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Gene Review

PTPN11  -  protein tyrosine phosphatase, non-receptor...

Homo sapiens

Synonyms: BPTP3, CFC, NS1, PTP-1D, PTP-2C, ...
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Disease relevance of PTPN11


Psychiatry related information on PTPN11

  • Individual differences in consideration of future consequences (CFC; A. Strathman, F. Gleicher, D. S. Boninger, & C. S. Edwards, 1994) moderated (a) the generation of positive and negative thoughts and (b) the persuasive impact of the different communications [7].
  • This study integrates social value orientation (Messick & McClintock, 1968) and the consideration of future consequences (CFC; Strathman, Gleicher, Boninger, & Edwards, 1994) within the extended norm activation model of proenvironmental behaviour (Stern, Dietz, & Kalof, 1993) [8].

High impact information on PTPN11


Chemical compound and disease context of PTPN11


Biological context of PTPN11

  • All PTPN11 missense mutations cluster in interacting portions of the amino N-SH2 domain and the phosphotyrosine phosphatase domains, which are involved in switching the protein between its inactive and active conformations [1].
  • We recently demonstrated that mutations in PTPN11, the gene encoding the non-receptor-type protein tyrosine phosphatase SHP-2 (src homology region 2-domain phosphatase-2), cause NS, accounting for approximately 50% of cases of this genetically heterogeneous disorder in a small cohort [4].
  • On the other hand, no defect in PTPN11 was observed, and no lesion affecting exons 11-27 of the NF1 gene was identified in 100 PTPN11 mutation-negative subjects with NS, which provides further evidence that NFNS and NS are genetically distinct disorders [18].
  • These data suggest that there is a genotype/phenotype correlation in the spectrum of PTPN11 mutations found in patients with JMML, NS/MPD, and NS [19].
  • Shp2 tyrosine phosphatase plays a critical role in hematopoiesis, and dominant active mutations have been detected in the human gene PTPN11, encoding Shp2, in child leukemia patients [20].

Anatomical context of PTPN11

  • A PTPN11 mutation was identified in a family inheriting Noonan-like/multiple giant-cell lesion syndrome, extending the phenotypic range of disease associated with this gene [4].
  • We identified PTPN11 mutations in blood or bone marrow specimens from 77 newly reported patients with JMML (n = 69) or NS/MPD (n = 8) [19].
  • Germ line PTPN11 mutations cause 50% of cases of Noonan syndrome (NS) [19].
  • Src homology 2 protein tyrosine phosphatase (SHPTP2)/Src homology 2 phosphatase 2 (SHP2) tyrosine phosphatase is a positive regulator of the interleukin 5 receptor signal transduction pathways leading to the prolongation of eosinophil survival [21].
  • Expression of the Shp-2 mutants induced progenitor cell hypersensitivity to GM-CSF compared with cells transduced with vector alone or WT Shp-2 [22].

Associations of PTPN11 with chemical compounds

  • Interestingly, SHP-2-C>S cells show a larger number of focal adhesion contacts than wild-type cells, suggesting that SHP-2 activity participates in the integrin deactivation process [23].
  • However, when the C-terminal 30 amino acids of SIRPalpha1 containing the proline-rich region and tyrosine 495 are deleted, tyrosyl phosphorylation of SIRPalpha1 by JAK2 and association of SHP-2 with SIRPalpha1 are reduced [24].
  • A cell-permeable peptide that contained a polyproline sequence from Shc selectively inhibited Shc/SHP-2 association and impaired Shc but not SHP-2 binding to SHPS-1 [25].
  • By screening the National Cancer Institute (NCI) Diversity Set chemical library, we identified 8-hydroxy-7-(6-sulfonaphthalen-2-yl)diazenyl-quinoline-5-sulfonic acid (NSC-87877) as a potent Shp2 PTP inhibitor [26].
  • Using point mutants of SHP2, we identified serine residues 576 and 591 as phosphorylation sites for PKC [27].
  • We demonstrate that the lipoxin A(4) (LXA(4)) receptor is coupled to activation and recruitment of the SHP-2 (SH2 domain-containing tyrosine phosphatase-2) within a lipid raft microdomain [28].

Physical interactions of PTPN11

  • On the other hand, ectopic overexpression of either a Gab1 mutant incapable of binding to SHP-2 (Y627F) or a phosphatase-inactive SHP-2 mutant (C459S) caused a significant increase in NF-kappaB activity [29].
  • Furthermore, we screened an adult human brain cDNA library with the yeast two-and-a-half-hybrid system in order to identify other Shp2-binding proteins in TrkB-stimulated tyrosine phosphorylation signaling [30].
  • RESULTS: SHP-2 bound IL-4Ralpha synthetic peptide; this binding was reduced in the presence of the R551 variant [31].
  • PECAM-1 was coimmunoprecipitated by anti-SH-PTP2 from EC extracts as a major binding protein, and the level of association increased when PECAM-1 was tyrosine phosphorylated [32].
  • Multiple in vivo phosphorylated tyrosine phosphatase SHP-2 engages binding to Grb2 via tyrosine 584 [33].

Enzymatic interactions of PTPN11


Regulatory relationships of PTPN11


Other interactions of PTPN11

  • Overexpression of SHP-2, Gab1, and myristoylated Akt significantly upregulated NF-kappaB transcriptional activity and DNA binding activity in glioblastoma cells [29].
  • Interestingly, both JAK/STAT and SHP-2 pathways regulate the induction of the junB gene [39].
  • Beta-chemokine receptor CCR5 signals through SHP1, SHP2, and Syk [40].
  • Western blot analysis of anti-PTP1D immune complexes derived from EGF-treated cells demonstrated a ligand-dependent coupling between the phosphatase and GRB2 in vivo [41].
  • Thus, our data suggest that in addition to mediating SHP-2 binding and ERK activation during acute stimulation, Tyr(985) of LRb mediates feedback inhibition of LRb signaling by binding to LRb-induced SOCS3 [42].
  • Nuclear Shp-2 associates with TERT in endothelial cells and dissociates from TERT prior to its nuclear export [43].

Analytical, diagnostic and therapeutic context of PTPN11


  1. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Tartaglia, M., Mehler, E.L., Goldberg, R., Zampino, G., Brunner, H.G., Kremer, H., van der Burgt, I., Crosby, A.H., Ion, A., Jeffery, S., Kalidas, K., Patton, M.A., Kucherlapati, R.S., Gelb, B.D. Nat. Genet. (2001) [Pubmed]
  2. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Tartaglia, M., Niemeyer, C.M., Fragale, A., Song, X., Buechner, J., Jung, A., Hählen, K., Hasle, H., Licht, J.D., Gelb, B.D. Nat. Genet. (2003) [Pubmed]
  3. Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Digilio, M.C., Conti, E., Sarkozy, A., Mingarelli, R., Dottorini, T., Marino, B., Pizzuti, A., Dallapiccola, B. Am. J. Hum. Genet. (2002) [Pubmed]
  4. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Tartaglia, M., Kalidas, K., Shaw, A., Song, X., Musat, D.L., van der Burgt, I., Brunner, H.G., Bertola, D.R., Crosby, A., Ion, A., Kucherlapati, R.S., Jeffery, S., Patton, M.A., Gelb, B.D. Am. J. Hum. Genet. (2002) [Pubmed]
  5. Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia. Tartaglia, M., Martinelli, S., Cazzaniga, G., Cordeddu, V., Iavarone, I., Spinelli, M., Palmi, C., Carta, C., Pession, A., Aricò, M., Masera, G., Basso, G., Sorcini, M., Gelb, B.D., Biondi, A. Blood (2004) [Pubmed]
  6. Negative regulation of Stat3 by activating PTPN11 mutants contributes to the pathogenesis of Noonan syndrome and juvenile myelomonocytic leukemia. Zhang, W., Chan, R.J., Chen, H., Yang, Z., He, Y., Zhang, X., Luo, Y., Yin, F., Moh, A., Miller, L.C., Payne, R.M., Zhang, Z.Y., Fu, X.Y., Shou, W. J. Biol. Chem. (2009) [Pubmed]
  7. Temporal framing and the decision to take part in type 2 diabetes screening: effects of individual differences in consideration of future consequences on persuasion. Orbell, S., Hagger, M. Health psychology : official journal of the Division of Health Psychology, American Psychological Association. (2006) [Pubmed]
  8. Integrating social value orientation and the consideration of future consequences within the extended norm activation model of proenvironmental behaviour. Joireman, J.A., Lasane, T.P., Bennett, J., Richards, D., Solaimani, S. The British journal of social psychology / the British Psychological Society. (2001) [Pubmed]
  9. NK cell receptors. Lanier, L.L. Annu. Rev. Immunol. (1998) [Pubmed]
  10. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Tartaglia, M., Pennacchio, L.A., Zhao, C., Yadav, K.K., Fodale, V., Sarkozy, A., Pandit, B., Oishi, K., Martinelli, S., Schackwitz, W., Ustaszewska, A., Martin, J., Bristow, J., Carta, C., Lepri, F., Neri, C., Vasta, I., Gibson, K., Curry, C.J., Siguero, J.P., Digilio, M.C., Zampino, G., Dallapiccola, B., Bar-Sagi, D., Gelb, B.D. Nat. Genet. (2007) [Pubmed]
  11. Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Niihori, T., Aoki, Y., Narumi, Y., Neri, G., Cavé, H., Verloes, A., Okamoto, N., Hennekam, R.C., Gillessen-Kaesbach, G., Wieczorek, D., Kavamura, M.I., Kurosawa, K., Ohashi, H., Wilson, L., Heron, D., Bonneau, D., Corona, G., Kaname, T., Naritomi, K., Baumann, C., Matsumoto, N., Kato, K., Kure, S., Matsubara, Y. Nat. Genet. (2006) [Pubmed]
  12. Germline KRAS mutations cause Noonan syndrome. Schubbert, S., Zenker, M., Rowe, S.L., Böll, S., Klein, C., Bollag, G., van der Burgt, I., Musante, L., Kalscheuer, V., Wehner, L.E., Nguyen, H., West, B., Zhang, K.Y., Sistermans, E., Rauch, A., Niemeyer, C.M., Shannon, K., Kratz, C.P. Nat. Genet. (2006) [Pubmed]
  13. Vanadate regulates the insulin mitogenic effect by modulating SHP-2 association with insulin receptor substrate 1 in JAr human choriocarcinoma cells. Bifulco, G., Caruso, M., Di Carlo, C., Acunzo, G., Votino, C., Pellicano, M., Beguinot, F., Nappi, C. Gynecol. Endocrinol. (2003) [Pubmed]
  14. Growth hormone inhibits signal transducer and activator of transcription 3 activation and reduces disease activity in murine colitis. Han, X., Sosnowska, D., Bonkowski, E.L., Denson, L.A. Gastroenterology (2005) [Pubmed]
  15. Silencing of SH-PTP2 defines a crucial role in the inactivation of epidermal growth factor receptor by 5-aminosalicylic acid in colon cancer cells. Monteleone, G., Franchi, L., Fina, D., Caruso, R., Vavassori, P., Monteleone, I., Calabrese, E., Naccari, G.C., Bellinvia, S., Testi, R., Pallone, F. Cell Death Differ. (2006) [Pubmed]
  16. In vivo protection of normal mouse hematopoiesis by a beta 2 blocking agent during S-phase chemotherapy. Dresch, C., Minc, J., Mary, J.Y. Cancer Res. (1984) [Pubmed]
  17. Expression of HCV E2/NS1 protein as a fusion protein with maltose binding protein: detection of anti-E2/NS1 antibody in chronic liver disease. Yokosuka, O., Omata, M., Ito, Y., Ohto, M. Gut (1993) [Pubmed]
  18. NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome. De Luca, A., Bottillo, I., Sarkozy, A., Carta, C., Neri, C., Bellacchio, E., Schirinzi, A., Conti, E., Zampino, G., Battaglia, A., Majore, S., Rinaldi, M.M., Carella, M., Marino, B., Pizzuti, A., Digilio, M.C., Tartaglia, M., Dallapiccola, B. Am. J. Hum. Genet. (2005) [Pubmed]
  19. The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease. Kratz, C.P., Niemeyer, C.M., Castleberry, R.P., Cetin, M., Bergsträsser, E., Emanuel, P.D., Hasle, H., Kardos, G., Klein, C., Kojima, S., Stary, J., Trebo, M., Zecca, M., Gelb, B.D., Tartaglia, M., Loh, M.L. Blood (2005) [Pubmed]
  20. Overexpression of Shp2 tyrosine phosphatase is implicated in leukemogenesis in adult human leukemia. Xu, R., Yu, Y., Zheng, S., Zhao, X., Dong, Q., He, Z., Liang, Y., Lu, Q., Fang, Y., Gan, X., Xu, X., Zhang, S., Dong, Q., Zhang, X., Feng, G.S. Blood (2005) [Pubmed]
  21. Src homology 2 protein tyrosine phosphatase (SHPTP2)/Src homology 2 phosphatase 2 (SHP2) tyrosine phosphatase is a positive regulator of the interleukin 5 receptor signal transduction pathways leading to the prolongation of eosinophil survival. Pazdrak, K., Adachi, T., Alam, R. J. Exp. Med. (1997) [Pubmed]
  22. Human somatic PTPN11 mutations induce hematopoietic-cell hypersensitivity to granulocyte-macrophage colony-stimulating factor. Chan, R.J., Leedy, M.B., Munugalavadla, V., Voorhorst, C.S., Li, Y., Yu, M., Kapur, R. Blood (2005) [Pubmed]
  23. Concerted activity of tyrosine phosphatase SHP-2 and focal adhesion kinase in regulation of cell motility. Mañes, S., Mira, E., Gómez-Mouton, C., Zhao, Z.J., Lacalle, R.A., Martínez-A, C. Mol. Cell. Biol. (1999) [Pubmed]
  24. Negative regulation of growth hormone receptor/JAK2 signaling by signal regulatory protein alpha. Stofega, M.R., Argetsinger, L.S., Wang, H., Ullrich, A., Carter-Su, C. J. Biol. Chem. (2000) [Pubmed]
  25. Role of SHPS-1 in the regulation of insulin-like growth factor I-stimulated Shc and mitogen-activated protein kinase activation in vascular smooth muscle cells. Ling, Y., Maile, L.A., Lieskovska, J., Badley-Clarke, J., Clemmons, D.R. Mol. Biol. Cell (2005) [Pubmed]
  26. Discovery of a novel shp2 protein tyrosine phosphatase inhibitor. Chen, L., Sung, S.S., Yip, M.L., Lawrence, H.R., Ren, Y., Guida, W.C., Sebti, S.M., Lawrence, N.J., Wu, J. Mol. Pharmacol. (2006) [Pubmed]
  27. The Protein-tyrosine-phosphatase SHP2 is phosphorylated on serine residues 576 and 591 by protein kinase C isoforms alpha, beta 1, beta 2, and eta. Strack, V., Krützfeldt, J., Kellerer, M., Ullrich, A., Lammers, R., Häring, H.U. Biochemistry (2002) [Pubmed]
  28. The Lipoxin A4 receptor is coupled to SHP-2 activation: implications for regulation of receptor tyrosine kinases. Mitchell, D., O'Meara, S.J., Gaffney, A., Crean, J.K., Kinsella, B.T., Godson, C. J. Biol. Chem. (2007) [Pubmed]
  29. Distinct domains in the SHP-2 phosphatase differentially regulate epidermal growth factor receptor/NF-kappaB activation through Gab1 in glioblastoma cells. Kapoor, G.S., Zhan, Y., Johnson, G.R., O'Rourke, D.M. Mol. Cell. Biol. (2004) [Pubmed]
  30. Analysis of tyrosine phosphorylation-dependent protein-protein interactions in TrkB-mediated intracellular signaling using modified yeast two-hybrid system. Yamada, M., Suzuki, K., Mizutani, M., Asada, A., Matozaki, T., Ikeuchi, T., Koizumi, S., Hatanaka, H. J. Biochem. (2001) [Pubmed]
  31. Distinct signal transduction processes by IL-4 and IL-13 and influences from the Q551R variant of the human IL-4 receptor alpha chain. Kruse, S., Braun, S., Deichmann, K.A. Respir. Res. (2002) [Pubmed]
  32. Platelet endothelial cell adhesion molecule-1 is a major SH-PTP2 binding protein in vascular endothelial cells. Masuda, M., Osawa, M., Shigematsu, H., Harada, N., Fujiwara, K. FEBS Lett. (1997) [Pubmed]
  33. Multiple in vivo phosphorylated tyrosine phosphatase SHP-2 engages binding to Grb2 via tyrosine 584. Vogel, W., Ullrich, A. Cell Growth Differ. (1996) [Pubmed]
  34. Role of SH-PTP2, a protein-tyrosine phosphatase with Src homology 2 domains, in insulin-stimulated Ras activation. Noguchi, T., Matozaki, T., Horita, K., Fujioka, Y., Kasuga, M. Mol. Cell. Biol. (1994) [Pubmed]
  35. Activation of a phosphotyrosine phosphatase by tyrosine phosphorylation. Vogel, W., Lammers, R., Huang, J., Ullrich, A. Science (1993) [Pubmed]
  36. Phosphotyrosines 627 and 659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) conferring binding and activation of SHP2. Cunnick, J.M., Mei, L., Doupnik, C.A., Wu, J. J. Biol. Chem. (2001) [Pubmed]
  37. Protein-tyrosine-phosphatase 2C is phosphorylated and inhibited by 44-kDa mitogen-activated protein kinase. Peraldi, P., Zhao, Z., Filloux, C., Fischer, E.H., Van Obberghen, E. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  38. SHP2 regulates IL-2 induced MAPK activation, but not Stat3 or Stat5 tyrosine phosphorylation, in cutaneous T cell lymphoma cells. Lundin Brockdorff, J., Woetmann, A., Mustelin, T., Kaltoft, K., Zhang, Q., Wasik, M.A., Röpke, C., Ødum, N. Cytokine (2002) [Pubmed]
  39. Dual signaling role of the protein tyrosine phosphatase SHP-2 in regulating expression of acute-phase plasma proteins by interleukin-6 cytokine receptors in hepatic cells. Kim, H., Baumann, H. Mol. Cell. Biol. (1999) [Pubmed]
  40. 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]
  41. Epidermal growth factor induces coupling of protein-tyrosine phosphatase 1D to GRB2 via the COOH-terminal SH3 domain of GRB2. Wong, L., Johnson, G.R. J. Biol. Chem. (1996) [Pubmed]
  42. SOCS3 mediates feedback inhibition of the leptin receptor via Tyr985. Bjorbak, C., Lavery, H.J., Bates, S.H., Olson, R.K., Davis, S.M., Flier, J.S., Myers, M.G. J. Biol. Chem. (2000) [Pubmed]
  43. Nuclear protein tyrosine phosphatase Shp-2 is one important negative regulator of nuclear export of telomerase reverse transcriptase. Jakob, S., Schroeder, P., Lukosz, M., Büchner, N., Spyridopoulos, I., Altschmied, J., Haendeler, J. J. Biol. Chem. (2008) [Pubmed]
  44. PTPN11 mutations are associated with mild growth hormone resistance in individuals with Noonan syndrome. Binder, G., Neuer, K., Ranke, M.B., Wittekindt, N.E. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  45. Protein-tyrosine phosphatase, nonreceptor type 11 mutation analysis and clinical assessment in 45 patients with Noonan syndrome. Yoshida, R., Hasegawa, T., Hasegawa, Y., Nagai, T., Kinoshita, E., Tanaka, Y., Kanegane, H., Ohyama, K., Onishi, T., Hanew, K., Okuyama, T., Horikawa, R., Tanaka, T., Ogata, T. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  46. Exclusion of PTPN11 mutations in Costello syndrome: further evidence for distinct genetic etiologies for Noonan, cardio-facio-cutaneous and Costello syndromes. Tartaglia, M., Cotter, P.D., Zampino, G., Gelb, B.D., Rauen, K.A. Clin. Genet. (2003) [Pubmed]
  47. Noonan syndrome-associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation. Fragale, A., Tartaglia, M., Wu, J., Gelb, B.D. Hum. Mutat. (2004) [Pubmed]
  48. Leptin receptor signaling and the regulation of mammalian physiology. Myers, M.G. Recent Prog. Horm. Res. (2004) [Pubmed]
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