Regulation of the Mitogen-activated Protein Kinase Signaling Pathway by SHP2

Cunnick, Joan E.; Shao, Meng; Ren, Yuan; Desponts, Caroline; Wang, Hong Gang; Djeu, Julie Y.; Wu, Jie

doi:10.1074/jbc.m110547200

Cited by 145 publications

(118 citation statements)

References 32 publications

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“…SRC and SHP2, two putative Tyr-567 interactors, are likely to be upstream activators of MAPKs in KIT signaling (37,43). We observed that SOCS6 partially inhibited ERK and p38 FIG.…”

Section: Discussionmentioning

confidence: 64%

Suppressor of Cytokine Signaling 6 Associates with KIT and Regulates KIT Receptor Signaling

Bayle

Letard

Frank

et al. 2004

Journal of Biological Chemistry

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Suppressor of cytokine signaling (SOCS) proteins are a family of Src homology 2-containing adaptor proteins. Cytokine-inducible Src homology domain 2-containing protein, SOCS1, SOCS2, and SOCS3 have been implicated in the down-regulation of cytokine signaling. The function of SOCS4, 5, 6, and 7 are not known. KIT receptor signaling is regulated by protein tyrosine phosphatases and adaptor proteins. We previously reported that SOCS1 inhibited cell proliferation in response to stem cell factor (SCF Cytokines and growth factors regulate the survival, proliferation, differentiation, and migration of hematopoietic cells. Binding of these factors to transmembrane receptors induces receptor activation, which in turn results in the recruitment of signaling complexes in the vicinity of the plasma membrane. The kinetics and magnitude of signal transduction are tightly regulated by multiple mechanisms. Among proteins that modulate signaling, members of the suppressor of cytokine signaling (SOCS) 1 family have been shown to down-regulate the function of cytokines or growth factors (1-3).The eight members of the SOCS family, SOCS1-7 and CIS (cytokine-inducible Src homology domain (SH2)-containing protein), are structurally characterized by a SH2 domain followed by a conserved C-terminal motif, the SOCS box (4). The N-terminal region of SOCS proteins is variable both in length and in the primary amino acid sequence. Although many reports including knock-out studies shed light on the function of CIS (5, 6), SOCS1 (7, 8), SOCS2 (9, 10), and SOCS3 (11-13), very little is known regarding the function of SOCS4, SOCS5, SOCS6, and SOCS7.The mechanisms whereby CIS, SOCS1, and SOCS3 inhibit signaling by classical cytokine receptor (i.e. receptors without catalytic activity that associate with JAK tyrosine kinases) are the best characterized. All three are involved in the downregulation of the JAK/STAT pathway. SOCS1 has a dual function as a direct potent JAK kinase inhibitor (14 -17) and as a component of an E3 ubiquitin-ligase complex recruiting substrates to the protein degradation machinery (18 -20). SOCS3 also inhibits JAK activity but indirectly through recruitment to the cytokine receptors (1, 21). More recently, SOCS3 has been suggested to compete with SHP2 for the same binding sites on glycoprotein 130 (22, 23), erythropoietin receptor (21), and leptin receptor (24). CIS binds to cytokine receptors at STAT5-docking sites, which impairs recruitment of STAT5 to the receptor signaling complex and results in the down-regulation of STAT5 activation (6,25).Mice lacking SOCS6 have been generated, and they developed normally with the exception of a 10% reduction in weight compared with wild-type littermates (26). SOCS6 mRNA was induced by erythropoietin in cell lines (27) and was ubiquitously expressed in murine tissues (26). SOCS6 does not interact with JAKs, but the interaction with elongins B and C suggests that, as all SOCS proteins, it might be part of an E3 ubiquitin-ligase complex (28). Yet, there is no evidence so far suggesti...

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“…SRC and SHP2, two putative Tyr-567 interactors, are likely to be upstream activators of MAPKs in KIT signaling (37,43). We observed that SOCS6 partially inhibited ERK and p38 FIG.…”

Section: Discussionmentioning

confidence: 64%

Suppressor of Cytokine Signaling 6 Associates with KIT and Regulates KIT Receptor Signaling

Bayle

Letard

Frank

et al. 2004

Journal of Biological Chemistry

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“…2g). This fusion protein was shown to constitutively induce MAP kinase activation without extracellular ligand stimulation (42). We found that daSHP2-transfected MDCK cells were capable of forming tubular structures in collagen gels in the absence of HGF/SF (Fig.…”

Section: Phps1mentioning

confidence: 80%

Specific inhibitors of the protein tyrosine phosphatase Shp2 identified by high-throughput docking

Hellmuth

Grosskopf

Lum

et al. 2008

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

200

182

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The protein tyrosine phosphatase Shp2 is a positive regulator of growth factor signaling. Gain-of-function mutations in several types of leukemia define Shp2 as a bona fide oncogene. We performed a high-throughput in silico screen for small-molecular-weight compounds that bind the catalytic site of Shp2. We have identified the phenylhydrazonopyrazolone sulfonate PHPS1 as a potent and cellpermeable inhibitor, which is specific for Shp2 over the closely related tyrosine phosphatases Shp1 and PTP1B. PHPS1 inhibits Shp2-dependent cellular events such as hepatocyte growth factor/scatter factor (HGF/SF)-induced epithelial cell scattering and branching morphogenesis. PHPS1 also blocks Shp2-dependent downstream signaling, namely HGF/SF-induced sustained phosphorylation of the Erk1/2 MAP kinases and dephosphorylation of paxillin. Furthermore, PHPS1 efficiently inhibits activation of Erk1/2 by the leukemia-associated Shp2 mutant, Shp2-E76K, and blocks the anchorage-independent growth of a variety of human tumor cell lines. The PHPS compound class is therefore suitable for further development of therapeutics for the treatment of Shp2-dependent diseases.chemical biology ͉ growth factor signaling ͉ phosphatase inhibition ͉ virtual drug screening

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“…Activity of this phosphatase is often associated with increased signaling activity (43,44). This phosphatase was highly phosphorylated on Y 62 and Y 584 in AKT/AR and AKT/ ERG tumors, respectively.…”

Section: Discussionmentioning

confidence: 99%

Oncogene-specific activation of tyrosine kinase networks during prostate cancer progression

Drake

Graham²,

Stoyanova

et al. 2012

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

144

148

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Dominant mutations or DNA amplification of tyrosine kinases are rare among the oncogenic alterations implicated in prostate cancer. We demonstrate that castration-resistant prostate cancer (CRPC) in men exhibits increased tyrosine phosphorylation, raising the question of whether enhanced tyrosine kinase activity is observed in prostate cancer in the absence of specific tyrosine kinase mutation or DNA amplification. We generated a mouse model of prostate cancer progression using commonly perturbed non-tyrosine kinase oncogenes and pathways and detected a significant up-regulation of tyrosine phosphorylation at the carcinoma stage. Phosphotyrosine peptide enrichment and quantitative mass spectrometry identified oncogene-specific tyrosine kinase signatures, including activation of EGFR, ephrin type-A receptor 2 (EPHA2), and JAK2. Kinase:substrate relationship analysis of the phosphopeptides also revealed ABL1 and SRC tyrosine kinase activation. The observation of elevated tyrosine kinase signaling in advanced prostate cancer and identification of specific tyrosine kinase pathways from genetically defined tumor models point to unique therapeutic approaches using tyrosine kinase inhibitors for advanced prostate cancer.AKT | androgen receptor | ERG | K-RAS | bioinformatics

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Regulation of the Mitogen-activated Protein Kinase Signaling Pathway by SHP2

Cited by 145 publications

References 32 publications

Suppressor of Cytokine Signaling 6 Associates with KIT and Regulates KIT Receptor Signaling

Suppressor of Cytokine Signaling 6 Associates with KIT and Regulates KIT Receptor Signaling

Specific inhibitors of the protein tyrosine phosphatase Shp2 identified by high-throughput docking

Oncogene-specific activation of tyrosine kinase networks during prostate cancer progression

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