The role of protein tyrosine phosphatase 1B in Ras signaling

Dubé, Nadia; Cheng, Alan; Tremblay, Michel L.

doi:10.1073/pnas.0304242101

Cited by 130 publications

(108 citation statements)

References 36 publications

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“…It is interesting to note that PTP1B has also been reported to promote RAS signaling through an indirect mechanism. It does so by dephosphorylation of the p62DOK scaffold protein, which in turn leads to decreased levels of the Ras GTPase-activating protein p120RasGAP, an inhibitor of RAS signaling (44). These observations provide further illustration of the potential for PTP1B to exert specific effects on the regulation of cell signaling.…”

Section: Discussionmentioning

confidence: 72%

Protein-tyrosine Phosphatase and Kinase Specificity in Regulation of SRC and Breast Tumor Kinase*

Fan

Aleem

Yang

et al. 2015

Journal of Biological Chemistry

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Background:The view that, unlike kinases, phosphatases are "nonspecific" pervades the field. Results: PTP1B inhibited BRK by dephosphorylating Tyr-342, but activated SRC by antagonizing PAG-dependent inhibition by CSK. Conclusion: Signaling is regulated by combinatorial effects of PTKs and PTPs, with both enzyme classes displaying exquisite specificity. Significance: Defining phosphatase substrate specificity will reveal new, more effective strategies for therapeutic intervention in major human diseases.

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Section: Discussionmentioning

confidence: 72%

Protein-tyrosine Phosphatase and Kinase Specificity in Regulation of SRC and Breast Tumor Kinase*

Fan

Aleem

Yang

et al. 2015

Journal of Biological Chemistry

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“…Of note, tyrosine phosphorylation of cellular proteins (including Dok-1) reached the maximum after 15 min of PDGF treatment, after which it gradually declined, reaching basal levels at 2 h following PDGF addition. Thus, Dok-1 degradation could be dependent on prolonged activation of tyrosine kinase signaling, as opposed to only transient activation by growth factor stimulation (22). Alternatively, however, growth factors and OTKs may induce distinct patterns of posttranslational modifications on Dok-1, thereby differently influencing its stability.…”

Section: Discussionmentioning

confidence: 99%

Oncogenic Tyrosine Kinases Target Dok-1 for Ubiquitin-Mediated Proteasomal Degradation To Promote Cell Transformation

Janas

Aelst

2011

Molecular and Cellular Biology

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Cellular transformation induced by oncogenic tyrosine kinases is a multistep process involving activation of growth-promoting signaling pathways and inactivation of suppressor molecules. Dok-1 is an adaptor protein that acts as a negative regulator of tyrosine kinase-initiated signaling and opposes oncogenic tyrosine kinasemediated cell transformation. Findings that its loss facilitates transformation induced by oncogenic tyrosine kinases suggest that Dok-1 inactivation could constitute an intermediate step in oncogenesis driven by these oncoproteins. However, whether Dok-1 is subject to regulation by oncogenic tyrosine kinases remained unknown. In this study, we show that oncogenic tyrosine kinases, including p210 bcr-abl and oncogenic forms of Src, downregulate Dok-1 by targeting it for degradation through the ubiquitin-proteasome pathway. This process is dependent on the tyrosine kinase activity of the oncoproteins and is mediated primarily by lysine-dependent polyubiquitination of Dok-1. Importantly, restoration of Dok-1 levels strongly suppresses transformation of cells expressing oncogenic tyrosine kinases, and this suppression is more pronounced in the context of a Dok-1 mutant that is largely refractory to oncogenic tyrosine kinase-induced degradation. Our findings suggest that proteasome-mediated downregulation of Dok-1 is a key mechanism by which oncogenic tyrosine kinases overcome the inhibitory effect of Dok-1 on cellular transformation and tumor progression.Protein tyrosine kinases (PTKs), of which more than 90 are encoded by the human genome, are key regulators of intracellular signal transduction pathways that control a variety of cellular processes, such as proliferation, differentiation, survival, cell movement, and cytoskeletal organization (46,52). Under physiological conditions, the activity of these kinases, including receptor and cytoplasmic PTKs, is tightly controlled to maintain cell and tissue homeostasis. However, when deregulated, due to, for example, mutations, gene amplifications, or impaired deactivation of the PTK, this control is lost, leading to aberrant downstream signaling, which can result in malignant transformation. To date, deregulation of more than 50 human PTKs has been implicated in the pathogenesis of various solid tumors and hematologic malignancies (2, 7, 36).Significant progress has been made toward unraveling the mechanisms of oncogenic activation of PTKs. Also, numerous studies have identified key signaling molecules and pathways that are activated by oncogenic tyrosine kinases (OTKs) and participate in mediating their effects on malignant transformation (45,55,57,71,72,75). However, besides triggering positive signaling events, OTKs also need to overcome negative regulatory constraints to drive tumor initiation and/or progression (7,24,42,57). These include, for instance, constraints brought about by tumor suppressors or inhibitory molecules that counteract the signaling activity triggered by the OTKs (17, 69). The nature of these "negative regulators" and, import...

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“…The list of genes highly expressed in the INV library (Table 2) includes some genes already known to be linked to cancer, such as ADNP, implicated in maintaining cell survival (28); TGFA, which has a role in breast tumor growth and progression (29,30); CTGF, which stimulates angiogenesis (31); CCNA2, an oncogene overexpressed in liver tumors (32); SPY1, which induces cellcycle progression (33); PTPN1, an activator of the cSrc and RAS signaling pathway, amplified in ovarian cancer (34); and YKT6 (also called SNARE), which is associated with invasive and metastatic phenotypes in breast cancer (35). The list of genes highly expressed in the INV library also includes genes not previously associated with the genesis of cancer, such as CYFIP1, SNCAIP, and ANKRD10; 11 no-matching tags and 29 tags matching to ESTs or mRNAs encoding for hypothetical proteins.…”

Section: Sage Librarymentioning

confidence: 99%

Gene expression profiles of epithelial cells microscopically isolated from a breast-invasive ductal carcinoma and a nodal metastasis

Zucchi

Mento

Kuznetsov

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Expression profiles of breast carcinomas are difficult to interpret when they are obtained from tissue in toto, which may contain a large proportion of non-cancer cells. To avoid this problem, we microscopically isolated cells from a primary invasive ductal carcinoma of the breast and from an axillary node harboring a metastatic breast carcinoma, to obtain pure populations of carcinoma cells (Ϸ500) and used them for serial analysis of gene expression. The expression profiles generated from both populations of cells were compared with the profile of a disease-free mammary epithelium. We showed that the expression profiles obtained are exclusive of carcinoma cells with no contribution of non-epithelial cells. From a total of 16,939 unique tags analyzed, we detected 559 statistically significant changes in gene expression; some of these genes have not been previously associated with breast cancer. We observed that many of the down-regulated genes are the same in both cancers, whereas the up-regulated genes are completely different, suggesting that the down-regulation of a set of genes may be the basic mechanism of cancer formation, while the up-regulation may characterize and possibly control the state of evolution of individual cancers. The results obtained may help in characterizing the neoplastic process of breast cancer.breast cancer ͉ serial analysis of gene expression ͉ cell microdissection ͉ carcinoma

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The role of protein tyrosine phosphatase 1B in Ras signaling

Cited by 130 publications

References 36 publications

Protein-tyrosine Phosphatase and Kinase Specificity in Regulation of SRC and Breast Tumor Kinase*

Protein-tyrosine Phosphatase and Kinase Specificity in Regulation of SRC and Breast Tumor Kinase*

Oncogenic Tyrosine Kinases Target Dok-1 for Ubiquitin-Mediated Proteasomal Degradation To Promote Cell Transformation

Gene expression profiles of epithelial cells microscopically isolated from a breast-invasive ductal carcinoma and a nodal metastasis

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