SHP-2

Summary

Gene Symbol: SHP-2
Description: protein tyrosine phosphatase, non-receptor type 11
Alias: BPTP3, CFC, JMML, METCDS, NS1, PTP-1D, PTP2C, SH-PTP2, SH-PTP3, SHP2, tyrosine-protein phosphatase non-receptor type 11, PTP-2C, protein-tyrosine phosphatase 1D, protein-tyrosine phosphatase 2C
Species: human
Products:     SHP-2

Top Publications

  1. Edouard T, Combier J, Nédélec A, Bel Vialar S, Métrich M, Conte Auriol F, et al. Functional effects of PTPN11 (SHP2) mutations causing LEOPARD syndrome on epidermal growth factor-induced phosphoinositide 3-kinase/AKT/glycogen synthase kinase 3beta signaling. Mol Cell Biol. 2010;30:2498-507 pubmed publisher
    ..developmental abnormalities, is mainly due to mutations that impair the activity of the tyrosine phosphatase SHP2 (PTPN11). How these alterations cause the disease remains unknown...
  2. Higashi H, Nakaya A, Tsutsumi R, Yokoyama K, Fujii Y, Ishikawa S, et al. Helicobacter pylori CagA induces Ras-independent morphogenetic response through SHP-2 recruitment and activation. J Biol Chem. 2004;279:17205-16 pubmed
    ..Our work therefore suggests a key role of SHP-2 in the pathological activity of H. pylori virulence factor CagA. ..
  3. Mitola S, Brenchio B, Piccinini M, Tertoolen L, Zammataro L, Breier G, et al. Type I collagen limits VEGFR-2 signaling by a SHP2 protein-tyrosine phosphatase-dependent mechanism 1. Circ Res. 2006;98:45-54 pubmed
    ..This activity requires the tyrosine phosphatase SHP2, which is recruited to the activated VEGFR-2 when cells are plated on collagen I, but not on vitronectin...
  4. He C, Tu H, Sun L, Xu Q, Li P, Gong Y, et al. Helicobacter pylori-related host gene polymorphisms associated with susceptibility of gastric carcinogenesis: a two-stage case-control study in Chinese. Carcinogenesis. 2013;34:1450-7 pubmed publisher
    ..pylori, were associated with the risks of GC and/or GA that precede carcinoma. Functional studies and further independent large-scale studies especially in other ethnic populations are still needed to confirm our results. ..
  5. Papadopoulou A, Issakidis M, Gole E, Kosma K, Fryssira H, Fretzayas A, et al. Phenotypic spectrum of 80 Greek patients referred as Noonan syndrome and PTPN11 mutation analysis: the value of initial clinical assessment. Eur J Pediatr. 2012;171:51-8 pubmed publisher
  6. Cai T, Nishida K, Hirano T, Khavari P. Gab1 and SHP-2 promote Ras/MAPK regulation of epidermal growth and differentiation. J Cell Biol. 2002;159:103-12 pubmed
    ..These data provide support for a Ras role in promoting epidermal proliferation and opposing differentiation and indicate that Gab1 and SHP-2 promote the undifferentiated epidermal cell state by facilitating Ras/MAPK signaling. ..
  7. Feng G. Shp2-mediated molecular signaling in control of embryonic stem cell self-renewal and differentiation. Cell Res. 2007;17:37-41 pubmed
    ..This short review discusses the physiological role of Shp2, a cytoplasmic tyrosine phosphatase, in the molecular switch governing ES cell self-renewal versus differentiation...
  8. Koyama T, Nakaoka Y, Fujio Y, Hirota H, Nishida K, Sugiyama S, et al. Interaction of scaffolding adaptor protein Gab1 with tyrosine phosphatase SHP2 negatively regulates IGF-I-dependent myogenic differentiation via the ERK1/2 signaling pathway. J Biol Chem. 2008;283:24234-44 pubmed publisher
    ..Gab1 underwent tyrosine phosphorylation and subsequent complex formation with protein-tyrosine phosphatase SHP2 upon IGF-I stimulation in C2C12 myoblasts...
  9. Morales L, Peña K, Kim D, Lieman J. SHP-2 and PTP-pest induction during Rb-E2F associated apoptosis. Cell Mol Biol Lett. 2012;17:422-32 pubmed publisher
    ..This report identifies two additional PTPs, SHP-2 and PTP-PEST, that are also directly activated by the Rb-E2F pathway and which can contribute to signal transduction during p53-independent apoptosis. ..

More Information

Publications98

  1. Carver K, Piazza T, Schuler L. Prolactin enhances insulin-like growth factor I receptor phosphorylation by decreasing its association with the tyrosine phosphatase SHP-2 in MCF-7 breast cancer cells. J Biol Chem. 2010;285:8003-12 pubmed publisher
    ..Together, these findings describe a novel mechanism of cross-talk between PRL and IGF-I in breast cancer cells, with implications for our understanding of tumor progression and potential therapeutic strategies. ..
  2. Hishida A, Matsuo K, Goto Y, Naito M, Wakai K, Tajima K, et al. Associations of a PTPN11 G/A polymorphism at intron 3 with Helicobactor pylori seropositivity, gastric atrophy and gastric cancer in Japanese. BMC Gastroenterol. 2009;9:51 pubmed publisher
    ..pylori infected Japanese. The biological roles of this PTPN11 polymorphism require further investigation. ..
  3. Jongmans M, Sistermans E, Rikken A, Nillesen W, Tamminga R, Patton M, et al. Genotypic and phenotypic characterization of Noonan syndrome: new data and review of the literature. Am J Med Genet A. 2005;134A:165-70 pubmed
    ..In one patient with NS and mild juvenile myelomonocytic leukemia (JMML) the mutation 218C --> T (Thr73Ile) was found...
  4. Sayos J, Martin M, Chen A, Simarro M, Howie D, Morra M, et al. Cell surface receptors Ly-9 and CD84 recruit the X-linked lymphoproliferative disease gene product SAP. Blood. 2001;97:3867-74 pubmed
    ..This suggests that combinations of dysfunctional signaling pathways initiated by these 4 cell surface receptors may cause the complex phenotypes of XLP. (Blood. 2001;97:3867-3874) ..
  5. Jongmans M, van der Burgt I, Hoogerbrugge P, Noordam K, Yntema H, Nillesen W, et al. Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. Eur J Hum Genet. 2011;19:870-4 pubmed publisher
    ..In conclusion, this study provides first evidence of an increased risk of cancer in patients with NS and a PTPN11 mutation, compared with that in the general population. Our data do not warrant specific cancer surveillance. ..
  6. Tartaglia M, Martinelli S, Cazzaniga G, Cordeddu V, Iavarone I, Spinelli M, et al. Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia. Blood. 2004;104:307-13 pubmed
    ..Our findings provide evidence for a wider role of PTPN11 lesions in leukemogenesis, but also suggest a lineage-related and differentiation stage-related contribution of these lesions to clonal expansion. ..
  7. Tartaglia M, Gelb B. Germ-line and somatic PTPN11 mutations in human disease. Eur J Med Genet. 2005;48:81-96 pubmed
    ..This review focuses on the role of SHP-2 in signal transduction, development and hematopoiesis, as well as on the consequences of SHP-2 gain-of-function. ..
  8. Tartaglia M, Mehler E, Goldberg R, Zampino G, Brunner H, Kremer H, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001;29:465-8 pubmed
    ..It has been mapped to a 5-cM region (NS1) [corrected] on chromosome 12q24.1, and genetic heterogeneity has also been documented...
  9. Roberts A, Araki T, Swanson K, Montgomery K, Schiripo T, Joshi V, et al. Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat Genet. 2007;39:70-4 pubmed
    ..Gain-of-function mutations in PTPN11, encoding the tyrosine phosphatase SHP2, cause approximately 50% of Noonan syndrome cases...
  10. Wang Q, Downey G, Herrera Abreu M, Kapus A, McCulloch C. SHP-2 modulates interleukin-1-induced Ca2+ flux and ERK activation via phosphorylation of phospholipase Cgamma1. J Biol Chem. 2005;280:8397-406 pubmed
    ..Focal adhesions co-localizing with the endoplasmic reticulum may provide molecular staging sites required for ERK activation. ..
  11. Bowen M, Boyden E, Holm I, Campos Xavier B, Bonafe L, Superti Furga A, et al. Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome. PLoS Genet. 2011;7:e1002050 pubmed publisher
  12. Yamazaki S, Yamakawa A, Ito Y, Ohtani M, Higashi H, Hatakeyama M, et al. The CagA protein of Helicobacter pylori is translocated into epithelial cells and binds to SHP-2 in human gastric mucosa. J Infect Dis. 2003;187:334-7 pubmed
    ..Deregulation of SHP-2 by CagA may play a role in the acquisition of a cellular-transformed phenotype at a relatively early stage of multistep gastric carcinogenesis. ..
  13. Chan R, Leedy M, Munugalavadla V, Voorhorst C, 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 pubmed
    Juvenile myelomonocytic leukemia (JMML) is a lethal disease of young children characterized by hypersensitivity of hematopoietic progenitors to granulocyte-macrophage colony-stimulating factor (GM-CSF)...
  14. Yart A, Laffargue M, Mayeux P, Chretien S, Peres C, Tonks N, et al. A critical role for phosphoinositide 3-kinase upstream of Gab1 and SHP2 in the activation of ras and mitogen-activated protein kinases by epidermal growth factor. J Biol Chem. 2001;276:8856-64 pubmed
    ..conventional effectors was independent of PI3K, we have observed that the recruitment of the tyrosine phosphatase SHP2 required PI3K...
  15. Cunnick J, Mei L, Doupnik C, Wu J. Phosphotyrosines 627 and 659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) conferring binding and activation of SHP2. J Biol Chem. 2001;276:24380-7 pubmed
    ..Gab1) binding partner in epidermal growth factor (EGF)-stimulated cells is protein-tyrosine phosphatase (PTPase) SHP2, which contains tandem SH2 domains...
  16. Jiang C, Hu F, Tai Y, Du J, Mao B, Yuan Z, et al. The tumor suppressor role of Src homology phosphotyrosine phosphatase 2 in hepatocellular carcinoma. J Cancer Res Clin Oncol. 2012;138:637-46 pubmed publisher
    ..PTPN11, which encodes the non-receptor protein tyrosine phosphatase of Src homology phosphotyrosine phosphatase 2 (Shp2), has been previously well interpreted as a proto-oncogene in a variety of malignancies...
  17. Jia Z, Cao X, Cao D, Kong F, Kharbuja P, Jiang J. Polymorphisms of PTPN11 gene could influence serum lipid levels in a sex-specific pattern. Lipids Health Dis. 2013;12:72 pubmed publisher
    ..SNPs of PTPN11 may play a role in serum lipids in a sex-specific pattern. However, more studies are needed to confirm the conclusion and explore the underlying mechanism. ..
  18. Nakaoka Y, Nishida K, Fujio Y, Izumi M, Terai K, Oshima Y, et al. Activation of gp130 transduces hypertrophic signal through interaction of scaffolding/docking protein Gab1 with tyrosine phosphatase SHP2 in cardiomyocytes. Circ Res. 2003;93:221-9 pubmed
    ..Gab1 is tyrosine phosphorylated and associates with protein tyrosine phosphatase SHP2 and p85 phosphatidylinositol 3-kinase on stimulation with various cytokines and growth factors, including ..
  19. Kontaridis M, Eminaga S, Fornaro M, Zito C, Sordella R, Settleman J, et al. SHP-2 positively regulates myogenesis by coupling to the Rho GTPase signaling pathway. Mol Cell Biol. 2004;24:5340-52 pubmed
    ..Collectively, these data provide a mechanistic basis for RhoA activation in myoblasts and demonstrate that myogenesis is critically regulated by the actions of SHP-2 on the p190-B Rho GAP/RhoA pathway. ..
  20. Li F, Shen J, Shen H, Zhang X, Cao R, Zhang Y, et al. Shp2 plays an important role in acute cigarette smoke-mediated lung inflammation. J Immunol. 2012;189:3159-67 pubmed publisher
    ..that were implicated in the regulation of Src homology domain 2-containing protein tyrosine phosphatase 2 (Shp2) activity...
  21. Leibowitz M, Srivastava R, Andrade Filho P, Egloff A, Wang L, Seethala R, et al. SHP2 is overexpressed and inhibits pSTAT1-mediated APM component expression, T-cell attracting chemokine secretion, and CTL recognition in head and neck cancer cells. Clin Cancer Res. 2013;19:798-808 pubmed publisher
    ..PCR of paired HNC tumors was performed for the phosphatases src homology domain-containing phosphatase (SHP)-1 and SHP2. Depletion of phosphatase activity in HNC and STAT1(-/-) tumor cells was achieved by siRNA knockdown...
  22. Coyne C, Kim K, Bergelson J. Poliovirus entry into human brain microvascular cells requires receptor-induced activation of SHP-2. EMBO J. 2007;26:4016-28 pubmed
    ..The results indicate that receptor-induced signals promote virus entry and suggest a role for tyrosine phosphatases in viral pathogenesis. ..
  23. Tsutsumi R, Takahashi A, Azuma T, Higashi H, Hatakeyama M. Focal adhesion kinase is a substrate and downstream effector of SHP-2 complexed with Helicobacter pylori CagA. Mol Cell Biol. 2006;26:261-76 pubmed
    ..Impaired cell adhesion and increased motility by CagA may be involved in the development of gastric lesions associated with cagA-positive H. pylori infection. ..
  24. Higashi H, Tsutsumi R, Muto S, Sugiyama T, Azuma T, Asaka M, et al. SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science. 2002;295:683-6 pubmed
    ..Conversely, the CagA effect on cells was reproduced by constitutively active SHP-2. Thus, upon translocation, CagA perturbs cellular functions by deregulating SHP-2. ..
  25. Mali R, Ma P, Zeng L, Martin H, Ramdas B, He Y, et al. Role of SHP2 phosphatase in KIT-induced transformation: identification of SHP2 as a druggable target in diseases involving oncogenic KIT. Blood. 2012;120:2669-78 pubmed
    ..We show that SHP2 phosphatase is essential for oncogenic KIT-induced growth and survival in vitro and myeloproliferative disease (MPD)..
  26. Lauriol J, Kontaridis M. PTPN11-associated mutations in the heart: has LEOPARD changed Its RASpots?. Trends Cardiovasc Med. 2011;21:97-104 pubmed publisher
    ..mutations in the PTPN11 gene, encoding the Src homology-2 (SH2) domain-containing protein tyrosine phosphatase SHP2. PTPN11 mutations cause LEOPARD syndrome (LS) and Noonan syndrome (NS), two disorders that are part of a newly ..
  27. Miyamoto D, Miyamoto M, Takahashi A, Yomogita Y, Higashi H, Kondo S, et al. Isolation of a distinct class of gain-of-function SHP-2 mutants with oncogenic RAS-like transforming activity from solid tumors. Oncogene. 2008;27:3508-15 pubmed publisher
    ..Although rare in solid tumors, the identified T507K SHP-2 represents a distinct class of SHP-2 mutants with oncogenic RAS-like transforming activity, which could contribute to the development of solid tumors. ..
  28. Loh M, Vattikuti S, Schubbert S, Reynolds M, Carlson E, Lieuw K, et al. Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. Blood. 2004;103:2325-31 pubmed
    ..NS is also associated with a spectrum of hematologic disorders, including juvenile myelomonocytic leukemia (JMML)...
  29. Bard Chapeau E, Li S, Ding J, Zhang S, Zhu H, Princen F, et al. Ptpn11/Shp2 acts as a tumor suppressor in hepatocellular carcinogenesis. Cancer Cell. 2011;19:629-39 pubmed publisher
    The human gene Ptpn11, which encodes the tyrosine phosphatase Shp2, may act as a proto-oncogene because dominantly activating mutations have been detected in several types of leukemia. Herein we report a tumor-suppressor function of Shp2...
  30. Yu Z, Xu J, Walls C, Chen L, Zhang S, Zhang R, et al. Structural and mechanistic insights into LEOPARD syndrome-associated SHP2 mutations. J Biol Chem. 2013;288:10472-82 pubmed publisher
    b>SHP2 is an allosteric phosphatase essential for growth factor-mediated Ras activation...
  31. Keilhack H, David F, McGregor M, Cantley L, Neel B. Diverse biochemical properties of Shp2 mutants. Implications for disease phenotypes. J Biol Chem. 2005;280:30984-93 pubmed
    Mutations in the Src homology 2 (SH2)-containing protein-tyrosine phosphatase Shp2 (PTPN11) underlie half of the cases of the autosomal dominant genetic disorder Noonan syndrome, and somatic Shp2 mutations are found in several hematologic ..
  32. Doan T, Farmer P, Cooney T, Ali M. Selective down-regulation of angiotensin II receptor type 1A signaling by protein tyrosine phosphatase SHP-2 in vascular smooth muscle cells. Cell Signal. 2004;16:301-11 pubmed
    ..These data show SHP-2 represents a critical negative regulator of angiotensin II signaling, and further demonstrate a new function for this phosphatase in vascular smooth muscle cells. ..
  33. Tartaglia M, Kalidas K, Shaw A, Song X, Musat D, van der Burgt I, et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002;70:1555-63 pubmed
    ..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. ..
  34. Darian E, Guvench O, Yu B, Qu C, MacKerell A. Structural mechanism associated with domain opening in gain-of-function mutations in SHP2 phosphatase. Proteins. 2011;79:1573-88 pubmed publisher
    The SHP2 phosphatase plays a central role in a number of signaling pathways were it dephosphorylates various substrate proteins...
  35. Bauler T, Kamiya N, Lapinski P, Langewisch E, Mishina Y, Wilkinson J, et al. Development of severe skeletal defects in induced SHP-2-deficient adult mice: a model of skeletal malformation in humans with SHP-2 mutations. Dis Model Mech. 2011;4:228-39 pubmed publisher
  36. Goodship J, Hall D, Topf A, Mamasoula C, Griffin H, Rahman T, et al. A common variant in the PTPN11 gene contributes to the risk of tetralogy of Fallot. Circ Cardiovasc Genet. 2012;5:287-92 pubmed publisher
    ..Our results suggest a role for milder perturbations in PTPN11 function in sporadic, nonsyndromic congenital heart disease. ..
  37. Hamajima N, Rahimov B, Malikov Y, Abdiev S, Ahn K, Bahramov S, et al. Associations between a PTPN11 polymorphism and gastric atrophy--opposite in Uzbekistan to that in Japan. Asian Pac J Cancer Prev. 2008;9:217-20 pubmed
    ..18 (95% confidence interval, 0.04-0.86) for intron 3 GG genotype relative to AA genotype. Since the finding was opposite to that among Japanese, the H. pylori strains and/or lifestyle in Uzbekistan might modify the association. ..
  38. Lewis J, Eiben L, Nelson D, Cohen J, Nichols K, Ochs H, et al. Distinct interactions of the X-linked lymphoproliferative syndrome gene product SAP with cytoplasmic domains of members of the CD2 receptor family. Clin Immunol. 2001;100:15-23 pubmed
  39. Li S, Hsu D, Wang H, Feng G. Dual faces of SH2-containing protein-tyrosine phosphatase Shp2/PTPN11 in tumorigenesis. Front Med. 2012;6:275-9 pubmed publisher
    PTPN11, which encodes tyrosine phosphatase Shp2, is a critical gene mediating cellular responses to hormones and cytokines...
  40. Tartaglia M, Martinelli S, Stella L, Bocchinfuso G, Flex E, Cordeddu V, et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 2006;78:279-90 pubmed
    ..Furthermore, we show that the recurrent LS-causing Y279C and T468M amino acid substitutions engender loss of SHP-2 catalytic activity, identifying a previously unrecognized behavior for this class of missense PTPN11 mutations...
  41. Bocchinfuso G, Stella L, Martinelli S, Flex E, Carta C, Pantaleoni F, et al. Structural and functional effects of disease-causing amino acid substitutions affecting residues Ala72 and Glu76 of the protein tyrosine phosphatase SHP-2. Proteins. 2007;66:963-74 pubmed
  42. Kratz C, Niemeyer C, Castleberry R, Cetin M, Bergsträsser E, Emanuel P, et al. The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease. Blood. 2005;106:2183-5 pubmed
    ..Somatic mutations in PTPN11 occur in 35% of patients with de novo, nonsyndromic juvenile myelomonocytic leukemia (JMML)...
  43. Herrera Abreu M, Wang Q, Vachon E, Suzuki T, Chow C, Wang Y, et al. Tyrosine phosphatase SHP-2 regulates IL-1 signaling in fibroblasts through focal adhesions. J Cell Physiol. 2006;207:132-43 pubmed
    ..We conclude that IL-1beta mediated maturation of focal adhesions is dependent on tyrosine phosphorylation of SHP-2 at Y542, leading to recruitment of Gab1, a process that may influence the downstream activation of ERK. ..
  44. Goto Y, Ando T, Nishio K, Kawai S, Ishida Y, Naito M, et al. Grb2-associated binder 1 polymorphism was associated with the risk of Helicobactor pylori infection and gastric atrophy. Int J Med Sci. 2006;4:1-6 pubmed
    ..and the combination of PTPN11 gene encoding src homology 2 domain-containing protein tyrosine phosphatase-2 (SHP2) and Gab1 gene with gastric cancer and gastric atrophy among H. pylori seropositive subjects...
  45. Zhang X, He Y, Liu S, Yu Z, Jiang Z, Yang Z, et al. Salicylic acid based small molecule inhibitor for the oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2). J Med Chem. 2010;53:2482-93 pubmed publisher
    The Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) plays a pivotal role in growth factor and cytokine signaling...
  46. Purdy A, Campbell K. SHP-2 expression negatively regulates NK cell function. J Immunol. 2009;183:7234-43 pubmed publisher
    ..This suppression of activation impacts microtubule organizing center-based cytoskeletal rearrangement and granule release. ..
  47. Niihori T, Aoki Y, Ohashi H, Kurosawa K, Kondoh T, Ishikiriyama S, et al. Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia. J Hum Genet. 2005;50:192-202 pubmed
    ..showed that the phosphatase activities of five mutations identified in NS and juvenile myelomonocytic leukemia (JMML) were increased. However, the functional properties of the other mutations remain unidentified...
  48. Wu C, O Rourke D, Feng G, Johnson G, Wang Q, Greene M. The tyrosine phosphatase SHP-2 is required for mediating phosphatidylinositol 3-kinase/Akt activation by growth factors. Oncogene. 2001;20:6018-25 pubmed
    ..Based on these results, we conclude that SHP-2 is required for mediating PI3K/Akt activation, and the N-terminal SH2 domain is critically important for a "positive" role of SHP-2 in regulating PI3K pathway activation. ..
  49. Kolli S, Zito C, Mossink M, Wiemer E, Bennett A. The major vault protein is a novel substrate for the tyrosine phosphatase SHP-2 and scaffold protein in epidermal growth factor signaling. J Biol Chem. 2004;279:29374-85 pubmed
    ..We propose that MVP functions as a novel scaffold protein for both SHP-2 and Erk. The regulation of MVP tyrosyl phosphorylation by SHP-2 may play an important role in cell survival signaling...
  50. Balasubramanian A, Ganju R, Groopman J. Hepatitis C virus and HIV envelope proteins collaboratively mediate interleukin-8 secretion through activation of p38 MAP kinase and SHP2 in hepatocytes. J Biol Chem. 2003;278:35755-66 pubmed
    ..pathways that include activation of p38 mitogen-activated protein (MAP) kinase and the tyrosine phosphatase, SHP2. Both specific inhibitors of p38 MAP kinase and sodium vanadate, a potent protein-tyrosine phosphatase inhibitor, ..
  51. Ucar C, Calýskan U, Martini S, Heinritz W. Acute myelomonocytic leukemia in a boy with LEOPARD syndrome (PTPN11 gene mutation positive). J Pediatr Hematol Oncol. 2006;28:123-5 pubmed
    ..Leukemia has not previously been reported in patients with LEOPARD syndrome. The authors describe a 13-year-old boy diagnosed with both LEOPARD syndrome and acute myelomonocytic leukemia (AML-M4)...
  52. Betts G, van der Geer P, Komives E. Structural and functional consequences of tyrosine phosphorylation in the LRP1 cytoplasmic domain. J Biol Chem. 2008;283:15656-64 pubmed publisher
    ..Conversely, Shp2 binds most strongly when both of the NPXY motifs in LRP1 are phosphorylated.
  53. Martinelli S, Torreri P, Tinti M, Stella L, Bocchinfuso G, Flex E, et al. Diverse driving forces underlie the invariant occurrence of the T42A, E139D, I282V and T468M SHP2 amino acid substitutions causing Noonan and LEOPARD syndromes. Hum Mol Genet. 2008;17:2018-29 pubmed publisher
    ..PTPN11 encodes SHP2, an SH2 domain-containing protein tyrosine phosphatase functioning as a signal transducer...
  54. Ren Y, Meng S, Mei L, Zhao Z, Jove R, Wu J. Roles of Gab1 and SHP2 in paxillin tyrosine dephosphorylation and Src activation in response to epidermal growth factor. J Biol Chem. 2004;279:8497-505 pubmed
    ..We found that Gab1, a docking protein for the SHP2 protein-tyrosine phosphatase in EGF-stimulated cells, was associated with paxillin...
  55. Kondoh T, Ishii E, Aoki Y, Shimizu T, Zaitsu M, Matsubara Y, et al. Noonan syndrome with leukaemoid reaction and overproduction of catecholamines: a case report. Eur J Pediatr. 2003;162:548-549 pubmed publisher
  56. Goto Y, Ando T, Yamamoto K, Tamakoshi A, El Omar E, Goto H, et al. Association between serum pepsinogens and polymorphismof PTPN11 encoding SHP-2 among Helicobacter pylori seropositive Japanese. Int J Cancer. 2006;118:203-8 pubmed
    ..The functional consequences of the G/A polymorphism remain to be elucidated. ..
  57. Cooke M, Mele P, Maloberti P, Duarte A, Poderoso C, Orlando U, et al. Tyrosine phosphatases as key regulators of StAR induction and cholesterol transport: SHP2 as a potential tyrosine phosphatase involved in steroid synthesis. Mol Cell Endocrinol. 2011;336:63-9 pubmed publisher
    ..Here, we will describe the role of protein tyrosine phosphatases in the regulation of steroid biosynthesis, relating them to steroidogenic acute regulatory protein, arachidonic acid metabolism and mitochondrial rearrangement. ..
  58. Koo D, McFadden C, Huang Y, Abdulhussein R, Friese Hamim M, Vogel W. Pinpointing phosphotyrosine-dependent interactions downstream of the collagen receptor DDR1. FEBS Lett. 2006;580:15-22 pubmed
    ..Lastly, ablation of DDR1 in the mouse mammary gland resulted in delocalized expression of Nck2, suggesting that defects observed during alveologenesis are caused by the lack of the DDR1-Nck2 interaction. ..
  59. Cooke M, Orlando U, Maloberti P, Podesta E, Cornejo Maciel F. Tyrosine phosphatase SHP2 regulates the expression of acyl-CoA synthetase ACSL4. J Lipid Res. 2011;52:1936-48 pubmed publisher
    ..NSC87877, a specific inhibitor of the tyrosine phosphatase SHP2, reduced ACSL4 protein levels in ACSL4-rich breast cancer cells and steroidogenic cells...
  60. Legius E, Schrander Stumpel C, Schollen E, Pulles Heintzberger C, Gewillig M, Fryns J. PTPN11 mutations in LEOPARD syndrome. J Med Genet. 2002;39:571-4 pubmed
  61. Hatanaka K, Lanahan A, Murakami M, Simons M. Fibroblast growth factor signaling potentiates VE-cadherin stability at adherens junctions by regulating SHP2. PLoS ONE. 2012;7:e37600 pubmed publisher
    ..PTPs) known to be involved in the maintenance of the VE-cadherin complex, suppression of FGF signaling reduces SHP2 expression levels and SHP2/VE-cadherin interaction due to accelerated SHP2 protein degradation...
  62. Zhu F, Loh M, Hill J, Lee S, Koh K, Lai K, et al. Genetic factors associated with intestinal metaplasia in a high risk Singapore-Chinese population: a cohort study. BMC Gastroenterol. 2009;9:76 pubmed publisher
    ..46, 95%CI: 0.21-0.99, P = 0.048). Polymorphisms in NQO1, IL-10 and PTPN11, in combination with HP status, could be used to identify individuals who are more likely to develop IM and therefore GC. ..
  63. Kim J, Shin O, Kim H, Cho Y, An C, Lim K, et al. Overexpression of protein phosphatase non-receptor type 11 (PTPN11) in gastric carcinomas. Dig Dis Sci. 2010;55:1565-9 pubmed publisher
  64. Zhou X, Coad J, Ducatman B, Agazie Y. SHP2 is up-regulated in breast cancer cells and in infiltrating ductal carcinoma of the breast, implying its involvement in breast oncogenesis. Histopathology. 2008;53:389-402 pubmed publisher
    To determine whether Src homology phosphotyrosyl phosphatase 2 (SHP2) is up-regulated in breast cancer and, if so, to determine whether its up-regulation has any relationship with clinical variables of breast cancer...
  65. Coulombe G, Leblanc C, Cagnol S, Maloum F, Lemieux E, Perreault N, et al. Epithelial tyrosine phosphatase SHP-2 protects against intestinal inflammation in mice. Mol Cell Biol. 2013;33:2275-84 pubmed publisher
    ..Finally, SHP-2 mRNA levels were significantly reduced in intestinal biopsy specimens from UC patients. Our results establish intestinal epithelial SHP-2 as a critical determinant for prevention of gut inflammation. ..
  66. Jiang J, Jia Z, Kong F, Jin M, Wang Y, Tian S, et al. Association of polymorphism of PTPN 11 encoding SHP-2 with gastric atrophy but not gastric cancer in Helicobacter pylori seropositive Chinese population. BMC Gastroenterol. 2012;12:89 pubmed publisher
    ..pylori infected subjects. The biological roles of this polymorphism require a further investigation. ..
  67. Bottino C, Falco M, Parolini S, Marcenaro E, Augugliaro R, Sivori S, et al. NTB-A [correction of GNTB-A], a novel SH2D1A-associated surface molecule contributing to the inability of natural killer cells to kill Epstein-Barr virus-infected B cells in X-linked lymphoproliferative disease. J Exp Med. 2001;194:235-46 pubmed
    ..Thus, the altered function of NTB-A appears to play an important role in the inability of XLP-NK cells to kill EBV-infected target cells. ..
  68. Dong S, Li F, Zhang Q, Lv K, Yang H, Gao Y, et al. Expression and clinical significance of SHP2 in gastric cancer. J Int Med Res. 2012;40:2083-9 pubmed
    ..the expression and clinical significance of the protein tyrosine phosphatase, nonreceptor type 11 (PTPN11 or SHP2) gene, which encodes Src homology 2 domain-containing phosphatase (SHP-2) in gastric cancer...
  69. Zenker M, Buheitel G, Rauch R, Koenig R, Bosse K, Kress W, et al. Genotype-phenotype correlations in Noonan syndrome. J Pediatr. 2004;144:368-74 pubmed
    ..Mutational analysis was performed by direct sequencing of the entire coding sequence of the PTPN11 gene...
  70. Arnaud M, Mzali R, Gesbert F, Crouin C, Guenzi C, Vermot Desroches C, et al. Interaction of the tyrosine phosphatase SHP-2 with Gab2 regulates Rho-dependent activation of the c-fos serum response element by interleukin-2. Biochem J. 2004;382:545-56 pubmed
    ..Our studies thus provide new insights into the role of Gab2 and SHP-2 in IL-2 signal transduction. ..
  71. Sobreira N, Cirulli E, Avramopoulos D, Wohler E, Oswald G, Stevens E, et al. Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene. PLoS Genet. 2010;6:e1000991 pubmed publisher
    ..This combination of a new technology and a classical genetic approach provides a powerful strategy to discover the genes responsible for unexplained Mendelian disorders. ..
  72. Wu D, Pang Y, Ke Y, Yu J, He Z, Tautz L, et al. A conserved mechanism for control of human and mouse embryonic stem cell pluripotency and differentiation by shp2 tyrosine phosphatase. PLoS ONE. 2009;4:e4914 pubmed publisher
    ..Herein we report that Shp2, a protein tyrosine phosphatase with two SH2 domains, has a conserved role in orchestration of intracellular ..
  73. Edouard T, Montagner A, Dance M, Conte F, Yart A, Parfait B, et al. How do Shp2 mutations that oppositely influence its biochemical activity result in syndromes with overlapping symptoms?. Cell Mol Life Sci. 2007;64:1585-90 pubmed
    ..This suggests that a narrow range of MAPK signaling is required for appropriate development. We also discuss the possibility that LS mutations may not simply exhibit dominant negative activity. ..
  74. Kawai S, Goto Y, Ito L, Oba Shinjo S, Uno M, Shinjo S, et al. Significant association between PTPN11 polymorphism and gastric atrophy among Japanese Brazilians. Gastric Cancer. 2006;9:277-83 pubmed
    ..This fact may partly explain the distribution of gastric atrophy/cancer in the world. ..
  75. Liu X, Zheng H, Qu C. Protein tyrosine phosphatase Shp2 (Ptpn11) plays an important role in maintenance of chromosome stability. Cancer Res. 2012;72:5296-306 pubmed publisher
    Both activating and inactivating mutations in protein tyrosine phosphatase Ptpn11 (encoding Shp2) are associated with tumorigenesis. However, the underlying mechanisms remain unclear...
  76. Sarkozy A, Conti E, Seripa D, Digilio M, Grifone N, Tandoi C, et al. Correlation between PTPN11 gene mutations and congenital heart defects in Noonan and LEOPARD syndromes. J Med Genet. 2003;40:704-8 pubmed
  77. Chan R, Feng G. PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase. Blood. 2007;109:862-7 pubmed
    ..as the first proto-oncogene that encodes a cytoplasmic tyrosine phosphatase with 2 Src-homology 2 (SH2) domains (Shp2). This tyrosine phosphatase was previously shown to play an essential role in normal hematopoiesis...
  78. Jamshidi Y, Gooljar S, Snieder H, Wang X, Ge D, Swaminathan R, et al. SHP-2 and PI3-kinase genes PTPN11 and PIK3R1 may influence serum apoB and LDL cholesterol levels in normal women. Atherosclerosis. 2007;194:e26-33 pubmed
    ..009). Association of single tSNPs with both apoB and LDL cholesterol as well as interactions between the two genes suggest that variants influencing SHP-2 activity may modulate the acute pathway by which insulin regulates these lipids. ..
  79. Timmerman I, Hoogenboezem M, Bennett A, Geerts D, Hordijk P, van Buul J. The tyrosine phosphatase SHP2 regulates recovery of endothelial adherens junctions through control of ?-catenin phosphorylation. Mol Biol Cell. 2012;23:4212-25 pubmed publisher
    ..mediator thrombin, we demonstrate an important role for the Src homology 2-domain containing tyrosine phosphatase (SHP2) in mediating recovery of the VE-cadherin-controlled endothelial barrier...
  80. Wu X, Guo W, Wu L, Gu Y, Gu L, Xu S, et al. Selective sequestration of STAT1 in the cytoplasm via phosphorylated SHP-2 ameliorates murine experimental colitis. J Immunol. 2012;189:3497-507 pubmed
    ..These findings could lead to increased options for the treatment of Crohn's disease and other Th1-mediated inflammatory diseases. ..
  81. Lacalle R, Mira E, Gomez Mouton C, Jimenez Baranda S, Martinez A C, Manes S. Specific SHP-2 partitioning in raft domains triggers integrin-mediated signaling via Rho activation. J Cell Biol. 2002;157:277-89 pubmed
    ..Because raft recruitment of SHP-2 occurs physiologically after cell attachment, these results provide a mechanism by which SHP-2 may influence cell adhesion and migration by spatially regulating Rho activity. ..
  82. Higashi H, Tsutsumi R, Fujita A, Yamazaki S, Asaka M, Azuma T, et al. Biological activity of the Helicobacter pylori virulence factor CagA is determined by variation in the tyrosine phosphorylation sites. Proc Natl Acad Sci U S A. 2002;99:14428-33 pubmed publisher
    ..The presence of distinctly structured CagA proteins in Western and East Asian H. pylori isolates may underlie the strikingly different incidences of gastric carcinoma in these two geographic areas...
  83. Lo F, Kuo T, Wang C, Kuo M, Kuo M. Hodgkin's lymphoma in a patient with Noonan syndrome with germ-line PTPN11 mutations. Int J Hematol. 2008;88:287-290 pubmed publisher
    ..This somatic mutation has ever been reported in juvenile myelomonocytic leukemia (JMML). Furthermore, the functional analysis of this mutant SHP-2 has shown it to have enhanced phosphatase activity...
  84. Digilio M, Conti E, Sarkozy A, Mingarelli R, Dottorini T, Marino B, et al. Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet. 2002;71:389-94 pubmed
    ..The detected mutations suggest that distinct molecular and pathogenetic mechanisms cause the peculiar cutaneous manifestations of the ML/LEOPARD-syndrome subtype of NS. ..
  85. Morra M, Lu J, Poy F, Martin M, Sayos J, Calpe S, et al. Structural basis for the interaction of the free SH2 domain EAT-2 with SLAM receptors in hematopoietic cells. EMBO J. 2001;20:5840-52 pubmed
    ..We conclude that EAT-2 plays a role in controlling signal transduction through at least four receptors expressed on the surface of professional antigen-presenting cells. ..
  86. Zhou X, Agazie Y. Molecular mechanism for SHP2 in promoting HER2-induced signaling and transformation. J Biol Chem. 2009;284:12226-34 pubmed publisher
    The Src homology phosphotyrosyl phosphatase 2 (SHP2) plays a positive role in HER2-induced signaling and transformation, but its mechanism of action is poorly understood...
  87. Tartaglia M, Niemeyer C, Fragale A, Song X, Buechner J, Jung A, et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet. 2003;34:148-50 pubmed
    We report here that individuals with Noonan syndrome and juvenile myelomonocytic leukemia (JMML) have germline mutations in PTPN11 and that somatic mutations in PTPN11 account for 34% of non-syndromic JMML...
  88. Chemnitz J, Parry R, Nichols K, June C, Riley J. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol. 2004;173:945-54 pubmed
    ..Despite this interaction, the ability of PD-1 to block T cell activation required receptor ligation, suggesting that colocalization of PD-1 with CD3 and/or CD28 may be necessary for inhibition of T cell activation. ..
  89. Ikram M, Sim X, Xueling S, Jensen R, Cotch M, Hewitt A, et al. Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo. PLoS Genet. 2010;6:e1001184 pubmed publisher
    ..These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease. ..