PTPN11

PTPN11 encodes the protein tyrosine phosphatase SHP2, which has a modular structure essential for its regulatory function in cell signaling. SHP2 consists of two tandem Src homology 2 (SH2) domains at the N-terminus (N-SH2 and C-SH2), followed by a catalytic protein tyrosine phosphatase (PTP) domain and a C-terminal tail containing tyrosyl phosphorylation sites.{{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 }}{{cite journal | vauthors = Tartaglia M, Niemeyer CM, Fragale A, Song X, Buechner J, Jung A, Hählen K, Hasle H, Licht JD, Gelb BD | title = Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia | journal = Nature Genetics | volume = 34 | issue = 2 | pages = 148–150 | date = June 2003 | pmid = 12717436 | doi = 10.1038/ng1156 }} In its inactive, auto-inhibited conformation, the N-SH2 domain binds intramolecularly to the PTP catalytic domain, blocking substrate access to the active site.{{cite journal | vauthors = Clandinin TR, DeModena JA, Sternberg PW | title = Inositol trisphosphate mediates a RAS-independent response to LET-23 receptor tyrosine kinase activation in C. elegans | journal = Cell | volume = 92 | issue = 4 | pages = 523–533 | date = February 1998 | pmid = 9491893 | doi = 10.1016/s0092-8674(00)80945-9 | doi-access = free }} Upon binding to phosphotyrosyl residues on target proteins, the N-SH2 domain undergoes a conformational change that releases the PTP domain, thereby activating the enzyme. The catalytic domain itself adopts a conserved fold characteristic of classical PTPs, featuring a catalytic loop (WPD loop) that undergoes conformational changes during substrate binding and catalysis. This structural arrangement allows SHP2 to tightly regulate signaling pathways by selectively dephosphorylating substrates involved in cell growth, differentiation, and migration. Mutations disrupting the interface between the N-SH2 and PTP domains can lead to constitutive activation or impairment of SHP2, underlying diseases such as Noonan syndrome and certain leukemias.{{cite journal | vauthors = Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, van der Burgt I, Crosby AH, Ion A, Jeffery S, Kalidas K, Patton MA, Kucherlapati RS, Gelb BD | title = Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome | journal = Nature Genetics | volume = 29 | issue = 4 | pages = 465–468 | date = December 2001 | pmid = 11704759 | doi = 10.1038/ng772 }} The overall structure has been elucidated by multiple crystallographic studies, revealing both the auto-inhibited and active states, which provide insight into its mechanism of regulation and function in diverse cellular contexts.

PTPN11 encodes SHP2, a ubiquitously expressed protein tyrosine phosphatase that plays a important role in regulating cell signaling pathways, most notably the RAS/MAPK cascade, which controls cell proliferation, differentiation, migration, and survival. SHP2 acts as a positive regulator of signal transduction by dephosphorylating specific phosphotyrosine residues on target proteins, thereby facilitating the propagation of growth factor and cytokine signals. During embryonic development, SHP2 is essential for the formation of the heart, blood cells, bones, and other tissues. Germline mutations in PTPN11 cause developmental disorders such as Noonan syndrome and LEOPARD syndrome, while somatic mutations are frequently implicated in hematologic malignancies and solid tumors by promoting aberrant activation of oncogenic pathways.{{cite journal | vauthors = Li SM | title = [The Biological Function of SHP2 in Human Disease] | journal = Molekuliarnaia Biologiia | volume = 50 | issue = 1 | pages = 27–33 | date = 2016 | pmid = 27028808 | doi = 10.7868/S0026898416010110 | language = Russian }}{{cite journal | vauthors = Tartaglia M, Martinelli S, Stella L, Bocchinfuso G, Flex E, Cordeddu V, Zampino G, Burgt I, Palleschi A, Petrucci TC, Sorcini M, Schoch C, Foa R, Emanuel PD, Gelb BD | title = Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease | journal = American Journal of Human Genetics | volume = 78 | issue = 2 | pages = 279–290 | date = February 2006 | pmid = 16358218 | pmc = 1380235 | doi = 10.1086/499925 }} In cancer, SHP2 can function as an oncogenic driver by sustaining RAS/RAF/MAPK signaling and supporting tumor cell growth and survival.{{cite journal | vauthors = Hill KS, Roberts ER, Wang X, Marin E, Park TD, Son S, Ren Y, Fang B, Yoder S, Kim S, Wan L, Sarnaik AA, Koomen JM, Messina JL, Teer JK, Kim Y, Wu J, Chalfant CE, Kim M | title = PTPN11 Plays Oncogenic Roles and Is a Therapeutic Target for BRAF Wild-Type Melanomas | journal = Molecular Cancer Research | volume = 17 | issue = 2 | pages = 583–593 | date = February 2019 | pmid = 30355677 | pmc = 6386183 | doi = 10.1158/1541-7786.MCR-18-0777 }} Thus, PTPN11/SHP2 is a critical regulator of both normal cellular processes and disease states, with its dysregulation contributing to developmental syndromes and oncogenesis.

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 }}

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 = Nature Genetics | volume = 39 | issue = 1 | pages = 70–74 | date = January 2007 | pmid = 17143285 | doi = 10.1038/ng1926 | s2cid = 10222262 }}

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 = Journal of Biological Chemistry | volume = 281 | issue = 10 | pages = 6785–6792 | 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.

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 Genetics | volume = 6 | issue = 6 | pages = e1000991 | date = June 2010 | pmid = 20577567 | pmc = 2887469 | doi = 10.1371/journal.pgen.1000991 | doi-access = free }}

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 Research | volume = 64 | issue = 24 | pages = 8816–8820 | 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 = 629–639 | 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 | date = Dec 2005 | pmid = 16367902 | pmc = 11159386 | doi = 10.1111/j.1349-7006.2005.00130.x | s2cid = 5721063 | doi-access = free }}

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 = 688–694 | date = September 2004 | pmid = 15343275 | doi = 10.1038/nrc1433 | s2cid = 1218835 }}

PTPN11 has been shown to interact with

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• 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 = Molecular and Cellular Biology | volume = 28 | issue = 15 | pages = 4805–4818 | 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 = Journal of Biological Chemistry | volume = 269 | issue = 40 | pages = 25206–25211 | date = October 1994 | pmid = 7523381 | doi = 10.1016/S0021-9258(17)31518-1 | 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 = Molecular and Cellular Biology | volume = 18 | issue = 4 | pages = 2089–2099 | 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 = Journal of Biological Chemistry | volume = 275 | issue = 28 | pages = 21435–21443 | 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 Letters | 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 | bibcode = 1999FEBSL.450...77P }}{{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 = Journal of Biological Chemistry | volume = 273 | issue = 43 | pages = 28332–28340 | 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 = Journal of Biological Chemistry | volume = 272 | issue = 11 | pages = 6986–6993 | 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 = Journal of Biological Chemistry | volume = 274 | issue = 1 | pages = 335–344 | 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 = Molecular Systems Biology | volume = 1 | issue = 1 | pages = 2005.0008 | 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 = Journal of Biological Chemistry | volume = 270 | issue = 36 | pages = 21277–21284 | date = Sep 1995 | pmid = 7673163 | doi = 10.1074/jbc.270.36.21277 | doi-access = free }}
• Erk{{cite book | vauthors = Lai LA, Zhao C, Zhang EE, Feng GS | chapter = 14 The Shp-2 tyrosine phosphatase | title = Protein phosphatases | pages = 275–299 | year = 2004 | publisher = Springer | isbn = 978-3-540-20560-9 | chapter-url = https://books.google.com/books?id=EotzHJrTu3sC&q=The+Shp-2+tyrosine+phosphatase | veditors = Ariño J, Alexander D }}{{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 = 621–628 | 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 = 1929–1938 | date = Apr 2001 | pmid = 11360177 | doi = 10.1038/sj.onc.1204290 | s2cid = 25346661 }}{{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 = Molecular and Cellular Biology | volume = 18 | issue = 7 | pages = 3966–3973 | 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 = Journal of Biological Chemistry | volume = 277 | issue = 26 | pages = 23216–23222 | 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 = Molecular Endocrinology | location = Baltimore, Md. | volume = 12 | issue = 7 | pages = 914–923 | 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 = The EMBO Journal | 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 = Journal of Biological Chemistry | volume = 274 | issue = 28 | pages = 19649–19654 | 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 Letters | volume = 495 | issue = 3 | pages = 148–153 | date = April 2001 | pmid = 11334882 | doi = 10.1016/S0014-5793(01)02373-0 | bibcode = 2001FEBSL.495..148C | s2cid = 24499468 }}
• GAB3,{{cite journal | vauthors = Wolf I, Jenkins BJ, Liu Y, Seiffert M, Custodio JM, Young P, Rohrschneider LR | title = Gab3, a New DOS/Gab Family Member, Facilitates Macrophage Differentiation | journal = Molecular and Cellular Biology | volume = 22 | issue = 1 | pages = 231–244 | date = Jan 2002 | pmid = 11739737 | pmc = 134230 | doi = 10.1128/MCB.22.1.231-244.2002 | issn = 0270-7306 | 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 | location = Baltimore, Md. | volume = 165 | issue = 5 | pages = 2535–2543 | 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 = Journal of Biological Chemistry | volume = 272 | issue = 49 | pages = 30741–30747 | 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 = Journal of Biological Chemistry | volume = 275 | issue = 23 | pages = 17263–17268 | 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 = Proceedings of the National Academy of Sciences of the United States of America | volume = 91 | issue = 15 | pages = 7335–7339 | 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 = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1448 | issue = 1 | pages = 70–76 | 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 = 1823–1832 | 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 = Journal of Biological Chemistry | volume = 274 | issue = 18 | pages = 12401–12407 | 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 = Journal of Leukocyte Biology | volume = 65 | issue = 3 | pages = 372–380 | 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 = Journal of Biological Chemistry | volume = 271 | issue = 35 | pages = 20981–20984 | 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 = Molecular Endocrinology | location = Baltimore, Md. | volume = 14 | issue = 9 | pages = 1338–1350 | 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 = Journal of Biological Chemistry | volume = 273 | issue = 26 | pages = 15906–15912 | 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 = Journal of Biological Chemistry | volume = 284 | issue = 4 | pages = 2549–2567 | 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 = Biochemical and Biophysical Research Communications | volume = 199 | issue = 2 | pages = 780–785 | date = Mar 1994 | pmid = 8135823 | doi = 10.1006/bbrc.1994.1297 | bibcode = 1994BBRC..199..780M }}{{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 = Journal of Biological Chemistry | volume = 270 | issue = 49 | pages = 29189–29193 | 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 = Molecular and Cellular Biology | volume = 19 | issue = 4 | pages = 3125–3135 | 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 = Journal of Biological Chemistry | volume = 270 | issue = 32 | pages = 19151–19157 | 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 = Journal of Biological Chemistry | volume = 268 | issue = 16 | pages = 11479–11481 | date = Jun 1993 | pmid = 8505282 | doi = 10.1016/S0021-9258(19)50220-4 | 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 = Journal of Biological Chemistry | volume = 273 | issue = 41 | pages = 26908–26914 | 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 = Journal of Biological Chemistry | volume = 278 | issue = 1 | pages = 661–671 | 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 = Journal of Biological Chemistry | volume = 272 | issue = 2 | pages = 1032–1037 | 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 = 4495–4501 | 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 = Biochemical and Biophysical Research Communications | volume = 228 | issue = 1 | pages = 122–127 | date = November 1996 | pmid = 8912646 | doi = 10.1006/bbrc.1996.1626 | bibcode = 1996BBRC..228..122M }}
• 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 | location = Baltimore, Md. | volume = 165 | issue = 3 | pages = 1197–1209 | 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 | title = LAIR-1, a novel inhibitory receptor expressed on human mononuclear leukocytes | journal = Immunity | volume = 7 | issue = 2 | pages = 283–290 | date = Aug 1997 | pmid = 9285412 | doi = 10.1016/S1074-7613(00)80530-0 | authorlink5 = Grant Robert Sutherland | 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 = Journal of Biological Chemistry | volume = 283 | issue = 23 | pages = 15656–15664 | 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 = The Journal of Cell Biology | volume = 152 | issue = 2 | pages = 325–334 | 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 = Journal of Biological Chemistry | volume = 268 | issue = 29 | pages = 21478–21481 | date = Oct 1993 | pmid = 7691811 | doi = 10.1016/S0021-9258(20)80562-6 | 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 = Cellular Signalling | volume = 14 | issue = 10 | pages = 869–878 | 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 = Journal of Biological Chemistry | volume = 275 | issue = 36 | pages = 27845–27850 | 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 = 957–965 | 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 = The EMBO Journal | volume = 20 | issue = 21 | pages = 5840–5852 | 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 = Biochemical and Biophysical Research Communications | volume = 239 | issue = 2 | pages = 412–417 | date = Oct 1997 | pmid = 9344843 | doi = 10.1006/bbrc.1997.7480 | bibcode = 1997BBRC..239..412C }}
• 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 = Journal of Biological Chemistry | 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 = Journal of Biological Chemistry | volume = 277 | issue = 34 | pages = 31107–31114 | date = Aug 2002 | pmid = 12060651 | doi = 10.1074/jbc.M200156200 | doi-access = free }} and
• STAT5B.

{{Div col end}}

{{reflist}}

{{Refbegin| 2}}

• {{Cite book | vauthors = Marron MB, Hughes DP, McCarthy MJ, Beaumont ER, Brindle NP | chapter = Tie-1 Receptor Tyrosine Kinase Endodomain Interaction with SHP2: Potential Signalling Mechanisms and Roles in Angiogenesis | title = Angiogenesis | volume = 476 | pages = 35–46 | year = 2000 | pmid = 10949653 | doi = 10.1007/978-1-4615-4221-6_3 | series = Advances in Experimental Medicine and Biology | isbn = 978-1-4613-6895-3 }}
• {{cite journal | vauthors = Carter-Su C, Rui L, Stofega MR | title = SH2-B and SIRP: JAK2 binding proteins that modulate the actions of growth hormone. | journal = Recent Progress in Hormone Research | volume = 55 | pages = 293–311 | year = 2000 | pmid = 11036942 }}
• {{cite journal | vauthors = Ion A, Tartaglia M, Song X, Kalidas K, van der Burgt I, Shaw AC, Ming JE, Zampino G, Zackai EH, Dean JC, Somer M, Parenti G, Crosby AH, Patton MA, Gelb BD, Jeffery S | title = Absence of PTPN11 mutations in 28 cases of cardiofaciocutaneous (CFC) syndrome | journal = Human Genetics | volume = 111 | issue = 4–5 | pages = 421–427 | date = Oct 2002 | pmid = 12384786 | doi = 10.1007/s00439-002-0803-6 | s2cid = 27085702 }}
• {{cite journal | vauthors = Hugues L, Cavé H, Philippe N, Pereira S, Fenaux P, Preudhomme C | title = Mutations of PTPN11 are rare in adult myeloid malignancies. | journal = Haematologica | volume = 90 | issue = 6 | pages = 853–854 | date = Jun 2005 | pmid = 15951301 }}
• {{cite journal | vauthors = Tartaglia M, Gelb BD | title = Germ-line and somatic PTPN11 mutations in human disease. | journal = European Journal of Medical Genetics | volume = 48 | issue = 2 | pages = 81–96 | year = 2005 | pmid = 16053901 | doi = 10.1016/j.ejmg.2005.03.001 }}
• {{cite journal | vauthors = Ogata T, Yoshida R | title = PTPN11 mutations and genotype-phenotype correlations in Noonan and LEOPARD syndromes. | journal = Pediatric Endocrinology Reviews | volume = 2 | issue = 4 | pages = 669–674 | date = Jun 2005 | pmid = 16208280 }}
• {{cite journal | vauthors = Feng GS | title = Shp2-mediated molecular signaling in control of embryonic stem cell self-renewal and differentiation. | journal = Cell Research | volume = 17 | issue = 1 | pages = 37–41 | date = Jan 2007 | pmid = 17211446 | doi = 10.1038/sj.cr.7310140 | doi-access = free }}
• {{cite journal | vauthors = Edouard T, Montagner A, Dance M, Conte F, Yart A, Parfait B, Tauber M, Salles JP, Raynal P | title = How do Shp2 mutations that oppositely influence its biochemical activity result in syndromes with overlapping symptoms? | journal = Cellular and Molecular Life Sciences | volume = 64 | issue = 13 | pages = 1585–1590 | date = Jul 2007 | pmid = 17453145 | pmc = 11136329 | doi = 10.1007/s00018-007-6509-0 | s2cid = 25934330 }}

{{Refend}}

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

{{PDB Gallery|geneid=5781}}

{{Protein tyrosine phosphatases}}

{{Esterases}}

{{Enzymes}}

{{Portal bar|Biology|border=no}}

{{DEFAULTSORT:Ptpn11}}

Category:EC 3.1.3