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Gene Review

PTPN6  -  protein tyrosine phosphatase, non-receptor...

Homo sapiens

Synonyms: HCP, HCPH, HPTP1C, Hematopoietic cell protein-tyrosine phosphatase, PTP-1C, ...
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Disease relevance of PTPN6


Psychiatry related information on PTPN6


High impact information on PTPN6

  • The natural killer inhibitory receptors fulfill this function by recruiting the tyrosine phosphatase SHP-1 through a cytoplasmic immunoreceptor tyrosine-based inhibition motif [7].
  • Upon ligand binding and activation, the inhibitory NK cell receptors become tyrosine phosphorylated and recruit tyrosine phosphatases, SHP-1 and possibly SHP-2, resulting in inhibition of NK cell-mediated cytotoxicity and cytokine expression [8].
  • The activated Jaks phosphorylate both themselves and the receptor subunits, creating docking sites for SH2-containing proteins including SHC, which couples receptor engagement to activation of the ras pathway, and HCP, a protein tyrosine phosphatase which negatively affects the response [9].
  • To address the necessity, interaction, or redundancy of these signaling molecules, we have generated SHP-1- or SHIP-deficient B cell lines and determined their ability to mediate inhibitory signaling [10].
  • SHP-1-mediated inhibitory signaling blocks apoptosis, while SHIP recruitment attenuates a proapoptotic signal initiated by Fc gammaRIIB [10].

Chemical compound and disease context of PTPN6


Biological context of PTPN6


Anatomical context of PTPN6


Associations of PTPN6 with chemical compounds


Physical interactions of PTPN6

  • We mapped the EGFR phosphotyrosine 1173 as the major binding site for SHP-1 by a combination of phosphopeptide activation, phosphopeptide competition, and receptor YF mutant analysis [22].
  • The present studies demonstrate that RAFTK binds constitutively to the protein tyrosine phosphatase SHPTP1 [24].
  • Based on the presence of a putative SHP-1 SH2-binding site within the TFG sequences, we have investigated the role of the SHP-1 phosphatase in TRK-T3 oncoprotein signaling [25].
  • In monocytes, phosphorylation of LIR-1 and LIR-2 results in the binding of the tyrosine phosphatase SHP-1 [26].
  • Therefore, receptor dephosphorylation may be the result of the combined activity of receptor-bound SHP-1 and SHP-1 bound to an auxiliary docking protein [22].

Enzymatic interactions of PTPN6

  • The protein-tyrosine phosphatase SHP-1 binds to and dephosphorylates the epidermal growth factor receptor (EGFR), and both SH2 domains of SHP-1 are important for this interaction (Tenev, T., Keilhack, H., Tomic, S., Stoyanov, B., Stein-Gerlach, M., Lammers, R., Krivtsov, A. V., Ullrich, A., and Böhmer, F. D. (1997) J. Biol. Chem. 272, 5966-5973) [22].
  • The protein-tyrosine phosphatase SHP-1 binds to and dephosphorylates p120 catenin [23].
  • After BCR stimulation in apoptotic cells, SHP-1 has been shown to be recruited to phosphorylated immunoreceptor tyrosine-based inhibitory motifs present in receptors such as CD22 and CD72 [27].
  • COS cell-expressed glutathione S-transferase-SHP-1L can dephosphorylate tyrosine-phosphorylated ZAP70 [28].
  • In order to study whether there was any correlation between SHP-1 protein expression and tyrosine phosphorylated state of JAK3, the state of phosphorylation of JAK3 was studied in the T cell line HUT-78, and found to be highly phosphorylated [29].

Regulatory relationships of PTPN6

  • Substrate phosphorylation was restored by expression of dominant negative mutants of SHP-1, whereas the SHP-1 mutants failed to enhance phosphorylation of the cellular substrates in the absence of CD72 [19].
  • Positive effects of SH2 domain-containing tyrosine phosphatase SHP-1 on epidermal growth factor- and interferon-gamma-stimulated activation of STAT transcription factors in HeLa cells [30].
  • Here we report that Fc gamma RIIa clustering induces SHP-1 phosphatase activity in THP-1 cells [20].
  • Various mutants of SHP-1 were transiently expressed in 293 or COS-7 cells and analyzed for their capacity to associate with immobilized autophosphorylated EGF receptor in vitro and to dephosphorylate coexpressed EGF receptor in intact cells [31].
  • In this study, we examined the possible role of SHP-1 in regulating FLT3 signaling [32].

Other interactions of PTPN6

  • Finally, we have also observed SDF-1alpha-induced activation and association of the tyrosine phosphatase Shp1 with the CXCR4 in a Galpha(i)-dependent manner [33].
  • Beta-chemokine receptor CCR5 signals through SHP1, SHP2, and Syk [34].
  • Upon BCR ligation, SHP-1 has been shown to associate with the BCR, the cytoplasmic protein-tyrosine kinases Lyn and Syk, and the inhibitory co-receptors CD22 and CD72 [19].
  • Furthermore, we observed that SHP1 associated with RAFTK [34].
  • Interaction of growth hormone-activated STATs with SH2-containing phosphotyrosine phosphatase SHP-1 and nuclear JAK2 tyrosine kinase [17].

Analytical, diagnostic and therapeutic context of PTPN6

  • Characterization of the 5' ends of the PTPN6 mRNAs by RT-PCR and analysis of the flanking genomic sequences identified putative initiation sites within the two promoters [18].
  • How SHP-1 is activated by BCR ligation and regulates BCR signaling is, however, not fully understood [19].
  • Total cellular PTPase activity was slightly increased, but SHP-1 activity could not be detected; its absence in this cell line was confirmed by Western blot [11].
  • Furthermore, we have found that SHP-1 expression is greatly decreased or undetectable in a number of IL-2 independent HTLV-I transformed T cell lines that exhibit constitutive Jak/signal transducer/activator of transcription activation [35].
  • Immunoprecipitation experiments revealed that beta-catenin is one of the main binding partners and a substrate for SHP-1 [36].


  1. Chromosomal localization of an SH2-containing tyrosine phosphatase (PTPN6). Plutzky, J., Neel, B.G., Rosenberg, R.D., Eddy, R.L., Byers, M.G., Jani-Sait, S., Shows, T.B. Genomics (1992) [Pubmed]
  2. STAT3- and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes. Zhang, Q., Wang, H.Y., Marzec, M., Raghunath, P.N., Nagasawa, T., Wasik, M.A. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  3. SOCS1 and SHP1 hypermethylation in multiple myeloma: implications for epigenetic activation of the Jak/STAT pathway. Chim, C.S., Fung, T.K., Cheung, W.C., Liang, R., Kwong, Y.L. Blood (2004) [Pubmed]
  4. Regulation of acidification and apoptosis by SHP-1 and Bcl-2. Thangaraju, M., Sharma, K., Leber, B., Andrews, D.W., Shen, S.H., Srikant, C.B. J. Biol. Chem. (1999) [Pubmed]
  5. Role of Host Protein Tyrosine Phosphatase SHP-1 in Leishmania donovani-Induced Inhibition of Nitric Oxide Production. Forget, G., Gregory, D.J., Whitcombe, L.A., Olivier, M. Infect. Immun. (2006) [Pubmed]
  6. Impaired motor imagery in right hemiparetic cerebral palsy. Mutsaarts, M., Steenbergen, B., Bekkering, H. Neuropsychologia (2007) [Pubmed]
  7. Regulation of immune responses through inhibitory receptors. Long, E.O. Annu. Rev. Immunol. (1999) [Pubmed]
  8. NK cell receptors. Lanier, L.L. Annu. Rev. Immunol. (1998) [Pubmed]
  9. Signaling through the hematopoietic cytokine receptors. Ihle, J.N., Witthuhn, B.A., Quelle, F.W., Yamamoto, K., Silvennoinen, O. Annu. Rev. Immunol. (1995) [Pubmed]
  10. Deletion of SHIP or SHP-1 reveals two distinct pathways for inhibitory signaling. Ono, M., Okada, H., Bolland, S., Yanagi, S., Kurosaki, T., Ravetch, J.V. Cell (1997) [Pubmed]
  11. Inhibitory and stimulatory effects of somatostatin on two human pancreatic cancer cell lines: a primary role for tyrosine phosphatase SHP-1. Douziech, N., Calvo, E., Coulombe, Z., Muradia, G., Bastien, J., Aubin, R.A., Lajas, A., Morisset, J. Endocrinology (1999) [Pubmed]
  12. Octapeptide somatostatin analog SMS 201-995 induces translocation of intracellular PTP1C to membranes in MCF-7 human breast adenocarcinoma cells. Srikant, C.B., Shen, S.H. Endocrinology (1996) [Pubmed]
  13. Tyrosine phosphorylation of an SH2-containing protein tyrosine phosphatase is coupled to platelet thrombin receptor via a pertussis toxin-sensitive heterotrimeric G-protein. Li, R.Y., Gaits, F., Ragab, A., Ragab-Thomas, J.M., Chap, H. EMBO J. (1995) [Pubmed]
  14. Negative regulation of the SHPTP1 protein tyrosine phosphatase by protein kinase C delta in response to DNA damage. Yoshida, K., Kufe, D. Mol. Pharmacol. (2001) [Pubmed]
  15. Lack of phosphotyrosine phosphatase SHP-1 expression in malignant T-cell lymphoma cells results from methylation of the SHP-1 promoter. Zhang, Q., Raghunath, P.N., Vonderheid, E., Odum, N., Wasik, M.A. Am. J. Pathol. (2000) [Pubmed]
  16. The carboxyl-terminal region of biliary glycoprotein controls its tyrosine phosphorylation and association with protein-tyrosine phosphatases SHP-1 and SHP-2 in epithelial cells. Huber, M., Izzi, L., Grondin, P., Houde, C., Kunath, T., Veillette, A., Beauchemin, N. J. Biol. Chem. (1999) [Pubmed]
  17. Interaction of growth hormone-activated STATs with SH2-containing phosphotyrosine phosphatase SHP-1 and nuclear JAK2 tyrosine kinase. Ram, P.A., Waxman, D.J. J. Biol. Chem. (1997) [Pubmed]
  18. Human protein tyrosine phosphatase 1C (PTPN6) gene structure: alternate promoter usage and exon skipping generate multiple transcripts. Banville, D., Stocco, R., Shen, S.H. Genomics (1995) [Pubmed]
  19. SHP-1 requires inhibitory co-receptors to down-modulate B cell antigen receptor-mediated phosphorylation of cellular substrates. Adachi, T., Wienands, J., Wakabayashi, C., Yakura, H., Reth, M., Tsubata, T. J. Biol. Chem. (2001) [Pubmed]
  20. The protein-tyrosine phosphatase SHP-1 associates with the phosphorylated immunoreceptor tyrosine-based activation motif of Fc gamma RIIa to modulate signaling events in myeloid cells. Ganesan, L.P., Fang, H., Marsh, C.B., Tridandapani, S. J. Biol. Chem. (2003) [Pubmed]
  21. High expression of inhibitory receptor SHPS-1 and its association with protein-tyrosine phosphatase SHP-1 in macrophages. Veillette, A., Thibaudeau, E., Latour, S. J. Biol. Chem. (1998) [Pubmed]
  22. Phosphotyrosine 1173 mediates binding of the protein-tyrosine phosphatase SHP-1 to the epidermal growth factor receptor and attenuation of receptor signaling. Keilhack, H., Tenev, T., Nyakatura, E., Godovac-Zimmermann, J., Nielsen, L., Seedorf, K., Böhmer, F.D. J. Biol. Chem. (1998) [Pubmed]
  23. The protein-tyrosine phosphatase SHP-1 binds to and dephosphorylates p120 catenin. Keilhack, H., Hellman, U., van Hengel, J., van Roy, F., Godovac-Zimmermann, J., Böhmer, F.D. J. Biol. Chem. (2000) [Pubmed]
  24. Negative regulation of PYK2/related adhesion focal tyrosine kinase signal transduction by hematopoietic tyrosine phosphatase SHPTP1. Kumar, S., Avraham, S., Bharti, A., Goyal, J., Pandey, P., Kharbanda, S. J. Biol. Chem. (1999) [Pubmed]
  25. Analysis of SHP-1-mediated down-regulation of the TRK-T3 oncoprotein identifies Trk-fused gene (TFG) as a novel SHP-1-interacting protein. Roccato, E., Miranda, C., Raho, G., Pagliardini, S., Pierotti, M.A., Greco, A. J. Biol. Chem. (2005) [Pubmed]
  26. The MHC class I binding proteins LIR-1 and LIR-2 inhibit Fc receptor-mediated signaling in monocytes. Fanger, N.A., Cosman, D., Peterson, L., Braddy, S.C., Maliszewski, C.R., Borges, L. Eur. J. Immunol. (1998) [Pubmed]
  27. Actin tyrosine dephosphorylation by the Src homology 1-containing protein tyrosine phosphatase is essential for actin depolymerization after membrane IgM cross-linking. Baba, T., Fusaki, N., Shinya, N., Iwamatsu, A., Hozumi, N. J. Immunol. (2003) [Pubmed]
  28. Human 70-kDa SHP-1L differs from 68-kDa SHP-1 in its C-terminal structure and catalytic activity. Jin, Y.J., Yu, C.L., Burakoff, S.J. J. Biol. Chem. (1999) [Pubmed]
  29. SHP-1 expression in peripheral T cells from patients with Sezary syndrome and in the T cell line HUT-78: implications in JAK3-mediated signaling. León, F., Cespón, C., Franco, A., Lombardía, M., Roldán, E., Escribano, L., Harto, A., González-Porqué, P., Roy, G. Leukemia (2002) [Pubmed]
  30. Positive effects of SH2 domain-containing tyrosine phosphatase SHP-1 on epidermal growth factor- and interferon-gamma-stimulated activation of STAT transcription factors in HeLa cells. You, M., Zhao, Z. J. Biol. Chem. (1997) [Pubmed]
  31. Both SH2 domains are involved in interaction of SHP-1 with the epidermal growth factor receptor but cannot confer receptor-directed activity to SHP-1/SHP-2 chimera. Tenev, T., Keilhack, H., Tomic, S., Stoyanov, B., Stein-Gerlach, M., Lammers, R., Krivtsov, A.V., Ullrich, A., Böhmer, F.D. J. Biol. Chem. (1997) [Pubmed]
  32. FLT3/ITD mutation signaling includes suppression of SHP-1. Chen, P., Levis, M., Brown, P., Kim, K.T., Allebach, J., Small, D. J. Biol. Chem. (2005) [Pubmed]
  33. The chemokine SDF-1alpha triggers CXCR4 receptor dimerization and activates the JAK/STAT pathway. Vila-Coro, A.J., Rodríguez-Frade, J.M., Martín De Ana, A., Moreno-Ortíz, M.C., Martínez-A, C., Mellado, M. FASEB J. (1999) [Pubmed]
  34. Beta-chemokine receptor CCR5 signals through SHP1, SHP2, and Syk. Ganju, R.K., Brubaker, S.A., Chernock, R.D., Avraham, S., Groopman, J.E. J. Biol. Chem. (2000) [Pubmed]
  35. Recruitment of SH2-containing protein tyrosine phosphatase SHP-1 to the interleukin 2 receptor; loss of SHP-1 expression in human T-lymphotropic virus type I-transformed T cells. Migone, T.S., Cacalano, N.A., Taylor, N., Yi, T., Waldmann, T.A., Johnston, J.A. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  36. Negative regulation of beta-catenin signaling by tyrosine phosphatase SHP-1 in intestinal epithelial cells. Duchesne, C., Charland, S., Asselin, C., Nahmias, C., Rivard, N. J. Biol. Chem. (2003) [Pubmed]
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