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Gene Review

Ptpn11  -  protein tyrosine phosphatase, non-receptor...

Rattus norvegicus

Synonyms: PTP-1D, Protein-tyrosine phosphatase 1D, Protein-tyrosine phosphatase SYP, SH-PTP2, SHP-2, ...
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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


Anatomical context of Ptpn11


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


Regulatory relationships of Ptpn11


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


  1. Shp-2 positively regulates brain-derived neurotrophic factor-promoted survival of cultured ventral mesencephalic dopaminergic neurons through a brain immunoglobulin-like molecule with tyrosine-based activation motifs/Shp substrate-1. Takai, S., Yamada, M., Araki, T., Koshimizu, H., Nawa, H., Hatanaka, H. J. Neurochem. (2002) [Pubmed]
  2. The tyrosine phosphatase Shp-2 mediates intracellular signaling initiated by Ret mutants. D'Alessio, A., Califano, D., Incoronato, M., Santelli, G., Florio, T., Schettini, G., Carlomagno, M.S., Cerchia, L., de Franciscis, V. Endocrinology (2003) [Pubmed]
  3. Dissociation of PTPase levels from their modulation of insulin receptor signal transduction. Bleyle, L.A., Peng, Y., Ellis, C., Mooney, R.A. Cell. Signal. (1999) [Pubmed]
  4. A family of proteins that inhibit signalling through tyrosine kinase receptors. Kharitonenkov, A., Chen, Z., Sures, I., Wang, H., Schilling, J., Ullrich, A. Nature (1997) [Pubmed]
  5. Role of the CD47-SHPS-1 system in regulation of cell migration. Motegi, S., Okazawa, H., Ohnishi, H., Sato, R., Kaneko, Y., Kobayashi, H., Tomizawa, K., Ito, T., Honma, N., Bühring, H.J., Ishikawa, O., Matozaki, T. EMBO J. (2003) [Pubmed]
  6. Characterization of inhibitory and stimulatory forms of the murine natural killer cell receptor 2B4. Schatzle, J.D., Sheu, S., Stepp, S.E., Mathew, P.A., Bennett, M., Kumar, V. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  7. Signal regulatory protein alpha ligation induces macrophage nitric oxide production through JAK/STAT- and phosphatidylinositol 3-kinase/Rac1/NAPDH oxidase/H2O2-dependent pathways. Alblas, J., Honing, H., de Lavalette, C.R., Brown, M.H., Dijkstra, C.D., van den Berg, T.K. Mol. Cell. Biol. (2005) [Pubmed]
  8. Angiotensin II stimulates tyrosine phosphorylation and activation of insulin receptor substrate 1 and protein-tyrosine phosphatase 1D in vascular smooth muscle cells. Ali, M.S., Schieffer, B., Delafontaine, P., Bernstein, K.E., Ling, B.N., Marrero, M.B. J. Biol. Chem. (1997) [Pubmed]
  9. Syp (SH-PTP2) is a positive mediator of growth factor-stimulated mitogenic signal transduction. Xiao, S., Rose, D.W., Sasaoka, T., Maegawa, H., Burke, T.R., Roller, P.P., Shoelson, S.E., Olefsky, J.M. J. Biol. Chem. (1994) [Pubmed]
  10. Activation of protein-tyrosine phosphatase SH-PTP2 by a tyrosine-based activation motif of a novel brain molecule. Ohnishi, H., Kubota, M., Ohtake, A., Sato, K., Sano, S. J. Biol. Chem. (1996) [Pubmed]
  11. RNA splicing regulates the activity of a SH2 domain-containing protein tyrosine phosphatase. Mei, L., Doherty, C.A., Huganir, R.L. J. Biol. Chem. (1994) [Pubmed]
  12. Insulin receptor substrate-1/SHP-2 interaction, a phenotype-dependent switching machinery of insulin-like growth factor-I signaling in vascular smooth muscle cells. Hayashi, K., Shibata, K., Morita, T., Iwasaki, K., Watanabe, M., Sobue, K. J. Biol. Chem. (2004) [Pubmed]
  13. Cytoskeletal remodeling in vascular smooth muscle cells in response to angiotensin II-induced activation of the SHP-2 tyrosine phosphatase. Fernstrom, K., Farmer, P., Ali, M.S. J. Cell. Physiol. (2005) [Pubmed]
  14. Tyrosine phosphatase activity in mitochondria: presence of Shp-2 phosphatase in mitochondria. Salvi, M., Stringaro, A., Brunati, A.M., Agostinelli, E., Arancia, G., Clari, G., Toninello, A. Cell. Mol. Life Sci. (2004) [Pubmed]
  15. The Shp-1 and Shp-2, tyrosine phosphatases, are recruited on cell membrane in two distinct molecular complexes including Ret oncogenes. Incoronato, M., D'Alessio, A., Paladino, S., Zurzolo, C., Carlomagno, M.S., Cerchia, L., de Franciscis, V. Cell. Signal. (2004) [Pubmed]
  16. Stimulation of the alveolar macrophage respiratory burst by ADP causes selective glutathionylation of protein tyrosine phosphatase 1B. Rinna, A., Torres, M., Forman, H.J. Free Radic. Biol. Med. (2006) [Pubmed]
  17. Ramipril increases the protein level of skeletal muscle IRS-1 and alters protein tyrosine phosphatase activity in spontaneously hypertensive rats. Krützfeldt, J., Raasch, W., Klein, H.H. Naunyn Schmiedebergs Arch. Pharmacol. (2000) [Pubmed]
  18. Regulation of calcium-sensitive tyrosine kinase Pyk2 by angiotensin II in endothelial cells. Roles of Yes tyrosine kinase and tyrosine phosphatase SHP-2. Tang, H., Zhao, Z.J., Landon, E.J., Inagami, T. J. Biol. Chem. (2000) [Pubmed]
  19. Brain-derived neurotrophic factor enhances association of protein tyrosine phosphatase PTP1D with the NMDA receptor subunit NR2B in the cortical postsynaptic density. Lin, S.Y., Wu, K., Len, G.W., Xu, J.L., Levine, E.S., Suen, P.C., Mount, H.T., Black, I.B. Brain Res. Mol. Brain Res. (1999) [Pubmed]
  20. Inhibition of a Src homology 2 domain containing protein tyrosine phosphatase by vanadate in the primary culture of hepatocytes. Pugazhenthi, S., Tanha, F., Dahl, B., Khandelwal, R.L. Arch. Biochem. Biophys. (1996) [Pubmed]
  21. Localization and subcellular distribution of SH-PTP2, a protein-tyrosine phosphatase with Src homology-2 domains, in rat brain. Suzuki, T., Matozaki, T., Mizoguchi, A., Kasuga, M. Biochem. Biophys. Res. Commun. (1995) [Pubmed]
  22. Shp-2 specifically regulates several tyrosine-phosphorylated proteins in brain-derived neurotrophic factor signaling in cultured cerebral cortical neurons. Araki, T., Yamada, M., Ohnishi, H., Sano, S., Uetsuki, T., Hatanaka, H. J. Neurochem. (2000) [Pubmed]
  23. Hepatocyte growth factor activates several transduction pathways in rat pancreatic acini. Aparicio, I.M., Garcia-Marin, L.J., Andreolotti, A.G., Bodega, G., Jensen, R.T., Bragado, M.J. Biochim. Biophys. Acta (2003) [Pubmed]
  24. Role of protein-tyrosine phosphatase SHP2 in focal adhesion kinase down-regulation during neutrophil cathepsin G-induced cardiomyocytes anoikis. Rafiq, K., Kolpakov, M.A., Abdelfettah, M., Streblow, D.N., Hassid, A., Dell'Italia, L.J., Sabri, A. J. Biol. Chem. (2006) [Pubmed]
  25. Brain-derived neurotrophic factor stimulates interactions of Shp2 with phosphatidylinositol 3-kinase and Grb2 in cultured cerebral cortical neurons. Yamada, M., Ohnishi, H., Sano, S., Araki, T., Nakatani, A., Ikeuchi, T., Hatanaka, H. J. Neurochem. (1999) [Pubmed]
  26. Coordinate regulation of STAT signaling and c-fos expression by the tyrosine phosphatase SHP-2. Servidei, T., Aoki, Y., Lewis, S.E., Symes, A., Fink, J.S., Reeves, S.A. J. Biol. Chem. (1998) [Pubmed]
  27. Transient association of the phosphotyrosine phosphatase SHP-2 with TrkA is induced by nerve growth factor. Goldsmith, B.A., Koizumi, S. J. Neurochem. (1997) [Pubmed]
  28. Regulation of IRS-1/SHP2 interaction and AKT phosphorylation in animal models of insulin resistance. Lima, M.H., Ueno, M., Thirone, A.C., Rocha, E.M., Carvalho, C.R., Saad, M.J. Endocrine (2002) [Pubmed]
  29. Treatment with insulin uncovers the motogenic capacity of nitric oxide in aortic smooth muscle cells: dependence on Gab1 and Gab1-SHP2 association. Dixit, M., Zhuang, D., Ceacareanu, B., Hassid, A. Circ. Res. (2003) [Pubmed]
  30. SHP-2 is involved in neurotrophin signaling. Okada, N., Wada, K., Goldsmith, B.A., Koizumi, S. Biochem. Biophys. Res. Commun. (1996) [Pubmed]
  31. The insulin receptor substrate 1 associates with phosphotyrosine phosphatase SHPTP2 in liver and muscle of rats. Lima, M.H., Zambelli, J.E., Carvalho, C.R., Saad, M.J. Braz. J. Med. Biol. Res. (1998) [Pubmed]
  32. Protein-tyrosine phosphatase reduces the number of apical small conductance K+ channels in the rat cortical collecting duct. Wei, Y., Bloom, P., Gu, R., Wang, W. J. Biol. Chem. (2000) [Pubmed]
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