Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Tyrosine-Protein Phosphatase Nonreceptor Type 11 (PTPN11)

  • Takenori KotaniEmail author
  • Yoji Murata
  • Yasuyuki Saito
  • Takashi MatozakiEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101832


Historical Background

Src homology 2-containing protein tyrosine phosphatase (SHP2, also known as PTPN11) is a member of the non-receptor-type protein tyrosine phosphatase (PTP) family and is encoded by PTPN11gene. In the early 1990s, this PTP was identified on the basis of its sequence similarity to the catalytic domain of known PTPs. PTPs dephosphorylate tyrosine-phosphorylated proteins, which generally promote cellular events such as cell growth, differentiation, migration, adhesion, and apoptosis. Therefore, PTPs are considered to be negative regulators in intracellular signal transductions. However, biochemical and genetic analyses in 1990s showed that SHP2 promotes...

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  1. Allard JD, Chang HC, Herbst R, McNeill H, Simon MA. The SH2-containing tyrosine phosphatase corkscrew is required during signaling by sevenless, Ras1 and Raf. Development. 1996;122:1137–46.PubMedPubMedCentralGoogle Scholar
  2. Araki T, Mohi MG, Ismat FA, Bronson RT, Williams IR, Kutok JL, et al. Mouse model of Noonan syndrome reveals cell type- and gene dosage-dependent effects of Ptpn11 mutation. Nat Med. 2004;10:849–57. doi:10.1038/nm1084.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Bentires-Alj M, Gil SG, Chan R, Wang ZC, Wang Y, Imanaka N, et al. A role for the scaffolding adapter GAB2 in breast cancer. Nat Med. 2006;12:114–21. doi:10.1038/nm1341.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Chan RJ, Leedy MB, Munugalavadla V, Voorhorst CS, Li Y, Yu M, et al. Human somatic PTPN11 mutations induce hematopoietic-cell hypersensitivity to granulocyte-macrophage colony-stimulating factor. Blood. 2005;105:3737–42. doi:10.1182/blood-2004-10-4002.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Chen YN, LaMarche MJ, Chan HM, Fekkes P, Garcia-Fortanet J, Acker MG, et al. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature. 2016;535:148–52. doi:10.1038/nature18621.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Gauthier AS, Furstoss O, Araki T, Chan R, Neel BG, Kaplan DR, et al. Control of CNS cell-fate decisions by SHP-2 and its dysregulation in Noonan syndrome. Neuron. 2007;54:245–62. doi:10.1016/j.neuron.2007.03.027.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Gutch MJ, Flint AJ, Keller J, Tonks NK, Hengartner MO. The Caenorhabditis elegans SH2 domain-containing protein tyrosine phosphatase PTP-2 participates in signal transduction during oogenesis and vulval development. Genes Dev. 1998;12:571–85.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Hatakeyama M, Higashi H. Helicobacter pylori CagA: a new paradigm for bacterial carcinogenesis. Cancer Sci. 2005;96:835–43. doi:10.1111/j.1349-7006.2005.00130.x.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Heuberger J, Kosel F, Qi J, Grossmann KS, Rajewsky K, Birchmeier W. Shp2/MAPK signaling controls goblet/Paneth cell fate decisions in the intestine. Proc Natl Acad Sci U S A. 2014;111:3472–7. doi:10.1073/pnas.1309342111.CrossRefPubMedPubMedCentralGoogle Scholar
  10. Hof P, Pluskey S, Dhe-Paganon S, Eck MJ, Shoelson SE. Crystal structure of the tyrosine phosphatase SHP-2. Cell. 1998;92:441–50.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Ke Y, Zhang EE, Hagihara K, Wu D, Pang Y, Klein R, et al. Deletion of Shp2 in the brain leads to defective proliferation and differentiation in neural stem cells and early postnatal lethality. Mol Cell Biol. 2007;27:6706–17. doi:10.1128/MCB.01225-07.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Kontaridis MI, Yang W, Bence KK, Cullen D, Wang B, Bodyak N, et al. Deletion of Ptpn11 (Shp2) in cardiomyocytes causes dilated cardiomyopathy via effects on the extracellular signal-regulated kinase/mitogen-activated protein kinase and RhoA signaling pathways. Circulation. 2008;117:1423–35. doi:10.1161/CIRCULATIONAHA.107.728865.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Kusakari S, Saitow F, Ago Y, Shibasaki K, Sato-Hashimoto M, Matsuzaki Y, et al. Shp2 in forebrain neurons regulates synaptic plasticity, locomotion, and memory formation in mice. Mol Cell Biol. 2015;35:1557–72. doi:10.1128/MCB.01339-14.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Lechleider RJ, Sugimoto S, Bennett AM, Kashishian AS, Cooper JA, Shoelson SE, et al. Activation of the SH2-containing phosphotyrosine phosphatase SH-PTP2 by its binding site, phosphotyrosine 1009, on the human platelet-derived growth factor receptor. J Biol Chem. 1993;268:21478–81.PubMedPubMedCentralGoogle Scholar
  15. Milarski KL, Saltiel AR. Expression of catalytically inactive Syp phosphatase in 3T3 cells blocks stimulation of mitogen-activated protein kinase by insulin. J Biol Chem. 1994;269:21239–43.PubMedPubMedCentralGoogle Scholar
  16. Mohi MG, Williams IR, Dearolf CR, Chan G, Kutok JL, Cohen S, et al. Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations. Cancer cell. 2005;7:179–91. doi:10.1016/j.ccr.2005.01.010.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Noguchi T, Matozaki T, Horita K, Fujioka Y, Kasuga M. Role of SH-PTP2, a protein-tyrosine phosphatase with Src homology 2 domains, in insulin-stimulated Ras activation. Mol Cell Biol. 1994;14:6674–82.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Pluskey S, Wandless TJ, Walsh CT, Shoelson SE. Potent stimulation of SH-PTP2 phosphatase activity by simultaneous occupancy of both SH2 domains. J Biol Chem. 1995;270:2897–900.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Saxton TM, Henkemeyer M, Gasca S, Shen R, Rossi DJ, Shalaby F, et al. Abnormal mesoderm patterning in mouse embryos mutant for the SH2 tyrosine phosphatase Shp-2. EMBO J. 1997;16:2352–64. doi:10.1093/emboj/16.9.2352.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Sugimoto S, Wandless TJ, Shoelson SE, Neel BG, Walsh CT. Activation of the SH2-containing protein tyrosine phosphatase, SH-PTP2, by phosphotyrosine-containing peptides derived from insulin receptor substrate-1. J Biol Chem. 1994;269:13614–22.PubMedPubMedCentralGoogle Scholar
  21. Tang TL, Freeman Jr RM, O’Reilly AM, Neel BG, Sokol SY. The SH2-containing protein-tyrosine phosphatase SH-PTP2 is required upstream of MAP kinase for early Xenopus development. Cell. 1995;80:473–83.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Tartaglia M, Gelb BD. Noonan syndrome and related disorders: genetics and pathogenesis. Annu Rev Genomics Hum Genet. 2005;6:45–68. doi:10.1146/annurev.genom.6.080604.162305.CrossRefPubMedPubMedCentralGoogle Scholar
  23. Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001;29:465–8. doi:10.1038/ng772.CrossRefPubMedPubMedCentralGoogle Scholar
  24. Tsutsumi R, Masoudi M, Takahashi A, Fujii Y, Hayashi T, Kikuchi I, et al. YAP and TAZ, Hippo signaling targets, act as a rheostat for nuclear SHP2 function. Dev Cell. 2013;26:658–65. doi:10.1016/j.devcel.2013.08.013.CrossRefPubMedPubMedCentralGoogle Scholar
  25. Yamashita H, Kotani T, Park JH, Murata Y, Okazawa H, Ohnishi H, et al. Role of the protein tyrosine phosphatase Shp2 in homeostasis of the intestinal epithelium. PloS One. 2014;9:e92904. doi:10.1371/journal.pone.0092904.CrossRefPubMedPubMedCentralGoogle Scholar
  26. Yamauchi K, Milarski KL, Saltiel AR, Pessin JE. Protein-tyrosine-phosphatase SHPTP2 is a required positive effector for insulin downstream signaling. Proc Natl Acad Sci U S A. 1995;92:664–8.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Yang W, Klaman LD, Chen B, Araki T, Harada H, Thomas SM, et al. An Shp2/SFK/Ras/Erk signaling pathway controls trophoblast stem cell survival. Dev Cell. 2006;10:317–27. doi:10.1016/j.devcel.2006.01.002.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular BiologyKobe University Graduate School of MedicineKobeJapan