45]HRRILpSNDR1/2AAK1 on Ser635 [101]HTRNKpSNDR/2Rabin8(mouse) on Ser240 [>>101<<]HTRNKpSNDR2Rabin8(human) on Ser272 [102]HXRXXpS/T
n3:mentions
n2:22445341
Subject Item
_:vb24745386
rdf:type
n3:Context
rdf:value
on Ser445 [99]GARRSpSLATS214-3-3γ on Ser59 [55]HVRTHpTLATS2Snail1 on Thr203 [100]KRRQTpSNDR1/2p21 on Ser146 [45]HRRILpSNDR1/2AAK1 on Ser635 [101]HTRNKpSNDR/2Rabin8(mouse) on Ser240 [101]HTRNKpSNDR2Rabin8(human) on Ser272 [>>102<<]HXRXXpS/T
n3:mentions
n2:23435566
Subject Item
_:vb24745387
rdf:type
n3:Context
rdf:value
PI4KB, Panx2, and Rab11fip5 sequences are not shown, since they are not yet confirmed as direct substrates of NDR1/2 [>>101<<]. However, these three substrates also display the HXRXXS/T motif [101].
n3:mentions
n2:22445341
Subject Item
_:vb24745388
rdf:type
n3:Context
rdf:value
However, these three substrates also display the HXRXXS/T motif [>>101<<].
n3:mentions
n2:22445341
Subject Item
_:vb24745389
rdf:type
n3:Context
rdf:value
Kinase(s)SubstrateRole of phosphorylationLATS1/2YAP on Ser61Not specifically determined [>>29<<,92]LATS1/2YAP on Ser109Not specifically determined [29,92]LATS1/2YAP on Ser127Facilitates 14-3-3 binding/cytoplasmic retention [9,29,94]LATS1/2YAP on Ser164Not specifically determined [29,92]LATS1/2YAP on Ser381Regulation of YAP protein
n3:mentions
n2:17974916
Subject Item
_:vb24745390
rdf:type
n3:Context
rdf:value
Kinase(s)SubstrateRole of phosphorylationLATS1/2YAP on Ser61Not specifically determined [29,>>92<<]LATS1/2YAP on Ser109Not specifically determined [29,92]LATS1/2YAP on Ser127Facilitates 14-3-3 binding/cytoplasmic retention [9,29,94]LATS1/2YAP on Ser164Not specifically determined [29,92]LATS1/2YAP on Ser381Regulation of YAP protein
n3:mentions
n2:18158288
Subject Item
_:vb24745391
rdf:type
n3:Context
rdf:value
Kinase(s)SubstrateRole of phosphorylationLATS1/2YAP on Ser61Not specifically determined [29,92]LATS1/2YAP on Ser109Not specifically determined [>>29<<,92]LATS1/2YAP on Ser127Facilitates 14-3-3 binding/cytoplasmic retention [9,29,94]LATS1/2YAP on Ser164Not specifically determined [29,92]LATS1/2YAP on Ser381Regulation of YAP protein stability [95]LATS1/2TAZ on Ser66Not specifically
n3:mentions
n2:17974916
Subject Item
_:vb24745392
rdf:type
n3:Context
rdf:value
Kinase(s)SubstrateRole of phosphorylationLATS1/2YAP on Ser61Not specifically determined [29,92]LATS1/2YAP on Ser109Not specifically determined [29,>>92<<]LATS1/2YAP on Ser127Facilitates 14-3-3 binding/cytoplasmic retention [9,29,94]LATS1/2YAP on Ser164Not specifically determined [29,92]LATS1/2YAP on Ser381Regulation of YAP protein stability [95]LATS1/2TAZ on Ser66Not specifically
n3:mentions
n2:18158288
Subject Item
_:vb24745393
rdf:type
n3:Context
rdf:value
Kinase(s)SubstrateRole of phosphorylationLATS1/2YAP on Ser61Not specifically determined [29,92]LATS1/2YAP on Ser109Not specifically determined [29,92]LATS1/2YAP on Ser127Facilitates 14-3-3 binding/cytoplasmic retention [>>9<<,29,94]LATS1/2YAP on Ser164Not specifically determined [29,92]LATS1/2YAP on Ser381Regulation of YAP protein stability [95]LATS1/2TAZ on Ser66Not specifically determined [93]LATS1/2TAZ on Ser89Facilitates 14-3-3 binding/cytoplasmic
n3:mentions
n2:17889654
Subject Item
_:vb24745394
rdf:type
n3:Context
rdf:value
Kinase(s)SubstrateRole of phosphorylationLATS1/2YAP on Ser61Not specifically determined [29,92]LATS1/2YAP on Ser109Not specifically determined [29,92]LATS1/2YAP on Ser127Facilitates 14-3-3 binding/cytoplasmic retention [9,>>29<<,94]LATS1/2YAP on Ser164Not specifically determined [29,92]LATS1/2YAP on Ser381Regulation of YAP protein stability [95]LATS1/2TAZ on Ser66Not specifically determined [93]LATS1/2TAZ on Ser89Facilitates 14-3-3 binding/cytoplasmic retention
n3:mentions
n2:17974916
Subject Item
_:vb24745395
rdf:type
n3:Context
rdf:value
Kinase(s)SubstrateRole of phosphorylationLATS1/2YAP on Ser61Not specifically determined [29,92]LATS1/2YAP on Ser109Not specifically determined [29,92]LATS1/2YAP on Ser127Facilitates 14-3-3 binding/cytoplasmic retention [9,29,>>94<<]LATS1/2YAP on Ser164Not specifically determined [29,92]LATS1/2YAP on Ser381Regulation of YAP protein stability [95]LATS1/2TAZ on Ser66Not specifically determined [93]LATS1/2TAZ on Ser89Facilitates 14-3-3 binding/cytoplasmic retention
n3:mentions
n2:18640976
Subject Item
_:vb24745396
rdf:type
n3:Context
rdf:value
on Ser61Not specifically determined [29,92]LATS1/2YAP on Ser109Not specifically determined [29,92]LATS1/2YAP on Ser127Facilitates 14-3-3 binding/cytoplasmic retention [9,29,94]LATS1/2YAP on Ser164Not specifically determined [>>29<<,92]LATS1/2YAP on Ser381Regulation of YAP protein stability [95]LATS1/2TAZ on Ser66Not specifically determined [93]LATS1/2TAZ on Ser89Facilitates 14-3-3 binding/cytoplasmic retention [93,96,97]LATS1/2TAZ on Ser117Not specifically
n3:mentions
n2:17974916
Subject Item
_:vb24745397
rdf:type
n3:Context
rdf:value
on Ser61Not specifically determined [29,92]LATS1/2YAP on Ser109Not specifically determined [29,92]LATS1/2YAP on Ser127Facilitates 14-3-3 binding/cytoplasmic retention [9,29,94]LATS1/2YAP on Ser164Not specifically determined [29,>>92<<]LATS1/2YAP on Ser381Regulation of YAP protein stability [95]LATS1/2TAZ on Ser66Not specifically determined [93]LATS1/2TAZ on Ser89Facilitates 14-3-3 binding/cytoplasmic retention [93,96,97]LATS1/2TAZ on Ser117Not specifically determined
n3:mentions
n2:18158288
Subject Item
_:vb24745398
rdf:type
n3:Context
rdf:value
on Ser109Not specifically determined [29,92]LATS1/2YAP on Ser127Facilitates 14-3-3 binding/cytoplasmic retention [9,29,94]LATS1/2YAP on Ser164Not specifically determined [29,92]LATS1/2YAP on Ser381Regulation of YAP protein stability [>>95<<]LATS1/2TAZ on Ser66Not specifically determined [93]LATS1/2TAZ on Ser89Facilitates 14-3-3 binding/cytoplasmic retention [93,96,97]LATS1/2TAZ on Ser117Not specifically determined [93]LATS1/2TAZ on Ser311Regulation of TAZ protein stability
n3:mentions
n2:20048001
Subject Item
_:vb24745399
rdf:type
n3:Context
rdf:value
on Ser127Facilitates 14-3-3 binding/cytoplasmic retention [9,29,94]LATS1/2YAP on Ser164Not specifically determined [29,92]LATS1/2YAP on Ser381Regulation of YAP protein stability [95]LATS1/2TAZ on Ser66Not specifically determined [>>93<<]LATS1/2TAZ on Ser89Facilitates 14-3-3 binding/cytoplasmic retention [93,96,97]LATS1/2TAZ on Ser117Not specifically determined [93]LATS1/2TAZ on Ser311Regulation of TAZ protein stability [98]LATS1MYPT1 on Ser445Promotes MYPT1 phosphatase
n3:mentions
n2:18227151
Subject Item
_:vb24745400
rdf:type
n3:Context
rdf:value
on Ser164Not specifically determined [29,92]LATS1/2YAP on Ser381Regulation of YAP protein stability [95]LATS1/2TAZ on Ser66Not specifically determined [93]LATS1/2TAZ on Ser89Facilitates 14-3-3 binding/cytoplasmic retention [>>93<<,96,97]LATS1/2TAZ on Ser117Not specifically determined [93]LATS1/2TAZ on Ser311Regulation of TAZ protein stability [98]LATS1MYPT1 on Ser445Promotes MYPT1 phosphatase activity [99]LATS214-3-3γ on Ser59Regulation of 14-3-3γ in P-body
n3:mentions
n2:18227151
Subject Item
_:vb24745401
rdf:type
n3:Context
rdf:value
on Ser164Not specifically determined [29,92]LATS1/2YAP on Ser381Regulation of YAP protein stability [95]LATS1/2TAZ on Ser66Not specifically determined [93]LATS1/2TAZ on Ser89Facilitates 14-3-3 binding/cytoplasmic retention [93,>>96<<,97]LATS1/2TAZ on Ser117Not specifically determined [93]LATS1/2TAZ on Ser311Regulation of TAZ protein stability [98]LATS1MYPT1 on Ser445Promotes MYPT1 phosphatase activity [99]LATS214-3-3γ on Ser59Regulation of 14-3-3γ in P-body formation
n3:mentions
n2:11118213
Subject Item
_:vb24745402
rdf:type
n3:Context
rdf:value
on Ser164Not specifically determined [29,92]LATS1/2YAP on Ser381Regulation of YAP protein stability [95]LATS1/2TAZ on Ser66Not specifically determined [93]LATS1/2TAZ on Ser89Facilitates 14-3-3 binding/cytoplasmic retention [93,96,>>97<<]LATS1/2TAZ on Ser117Not specifically determined [93]LATS1/2TAZ on Ser311Regulation of TAZ protein stability [98]LATS1MYPT1 on Ser445Promotes MYPT1 phosphatase activity [99]LATS214-3-3γ on Ser59Regulation of 14-3-3γ in P-body formation
n3:mentions
n2:18568018
Subject Item
_:vb24745403
rdf:type
n3:Context
rdf:value
on Ser381Regulation of YAP protein stability [95]LATS1/2TAZ on Ser66Not specifically determined [93]LATS1/2TAZ on Ser89Facilitates 14-3-3 binding/cytoplasmic retention [93,96,97]LATS1/2TAZ on Ser117Not specifically determined [>>93<<]LATS1/2TAZ on Ser311Regulation of TAZ protein stability [98]LATS1MYPT1 on Ser445Promotes MYPT1 phosphatase activity [99]LATS214-3-3γ on Ser59Regulation of 14-3-3γ in P-body formation [55]LATS2Snail on Thr203Regulating of Snail1 protein
n3:mentions
n2:18227151
Subject Item
_:vb24745404
rdf:type
n3:Context
rdf:value
on Ser66Not specifically determined [93]LATS1/2TAZ on Ser89Facilitates 14-3-3 binding/cytoplasmic retention [93,96,97]LATS1/2TAZ on Ser117Not specifically determined [93]LATS1/2TAZ on Ser311Regulation of TAZ protein stability [>>98<<]LATS1MYPT1 on Ser445Promotes MYPT1 phosphatase activity [99]LATS214-3-3γ on Ser59Regulation of 14-3-3γ in P-body formation [55]LATS2Snail on Thr203Regulating of Snail1 protein stability [100]NDR1/2p21/Cip1 on Ser146Regulates p21 protein
n3:mentions
n2:20858893
Subject Item
_:vb24745405
rdf:type
n3:Context
rdf:value
on Ser89Facilitates 14-3-3 binding/cytoplasmic retention [93,96,97]LATS1/2TAZ on Ser117Not specifically determined [93]LATS1/2TAZ on Ser311Regulation of TAZ protein stability [98]LATS1MYPT1 on Ser445Promotes MYPT1 phosphatase activity [>>99<<]LATS214-3-3γ on Ser59Regulation of 14-3-3γ in P-body formation [55]LATS2Snail on Thr203Regulating of Snail1 protein stability [100]NDR1/2p21/Cip1 on Ser146Regulates p21 protein stability [45]NDR1/2AAK1 on Ser635Dendrite and spine
n3:mentions
n2:22641346
Subject Item
_:vb24745406
rdf:type
n3:Context
rdf:value
on Ser117Not specifically determined [93]LATS1/2TAZ on Ser311Regulation of TAZ protein stability [98]LATS1MYPT1 on Ser445Promotes MYPT1 phosphatase activity [99]LATS214-3-3γ on Ser59Regulation of 14-3-3γ in P-body formation [>>55<<]LATS2Snail on Thr203Regulating of Snail1 protein stability [100]NDR1/2p21/Cip1 on Ser146Regulates p21 protein stability [45]NDR1/2AAK1 on Ser635Dendrite and spine development in neurons [101]NDR1/2Rabin8 on Ser240#Dendrite and spine
n3:mentions
n2:21118956
Subject Item
_:vb24745407
rdf:type
n3:Context
rdf:value
on Ser311Regulation of TAZ protein stability [98]LATS1MYPT1 on Ser445Promotes MYPT1 phosphatase activity [99]LATS214-3-3γ on Ser59Regulation of 14-3-3γ in P-body formation [55]LATS2Snail on Thr203Regulating of Snail1 protein stability [>>100<<]NDR1/2p21/Cip1 on Ser146Regulates p21 protein stability [45]NDR1/2AAK1 on Ser635Dendrite and spine development in neurons [101]NDR1/2Rabin8 on Ser240#Dendrite and spine development in neurons [101]NDR2Rabin8 on Ser272#Primary cilia
n3:mentions
n2:21952048
Subject Item
_:vb24745408
rdf:type
n3:Context
rdf:value
on Ser445Promotes MYPT1 phosphatase activity [99]LATS214-3-3γ on Ser59Regulation of 14-3-3γ in P-body formation [55]LATS2Snail on Thr203Regulating of Snail1 protein stability [100]NDR1/2p21/Cip1 on Ser146Regulates p21 protein stability [>>45<<]NDR1/2AAK1 on Ser635Dendrite and spine development in neurons [101]NDR1/2Rabin8 on Ser240#Dendrite and spine development in neurons [101]NDR2Rabin8 on Ser272#Primary cilia biology [102]NDR1/2PI4KB on Ser277*Not determined [101]NDR1/2Panx2
n3:mentions
n2:21262772
Subject Item
_:vb24745409
rdf:type
n3:Context
rdf:value
of 14-3-3γ in P-body formation [55]LATS2Snail on Thr203Regulating of Snail1 protein stability [100]NDR1/2p21/Cip1 on Ser146Regulates p21 protein stability [45]NDR1/2AAK1 on Ser635Dendrite and spine development in neurons [>>101<<]NDR1/2Rabin8 on Ser240#Dendrite and spine development in neurons [101]NDR2Rabin8 on Ser272#Primary cilia biology [102]NDR1/2PI4KB on Ser277*Not determined [101]NDR1/2Panx2 on Ser514*Not determined [101]NDR1/2Rab11fip5 on Ser307*Not
n3:mentions
n2:22445341
Subject Item
_:vb24745410
rdf:type
n3:Context
rdf:value
of Snail1 protein stability [100]NDR1/2p21/Cip1 on Ser146Regulates p21 protein stability [45]NDR1/2AAK1 on Ser635Dendrite and spine development in neurons [101]NDR1/2Rabin8 on Ser240#Dendrite and spine development in neurons [>>101<<]NDR2Rabin8 on Ser272#Primary cilia biology [102]NDR1/2PI4KB on Ser277*Not determined [101]NDR1/2Panx2 on Ser514*Not determined [101]NDR1/2Rab11fip5 on Ser307*Not determined
n3:mentions
n2:22445341
Subject Item
_:vb24745411
rdf:type
n3:Context
rdf:value
on Ser146Regulates p21 protein stability [45]NDR1/2AAK1 on Ser635Dendrite and spine development in neurons [101]NDR1/2Rabin8 on Ser240#Dendrite and spine development in neurons [101]NDR2Rabin8 on Ser272#Primary cilia biology [>>102<<]NDR1/2PI4KB on Ser277*Not determined [101]NDR1/2Panx2 on Ser514*Not determined [101]NDR1/2Rab11fip5 on Ser307*Not determined
n3:mentions
n2:23435566
Subject Item
_:vb24745412
rdf:type
n3:Context
rdf:value
[45]NDR1/2AAK1 on Ser635Dendrite and spine development in neurons [101]NDR1/2Rabin8 on Ser240#Dendrite and spine development in neurons [101]NDR2Rabin8 on Ser272#Primary cilia biology [102]NDR1/2PI4KB on Ser277*Not determined [>>101<<]NDR1/2Panx2 on Ser514*Not determined [101]NDR1/2Rab11fip5 on Ser307*Not determined
n3:mentions
n2:22445341
Subject Item
_:vb24745413
rdf:type
n3:Context
rdf:value
and spine development in neurons [101]NDR1/2Rabin8 on Ser240#Dendrite and spine development in neurons [101]NDR2Rabin8 on Ser272#Primary cilia biology [102]NDR1/2PI4KB on Ser277*Not determined [101]NDR1/2Panx2 on Ser514*Not determined [>>101<<]NDR1/2Rab11fip5 on Ser307*Not determined
n3:mentions
n2:22445341
Subject Item
_:vb24745414
rdf:type
n3:Context
rdf:value
on Ser240#Dendrite and spine development in neurons [101]NDR2Rabin8 on Ser272#Primary cilia biology [102]NDR1/2PI4KB on Ser277*Not determined [101]NDR1/2Panx2 on Ser514*Not determined [101]NDR1/2Rab11fip5 on Ser307*Not determined [>>101<<
n3:mentions
n2:22445341
Subject Item
_:vb24745415
rdf:type
n3:Context
rdf:value
LATS1 phosphorylates MYPT1 (myosin phosphatase-targeting subunit 1) on Ser445, thereby promoting MYPT1 phosphatase activity [>>99<<]. LATS2 also phosphorylates 14-3-3γ on Ser59 [55] and Snail1 on Thr203 [100], which influences P-body formation and Snail1 protein stability, respectively. The phosphorylation of 14-3-3 by LATS2 is particularly intriguing, since this
n3:mentions
n2:22641346
Subject Item
_:vb24745416
rdf:type
n3:Context
rdf:value
LATS2 also phosphorylates 14-3-3γ on Ser59 [>>55<<] and Snail1 on Thr203 [100], which influences P-body formation and Snail1 protein stability, respectively.
n3:mentions
n2:21118956
Subject Item
_:vb24745417
rdf:type
n3:Context
rdf:value
LATS2 also phosphorylates 14-3-3γ on Ser59 [55] and Snail1 on Thr203 [>>100<<], which influences P-body formation and Snail1 protein stability, respectively.
n3:mentions
n2:21952048
Subject Item
_:vb24745418
rdf:type
n3:Context
rdf:value
LATS2 can also phosphorylate DYRK1A (dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A), which enhances DYRK1A kinase activity and thereby possibly plays a role in RB-mediated senescence [>>103<<]. Significantly, the phosphorylation motifs in MYPT1 and 14-3-3γ do not align with the postulated HXRXXS/T consensus motif for LATS1/2 kinases, but rather display the basic R/KXXS/T motif, which is very common amongst AGC kinases [13].
n3:mentions
n2:21498571
Subject Item
_:vb24745419
rdf:type
n3:Context
rdf:value
Significantly, the phosphorylation motifs in MYPT1 and 14-3-3γ do not align with the postulated HXRXXS/T consensus motif for LATS1/2 kinases, but rather display the basic R/KXXS/T motif, which is very common amongst AGC kinases [>>13<<].
n3:mentions
n2:20027184
Subject Item
_:vb24745420
rdf:type
n3:Context
rdf:value
NDR1/2 phosphorylate the cell cycle regulator p21/Cip1 on Ser146, thereby regulating p21 protein stability [>>45<<]. NDR1/2 also phosphorylate murine AAK1 (AP-2 associated kinase-1) and Rabin8 (Rab8 guanine nucleotide exchange factor) on Ser635 and Ser240, respectively [101]. NDR2 has further been shown to phosphorylate Rabin8 on Ser272 in human cells
n3:mentions
n2:21262772
Subject Item
_:vb24745421
rdf:type
n3:Context
rdf:value
NDR1/2 also phosphorylate murine AAK1 (AP-2 associated kinase-1) and Rabin8 (Rab8 guanine nucleotide exchange factor) on Ser635 and Ser240, respectively [>>101<<]. NDR2 has further been shown to phosphorylate Rabin8 on Ser272 in human cells [102], which is the same site as previously reported for mouse Rabin8 phosphorylation on Ser240 (Tables  2 and 3). NDR1 can also phosphorylate YAP in
n3:mentions
n2:22445341
Subject Item
_:vb24745422
rdf:type
n3:Context
rdf:value
NDR2 has further been shown to phosphorylate Rabin8 on Ser272 in human cells [>>102<<], which is the same site as previously reported for mouse Rabin8 phosphorylation on Ser240 (Tables  2 and 3).
n3:mentions
n2:23435566
Subject Item
_:vb24745423
rdf:type
n3:Context
rdf:value
NDR1 can also phosphorylate YAP in vitro[>>92<<], however, the in vivo phosphorylation of YAP by NDR1/2 has not been documented so far.
n3:mentions
n2:18158288
Subject Item
_:vb24745424
rdf:type
n3:Context
rdf:value
This speculation is further support by the notion that LATS1 and NDR1 display the same peptide substrate preferences in vitro, with the ideal substrate peptide containing the HXRXXS/T motif [>>92<<].
n3:mentions
n2:18158288
Subject Item
_:vb24745425
rdf:type
n3:Context
rdf:value
substrate phosphorylations by LATS/NDR are counteracted by protein phosphatases to enable cells to rapidly adapt their signalling outputs, hence it is not surprising that PP1A was reported to mediate the dephosphorylation of YAP/TAZ [>>104<<,105]. PTPN14 (non-receptor tyrosine phosphatase 14) has also been shown to regulate YAP function, but whether this regulation is dependent of PTPN14 tyrosine phosphatase activity is currently debatable [106].
n3:mentions
n2:21189257
Subject Item
_:vb24745426
rdf:type
n3:Context
rdf:value
phosphorylations by LATS/NDR are counteracted by protein phosphatases to enable cells to rapidly adapt their signalling outputs, hence it is not surprising that PP1A was reported to mediate the dephosphorylation of YAP/TAZ [104,>>105<<]. PTPN14 (non-receptor tyrosine phosphatase 14) has also been shown to regulate YAP function, but whether this regulation is dependent of PTPN14 tyrosine phosphatase activity is currently debatable [106].
n3:mentions
n2:21909427
Subject Item
_:vb24745427
rdf:type
n3:Context
rdf:value
PTPN14 (non-receptor tyrosine phosphatase 14) has also been shown to regulate YAP function, but whether this regulation is dependent of PTPN14 tyrosine phosphatase activity is currently debatable [>>106<<]. Possibly, PTPN14 influences the Tyr phosphorylation of YAP by c-Abl [107] than playing a role in counter balancing LATS1/2 substrate phosphorylation. However, since PKL01, a LATS/NDR homologue in plants, has recently been shown to be a
n3:mentions
n2:23354686
Subject Item
_:vb24745428
rdf:type
n3:Context
rdf:value
Possibly, PTPN14 influences the Tyr phosphorylation of YAP by c-Abl [>>107<<] than playing a role in counter balancing LATS1/2 substrate phosphorylation.
n3:mentions
n2:18280240
Subject Item
_:vb24745429
rdf:type
n3:Context
rdf:value
However, since PKL01, a LATS/NDR homologue in plants, has recently been shown to be a dual-specificity kinase that can phosphorylate Ser/Thr and Tyr residues [>>108<<], it is tempting to speculate that it is just a question of time until the LATS/NDR substrate spectrum will be expanded to Tyr phosphorylations.
n3:mentions
n2:22753892
Subject Item
_:vb24745430
rdf:type
n3:Context
rdf:value
Last, but not least, we would like to stress that current genetic evidence from Drosophila studies [>>5<<] suggests Warts (the fly counterpart of LATS1/2) is very likely to have additional substrates besides Yorkie (the fly counterpart of YAP/TAZ).
n3:mentions
n2:22174083
Subject Item
_:vb24745431
rdf:type
n3:Context
rdf:value
In this context, it is noteworthy that Thompson and colleagues recently reported that Warts phosphorylates and inhibits the actin regulator Enabled, thereby restricting F-actin polymerization to local migrating clusters [>>109<<]. These findings suggest that the mammalian counterpart(s) of Enabled are very likely to also represent novel LATS1/2 substrates, besides pointing out that Drosophila genetics combined with biochemical approaches are likely to keep on
n3:mentions
n2:23733343
Subject Item
_:vb24745432
rdf:type
n3:Context
rdf:value
In Drosophila, loss of the tumour suppressor Warts (the fly counterpart of mammalian LATS1/2) is larval lethal [>>16<<,17]. In contrast, LATS1 knock-out (KO) mice are viable [8], while LATS2 knock-out mice die during embryonic development, most likely due to defective cytokinesis resulting in genomic instability [64,110].
n3:mentions
n2:7698644
Subject Item
_:vb24745433
rdf:type
n3:Context
rdf:value
In Drosophila, loss of the tumour suppressor Warts (the fly counterpart of mammalian LATS1/2) is larval lethal [16,>>17<<]. In contrast, LATS1 knock-out (KO) mice are viable [8], while LATS2 knock-out mice die during embryonic development, most likely due to defective cytokinesis resulting in genomic instability [64,110].
n3:mentions
n2:7743921
Subject Item
_:vb24745434
rdf:type
n3:Context
rdf:value
In contrast, LATS1 knock-out (KO) mice are viable [>>8<<], while LATS2 knock-out mice die during embryonic development, most likely due to defective cytokinesis resulting in genomic instability [64,110].
n3:mentions
n2:9988269
Subject Item
_:vb24745435
rdf:type
n3:Context
rdf:value
In contrast, LATS1 knock-out (KO) mice are viable [8], while LATS2 knock-out mice die during embryonic development, most likely due to defective cytokinesis resulting in genomic instability [>>64<<,110]. However, LATS1 null animals develop tumours [8], and immortalised LATS2 null MEFs display loss of contact inhibition [64,110], indicating that LATS1/2 might function as tumour suppressors in mammals [10]. LATS1/2 whole body DKO
n3:mentions
n2:17478426
Subject Item
_:vb24745436
rdf:type
n3:Context
rdf:value
In contrast, LATS1 knock-out (KO) mice are viable [8], while LATS2 knock-out mice die during embryonic development, most likely due to defective cytokinesis resulting in genomic instability [64,>>110<<]. However, LATS1 null animals develop tumours [8], and immortalised LATS2 null MEFs display loss of contact inhibition [64,110], indicating that LATS1/2 might function as tumour suppressors in mammals [10]. LATS1/2 whole body DKO animals
n3:mentions
n2:15343267
Subject Item
_:vb24745437
rdf:type
n3:Context
rdf:value
However, LATS1 null animals develop tumours [>>8<<], and immortalised LATS2 null MEFs display loss of contact inhibition [64,110], indicating that LATS1/2 might function as tumour suppressors in mammals [10].
n3:mentions
n2:9988269
Subject Item
_:vb24745438
rdf:type
n3:Context
rdf:value
However, LATS1 null animals develop tumours [8], and immortalised LATS2 null MEFs display loss of contact inhibition [>>64<<,110], indicating that LATS1/2 might function as tumour suppressors in mammals [10].
n3:mentions
n2:17478426
Subject Item
_:vb24745439
rdf:type
n3:Context
rdf:value
However, LATS1 null animals develop tumours [8], and immortalised LATS2 null MEFs display loss of contact inhibition [64,>>110<<], indicating that LATS1/2 might function as tumour suppressors in mammals [10].
n3:mentions
n2:15343267
Subject Item
_:vb24745440
rdf:type
n3:Context
rdf:value
However, LATS1 null animals develop tumours [8], and immortalised LATS2 null MEFs display loss of contact inhibition [64,110], indicating that LATS1/2 might function as tumour suppressors in mammals [>>10<<]. LATS1/2 whole body DKO animals have not been reported yet. Nevertheless, a study combining LATS2 KO with RNAi depletion of LATS1 has shown that LATS1/2 kinases are crucial for early embryonic development [111]. More specifically,
n3:mentions
n2:23467301
Subject Item
_:vb24745441
rdf:type
n3:Context
rdf:value
Nevertheless, a study combining LATS2 KO with RNAi depletion of LATS1 has shown that LATS1/2 kinases are crucial for early embryonic development [>>111<<]. More specifically, LATS1/2 are required to distinguish between trophectoderm and inner cell mass in preimplantation mouse embryos [111]. LATS1/2 also play a role in heart development [112,113], since interference with LATS1/2 function
n3:mentions
n2:19289085
Subject Item
_:vb24745442
rdf:type
n3:Context
rdf:value
More specifically, LATS1/2 are required to distinguish between trophectoderm and inner cell mass in preimplantation mouse embryos [>>111<<]. LATS1/2 also play a role in heart development [112,113], since interference with LATS1/2 function by either overexpressing dominant-negative LATS2 [112] or heart specific deletion of LATS1/2 [113] resulted in heart abnormalities. Taken
n3:mentions
n2:19289085
Subject Item
_:vb24745443
rdf:type
n3:Context
rdf:value
LATS1/2 also play a role in heart development [>>112<<,113], since interference with LATS1/2 function by either overexpressing dominant-negative LATS2 [112] or heart specific deletion of LATS1/2 [113] resulted in heart abnormalities.
n3:mentions
n2:18927464
Subject Item
_:vb24745444
rdf:type
n3:Context
rdf:value
LATS1/2 also play a role in heart development [112,>>113<<], since interference with LATS1/2 function by either overexpressing dominant-negative LATS2 [112] or heart specific deletion of LATS1/2 [113] resulted in heart abnormalities.
n3:mentions
n2:21512031
Subject Item
_:vb24745445
rdf:type
n3:Context
rdf:value
LATS1/2 also play a role in heart development [112,113], since interference with LATS1/2 function by either overexpressing dominant-negative LATS2 [>>112<<] or heart specific deletion of LATS1/2 [113] resulted in heart abnormalities.
n3:mentions
n2:18927464
Subject Item
_:vb24745446
rdf:type
n3:Context
rdf:value
LATS1/2 also play a role in heart development [112,113], since interference with LATS1/2 function by either overexpressing dominant-negative LATS2 [112] or heart specific deletion of LATS1/2 [>>113<<] resulted in heart abnormalities.
n3:mentions
n2:21512031
Subject Item
_:vb24745447
rdf:type
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rdf:value
While studies of tissue specific ablation of LATS1/2 function in animals are still limited in number, the roles of LATS1/2 as major regulators of the YAP/TAZ proto-proteins are well established [>>1<<,2]. In canonical Hippo signalling MST1/2 activated LATS1/2 phosphorylate YAP/TAZ on Ser127/89 and Ser381/311, respectively, thereby controlling YAP/TAZ on two levels:
n3:mentions
n2:22575479
Subject Item
_:vb24745448
rdf:type
n3:Context
rdf:value
While studies of tissue specific ablation of LATS1/2 function in animals are still limited in number, the roles of LATS1/2 as major regulators of the YAP/TAZ proto-proteins are well established [1,>>2<<]. In canonical Hippo signalling MST1/2 activated LATS1/2 phosphorylate YAP/TAZ on Ser127/89 and Ser381/311, respectively, thereby controlling YAP/TAZ on two levels:
n3:mentions
n2:23431053
Subject Item
_:vb24745449
rdf:type
n3:Context
rdf:value
However, the spatial regulation of YAP by LATS1/2 appears to be more complicated, since in sparse human and murine cell lines Ser127/112-phosphorylated YAP can also be detected in nuclei [>>114<<]. Moreover, the model of MST1/2-LATS1/2 mediated regulation of YAP has been challenged by studies of MST1/2 and YAP KO animals. First, liver specific deletion of MST1/2 in mice causes hepatocellular carcinoma (HCC) by YAP deregulation
n3:mentions
n2:21831922
Subject Item
_:vb24745450
rdf:type
n3:Context
rdf:value
First, liver specific deletion of MST1/2 in mice causes hepatocellular carcinoma (HCC) by YAP deregulation without any apparent involvement of LATS1/2 [>>6<<]. Second, YAP is negatively regulated in keratinocytes without any apparent involvement of MST1/2 or LATS1/2 signalling [115]. Third, in mouse thymocytes MST1/2 mainly signals through phosphorylation of MOB1A/B without any apparent
n3:mentions
n2:19878874
Subject Item
_:vb24745451
rdf:type
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rdf:value
Second, YAP is negatively regulated in keratinocytes without any apparent involvement of MST1/2 or LATS1/2 signalling [>>115<<]. Third, in mouse thymocytes MST1/2 mainly signals through phosphorylation of MOB1A/B without any apparent involvement of LATS1/2 or YAP [66]. Fourth, in the mouse intestine YAP displays a growth-suppressive function restricting Wnt
n3:mentions
n2:21376238
Subject Item
_:vb24745452
rdf:type
n3:Context
rdf:value
Third, in mouse thymocytes MST1/2 mainly signals through phosphorylation of MOB1A/B without any apparent involvement of LATS1/2 or YAP [>>66<<]. Fourth, in the mouse intestine YAP displays a growth-suppressive function restricting Wnt signals during intestinal regeneration [116]. These studies suggest that (1) MST1/2 does not always signal through LATS1/2 to YAP, (2) MST/LATS
n3:mentions
n2:22412158
Subject Item
_:vb24745453
rdf:type
n3:Context
rdf:value
Fourth, in the mouse intestine YAP displays a growth-suppressive function restricting Wnt signals during intestinal regeneration [>>116<<]. These studies suggest that (1) MST1/2 does not always signal through LATS1/2 to YAP, (2) MST/LATS signalling are dispensable for YAP regulation in specific cell types, (3) MST1/2 signalling can function completely independent of the
n3:mentions
n2:23312716
Subject Item
_:vb24745454
rdf:type
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rdf:value
This last point is also supported by studies of breast cancer patients, which currently suggest that YAP might have oncogenic and tumour suppressive functions dependent on the breast cancer subtype [>>117<<]. Now a similar picture appears to evolve with respect to the role of YAP in colon cancer, since Camargo and colleagues found that YAP is silenced in a subset of highly aggressive and undifferentiated human colorectal carcinomas [118],
n3:mentions
n2:23216692
Subject Item
_:vb24745455
rdf:type
n3:Context
rdf:value
Now a similar picture appears to evolve with respect to the role of YAP in colon cancer, since Camargo and colleagues found that YAP is silenced in a subset of highly aggressive and undifferentiated human colorectal carcinomas [>>118<<], while other studies suggest that YAP functions as a proto-oncoprotein in the colon [3].
n3:mentions
n2:23178811
Subject Item
_:vb24745456
rdf:type
n3:Context
rdf:value
cancer, since Camargo and colleagues found that YAP is silenced in a subset of highly aggressive and undifferentiated human colorectal carcinomas [118], while other studies suggest that YAP functions as a proto-oncoprotein in the colon [>>3<<]. The regulation of YAP in HCC is also not completely clear.
n3:mentions
n2:22659496
Subject Item
_:vb24745457
rdf:type
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rdf:value
In a significant fraction of human HCC samples Zhou et al. detected a correlation between decreased phospho-S127 YAP and decreased MST1 activity, arguing that MST1/2 activity is a key determinant upstream of YAP [>>6<<]. In contrast, Li et al. reported that in their HCC samples phospho-Ser127 YAP is decreased together with phosphorylated LATS1/2, while MST1/2 activity, as judged by the phosphorylation status of MST1/2, was not affected [119]. In
n3:mentions
n2:19878874
Subject Item
_:vb24745458
rdf:type
n3:Context
rdf:value
In contrast, Li et al. reported that in their HCC samples phospho-Ser127 YAP is decreased together with phosphorylated LATS1/2, while MST1/2 activity, as judged by the phosphorylation status of MST1/2, was not affected [>>119<<]. In summary, these findings illustrate that in human breast, colon and hepatic malignancies the role of the MST1/2-LATS1/2-YAP axis will most likely need to be defined based on cancer subtypes.
n3:mentions
n2:22098159
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_:vb24745459
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Significantly, LATS1/2 signalling could play a further role in mammalian stem cells [>>116<<,120]. YAP needs to be inactivated during the differentiation process of murine embryonic stem (ES) cells and elevated during iPS (induced pluripotent stem cells) reprogramming, illustrating that YAP is a critical regulator of stem cell
n3:mentions
n2:23312716
Subject Item
_:vb24745460
rdf:type
n3:Context
rdf:value
Significantly, LATS1/2 signalling could play a further role in mammalian stem cells [116,>>120<<]. YAP needs to be inactivated during the differentiation process of murine embryonic stem (ES) cells and elevated during iPS (induced pluripotent stem cells) reprogramming, illustrating that YAP is a critical regulator of stem cell
n3:mentions
n2:23034192
Subject Item
_:vb24745461
rdf:type
n3:Context
rdf:value
to be inactivated during the differentiation process of murine embryonic stem (ES) cells and elevated during iPS (induced pluripotent stem cells) reprogramming, illustrating that YAP is a critical regulator of stem cell pluripotency [>>121<<]. However, in these settings the regulation of YAP by LATS1/2 is yet to be defined.
n3:mentions
n2:20516196
Subject Item
_:vb24745462
rdf:type
n3:Context
rdf:value
This point is important, since Zhou et al. showed that MST1/2 signalling plays a crucial role in YAP regulation in colon stem cells without apparent involvement of LATS1/2 signalling [>>122<<], suggesting that the regulation of YAP in stem cells might not always depend on LATS1/2.
n3:mentions
n2:22042863
Subject Item
_:vb24745463
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Nevertheless, knockdown of LATS2 can increase the efficiency of the formation of human iPS, most likely by releasing the normal repressive function of LATS2 as TAZ antagonist [>>79<<]. Therefore, LATS1/2 appear to be key players in mammalian stem cell biology, although much work is yet to be done to understand precisely how LATS1/2 function upstream of YAP/TAZ in this specific cell type.
n3:mentions
n2:22286172
Subject Item
_:vb24745464
rdf:type
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the case might be in cancer and stem cells, in mostly normal human cell lines (in particular HEK293 and MCF10A cells) LATS1/2 function downstream of G-protein-coupled receptors (GPCRs) as central controllers of YAP/TAZ activities [>>2<<]. The Guan and Wu laboratories discovered that LPA (lysophosphatidic acid) and S1P (Sphingosine-1-phosphate) are major serum components responsible for YAP/TAZ activation [123,124].
n3:mentions
n2:23431053
Subject Item
_:vb24745465
rdf:type
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rdf:value
The Guan and Wu laboratories discovered that LPA (lysophosphatidic acid) and S1P (Sphingosine-1-phosphate) are major serum components responsible for YAP/TAZ activation [>>123<<,124]. More specifically, Yu et al. showed that LPA and S1P act through G12/13-coupled receptors to inhibit LATS1 S909/T1079 phosphorylation and activity, thereby allowing the dephosphorylation and consequent activation of YAP/TAZ [124].
n3:mentions
n2:22884261
Subject Item
_:vb24745466
rdf:type
n3:Context
rdf:value
The Guan and Wu laboratories discovered that LPA (lysophosphatidic acid) and S1P (Sphingosine-1-phosphate) are major serum components responsible for YAP/TAZ activation [123,>>124<<]. More specifically, Yu et al. showed that LPA and S1P act through G12/13-coupled receptors to inhibit LATS1 S909/T1079 phosphorylation and activity, thereby allowing the dephosphorylation and consequent activation of YAP/TAZ [124].
n3:mentions
n2:22863277
Subject Item
_:vb24745467
rdf:type
n3:Context
rdf:value
More specifically, Yu et al. showed that LPA and S1P act through G12/13-coupled receptors to inhibit LATS1 S909/T1079 phosphorylation and activity, thereby allowing the dephosphorylation and consequent activation of YAP/TAZ [>>124<<]. Stimulation of protease-activated receptors (PARs; another group of GPCRs) also results in the inhibition of LATS1 activity due to decreased Ser909 and Thr1079 phosphorylation, which results in decreased YAP1 S127 phosphorylation,
n3:mentions
n2:22863277
Subject Item
_:vb24745468
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group of GPCRs) also results in the inhibition of LATS1 activity due to decreased Ser909 and Thr1079 phosphorylation, which results in decreased YAP1 S127 phosphorylation, consequently allowing nuclear accumulation of active YAP [>>125<<]. Moreover, Guan and colleagues found that glucagon and epinephrine act through Gs-coupled receptors to stimulate LATS1 S909/T1079 phosphorylation, followed by phosphorylation and inhibition of YAP by activated LATS1/2 [124].
n3:mentions
n2:22972936
Subject Item
_:vb24745469
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Moreover, Guan and colleagues found that glucagon and epinephrine act through Gs-coupled receptors to stimulate LATS1 S909/T1079 phosphorylation, followed by phosphorylation and inhibition of YAP by activated LATS1/2 [>>124<<]. Significantly, these studies further suggest that GPCR signalling acts through Rho GTPases to trigger changes in LATS1/2 phosphorylation completely independent of MST1/2 signalling [124,125]. This raises the question how Ser909 and
n3:mentions
n2:22863277
Subject Item
_:vb24745470
rdf:type
n3:Context
rdf:value
Significantly, these studies further suggest that GPCR signalling acts through Rho GTPases to trigger changes in LATS1/2 phosphorylation completely independent of MST1/2 signalling [>>124<<,125]. This raises the question how Ser909 and Thr1079 phosphorylation of LATS1/2 is regulated in this setting (see also Table  1). Potentially, changes in actin dynamics modulate these phosphorylation events [2], but the molecular
n3:mentions
n2:22863277
Subject Item
_:vb24745471
rdf:type
n3:Context
rdf:value
Significantly, these studies further suggest that GPCR signalling acts through Rho GTPases to trigger changes in LATS1/2 phosphorylation completely independent of MST1/2 signalling [124,>>125<<]. This raises the question how Ser909 and Thr1079 phosphorylation of LATS1/2 is regulated in this setting (see also Table  1). Potentially, changes in actin dynamics modulate these phosphorylation events [2], but the molecular mechanisms
n3:mentions
n2:22972936
Subject Item
_:vb24745472
rdf:type
n3:Context
rdf:value
Potentially, changes in actin dynamics modulate these phosphorylation events [>>2<<], but the molecular mechanisms are currently not understood.
n3:mentions
n2:23431053
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_:vb24745473
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EGF (epidermal growth factor) signalling seems also to be able to regulate Hippo signalling in MCF10A cells [>>126<<], which is supported by a recent genetic study in Drosophila[89].
n3:mentions
n2:23359693
Subject Item
_:vb24745474
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EGF (epidermal growth factor) signalling seems also to be able to regulate Hippo signalling in MCF10A cells [126], which is supported by a recent genetic study in Drosophila[>>89<<]. However, the role of EGF/EGFR signalling upstream of the Hippo pathway is currently debatable, since data from the Guan laboratory suggest that EGF has no significant effect on YAP phosphorylation [29,124].
n3:mentions
n2:23484853
Subject Item
_:vb24745475
rdf:type
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However, the role of EGF/EGFR signalling upstream of the Hippo pathway is currently debatable, since data from the Guan laboratory suggest that EGF has no significant effect on YAP phosphorylation [>>29<<,124]. In spite of these conflicting results, it is currently undisputed that LATS1/2 also function outside of the canonical Hippo pathway [127]. The Kolch and O’Neill laboratories have shown that K-ras signalling can function upstream of
n3:mentions
n2:17974916
Subject Item
_:vb24745476
rdf:type
n3:Context
rdf:value
However, the role of EGF/EGFR signalling upstream of the Hippo pathway is currently debatable, since data from the Guan laboratory suggest that EGF has no significant effect on YAP phosphorylation [29,>>124<<]. In spite of these conflicting results, it is currently undisputed that LATS1/2 also function outside of the canonical Hippo pathway [127]. The Kolch and O’Neill laboratories have shown that K-ras signalling can function upstream of
n3:mentions
n2:22863277
Subject Item
_:vb24745477
rdf:type
n3:Context
rdf:value
In spite of these conflicting results, it is currently undisputed that LATS1/2 also function outside of the canonical Hippo pathway [>>127<<]. The Kolch and O’Neill laboratories have shown that K-ras signalling can function upstream of MST2-LATS1 in non-canonical Hippo signalling [128,129]. MST2 and LATS1/2 further play a role in Raf-1 activation by regulating the levels of
n3:mentions
n2:20935475
Subject Item
_:vb24745478
rdf:type
n3:Context
rdf:value
The Kolch and O’Neill laboratories have shown that K-ras signalling can function upstream of MST2-LATS1 in non-canonical Hippo signalling [>>128<<,129]. MST2 and LATS1/2 further play a role in Raf-1 activation by regulating the levels of the catalytic phosphatase subunit PP2A-C [130]. Moreover, LATS2 can regulate the levels of the p53 tumour suppressor by binding to Mdm2, the E3
n3:mentions
n2:22195963
Subject Item
_:vb24745479
rdf:type
n3:Context
rdf:value
The Kolch and O’Neill laboratories have shown that K-ras signalling can function upstream of MST2-LATS1 in non-canonical Hippo signalling [128,>>129<<]. MST2 and LATS1/2 further play a role in Raf-1 activation by regulating the levels of the catalytic phosphatase subunit PP2A-C [130]. Moreover, LATS2 can regulate the levels of the p53 tumour suppressor by binding to Mdm2, the E3 ligase
n3:mentions
n2:23459937
Subject Item
_:vb24745480
rdf:type
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rdf:value
MST2 and LATS1/2 further play a role in Raf-1 activation by regulating the levels of the catalytic phosphatase subunit PP2A-C [>>130<<]. Moreover, LATS2 can regulate the levels of the p53 tumour suppressor by binding to Mdm2, the E3 ligase of p53 [75]. LATS1/2 have also been reported as regulators of different G1/S, G2/M, and mitotic cell cycle checkpoints, which have
n3:mentions
n2:20212043
Subject Item
_:vb24745481
rdf:type
n3:Context
rdf:value
Moreover, LATS2 can regulate the levels of the p53 tumour suppressor by binding to Mdm2, the E3 ligase of p53 [>>75<<]. LATS1/2 have also been reported as regulators of different G1/S, G2/M, and mitotic cell cycle checkpoints, which have already been summarised elsewhere [14,127]. Taken together, LATS1/2 are central players in the regulation of YAP/TAZ
n3:mentions
n2:17015431
Subject Item
_:vb24745482
rdf:type
n3:Context
rdf:value
LATS1/2 have also been reported as regulators of different G1/S, G2/M, and mitotic cell cycle checkpoints, which have already been summarised elsewhere [>>14<<,127]. Taken together, LATS1/2 are central players in the regulation of YAP/TAZ functions in cancer and stem cell biology, although LATS1/2 also play significant roles in non-canonical Hippo signalling and even Hippo independent pathways.
n3:mentions
n2:22525225
Subject Item
_:vb24745483
rdf:type
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rdf:value
LATS1/2 have also been reported as regulators of different G1/S, G2/M, and mitotic cell cycle checkpoints, which have already been summarised elsewhere [14,>>127<<]. Taken together, LATS1/2 are central players in the regulation of YAP/TAZ functions in cancer and stem cell biology, although LATS1/2 also play significant roles in non-canonical Hippo signalling and even Hippo independent pathways.
n3:mentions
n2:20935475
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_:vb24745484
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NDR1 KO mice are viable, but develop T-cell lymphoma, most likely due to defective pro-apoptotic signalling [>>131<<]. NDR2 KO mice or NDR1/2 DKO animals have not been reported yet, however, dogs carrying a mutation in NDR2 display retinal degeneration [132]. Furthermore, it has been reported that human NDR1/2 play a role in centrosome duplication in
n3:mentions
n2:20551432
Subject Item
_:vb24745485
rdf:type
n3:Context
rdf:value
NDR2 KO mice or NDR1/2 DKO animals have not been reported yet, however, dogs carrying a mutation in NDR2 display retinal degeneration [>>132<<]. Furthermore, it has been reported that human NDR1/2 play a role in centrosome duplication in S-phase [43,133], contribute to mitotic progression [134,135], and regulate the G1/S cell cycle transition by phosphorylating p21 [45].
n3:mentions
n2:20887780
Subject Item
_:vb24745486
rdf:type
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rdf:value
Furthermore, it has been reported that human NDR1/2 play a role in centrosome duplication in S-phase [>>43<<,133], contribute to mitotic progression [134,135], and regulate the G1/S cell cycle transition by phosphorylating p21 [45].
n3:mentions
n2:19836237
Subject Item
_:vb24745487
rdf:type
n3:Context
rdf:value
Furthermore, it has been reported that human NDR1/2 play a role in centrosome duplication in S-phase [43,>>133<<], contribute to mitotic progression [134,135], and regulate the G1/S cell cycle transition by phosphorylating p21 [45].
n3:mentions
n2:17317633
Subject Item
_:vb24745488
rdf:type
n3:Context
rdf:value
Furthermore, it has been reported that human NDR1/2 play a role in centrosome duplication in S-phase [43,133], contribute to mitotic progression [>>134<<,135], and regulate the G1/S cell cycle transition by phosphorylating p21 [45].
n3:mentions
n2:19327996
Subject Item
_:vb24745489
rdf:type
n3:Context
rdf:value
Furthermore, it has been reported that human NDR1/2 play a role in centrosome duplication in S-phase [43,133], contribute to mitotic progression [134,>>135<<], and regulate the G1/S cell cycle transition by phosphorylating p21 [45].
n3:mentions
n2:20171103
Subject Item
_:vb24745490
rdf:type
n3:Context
rdf:value
Furthermore, it has been reported that human NDR1/2 play a role in centrosome duplication in S-phase [43,133], contribute to mitotic progression [134,135], and regulate the G1/S cell cycle transition by phosphorylating p21 [>>45<<]. Moreover, NDR1 regulates the protein stability of the proto-oncoprotein c-myc [45,136-138]. However, the mechanism of c-myc regulation by NDR1 is currently debatable, since Califano and colleagues reported that it is kinase activity
n3:mentions
n2:21262772
Subject Item
_:vb24745491
rdf:type
n3:Context
rdf:value
Moreover, NDR1 regulates the protein stability of the proto-oncoprotein c-myc [>>45<<,136-138]. However, the mechanism of c-myc regulation by NDR1 is currently debatable, since Califano and colleagues reported that it is kinase activity dependent [136], while the Hemmings laboratory argues it is independent of NDR1
n3:mentions
n2:21262772
Subject Item
_:vb24745492
rdf:type
n3:Context
rdf:value
Moreover, NDR1 regulates the protein stability of the proto-oncoprotein c-myc [45,>>136<<-138]. However, the mechanism of c-myc regulation by NDR1 is currently debatable, since Califano and colleagues reported that it is kinase activity dependent [136], while the Hemmings laboratory argues it is independent of NDR1 activity
n3:mentions
n2:21593588 n2:19741643
Subject Item
_:vb24745493
rdf:type
n3:Context
rdf:value
However, the mechanism of c-myc regulation by NDR1 is currently debatable, since Califano and colleagues reported that it is kinase activity dependent [136], while the Hemmings laboratory argues it is independent of NDR1 activity [>>45<<,137]. Taken together, these reports suggest that NDR1/2 are important cell cycle regulators.
n3:mentions
n2:21262772
Subject Item
_:vb24745494
rdf:type
n3:Context
rdf:value
However, the mechanism of c-myc regulation by NDR1 is currently debatable, since Califano and colleagues reported that it is kinase activity dependent [136], while the Hemmings laboratory argues it is independent of NDR1 activity [45,>>137<<]. Taken together, these reports suggest that NDR1/2 are important cell cycle regulators.
n3:mentions
n2:21593588
Subject Item
_:vb24745495
rdf:type
n3:Context
rdf:value
The regulation of the G1/S cell cycle transition by NDR1/2 can be explained by the negative regulation of the p21 cell cycle inhibitor combined with the positive regulation of c-myc levels [>>137<<]. However, the substrates functioning downstream of NDR1/2 in S-phase and mitosis are yet to be defined.
n3:mentions
n2:21593588
Subject Item
_:vb24745496
rdf:type
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NDR1 functions additionally in apoptotic signalling [>>44<<,60,131], and has also been reported to play some role in oxidative stress MAPK (mitogen-activated protein kinase) signalling [139,140].
n3:mentions
n2:19062280
Subject Item
_:vb24745497
rdf:type
n3:Context
rdf:value
NDR1 functions additionally in apoptotic signalling [44,>>60<<,131], and has also been reported to play some role in oxidative stress MAPK (mitogen-activated protein kinase) signalling [139,140].
n3:mentions
n2:21730291
Subject Item
_:vb24745498
rdf:type
n3:Context
rdf:value
NDR1 functions additionally in apoptotic signalling [44,60,>>131<<], and has also been reported to play some role in oxidative stress MAPK (mitogen-activated protein kinase) signalling [139,140].
n3:mentions
n2:20551432
Subject Item
_:vb24745499
rdf:type
n3:Context
rdf:value
NDR1 functions additionally in apoptotic signalling [44,60,131], and has also been reported to play some role in oxidative stress MAPK (mitogen-activated protein kinase) signalling [>>139<<,140]. Furthermore, NDR2 has recently been described as regulator of ciliogenesis via phosphorylating Rabin 8 [102].
n3:mentions
n2:17906693
Subject Item
_:vb24745500
rdf:type
n3:Context
rdf:value
NDR1 functions additionally in apoptotic signalling [44,60,131], and has also been reported to play some role in oxidative stress MAPK (mitogen-activated protein kinase) signalling [139,>>140<<]. Furthermore, NDR2 has recently been described as regulator of ciliogenesis via phosphorylating Rabin 8 [102].
n3:mentions
n2:22142472
Subject Item
_:vb24745501
rdf:type
n3:Context
rdf:value
Furthermore, NDR2 has recently been described as regulator of ciliogenesis via phosphorylating Rabin 8 [>>102<<]. Last, but not least, Jan and colleagues reported recently [101] the identification of the first NDR1/2 substrates in neurons (see Tables  2 and 3). The authors functionally validated two substrates, showing that AAK1 and Rabin 8
n3:mentions
n2:23435566
Subject Item
_:vb24745502
rdf:type
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rdf:value
Last, but not least, Jan and colleagues reported recently [>>101<<] the identification of the first NDR1/2 substrates in neurons (see Tables  2 and 3).
n3:mentions
n2:22445341
Subject Item
_:vb24745503
rdf:type
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rdf:value
The authors functionally validated two substrates, showing that AAK1 and Rabin 8 function downstream of NDR1/2 in neuronal dendrite and synapse formation [>>101<<]. In summary, NDR1/2 function in the regulation of cell cycle progression, centrosome biology, stress/apoptotic signalling, and neuronal dendrite/synapse formation.
n3:mentions
n2:22445341
Subject Item
_:vb24745504
rdf:type
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rdf:value
As already mentioned NDR1/2 kinases play a part in centrosome biology, most likely by associating with centrosomes [>>43<<,102,133]. LATS1/2 have also been detected on centrosomes [4], but the centrosomal function of LATS1/2 is currently not well understood.
n3:mentions
n2:19836237
Subject Item
_:vb24745505
rdf:type
n3:Context
rdf:value
As already mentioned NDR1/2 kinases play a part in centrosome biology, most likely by associating with centrosomes [43,>>102<<,133]. LATS1/2 have also been detected on centrosomes [4], but the centrosomal function of LATS1/2 is currently not well understood.
n3:mentions
n2:23435566
Subject Item
_:vb24745506
rdf:type
n3:Context
rdf:value
As already mentioned NDR1/2 kinases play a part in centrosome biology, most likely by associating with centrosomes [43,102,>>133<<]. LATS1/2 have also been detected on centrosomes [4], but the centrosomal function of LATS1/2 is currently not well understood.
n3:mentions
n2:17317633
Subject Item
_:vb24745507
rdf:type
n3:Context
rdf:value
LATS1/2 have also been detected on centrosomes [>>4<<], but the centrosomal function of LATS1/2 is currently not well understood.
n3:mentions
n2:16607288
Subject Item
_:vb24745508
rdf:type
n3:Context
rdf:value
Nevertheless, two factors involved in centrosome-based ciliogenesis, NPHP4 and 9 (nephrocystin proteins 4 and 9), have been shown to regulate YAP/TAZ function [>>141<<,142]. NPHP4 interacts with LATS1 and inhibits LATS1 mediated phosphorylation of YAP and TAZ [141,142], while NPHP9 targets TAZ to the nucleus in a TAZ/NPHP9 complex [142]. Whether these regulatory processes involve cytoskeletal changes is
n3:mentions
n2:21555462
Subject Item
_:vb24745509
rdf:type
n3:Context
rdf:value
Nevertheless, two factors involved in centrosome-based ciliogenesis, NPHP4 and 9 (nephrocystin proteins 4 and 9), have been shown to regulate YAP/TAZ function [141,>>142<<]. NPHP4 interacts with LATS1 and inhibits LATS1 mediated phosphorylation of YAP and TAZ [141,142], while NPHP9 targets TAZ to the nucleus in a TAZ/NPHP9 complex [142]. Whether these regulatory processes involve cytoskeletal changes is
n3:mentions
n2:23026745
Subject Item
_:vb24745510
rdf:type
n3:Context
rdf:value
NPHP4 interacts with LATS1 and inhibits LATS1 mediated phosphorylation of YAP and TAZ [>>141<<,142], while NPHP9 targets TAZ to the nucleus in a TAZ/NPHP9 complex [142].
n3:mentions
n2:21555462
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NPHP4 interacts with LATS1 and inhibits LATS1 mediated phosphorylation of YAP and TAZ [141,>>142<<], while NPHP9 targets TAZ to the nucleus in a TAZ/NPHP9 complex [142].
n3:mentions
n2:23026745
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NPHP4 interacts with LATS1 and inhibits LATS1 mediated phosphorylation of YAP and TAZ [141,142], while NPHP9 targets TAZ to the nucleus in a TAZ/NPHP9 complex [>>142<<]. Whether these regulatory processes involve cytoskeletal changes is currently unclear, although YAP/TAZ are downstream effectors of changes in the extracellular matrix, cell adhesion, cell shape and the cytoskeleton [143].
n3:mentions
n2:23026745
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Whether these regulatory processes involve cytoskeletal changes is currently unclear, although YAP/TAZ are downstream effectors of changes in the extracellular matrix, cell adhesion, cell shape and the cytoskeleton [>>143<<].
n3:mentions
n2:22895435
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In Drosophila and human cells F-actin remodelling alters Hippo signalling [>>144<<]. Piccolo and colleagues found that YAP/TAZ are downstream of mechanical signals that are influenced by extracellular matrix rigidity and cell shape [145]. Significantly, this process is dependent on Rho GTPase activity and F-actin
n3:mentions
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Piccolo and colleagues found that YAP/TAZ are downstream of mechanical signals that are influenced by extracellular matrix rigidity and cell shape [>>145<<]. Significantly, this process is dependent on Rho GTPase activity and F-actin dynamics, but appears to be independent of LATS1/2 signalling [145]. The Sasaki laboratory also reported a regulation of YAP by cell morphology in an F-actin
n3:mentions
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Significantly, this process is dependent on Rho GTPase activity and F-actin dynamics, but appears to be independent of LATS1/2 signalling [>>145<<]. The Sasaki laboratory also reported a regulation of YAP by cell morphology in an F-actin dependent manner, although their data suggest that LATS1/2 are involved in this process [114]. In support of the model which places F-actin
n3:mentions
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The Sasaki laboratory also reported a regulation of YAP by cell morphology in an F-actin dependent manner, although their data suggest that LATS1/2 are involved in this process [>>114<<]. In support of the model which places F-actin dynamics upstream of LATS1/2 to regulate YAP, Zhao et al. showed that cell attachment and cytoskeleton remodelling regulates LATS1/2 activity and consequently YAP activity [146]. Moreover, in
n3:mentions
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In support of the model which places F-actin dynamics upstream of LATS1/2 to regulate YAP, Zhao et al. showed that cell attachment and cytoskeleton remodelling regulates LATS1/2 activity and consequently YAP activity [>>146<<]. Moreover, in human cells GPCR signalling acts through F-actin remodelling to trigger changes in LATS1/2 activity towards YAP/TAZ [124,125]. Based on these findings the role of LATS1/2 in these settings is debatable, however, all these
n3:mentions
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Moreover, in human cells GPCR signalling acts through F-actin remodelling to trigger changes in LATS1/2 activity towards YAP/TAZ [>>124<<,125]. Based on these findings the role of LATS1/2 in these settings is debatable, however, all these studies fully agree that YAP/TAZ function as sensors and mediators of mechanical inputs which are influenced by the cellular architecture
n3:mentions
n2:22863277
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Moreover, in human cells GPCR signalling acts through F-actin remodelling to trigger changes in LATS1/2 activity towards YAP/TAZ [124,>>125<<]. Based on these findings the role of LATS1/2 in these settings is debatable, however, all these studies fully agree that YAP/TAZ function as sensors and mediators of mechanical inputs which are influenced by the cellular architecture and
n3:mentions
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Intriguingly, it has been reported that LATS1 can bind to actin and inhibit actin polymerisation [>>147<<]. Moreover, LATS1 interacts with Zyxin [148] and LIMK1 [149], two regulators of actin filament assembly.
n3:mentions
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Moreover, LATS1 interacts with Zyxin [>>148<<] and LIMK1 [149], two regulators of actin filament assembly.
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Moreover, LATS1 interacts with Zyxin [148] and LIMK1 [>>149<<], two regulators of actin filament assembly.
n3:mentions
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Whatever the case, in Drosophila, mutation of Warts results in altered F-actin levels [>>150<<], suggesting that Warts is required for normal actin dynamics.
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Not surprisingly, the same study also showed that Trc mutants have altered levels of F-actin [>>150<<], because it has already been speculated since the year 2000 that the actin cytoskeleton might be a Trc target [15].
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Not surprisingly, the same study also showed that Trc mutants have altered levels of F-actin [150], because it has already been speculated since the year 2000 that the actin cytoskeleton might be a Trc target [>>15<<]. However, it is currently not established whether NDR1/2 kinases can also regulate F-actin remodelling, although a NDR2/actin complex has been reported nearly a decade ago [151]. In summary, actinomyosin dynamics play an important role
n3:mentions
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However, it is currently not established whether NDR1/2 kinases can also regulate F-actin remodelling, although a NDR2/actin complex has been reported nearly a decade ago [>>151<<]. In summary, actinomyosin dynamics play an important role in the control of the Hippo pathway.
n3:mentions
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conclusions
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Besides F-actin remodelling, changes in the microtubule cytoskeleton should also to be considered in future studies, since the Guan laboratory could already show that LATS1/2 activity is modulated by anti-microtubule drugs [>>146<<]. It is noteworthy that hMOB1A/B, a key regulator of LATS/NDR kinases [39], has recently been shown to control microtubule dynamics [152], suggesting that LATS/NDR might also function as regulators of the microtubule cytoskeleton.
n3:mentions
n2:22215811
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It is noteworthy that hMOB1A/B, a key regulator of LATS/NDR kinases [>>39<<], has recently been shown to control microtubule dynamics [152], suggesting that LATS/NDR might also function as regulators of the microtubule cytoskeleton.
n3:mentions
n2:21539912
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It is noteworthy that hMOB1A/B, a key regulator of LATS/NDR kinases [39], has recently been shown to control microtubule dynamics [>>152<<], suggesting that LATS/NDR might also function as regulators of the microtubule cytoskeleton.
n3:mentions
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Importantly, in this context, cell type dependent roles must be considered, since MST1/2 is dispensable for LATS1/2 signalling in MEFs, but not in HeLa cells [>>146<<].
n3:mentions
n2:22215811
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it is worth mentioning that McCollum and colleagues recently reported that the activities of the yeast LATS/NDR kinases Sid2 and Orb6 are cross-regulated by Sid2 phosphorylating Nak1, the upstream Hippo kinase of Orb6 in yeast [>>153<<]. This raises the interesting possibility that human LATS1/2 and/or NDR1/2 might function upstream of each other in specific settings.
n3:mentions
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The recently reported mitochondrial role of Trc [>>154<<] will potentially provide a further platform to discover more roles of NDR1/2 in mammals.
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