PTPN11

Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), Src homology region 2 domain-containing phosphatase-2 (SHP-2), or protein-tyrosine phosphatase 2C (PTP-2C) is an enzyme that in humans is encoded by the PTPN11 gene. PTPN11 is a protein tyrosine phosphatase (PTP) Shp2.{{cite journal | vauthors = Jamieson CR, van der Burgt I, Brady AF, van Reen M, Elsawi MM, Hol F, Jeffery S, Patton MA, Mariman E | title = Mapping a gene for Noonan syndrome to the long arm of chromosome 12 | journal = Nat. Genet. | volume = 8 | issue = 4 | pages = 357–60 | date = December 1994 | pmid = 7894486 | doi = 10.1038/ng1294-357 | s2cid = 1582162 }}{{cite journal | vauthors = Freeman RM, Plutzky J, Neel BG | title = Identification of a human Src homology 2-containing protein-tyrosine-phosphatase: a putative homolog of Drosophila corkscrew | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 89 | issue = 23 | pages = 11239–43 | date = December 1992 | pmid = 1280823 | pmc = 50525 | doi = 10.1073/pnas.89.23.11239 | bibcode = 1992PNAS...8911239F | doi-access = free }}

PTPN11 is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains two tandem Src homology-2 domains, which function as phospho-tyrosine binding domains and mediate the interaction of this PTP with its substrates. This PTP is widely expressed in most tissues and plays a regulatory role in various cell signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration. Mutations in this gene are a cause of Noonan syndrome as well as acute myeloid leukemia.{{Cite web| title = Entrez Gene: PTPN11 protein tyrosine phosphatase, non-receptor type 11 (Noonan syndrome 1)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5781}}

Structure and function

This phosphatase, along with its paralogue, Shp1, possesses a domain structure that consists of two tandem SH2 domains in its N-terminus followed by a protein tyrosine phosphatase (PTP) domain. In the inactive state, the N-terminal SH2 domain binds the PTP domain and blocks access of potential substrates to the active site. Thus, Shp2 is auto-inhibited.

Upon binding to target phospho-tyrosyl residues, the N-terminal SH2 domain is released from the PTP domain, catalytically activating the enzyme by relieving this auto-inhibition.

Genetic diseases associated with PTPN11

Missense mutations in the PTPN11 locus are associated with both Noonan syndrome and Leopard syndrome. At least 79 disease-causing mutations in this gene have been discovered.{{cite journal | vauthors = Šimčíková D, Heneberg P | title = Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 18577 | date = December 2019 | pmid = 31819097 | pmc = 6901466 | doi = 10.1038/s41598-019-54976-4| bibcode = 2019NatSR...918577S }}

It has also been associated with metachondromatosis.{{cite journal | vauthors = Sobreira NL, Cirulli ET, Avramopoulos D, Wohler E, Oswald GL, Stevens EL, Ge D, Shianna KV, Smith JP, Maia JM, Gumbs CE, Pevsner J, Thomas G, Valle D, Hoover-Fong JE, Goldstein DB | title = Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene | journal = PLOS Genet. | volume = 6 | issue = 6 | pages = e1000991 | date = June 2010 | pmid = 20577567 | pmc = 2887469 | doi = 10.1371/journal.pgen.1000991 | doi-access = free }}

=Noonan syndrome=

In the case of Noonan syndrome, mutations are broadly distributed throughout the coding region of the gene but all appear to result in hyper-activated, or unregulated mutant forms of the protein. Most of these mutations disrupt the binding interface between the N-SH2 domain and catalytic core necessary for the enzyme to maintain its auto-inhibited conformation.{{cite journal | vauthors = Roberts AE, Araki T, Swanson KD, Montgomery KT, Schiripo TA, Joshi VA, Li L, Yassin Y, Tamburino AM, Neel BG, Kucherlapati RS | title = Germline gain-of-function mutations in SOS1 cause Noonan syndrome | journal = Nat. Genet. | volume = 39 | issue = 1 | pages = 70–4 | date = January 2007 | pmid = 17143285 | doi = 10.1038/ng1926 | s2cid = 10222262 }}

=Leopard syndrome=

The mutations that cause Leopard syndrome are restricted regions affecting the catalytic core of the enzyme producing catalytically impaired Shp2 variants.{{cite journal | vauthors = Kontaridis MI, Swanson KD, David FS, Barford D, Neel BG | title = PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects | journal = J. Biol. Chem. | volume = 281 | issue = 10 | pages = 6785–92 | date = March 2006 | pmid = 16377799 | doi = 10.1074/jbc.M513068200 | doi-access = free }} It is currently unclear how mutations that give rise to mutant variants of Shp2 with biochemically opposite characteristics result in similar human genetic syndromes.

Cancer associated with PTPN11

Patients with a subset of Noonan syndrome PTPN11 mutations also have a higher prevalence of juvenile myelomonocytic leukemias (JMML). Activating Shp2 mutations have also been detected in neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, lung cancer, colorectal cancer.{{cite journal | vauthors = Bentires-Alj M, Paez JG, David FS, Keilhack H, Halmos B, Naoki K, Maris JM, Richardson A, Bardelli A, Sugarbaker DJ, Richards WG, Du J, Girard L, Minna JD, Loh ML, Fisher DE, Velculescu VE, Vogelstein B, Meyerson M, Sellers WR, Neel BG | title = Activating mutations of the noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia | journal = Cancer Res. | volume = 64 | issue = 24 | pages = 8816–20 | date = December 2004 | pmid = 15604238 | doi = 10.1158/0008-5472.CAN-04-1923 | doi-access = free }} Recently, a relatively high prevalence of PTPN11 mutations (24%) were detected by next-generation sequencing in a cohort of NPM1-mutated acute myeloid leukemia patients,{{cite journal | vauthors = Patel SS, Kuo FC, Gibson CJ, Steensma DP, Soiffer RJ, Alyea EP, Chen YA, Fathi AT, Graubert TA, Brunner AM, Wadleigh M, Stone RM, DeAngelo DJ, Nardi V, Hasserjian RP, Weinberg OK | title = High NPM1 mutant allele burden at diagnosis predicts unfavorable outcomes in de novo AML | journal = Blood | volume = 131 | issue = 25 | pages = 2816–2825 | date = May 2018 | pmid = 29724895 | pmc = 6265642 | doi = 10.1182/blood-2018-01-828467 }} although the prognostic significance of such associations has not been clarified. These data suggests that Shp2 may be a proto-oncogene. However, it has been reported that PTPN11/Shp2 can act as either tumor promoter or suppressor. In aged mouse model, hepatocyte-specific deletion of PTPN11/Shp2 promotes inflammatory signaling through the STAT3 pathway and hepatic inflammation/necrosis, resulting in regenerative hyperplasia and spontaneous development of tumors. Decreased PTPN11/Shp2 expression was detected in a subfraction of human hepatocellular carcinoma (HCC) specimens.{{cite journal | vauthors = Bard-Chapeau EA, Li S, Ding J, Zhang SS, Zhu HH, Princen F, Fang DD, Han T, Bailly-Maitre B, Poli V, Varki NM, Wang H, Feng GS | title = Ptpn11/Shp2 acts as a tumor suppressor in hepatocellular carcinogenesis | journal = Cancer Cell | volume = 19 | issue = 5 | pages = 629–39 | date = May 2011 | pmid = 21575863 | pmc = 3098128 | doi = 10.1016/j.ccr.2011.03.023 }} The bacterium Helicobacter pylori has been associated with gastric cancer, and this is thought to be mediated in part by the interaction of its virulence factor CagA with SHP2.{{cite journal | vauthors = Hatakeyama M, Higashi H | title = Helicobacter pylori CagA: a new paradigm for bacterial carcinogenesis | journal = Cancer Science | volume = 96 | issue = 12 | pages = 835–843 | year = 2005 | pmid = 16367902 | doi = 10.1111/j.1349-7006.2005.00130.x | s2cid = 5721063 | doi-access = free | pmc = 11159386 }}

Interactions

PTPN11 has been shown to interact with

CagA,
Cbl gene,{{cite journal | vauthors = Tanaka Y, Tanaka N, Saeki Y, Tanaka K, Murakami M, Hirano T, Ishii N, Sugamura K | title = c-Cbl-dependent monoubiquitination and lysosomal degradation of gp130 | journal = Mol. Cell. Biol. | volume = 28 | issue = 15 | pages = 4805–18 | date = Aug 2008 | pmid = 18519587 | pmc = 2493370 | doi = 10.1128/MCB.01784-07 }}
CD117,{{cite journal | vauthors = Tauchi T, Feng GS, Marshall MS, Shen R, Mantel C, Pawson T, Broxmeyer HE | title = The ubiquitously expressed Syp phosphatase interacts with c-kit and Grb2 in hematopoietic cells | journal = J. Biol. Chem. | volume = 269 | issue = 40 | pages = 25206–11 | date = October 1994 | doi = 10.1016/S0021-9258(17)31518-1 | pmid = 7523381 | doi-access = free }}{{cite journal | vauthors = Kozlowski M, Larose L, Lee F, Le DM, Rottapel R, Siminovitch KA | title = SHP-1 binds and negatively modulates the c-Kit receptor by interaction with tyrosine 569 in the c-Kit juxtamembrane domain | journal = Mol. Cell. Biol. | volume = 18 | issue = 4 | pages = 2089–99 | date = April 1998 | pmid = 9528781 | pmc = 121439 | doi = 10.1128/MCB.18.4.2089}}
CD31,{{cite journal | vauthors = Ilan N, Cheung L, Pinter E, Madri JA | title = Platelet-endothelial cell adhesion molecule-1 (CD31), a scaffolding molecule for selected catenin family members whose binding is mediated by different tyrosine and serine/threonine phosphorylation | journal = J. Biol. Chem. | volume = 275 | issue = 28 | pages = 21435–43 | date = July 2000 | pmid = 10801826 | doi = 10.1074/jbc.M001857200 | doi-access = free }}{{cite journal | vauthors = Pumphrey NJ, Taylor V, Freeman S, Douglas MR, Bradfield PF, Young SP, Lord JM, Wakelam MJ, Bird IN, Salmon M, Buckley CD | title = Differential association of cytoplasmic signalling molecules SHP-1, SHP-2, SHIP and phospholipase C-gamma1 with PECAM-1/CD31 | journal = FEBS Lett. | volume = 450 | issue = 1–2 | pages = 77–83 | date = April 1999 | pmid = 10350061 | doi = 10.1016/S0014-5793(99)00446-9 | s2cid = 31471121 | doi-access = free }}{{cite journal | vauthors = Hua CT, Gamble JR, Vadas MA, Jackson DE | title = Recruitment and activation of SHP-1 protein-tyrosine phosphatase by human platelet endothelial cell adhesion molecule-1 (PECAM-1). Identification of immunoreceptor tyrosine-based inhibitory motif-like binding motifs and substrates | journal = J. Biol. Chem. | volume = 273 | issue = 43 | pages = 28332–40 | date = October 1998 | pmid = 9774457 | doi = 10.1074/jbc.273.43.28332 | doi-access = free}}{{cite journal | vauthors = Jackson DE, Ward CM, Wang R, Newman PJ | title = The protein-tyrosine phosphatase SHP-2 binds platelet/endothelial cell adhesion molecule-1 (PECAM-1) and forms a distinct signaling complex during platelet aggregation. Evidence for a mechanistic link between PECAM-1- and integrin-mediated cellular signaling | journal = J. Biol. Chem. | volume = 272 | issue = 11 | pages = 6986–93 | date = March 1997 | pmid = 9054388 | doi = 10.1074/jbc.272.11.6986 | doi-access = free }}
CEACAM1,{{cite journal | vauthors = Huber M, Izzi L, Grondin P, Houde C, Kunath T, Veillette A, Beauchemin N | title = 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 | journal = J. Biol. Chem. | volume = 274 | issue = 1 | pages = 335–44 | date = Jan 1999 | pmid = 9867848 | doi = 10.1074/jbc.274.1.335 | doi-access = free}}
Epidermal growth factor receptor,{{cite journal | vauthors = Schulze WX, Deng L, Mann M | title = Phosphotyrosine interactome of the ErbB-receptor kinase family | journal = Mol. Syst. Biol. | volume = 1 | issue = 1 | pages = E1–E13 | year = 2005 | pmid = 16729043 | pmc = 1681463 | doi = 10.1038/msb4100012 }}{{cite journal | vauthors = Tomic S, Greiser U, Lammers R, Kharitonenkov A, Imyanitov E, Ullrich A, Böhmer FD | title = Association of SH2 domain protein tyrosine phosphatases with the epidermal growth factor receptor in human tumor cells. Phosphatidic acid activates receptor dephosphorylation by PTP1C | journal = J. Biol. Chem. | volume = 270 | issue = 36 | pages = 21277–84 | date = Sep 1995 | pmid = 7673163 | doi = 10.1074/jbc.270.36.21277 | doi-access = free}}
Erk{{cite book|title=Protein phosphatases|year=2004|publisher=Springer|isbn=978-3-540-20560-9|pages=275–299|chapter-url=https://books.google.com/books?id=EotzHJrTu3sC&q=The+Shp-2+tyrosine+phosphatase|author1=L.A. Lai |author2=C. Zhao |author3=E.E. Zhang |author4=G.S. Feng |editor1=Joaquín Ariño |editor2=Denis Alexander |chapter=14 The Shp-2 tyrosine phosphatase}}{{cite journal | vauthors = Neel BG, Gu H, Pao L | title = The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling | journal = Trends in Biochemical Sciences | volume = 28 | issue = 6 | pages = 284–293 | date = June 2003 | pmid = 12826400 | doi = 10.1016/S0968-0004(03)00091-4 | issn = 0968-0004 }}
FRS2,{{cite journal | vauthors = Delahaye L, Rocchi S, Van Obberghen E | title = Potential involvement of FRS2 in insulin signaling | journal = Endocrinology | volume = 141 | issue = 2 | pages = 621–8 | date = Feb 2000 | pmid = 10650943 | doi = 10.1210/endo.141.2.7298 | doi-access = free }}{{cite journal | vauthors = Kurokawa K, Iwashita T, Murakami H, Hayashi H, Kawai K, Takahashi M | title = Identification of SNT/FRS2 docking site on RET receptor tyrosine kinase and its role for signal transduction | journal = Oncogene | volume = 20 | issue = 16 | pages = 1929–38 | date = Apr 2001 | pmid = 11360177 | doi = 10.1038/sj.onc.1204290 | s2cid = 25346661 | doi-access = }}{{cite journal | vauthors = Hadari YR, Kouhara H, Lax I, Schlessinger J | title = Binding of Shp2 tyrosine phosphatase to FRS2 is essential for fibroblast growth factor-induced PC12 cell differentiation | journal = Mol. Cell. Biol. | volume = 18 | issue = 7 | pages = 3966–73 | date = Jul 1998 | pmid = 9632781 | pmc = 108981 | doi = 10.1128/MCB.18.7.3966 }}
GAB1,{{cite journal | vauthors = Saito Y, Hojo Y, Tanimoto T, Abe J, Berk BC | title = Protein kinase C-alpha and protein kinase C-epsilon are required for Grb2-associated binder-1 tyrosine phosphorylation in response to platelet-derived growth factor | journal = J. Biol. Chem. | volume = 277 | issue = 26 | pages = 23216–22 | date = Jun 2002 | pmid = 11940581 | doi = 10.1074/jbc.M200605200 | doi-access = free }}{{cite journal | vauthors = Rocchi S, Tartare-Deckert S, Murdaca J, Holgado-Madruga M, Wong AJ, Van Obberghen E | title = Determination of Gab1 (Grb2-associated binder-1) interaction with insulin receptor-signaling molecules | journal = Mol. Endocrinol. | volume = 12 | issue = 7 | pages = 914–23 | date = Jul 1998 | pmid = 9658397 | doi = 10.1210/mend.12.7.0141 | doi-access = free }}
GAB2,{{cite journal | vauthors = Lynch DK, Daly RJ | title = PKB-mediated negative feedback tightly regulates mitogenic signalling via Gab2 | journal = EMBO J. | volume = 21 | issue = 1–2 | pages = 72–82 | date = January 2002 | pmid = 11782427 | pmc = 125816 | doi = 10.1093/emboj/21.1.72 }}{{cite journal | vauthors = Zhao C, Yu DH, Shen R, Feng GS | title = Gab2, a new pleckstrin homology domain-containing adapter protein, acts to uncouple signaling from ERK kinase to Elk-1 | journal = J. Biol. Chem. | volume = 274 | issue = 28 | pages = 19649–54 | date = July 1999 | pmid = 10391903 | doi = 10.1074/jbc.274.28.19649 | doi-access = free }}{{cite journal | vauthors = Crouin C, Arnaud M, Gesbert F, Camonis J, Bertoglio J | title = A yeast two-hybrid study of human p97/Gab2 interactions with its SH2 domain-containing binding partners | journal = FEBS Lett. | volume = 495 | issue = 3 | pages = 148–53 | date = April 2001 | pmid = 11334882 | doi = 10.1016/S0014-5793(01)02373-0 | s2cid = 24499468 }}
GAB3,{{cite journal|last1=Wolf|first1=I.|last2=Jenkins|first2=B. J.|last3=Liu|first3=Y.|last4=Seiffert|first4=M.|last5=Custodio|first5=J. M.|last6=Young|first6=P.|last7=Rohrschneider|first7=L. R.|title=Gab3, a New DOS/Gab Family Member, Facilitates Macrophage Differentiation|journal=Molecular and Cellular Biology|volume=22|issue=1|year=2002|pages=231–244|issn=0270-7306|doi=10.1128/MCB.22.1.231-244.2002|pmid=11739737|pmc=134230|quote=and associates transiently with the SH2 domain-containing proteins p85 and SHP2|doi-access=free}}
Glycoprotein 130,{{cite journal | vauthors = Anhuf D, Weissenbach M, Schmitz J, Sobota R, Hermanns HM, Radtke S, Linnemann S, Behrmann I, Heinrich PC, Schaper F | title = Signal transduction of IL-6, leukemia-inhibitory factor, and oncostatin M: structural receptor requirements for signal attenuation | journal = Journal of Immunology | volume = 165 | issue = 5 | pages = 2535–43 | date = Sep 2000 | pmid = 10946280 | doi = 10.4049/jimmunol.165.5.2535 | doi-access = free }}{{cite journal | vauthors = Kim H, Baumann H | title = Transmembrane domain of gp130 contributes to intracellular signal transduction in hepatic cells | journal = J. Biol. Chem. | volume = 272 | issue = 49 | pages = 30741–7 | date = Dec 1997 | pmid = 9388212 | doi = 10.1074/jbc.272.49.30741 | doi-access = free }}
Grb2,{{cite journal | vauthors = Ganju RK, Brubaker SA, Chernock RD, Avraham S, Groopman JE | title = Beta-chemokine receptor CCR5 signals through SHP1, SHP2, and Syk | journal = J. Biol. Chem. | volume = 275 | issue = 23 | pages = 17263–8 | date = Jun 2000 | pmid = 10747947 | doi = 10.1074/jbc.M000689200 | doi-access = free }}{{cite journal | vauthors = Bennett AM, Tang TL, Sugimoto S, Walsh CT, Neel BG | title = Protein-tyrosine-phosphatase SHPTP2 couples platelet-derived growth factor receptor beta to Ras | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 91 | issue = 15 | pages = 7335–9 | date = Jul 1994 | pmid = 8041791 | pmc = 44394 | doi = 10.1073/pnas.91.15.7335 | bibcode = 1994PNAS...91.7335B | doi-access = free }}{{cite journal | vauthors = Ward AC, Monkhouse JL, Hamilton JA, Csar XF | title = Direct binding of Shc, Grb2, SHP-2 and p40 to the murine granulocyte colony-stimulating factor receptor | journal = Biochim. Biophys. Acta | volume = 1448 | issue = 1 | pages = 70–6 | date = Nov 1998 | pmid = 9824671 | doi = 10.1016/S0167-4889(98)00120-7 | doi-access = free | hdl = 10536/DRO/DU:30096477 | hdl-access = free }}{{cite journal | vauthors = Tang J, Feng GS, Li W | title = Induced direct binding of the adapter protein Nck to the GTPase-activating protein-associated protein p62 by epidermal growth factor | journal = Oncogene | volume = 15 | issue = 15 | pages = 1823–32 | date = Oct 1997 | pmid = 9362449 | doi = 10.1038/sj.onc.1201351 | doi-access = free }}{{cite journal | vauthors = Tang H, Zhao ZJ, Huang XY, Landon EJ, Inagami T | title = Fyn kinase-directed activation of SH2 domain-containing protein-tyrosine phosphatase SHP-2 by Gi protein-coupled receptors in Madin-Darby canine kidney cells | journal = J. Biol. Chem. | volume = 274 | issue = 18 | pages = 12401–7 | date = Apr 1999 | pmid = 10212213 | doi = 10.1074/jbc.274.18.12401 | doi-access = free}}{{cite journal | vauthors = Zhang S, Mantel C, Broxmeyer HE | title = Flt3 signaling involves tyrosyl-phosphorylation of SHP-2 and SHIP and their association with Grb2 and Shc in Baf3/Flt3 cells | journal = J. Leukoc. Biol. | volume = 65 | issue = 3 | pages = 372–80 | date = Mar 1999 | pmid = 10080542 | doi = 10.1002/jlb.65.3.372 | s2cid = 38211235 | doi-access = free }}{{cite journal | vauthors = Wong L, Johnson GR | title = Epidermal growth factor induces coupling of protein-tyrosine phosphatase 1D to GRB2 via the COOH-terminal SH3 domain of GRB2 | journal = J. Biol. Chem. | volume = 271 | issue = 35 | pages = 20981–4 | date = Aug 1996 | pmid = 8702859 | doi = 10.1074/jbc.271.35.20981 | doi-access = free }}
Growth hormone receptor,{{cite journal | vauthors = Stofega MR, Herrington J, Billestrup N, Carter-Su C | title = Mutation of the SHP-2 binding site in growth hormone (GH) receptor prolongs GH-promoted tyrosyl phosphorylation of GH receptor, JAK2, and STAT5B | journal = Mol. Endocrinol. | volume = 14 | issue = 9 | pages = 1338–50 | date = September 2000 | pmid = 10976913 | doi = 10.1210/mend.14.9.0513 | doi-access = free }}{{cite journal | vauthors = Moutoussamy S, Renaudie F, Lago F, Kelly PA, Finidori J | title = Grb10 identified as a potential regulator of growth hormone (GH) signaling by cloning of GH receptor target proteins | journal = J. Biol. Chem. | volume = 273 | issue = 26 | pages = 15906–12 | date = June 1998 | pmid = 9632636 | doi = 10.1074/jbc.273.26.15906 | doi-access = free }}
HoxA10,{{cite journal | vauthors = Wang H, Lindsey S, Konieczna I, Bei L, Horvath E, Huang W, Saberwal G, Eklund EA | title = Constitutively active SHP2 cooperates with HoxA10 overexpression to induce acute myeloid leukemia. | journal = J Biol Chem | volume = 284 | issue = 4 | pages = 2549–67 | date = Jan 2009 | pmid = 19022774 | pmc = 2629090 | doi = 10.1074/jbc.M804704200 | doi-access = free }}
Insulin receptor,{{cite journal | vauthors = Maegawa H, Ugi S, Adachi M, Hinoda Y, Kikkawa R, Yachi A, Shigeta Y, Kashiwagi A | title = Insulin receptor kinase phosphorylates protein tyrosine phosphatase containing Src homology 2 regions and modulates its PTPase activity in vitro | journal = Biochem. Biophys. Res. Commun. | volume = 199 | issue = 2 | pages = 780–5 | date = Mar 1994 | pmid = 8135823 | doi = 10.1006/bbrc.1994.1297 }}{{cite journal | vauthors = Kharitonenkov A, Schnekenburger J, Chen Z, Knyazev P, Ali S, Zwick E, White M, Ullrich A | title = Adapter function of protein-tyrosine phosphatase 1D in insulin receptor/insulin receptor substrate-1 interaction | journal = J. Biol. Chem. | volume = 270 | issue = 49 | pages = 29189–93 | date = Dec 1995 | pmid = 7493946 | doi = 10.1074/jbc.270.49.29189 | doi-access = free }}
Insulin-like growth factor 1 receptor,{{cite journal | vauthors = Mañes S, Mira E, Gómez-Mouton C, Zhao ZJ, Lacalle RA, Martínez-A C | title = Concerted activity of tyrosine phosphatase SHP-2 and focal adhesion kinase in regulation of cell motility | journal = Mol. Cell. Biol. | volume = 19 | issue = 4 | pages = 3125–35 | date = Apr 1999 | pmid = 10082579 | pmc = 84106 | doi=10.1128/mcb.19.4.3125}}{{cite journal | vauthors = Seely BL, Reichart DR, Staubs PA, Jhun BH, Hsu D, Maegawa H, Milarski KL, Saltiel AR, Olefsky JM | title = Localization of the insulin-like growth factor I receptor binding sites for the SH2 domain proteins p85, Syp, and GTPase activating protein | journal = J. Biol. Chem. | volume = 270 | issue = 32 | pages = 19151–7 | date = Aug 1995 | pmid = 7642582 | doi = 10.1074/jbc.270.32.19151 | doi-access = free}}
IRS1,{{cite journal | vauthors = Kuhné MR, Pawson T, Lienhard GE, Feng GS | title = The insulin receptor substrate 1 associates with the SH2-containing phosphotyrosine phosphatase Syp | journal = J. Biol. Chem. | volume = 268 | issue = 16 | pages = 11479–81 | date = Jun 1993 | doi = 10.1016/S0021-9258(19)50220-4 | pmid = 8505282 | doi-access = free }}{{cite journal | vauthors = Myers MG, Mendez R, Shi P, Pierce JH, Rhoads R, White MF | title = The COOH-terminal tyrosine phosphorylation sites on IRS-1 bind SHP-2 and negatively regulate insulin signaling | journal = J. Biol. Chem. | volume = 273 | issue = 41 | pages = 26908–14 | date = Oct 1998 | pmid = 9756938 | doi = 10.1074/jbc.273.41.26908 | doi-access = free }}
Janus kinase 1,{{cite journal | vauthors = Lehmann U, Schmitz J, Weissenbach M, Sobota RM, Hortner M, Friederichs K, Behrmann I, Tsiaris W, Sasaki A, Schneider-Mergener J, Yoshimura A, Neel BG, Heinrich PC, Schaper F | title = SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6 signaling through gp130 | journal = J. Biol. Chem. | volume = 278 | issue = 1 | pages = 661–71 | date = January 2003 | pmid = 12403768 | doi = 10.1074/jbc.M210552200 | doi-access = free }}
Janus kinase 2,{{cite journal | vauthors = Yin T, Shen R, Feng GS, Yang YC | title = Molecular characterization of specific interactions between SHP-2 phosphatase and JAK tyrosine kinases | journal = J. Biol. Chem. | volume = 272 | issue = 2 | pages = 1032–7 | date = January 1997 | pmid = 8995399 | doi = 10.1074/jbc.272.2.1032 | doi-access = free }}{{cite journal | vauthors = Tauchi T, Damen JE, Toyama K, Feng GS, Broxmeyer HE, Krystal G | title = Tyrosine 425 within the activated erythropoietin receptor binds Syp, reduces the erythropoietin required for Syp tyrosine phosphorylation, and promotes mitogenesis | journal = Blood | volume = 87 | issue = 11 | pages = 4495–501 | date = June 1996 | pmid = 8639815 | doi = 10.1182/blood.V87.11.4495.bloodjournal87114495| doi-access = free }}{{cite journal | vauthors = Maegawa H, Kashiwagi A, Fujita T, Ugi S, Hasegawa M, Obata T, Nishio Y, Kojima H, Hidaka H, Kikkawa R | title = SHPTP2 serves adapter protein linking between Janus kinase 2 and insulin receptor substrates | journal = Biochem. Biophys. Res. Commun. | volume = 228 | issue = 1 | pages = 122–7 | date = November 1996 | pmid = 8912646 | doi = 10.1006/bbrc.1996.1626 }}
LAIR1,{{cite journal | vauthors = Fournier N, Chalus L, Durand I, Garcia E, Pin JJ, Churakova T, Patel S, Zlot C, Gorman D, Zurawski S, Abrams J, Bates EE, Garrone P | title = FDF03, a novel inhibitory receptor of the immunoglobulin superfamily, is expressed by human dendritic and myeloid cells | journal = Journal of Immunology | volume = 165 | issue = 3 | pages = 1197–209 | date = Aug 2000 | pmid = 10903717 | doi = 10.4049/jimmunol.165.3.1197 | doi-access = free }}{{cite journal | vauthors = Meyaard L, Adema GJ, Chang C, Woollatt E, Sutherland GR, Lanier LL, Phillips JH |authorlink5=Grant Robert Sutherland | title = LAIR-1, a novel inhibitory receptor expressed on human mononuclear leukocytes | journal = Immunity | volume = 7 | issue = 2 | pages = 283–90 | date = Aug 1997 | pmid = 9285412 | doi = 10.1016/S1074-7613(00)80530-0 | doi-access = free | hdl = 2066/26173 | hdl-access = free }}
LRP1,{{cite journal | vauthors = Betts GN, van der Geer P, Komives EA | title = Structural and functional consequences of tyrosine phosphorylation in the LRP1 cytoplasmic domain | journal = J. Biol. Chem. | volume = 283 | issue = 23 | pages = 15656–64 | date = June 2008 | pmid = 18381291 | pmc = 2414285 | doi = 10.1074/jbc.M709514200 | doi-access = free }}
PDGFRB,{{cite journal | vauthors = Keilhack H, Müller M, Böhmer SA, Frank C, Weidner KM, Birchmeier W, Ligensa T, Berndt A, Kosmehl H, Günther B, Müller T, Birchmeier C, Böhmer FD | title = Negative regulation of Ros receptor tyrosine kinase signaling. An epithelial function of the SH2 domain protein tyrosine phosphatase SHP-1 | journal = J. Cell Biol. | volume = 152 | issue = 2 | pages = 325–34 | date = Jan 2001 | pmid = 11266449 | pmc = 2199605 | doi = 10.1083/jcb.152.2.325 }}{{cite journal | vauthors = Lechleider RJ, Sugimoto S, Bennett AM, Kashishian AS, Cooper JA, Shoelson SE, Walsh CT, Neel BG | title = Activation of the SH2-containing phosphotyrosine phosphatase SH-PTP2 by its binding site, phosphotyrosine 1009, on the human platelet-derived growth factor receptor | journal = J. Biol. Chem. | volume = 268 | issue = 29 | pages = 21478–81 | date = Oct 1993 | doi = 10.1016/S0021-9258(20)80562-6 | pmid = 7691811 | doi-access = free }}
PI3K → Akt
PLCG2,{{cite journal | vauthors = Boudot C, Kadri Z, Petitfrère E, Lambert E, Chrétien S, Mayeux P, Haye B, Billat C | title = Phosphatidylinositol 3-kinase regulates glycosylphosphatidylinositol hydrolysis through PLC-gamma(2) activation in erythropoietin-stimulated cells | journal = Cell. Signal. | volume = 14 | issue = 10 | pages = 869–78 | date = October 2002 | pmid = 12135708 | doi = 10.1016/S0898-6568(02)00036-0 }}
PTK2B,{{cite journal | vauthors = Chauhan D, Pandey P, Hideshima T, Treon S, Raje N, Davies FE, Shima Y, Tai YT, Rosen S, Avraham S, Kharbanda S, Anderson KC | title = SHP2 mediates the protective effect of interleukin-6 against dexamethasone-induced apoptosis in multiple myeloma cells | journal = J. Biol. Chem. | volume = 275 | issue = 36 | pages = 27845–50 | date = September 2000 | pmid = 10880513 | doi = 10.1074/jbc.M003428200 | doi-access = free }}
Ras
SLAMF1,{{cite journal | vauthors = Howie D, Simarro M, Sayos J, Guirado M, Sancho J, Terhorst C | title = Molecular dissection of the signaling and costimulatory functions of CD150 (SLAM): CD150/SAP binding and CD150-mediated costimulation | journal = Blood | volume = 99 | issue = 3 | pages = 957–65 | date = Feb 2000 | pmid = 11806999 | doi = 10.1182/blood.V99.3.957 | doi-access = free }}{{cite journal | vauthors = Morra M, Lu J, Poy F, Martin M, Sayos J, Calpe S, Gullo C, Howie D, Rietdijk S, Thompson A, Coyle AJ, Denny C, Yaffe MB, Engel P, Eck MJ, Terhorst C | title = Structural basis for the interaction of the free SH2 domain EAT-2 with SLAM receptors in hematopoietic cells | journal = EMBO J. | volume = 20 | issue = 21 | pages = 5840–52 | date = Nov 2001 | pmid = 11689425 | pmc = 125701 | doi = 10.1093/emboj/20.21.5840 }}
SOCS3,
SOS1,{{cite journal | vauthors = Chin H, Saito T, Arai A, Yamamoto K, Kamiyama R, Miyasaka N, Miura O | title = Erythropoietin and IL-3 induce tyrosine phosphorylation of CrkL and its association with Shc, SHP-2, and Cbl in hematopoietic cells | journal = Biochem. Biophys. Res. Commun. | volume = 239 | issue = 2 | pages = 412–7 | date = Oct 1997 | pmid = 9344843 | doi = 10.1006/bbrc.1997.7480 }}
STAT3,
STAT5A,{{cite journal | vauthors = Yu CL, Jin YJ, Burakoff SJ | title = Cytosolic tyrosine dephosphorylation of STAT5. Potential role of SHP-2 in STAT5 regulation | journal = J. Biol. Chem. | volume = 275 | issue = 1 | pages = 599–604 | date = Jan 2000 | pmid = 10617656 | doi = 10.1074/jbc.275.1.599 | doi-access = free }}{{cite journal | vauthors = Chughtai N, Schimchowitsch S, Lebrun JJ, Ali S | title = Prolactin induces SHP-2 association with Stat5, nuclear translocation, and binding to the beta-casein gene promoter in mammary cells | journal = J. Biol. Chem. | volume = 277 | issue = 34 | pages = 31107–14 | date = Aug 2002 | pmid = 12060651 | doi = 10.1074/jbc.M200156200 | doi-access = free }} and
STAT5B.

=H Pylori CagA virulence factor=

CagA is a protein and virulence factor inserted by Helicobacter pylori into gastric epithelia. Once activated by SRC phosphorylation, CagA binds to SHP2, allosterically activating it. This leads to morphological changes, abnormal mitogenic signals and sustained activity can result in apoptosis of the host cell. Epidemiological studies have shown roles of cagA- positive H. pylori in the development of atrophic gastritis, peptic ulcer disease and gastric carcinoma.{{cite journal | vauthors = Hatakeyama M | title = Oncogenic mechanisms of the Helicobacter pylori CagA protein | journal = Nature Reviews Cancer | volume = 4 | issue = 9 | pages = 688–94 | date = September 2004 | pmid = 15343275 | doi = 10.1038/nrc1433 | s2cid = 1218835 }}

References

External links

[https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=noonan GeneReviews/NCBI/NIH/UW entry on Noonan syndrome]

Category:EC 3.1.3