Disease relevance of Ptpn11

• To examine the roles of Shp-2, a cytoplasmic tyrosine phosphatase, in neuronal survival, we generated and used recombinant adenoviruses expressing wild type and phosphatase-inactive (C/S), phosphatase domain-deficient (delta P) and constitutively active (D61A and E76A) mutants of Shp-2 [1].
• Using the PC12, rat pheochromocytoma cell line, as model system, we show that Shp-2 mediates immediate-early gene expression if induced by either of the mutant alleles [2].
• The results indicate that Shp-2 is a downstream mediator of the mutated receptors RetC634Y and RetM918T, thus suggesting that it may act as a limiting factor in Ret-associated endocrine tumors, in the neoplastic syndromes multiple endocrine neoplasia types 2A and 2B [2].
• Increasing cell density (20%, 50%, and >90%) in the rat McA-RH7777 hepatoma cell line resulted in increased protein expression of the receptor-like PTPase LAR (14-fold), and the nonreceptor PTPases PTP1B (11-fold) and SHP2 (10-fold) [3].

High impact information on Ptpn11

• The SH2-domain-containing phosphotyrosine phosphatase SHP-2 is a positive signal transducer for several receptor tyrosine kinases (RTKs) and cytokine receptors [4].
• To investigate its mechanism of action we purified a tyrosine-phosphorylated glycoprotein which in different cell types associates tightly with SHP-2 and appears to serve as its substrate [4].
• Overexpression of wild-type SHPS-1 promoted CHO cell migration, whereas expression of the SHPS-1-4F mutant, which lacks the phosphorylation sites required for SHP-2 binding, had no effect [5].
• Like other inhibitory receptors, 2B4L associates with the tyrosine phosphatase SHP-2 [6].
• Signal regulatory protein alpha (SIRPalpha) is a glycoprotein receptor that recruits and signals via the tyrosine phosphatases SHP-1 and SHP-2 [7].

Biological context of Ptpn11

• Anti-PTP-1D antibody electroporation attenuated Ang II-induced PTP-1D.IRS-1 complex formation and PTP-1D tyrosine phosphorylation and activation [8].
• Syp (SH-PTP2) is a positive mediator of growth factor-stimulated mitogenic signal transduction [9].
• A mouse brain cDNA library in lambdagt11 was screened for this association, and two positive clones encoding tyrosine phosphatase SH-PTP2 were isolated [10].
• This phosphatase appears to be a rat homologue of PTP1D based on its amino acid sequence [11].
• These results demonstrate that the 4-amino acid insert in the catalytic domains of PTP1D down-regulates its phosphatase activity and suggests that RNA splicing may serve as a regulatory mechanism of protein tyrosine phosphatase activity [11].

Anatomical context of Ptpn11

• Insulin receptor substrate-1/SHP-2 interaction, a phenotype-dependent switching machinery of insulin-like growth factor-I signaling in vascular smooth muscle cells [12].
• The expression of wild-type SHP-2 caused a dephosphorylation of several focal adhesion associated proteins including paxillin, p130Cas, and tensin in VSMC [13].
• In contrast, the catalytically inactive mutant SHP-2 increased stress fiber formation [13].
• Additional observations further established that SHP-2 regulates the reorganization of the actin cytoskeleton through RhoA- and Vav2-dependent signaling pathways [13].
• Using a combination of approaches, we identified the tyrosine phosphatase Shp-2 in mitochondria [14].

Associations of Ptpn11 with chemical compounds

• The Shp-2 and Shp-1 non-transmembrane tyrosine phosphatases display different and even opposing effects on downstream signaling events initiated by Ret activation [15].
• Syp (SH-PTP2) was recently identified as a phosphotyrosine phosphatase containing two SH2 domains within its primary structure [9].
• The Km values of PTP1Di were lower than those of PTP1D for both nicotinic acetylcholine receptor and myelin basic protein, suggesting a higher affinity of PTP1Di for a protein substrate [11].
• Interestingly, other PTPs, i.e., SHP-1 and SHP-2, did not undergo glutathionylation in response to ADP stimulation of the respiratory burst, although glutathionylation of these proteins could be shown by reaction with 25 mM glutathione disulfide in vitro [16].
• The expression of wild-type SHP-2 prevented an angiotensin II dependent increase in stress fiber formation [13].

Physical interactions of Ptpn11

• No effects were observed on IRS-1 content in liver or on insulin binding or protein expression of p85 or SHP2 in both tissues [17].
• SHP-2 interacts with Pyk2 through a region other than its SH2 domains [18].
• In addition, NR2B was co-immunoprecipitated with PTP1D using anti-NR2B antibodies or anti-PTP1D antibodies, indicating physical association of the subunit with PTP1D [19].
• Immunoprecipitation of this PTP with Syp-antibody coupled to protein A-agarose confirmed the vanadate-induced decrease in SHPTP2 activity [20].
• Furthermore, SH-PTP2 was coimmunoprecipitated with a 100 kDa tyrosine-phosphorylated membrane protein, which may couple SH-PTP2 to brain membranes [21].

Enzymatic interactions of Ptpn11

• Shp-2 specifically regulates several tyrosine-phosphorylated proteins in brain-derived neurotrophic factor signaling in cultured cerebral cortical neurons [22].
• Pyk2 can be dephosphorylated in vitro in SHP-2 immunoprecipitates and in intact cells expressing an NH(2) terminus-truncated form of SHP-2, which lacks the two SH2 domains but has an enhanced phosphatase activity [18].

Regulatory relationships of Ptpn11

• HGF selectively stimulated tyrosine phosphorylation of phosphatase PTP1D [23].
• In contrast, increased SHP2 expression exacerbates Cat.G-induced FAK tyrosine dephosphorylation and myocyte apoptosis [24].
• Brain-derived neurotrophic factor stimulates interactions of Shp2 with phosphatidylinositol 3-kinase and Grb2 in cultured cerebral cortical neurons [25].
• In CNTF-stimulated NBFL cells that constitutively express the SHP-2 interfering mutant, there was increased and prolonged formation of STAT/DNA complexes, but decreased AP-1 binding activity, that mirrored a down-regulation of c-fos expression both at the mRNA and protein level [26].
• This is the first demonstration that the association of SHP-2 with TrkA is induced by NGF and that this association leads to SHP-2 activation and tyrosine phosphorylation [27].

Other interactions of Ptpn11

• Insulin stimulates tyrosine kinase activity of its receptor, resulting in phosphorylation of its cytosolic substrate, insulin receptor substrate-1, which, in turn, associates with proteins containing SH2 domains, including phosphatidylinositol 3-kinase (PI 3-kinase) and the phosphotyrosine phosphatase SHP2 [28].
• We also demonstrate that the scaffold adapter protein Gab1, considered a physiological activator of protein tyrosine phosphatase SHP2, increases cell motility in the presence but not the absence of insulin [29].
• Taken together, these results show that Cat.G induces SHP2 activation that leads to FAK tyrosine dephosphorylation and promotes cardiomyocyte anoikis [24].
• We examined how BDNF utilizes Shp2 in its signaling pathway in cultured cerebral cortical neurons [25].
• In addition, a tyrosine-phosphorylated protein, which is probably TrkB, was coimmunoprecipitated with SHP-2 in both cultures [30].

Analytical, diagnostic and therapeutic context of Ptpn11

• Regulation of IRS-1/SHP2 interaction and AKT phosphorylation in animal models of insulin resistance [28].
• In the present study we investigated the ability of insulin to induce association between IRS-1 and SHPTP2 in liver and muscle of intact rats, by co-immunoprecipitation with anti-IRS-1 antibody and anti-SHPTP2 antibody [31].
• It has been shown that IRS-1 associates with the tyrosine phosphatase SHPTP2 in cell cultures [31].
• These results show that SHP-2 becomes associated with signaling proteins after treatment with neurotrophins and suggest that SHP-2 plays a fundamental role in neurotrophin signaling [30].
• Western blot analysis indicated that PTP-1D is expressed in the renal cortex [32].

References