The Tumor Suppressor DAPK Is Reciprocally Regulated by Tyrosine Kinase Src and Phosphatase LAR

Wang, Won Jing; Kuo, Jean Cheng; Ku, Wei-Chi; Lee, Yu-Ru; Lin, Feng; Chang, Yih‐Leong; Lin, Yu Min; Chen, Chun Hau; Huang, Yuan; Chiang, Meng Jung; Yeh, Sheng Wen; Wu, Pei-Shan; Shen, Che Hung; Wu, Chen; Chen, Ruey‐Hwa

doi:10.1016/j.molcel.2007.06.037

Cited by 70 publications

(73 citation statements)

References 36 publications

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“…6A) (Wang et al, 2007). These mutations within the intracellular phosphatase domain D1 allow LAR to interact with substrates but reduce its dephosphorylation activity (Wang et al, 2007). Using this approach, we identified that both the LAR trapping mutants and WT LAR interacted with c-Abl (Fig.…”

Section: Inhibition Of C-abl Restores Activation Of Akt and Cdk1 In Cmentioning

confidence: 98%

“…To establish whether c-Abl is a LAR substrate, we transfected 293T cells with cDNA constructs expressing either WT LAR or one of two LAR substrate-trapping mutants, LAR C/S (C1548S) or LAR D/A (D1516A) (Fig. 6A) (Wang et al, 2007). These mutations within the intracellular phosphatase domain D1 allow LAR to interact with substrates but reduce its dephosphorylation activity (Wang et al, 2007).…”

Section: Inhibition Of C-abl Restores Activation Of Akt and Cdk1 In Cmentioning

confidence: 99%

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LAR protein tyrosine phosphatase regulates focal adhesions through CDK1

Sarhan

Patel

Cowell

et al. 2016

Journal of Cell Science

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Focal adhesions are complex multi-molecular structures that link the actin cytoskeleton to the extracellular matrix through integrin adhesion receptors and play a key role in regulation of many cellular functions. LAR (also known as PTPRF) is a receptor protein tyrosine phosphatase that regulates PDGF signalling and localises to focal adhesions. We have observed that loss of LAR phosphatase activity in mouse embryonic fibroblasts results in reduced numbers of focal adhesions and decreased adhesion to fibronectin. To understand how LAR regulates cell adhesion we used phosphoproteomic data, comparing global phosphorylation events in wild-type and LAR phosphatase-deficient cells, to analyse differential kinase activity. Kinase prediction analysis of LAR-regulated phosphosites identified a node of cytoskeleton-and adhesion-related proteins centred on cyclin-dependent kinase-1 (CDK1). We found that loss of LAR activity resulted in reduced activity of CDK1, and that CDK1 activity was required for LAR-mediated focal adhesion complex formation. We also established that LAR regulates CDK1 activity through c-Abl and Akt family proteins. In summary, we have identified a new role for a receptor protein tyrosine phosphatase in regulating CDK1 activity and hence cell adhesion to the extracellular matrix.

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Section: Inhibition Of C-abl Restores Activation Of Akt and Cdk1 In Cmentioning

confidence: 98%

Section: Inhibition Of C-abl Restores Activation Of Akt and Cdk1 In Cmentioning

confidence: 99%

LAR protein tyrosine phosphatase regulates focal adhesions through CDK1

Sarhan

Patel

Cowell

et al. 2016

Journal of Cell Science

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“…For this reason, we decided to go deeply in methylation study of control of Src pathway. We selected genes involved or related with Src pathway, already described in the literature as methylated-controled genes: SOCS1, competitive inhibition with Src protein for the receptor [17]; TWIST1, directly involve in Src control of Epithelial Mesenquimal Transition (EMT) and ductal carcinomas specificity, mainly through cadherins [18]; TIMP3 related with Src control of metastasis via matrix metalloproteases (MMPs) [19]; and DAPK, as key point in Src control of migration/invasion and apoptosis [20]. Epigenetic studies of new genes directly involved in Src pathway (SOCS1, TIMP3, TWIST1 and DAPK) results in a clear epigenetic expression control from 23.5 to 98% as mechanism implicated in development and progression of PDA.…”

Section: Discussionmentioning

confidence: 99%

Pancreatic Ductal Adenocarcinoma: Implications of Epigenetic Role Related the Src Pathway

Me¹

2013

J Cancer Sci Ther

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Epigenetic has become, in recent years, in a very important process in the control of several pathologies, including cancer. DNA methylation has been described in numerous studies as crucial for differentiation control, cell proliferation and invasion in cancer.Pancreas ductal adenocarcinoma is one of the most deadly diseases of our society; its complexity and variability have become one of the medical challenges of this decade. Combining the potential of epigenetic with the high mortality and the limited knowledge of pancreatic ductal adenocarcinoma origin, may result in new approaches for diagnosis, treatment and monitoring, crucial in this pathology.For this purpose, we analyzed genes involved in different cellular processes (GSTP1, p16, RASFF1A, RARβ2, CyclinD2, HIN-1, SOCS1, TIMP3, DAPK and TWIST1) in 61 cases of pancreatic ductal adenocarcinoma. A first approach led us to analyze the Src pathway, never studied in this sense, as crucial in the development of this pathology. Clusters for clinicopathological characteristics and epigenetic profiles were obtained.The high degree of methylation of these adenocarcinomas, and the statistical relationship between Src pathway methylation and clinicopathological profile, has been postulated, for the first time. These results show the importance of this pathway in pancreatic disease, opening a new challenge for research and therapy.

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“…Src phosphorylates DAPK at Y491/492, which induces DAPK intra-/intermolecular interaction and inactivation (Wang et al, 2007).…”

Section: Phosphorylation Sitesmentioning

confidence: 99%