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Gene Review

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

Mus musculus

Synonyms: 2700084A17Rik, AW536184, PTP1D, PTP2C, Protein-tyrosine phosphatase SYP, ...
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Disease relevance of Ptpn11


High impact information on Ptpn11

  • The penetrance and severity of the defects in Egfrwa2/wa2 mice are enhanced by heterozygosity for a targeted mutation of exon 2 of Ptpn11 (ref. 3). Compound (Egfrwa2/wa2:Ptpn11+/-) mutant mice also show premature lethality [6].
  • The SH2 tyrosine phosphatase shp2 is required for mammalian limb development [7].
  • Thus, Shp2 regulates phosphotyrosine-signalling events during the complex ectodermal-mesenchymal interactions that regulate mammalian budding morphogenesis [7].
  • Furthermore, the branchial arches, which also use Fgfs during bud outgrowth, similarly require Shp2 [7].
  • Rather than integrating proliferative signals, Shp2 probably exerts its effects on limb development by influencing cell shape, movement or adhesion [7].

Chemical compound and disease context of Ptpn11


Biological context of Ptpn11


Anatomical context of Ptpn11

  • Shp2 is specifically required in mesenchyme cells of the progress zone (PZ), directly beneath the distal ectoderm of the limb bud [7].
  • Biochemical analysis revealed that signal propagation proximal to the EGF-R upon EGF stimulation was significantly attenuated in wa-2 fibroblast cells, which was exacerbated by the additional Shp-2 mutation [8].
  • By aggregating Shp-2(-/-) embryonic stem cells with wild-type embryos, we created Shp-2(-/-)/wild-type chimeric animals [8].
  • To further explore the role of SHP-2 in integrin signaling, we analyzed the responses of SHP-2 exon 3(-/-) and wild-type cell lines to being plated on fibronectin [11].
  • Previous studies revealed that a fraction of SHP-2 moves to focal contacts upon integrin engagement and that SHP-2 binds to SHP substrate 1 (SHPS-1)/SIRP-1alpha, a transmembrane glycoprotein with adhesion molecule characteristics (Y. Fujioka et al., Mol. Cell. Biol. 16:6887-6899, 1996; M. Tsuda et al., J. Biol. Chem. 273:13223-13229) [11].

Associations of Ptpn11 with chemical compounds

  • We analyzed mice with a null mutation of Shp2 (Ptpn11), a key component of receptor tyrosine kinase signaling [12].
  • Regulation of early events in integrin signaling by protein tyrosine phosphatase SHP-2 [11].
  • Deletion of the Shp2 gene in neuronal cultures reverses inhibition of TrkB function and increases neuronal survival after extended depolarization or glutamate treatment [13].
  • Two categories of phosphatases are recruited by the ITIM-bearing receptors: the protein-tyrosine phosphatases, SHP-1 and SHP-2, and the polyphosphate inositol 5-phosphatase, SHIP [14].
  • Mutant embryonic fibroblasts with the Exon 3 deletion mutation in SHP-2 showed decreased apoptosis and diminished G2/M arrest in response to cisplatin treatment [15].
  • In response to beta1 integrin cross-linking or fibronectin stimulation, activation of ERK and Akt kinases is greatly increased by SHP-2 GOF mutations [16].

Physical interactions of Ptpn11


Enzymatic interactions of Ptpn11

  • Partial hepatectomy (PH) rapidly and transiently induced assembly of a complex comprising Shp2 and tyrosine-phosphorylated Gab1 in wild-type hepatocytes [9].
  • These observations strongly suggest that SHP-2 dephosphorylates p190-B RhoGAP, leading to the activation of RhoA [22].
  • These findings suggest that Shp2 acts as a positive regulator in RTK signaling by dephosphorylating and inactivating Spry [23].

Regulatory relationships of Ptpn11

  • The phosphotyrosine phosphatase SHP2 is a critical mediator of transformation induced by the oncogenic fibroblast growth factor receptor 3 [2].
  • Collectively, this study establishes the physiological significance of the Gab1/Shp2 link in promoting mitogenic signaling through the Erk pathway in mammalian liver regeneration [9].
  • We observed that a Gab1 construct preventing SHP2 recruitment promoted membrane relocation of RasGAP [24].
  • We established immortalized SHP-2(-/-) hematopoietic cell pools and showed that IL-3-induced proliferative response was diminished in SHP-2(-/-) cells [25].
  • Moreover, overexpression of a catalytically inactive mutant of SHP-2 inhibited p190-B RhoGAP tyrosyl dephosphorylation, RhoA activity, and myogenesis [22].
  • We found that SHP-2 promoted AMPK activity under conditions of growth factor deprivation (low energy), suggesting that SHP-2 negatively regulates S6K1 via an AMPK-dependent pathway [26].

Other interactions of Ptpn11

  • Mice mutant for Egfr and Shp2 have defective cardiac semilunar valvulogenesis [6].
  • We show here that association of Gab1 adaptor protein and Shp2 tyrosine phosphatase is a critical event at the early phase of liver regeneration [9].
  • Although similar in composition, the MGDF- and IL-3-induced complexes of signal transducers appear to be assembled in different configurations, especially with respect to SHPTP-2 [27].
  • In addition, we demonstrated that the Src-induced response was down-regulated by Gab2-associated SHP2 [28].
  • However, the C/S SHP2 protein did not show any effect on receptor autophosphorylation, FRS2 tyrosine phosphorylation or interaction of Grb2 with K/E-FR3 or FRS2 [2].
  • During embryogenesis in a mouse model of NS, SIRPalpha and PZR were hypertyrosyl-phosphorylated and bound increased levels of the NS-associated SHP-2 mutant [29].

Analytical, diagnostic and therapeutic context of Ptpn11


  1. Gastric cancer development in mice lacking the SHP2 binding site on the IL-6 family co-receptor gp130. Judd, L.M., Alderman, B.M., Howlett, M., Shulkes, A., Dow, C., Moverley, J., Grail, D., Jenkins, B.J., Ernst, M., Giraud, A.S. Gastroenterology (2004) [Pubmed]
  2. The phosphotyrosine phosphatase SHP2 is a critical mediator of transformation induced by the oncogenic fibroblast growth factor receptor 3. Agazie, Y.M., Movilla, N., Ischenko, I., Hayman, M.J. Oncogene (2003) [Pubmed]
  3. Altered regulation of SHP-2 and PTP 1B tyrosine phosphatases in cystic kidneys from bcl-2 -/- mice. Sorenson, C.M., Sheibani, N. Am. J. Physiol. Renal Physiol. (2002) [Pubmed]
  4. Gain-of-function/Noonan syndrome SHP-2/Ptpn11 mutants enhance calcium oscillations and impair NFAT signaling. Uhlén, P., Burch, P.M., Zito, C.I., Estrada, M., Ehrlich, B.E., Bennett, A.M. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  5. Morphogenetic movements at gastrulation require the SH2 tyrosine phosphatase Shp2. Saxton, T.M., Pawson, T. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  6. Mice mutant for Egfr and Shp2 have defective cardiac semilunar valvulogenesis. Chen, B., Bronson, R.T., Klaman, L.D., Hampton, T.G., Wang, J.F., Green, P.J., Magnuson, T., Douglas, P.S., Morgan, J.P., Neel, B.G. Nat. Genet. (2000) [Pubmed]
  7. The SH2 tyrosine phosphatase shp2 is required for mammalian limb development. Saxton, T.M., Ciruna, B.G., Holmyard, D., Kulkarni, S., Harpal, K., Rossant, J., Pawson, T. Nat. Genet. (2000) [Pubmed]
  8. Genetic evidence that Shp-2 tyrosine phosphatase is a signal enhancer of the epidermal growth factor receptor in mammals. Qu, C.K., Yu, W.M., Azzarelli, B., Feng, G.S. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  9. Concerted functions of Gab1 and Shp2 in liver regeneration and hepatoprotection. Bard-Chapeau, E.A., Yuan, J., Droin, N., Long, S., Zhang, E.E., Nguyen, T.V., Feng, G.S. Mol. Cell. Biol. (2006) [Pubmed]
  10. Receptor-specific regulation of phosphatidylinositol 3'-kinase activation by the protein tyrosine phosphatase Shp2. Zhang, S.Q., Tsiaras, W.G., Araki, T., Wen, G., Minichiello, L., Klein, R., Neel, B.G. Mol. Cell. Biol. (2002) [Pubmed]
  11. Regulation of early events in integrin signaling by protein tyrosine phosphatase SHP-2. Oh, E.S., Gu, H., Saxton, T.M., Timms, J.F., Hausdorff, S., Frevert, E.U., Kahn, B.B., Pawson, T., Neel, B.G., Thomas, S.M. Mol. Cell. Biol. (1999) [Pubmed]
  12. An Shp2/SFK/Ras/Erk signaling pathway controls trophoblast stem cell survival. Yang, W., Klaman, L.D., Chen, B., Araki, T., Harada, H., Thomas, S.M., George, E.L., Neel, B.G. Dev. Cell (2006) [Pubmed]
  13. Tyrosine phosphatase SHP-2 is a mediator of activity-dependent neuronal excitotoxicity. Rusanescu, G., Yang, W., Bai, A., Neel, B.G., Feig, L.A. EMBO J. (2005) [Pubmed]
  14. The paired Ig-like receptor PIR-B is an inhibitory receptor that recruits the protein-tyrosine phosphatase SHP-1. Bléry, M., Kubagawa, H., Chen, C.C., Vély, F., Cooper, M.D., Vivier, E. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  15. SHP-2 phosphatase regulates DNA damage-induced apoptosis and G2/M arrest in catalytically dependent and independent manners, respectively. Yuan, L., Yu, W.M., Xu, M., Qu, C.K. J. Biol. Chem. (2005) [Pubmed]
  16. Noonan syndrome/leukemia-associated gain-of-function mutations in SHP-2 phosphatase (PTPN11) enhance cell migration and angiogenesis. Wang, S., Yu, W.M., Zhang, W., McCrae, K.R., Neel, B.G., Qu, C.K. J. Biol. Chem. (2009) [Pubmed]
  17. SHP-2 complex formation with the SHP-2 substrate-1 during C2C12 myogenesis. Kontaridis, M.I., Liu, X., Zhang, L., Bennett, A.M. J. Cell. Sci. (2001) [Pubmed]
  18. Modulation of the nuclear factor kappa B pathway by Shp-2 tyrosine phosphatase in mediating the induction of interleukin (IL)-6 by IL-1 or tumor necrosis factor. You, M., Flick, L.M., Yu, D., Feng, G.S. J. Exp. Med. (2001) [Pubmed]
  19. Unique features of SHIP, SHP-1 and SHP-2 binding to FcgammaRIIb revealed by surface plasmon resonance analysis. Famiglietti, S.J., Nakamura, K., Cambier, J.C. Immunol. Lett. (1999) [Pubmed]
  20. Effects of Src homology domain 2 (SH2)-containing inositol phosphatase (SHIP), SH2-containing phosphotyrosine phosphatase (SHP)-1, and SHP-2 SH2 decoy proteins on Fc gamma RIIB1-effector interactions and inhibitory functions. Nakamura, K., Brauweiler, A., Cambier, J.C. J. Immunol. (2000) [Pubmed]
  21. Tyrosine phosphatase SHP-2 binding to CTLA-4: absence of direct YVKM/YFIP motif recognition. Schneider, H., Rudd, C.E. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  22. SHP-2 positively regulates myogenesis by coupling to the Rho GTPase signaling pathway. Kontaridis, M.I., Eminaga, S., Fornaro, M., Zito, C.I., Sordella, R., Settleman, J., Bennett, A.M. Mol. Cell. Biol. (2004) [Pubmed]
  23. Shp2, an SH2-containing protein-tyrosine phosphatase, positively regulates receptor tyrosine kinase signaling by dephosphorylating and inactivating the inhibitor Sprouty. Hanafusa, H., Torii, S., Yasunaga, T., Matsumoto, K., Nishida, E. J. Biol. Chem. (2004) [Pubmed]
  24. A novel role for Gab1 and SHP2 in epidermal growth factor-induced Ras activation. Montagner, A., Yart, A., Dance, M., Perret, B., Salles, J.P., Raynal, P. J. Biol. Chem. (2005) [Pubmed]
  25. Catalytic-dependent and -independent roles of SHP-2 tyrosine phosphatase in interleukin-3 signaling. Yu, W.M., Hawley, T.S., Hawley, R.G., Qu, C.K. Oncogene (2003) [Pubmed]
  26. SHP-2 regulates cell growth by controlling the mTOR/S6 kinase 1 pathway. Zito, C.I., Qin, H., Blenis, J., Bennett, A.M. J. Biol. Chem. (2007) [Pubmed]
  27. Megakaryocyte growth and development factor and interleukin-3 induce patterns of protein-tyrosine phosphorylation that correlate with dominant differentiation over proliferation of mpl-transfected 32D cells. Mu, S.X., Xia, M., Elliott, G., Bogenberger, J., Swift, S., Bennett, L., Lappinga, D.L., Hecht, R., Lee, R., Saris, C.J. Blood (1995) [Pubmed]
  28. Epidermal growth factor-induced DNA synthesis. Key role for Src phosphorylation of the docking protein Gab2. Kong, M., Mounier, C., Dumas, V., Posner, B.I. J. Biol. Chem. (2003) [Pubmed]
  29. Noonan syndrome-associated SHP-2/Ptpn11 mutants enhance SIRPalpha and PZR tyrosyl phosphorylation and promote adhesion-mediated ERK activation. Eminaga, S., Bennett, A.M. J. Biol. Chem. (2008) [Pubmed]
  30. Receptor-binding, tyrosine phosphorylation and chromosome localization of the mouse SH2-containing phosphotyrosine phosphatase Syp. Feng, G.S., Shen, R., Heng, H.H., Tsui, L.C., Kazlauskas, A., Pawson, T. Oncogene (1994) [Pubmed]
  31. Increased susceptibility to ischemia-induced brain damage in transgenic mice overexpressing a dominant negative form of SHP2. Aoki, Y., Huang, Z., Thomas, S.S., Bhide, P.G., Huang, I., Moskowitz, M.A., Reeves, S.A. FASEB J. (2000) [Pubmed]
  32. Different signaling roles of SHPTP2 in insulin-induced GLUT1 expression and GLUT4 translocation. Hausdorff, S.F., Bennett, A.M., Neel, B.G., Birnbaum, M.J. J. Biol. Chem. (1995) [Pubmed]
  33. DNA damage-induced G2/M checkpoint in SV40 large T antigen-immortalized embryonic fibroblast cells requires SHP-2 tyrosine phosphatase. Yuan, L., Yu, W.M., Qu, C.K. J. Biol. Chem. (2003) [Pubmed]
  34. Expression of a dominant negative SHP-2 in transgenic mice induces insulin resistance. Maegawa, H., Hasegawa, M., Sugai, S., Obata, T., Ugi, S., Morino, K., Egawa, K., Fujita, T., Sakamoto, T., Nishio, Y., Kojima, H., Haneda, M., Yasuda, H., Kikkawa, R., Kashiwagi, A. J. Biol. Chem. (1999) [Pubmed]
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