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{{PBB|geneid=5781}}
{{Short description|Protein-coding gene in humans}}
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'''Tyrosine-protein phosphatase non-receptor type 11''' (PTPN11) also known as '''protein-tyrosine phosphatase 1D''' (PTP-1D) 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.<ref name="pmid7894486">{{vcite2 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 }}</ref><ref name="pmid1280823">{{vcite2 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 }}</ref>
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{{Use dmy dates|date=March 2020}}
{{Infobox_gene}}
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'''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.<ref name="pmid7894486">{{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 }}</ref><ref name="pmid1280823">{{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 }}</ref>


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.<ref>{{Cite web| title = Entrez Gene: PTPN11 protein tyrosine phosphatase, non-receptor type 11 (Noonan syndrome 1)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5781| accessdate = }}</ref>
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.<ref>{{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}}</ref>


==Structure and function==
==Structure and function==
{{unsourced|section|date=November 2023}}
This phosphatase, along with its paralogue, [[Shp1]], possesses a domain structure that consists of two tandem [[SH2 domain]]s 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.
This phosphatase, along with its paralogue, [[Shp1]], possesses a domain structure that consists of two tandem [[SH2 domain]]s 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.


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==Genetic diseases associated with PTPN11==
==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.<ref name = "Šimčíková_2019 - supplementary table S7">{{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 }}</ref>
Missense mutations in the PTPN11 locus are associated with both [[Noonan syndrome]] and [[Leopard syndrome]].


It has also been associated with [[Metachondromatosis]].<ref name="pmid20577567">{{vcite2 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 }}</ref>
It has also been associated with [[metachondromatosis]].<ref name="pmid20577567">{{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 }}</ref>


===Noonan syndrome===
===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.<ref name="pmid17143285">{{vcite2 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 }}</ref>
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.<ref name="pmid17143285">{{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 }}</ref>


===Leopard syndrome===
===Leopard syndrome===
The mutations that cause Leopard syndrome are restricted regions affecting the catalytic core of the enzyme producing catalytically impaired Shp2 variants.<ref name="pmid16377799">{{vcite2 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 }}</ref> It is currently unclear how mutations that give rise to mutant variants of Shp2 with biochemically opposite characteristics result in similar human genetic syndromes.
The mutations that cause Leopard syndrome are restricted regions affecting the catalytic core of the enzyme producing catalytically impaired Shp2 variants.<ref name="pmid16377799">{{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 }}</ref> 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==
==Cancer associated with PTPN11==
Patients with a subset of Noonan syndrome PTPN11 mutations also have a higher prevalence of [[juvenile myelomonocytic leukemia]]s (JMML). Activating Shp2 mutations have also been detected in [[neuroblastoma]], [[melanoma]], [[acute myeloid leukemia]], [[breast cancer]], [[lung cancer]], [[colorectal cancer]].<ref name="pmid15604238">{{vcite2 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 }}</ref> These data suggests that Shp2 may be a [[proto-oncogene]]. However, it has been reported that PTPN11/Shp2 can act as either tumor [[Proto-oncogene|promoter]] or [[Tumor suppressor gene|suppressor]].<ref name="Gen-Sheng Feng"/> 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|hepatocellular carcinoma (HCC)]] specimens.<ref name="Gen-Sheng Feng">{{vcite2 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 }}</ref> 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.<ref name="pmid16367902">{{vcite2 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 }}</ref>
Patients with a subset of Noonan syndrome PTPN11 mutations also have a higher prevalence of [[juvenile myelomonocytic leukemia]]s (JMML). Activating Shp2 mutations have also been detected in [[neuroblastoma]], [[melanoma]], [[acute myeloid leukemia]], [[breast cancer]], [[lung cancer]], [[colorectal cancer]].<ref name="pmid15604238">{{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 }}</ref> 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,<ref>{{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 }}</ref> 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 [[Proto-oncogene|promoter]] or [[Tumor suppressor gene|suppressor]].<ref name="Gen-Sheng Feng"/> 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.<ref name="Gen-Sheng Feng">{{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 }}</ref> 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.<ref name="pmid16367902">{{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 }}</ref>


== Interactions ==
== Interactions ==
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{{div col|colwidth=20em}}
{{div col|colwidth=20em}}
*[[CagA]],<ref name="pmid16367902"/>
*[[CagA]],<ref name="pmid16367902"/>
* [[Cbl gene]],<ref name=pmid18519587>{{vcite2 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 | authorlink = }}</ref>
* [[Cbl gene]],<ref name=pmid18519587>{{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 }}</ref>
* [[CD117]],<ref name="pmid7523381">{{vcite2 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 | pmid = 7523381 | doi = }}</ref><ref name="pmid9528781">{{vcite2 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 = }}</ref>
* [[CD117]],<ref name="pmid7523381">{{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 }}</ref><ref name="pmid9528781">{{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}}</ref>
* [[CD31]],<ref name="pmid10801826">{{vcite2 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 }}</ref><ref name="pmid10350061">{{vcite2 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 }}</ref><ref name="pmid9774457">{{vcite2 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 }}</ref><ref name="pmid9054388">{{vcite2 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 }}</ref>
* [[CD31]],<ref name="pmid10801826">{{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 }}</ref><ref name="pmid10350061">{{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 }}</ref><ref name="pmid9774457">{{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}}</ref><ref name="pmid9054388">{{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 }}</ref>
* [[CEACAM1]],<ref name=pmid9867848>{{vcite2 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 | authorlink = }}</ref>
* [[CEACAM1]],<ref name=pmid9867848>{{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}}</ref>
* [[Epidermal growth factor receptor]],<ref name=pmid16729043>{{vcite2 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 = 2005.0008 | year = 2005 | pmid = 16729043 | pmc = 1681463 | doi = 10.1038/msb4100012 | authorlink = }}</ref><ref name=pmid7673163>{{vcite2 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 | authorlink = }}</ref>
* [[Epidermal growth factor receptor]],<ref name=pmid16729043>{{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 }}</ref><ref name=pmid7673163>{{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}}</ref>
* [[Extracellular signal-regulated kinases|Erk]] <ref name="Shp2 Erk PI3K">{{cite book|title=Protein phosphatases|year=2004|publisher=Springer|isbn=3-540-20560-8|pages=275–299|url=http://books.google.com/books?id=EotzHJrTu3sC&printsec=frontcover&dq=protein+phosphatases&hl=en&ei=xxJdTpmXMtSy0AHY3MDTAg&sa=X&oi=book_result&ct=result&resnum=1&ved=0CC0Q6AEwAA#v=onepage&q=The%20Shp-2%20tyrosine%20phosphatase&f=false|author=L.A. Lai, C. Zhao, E.E. Zhang and G.S. Feng|editor=Joaquín Ariño, Denis Alexander|chapter=14 The Shp-2 tyrosine phosphatase}}</ref><ref name="B.G. Neel">{{vcite2 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 | publisher = ELSEVIER SCIENCE LONDON | issn = 0968-0004 | location = LONDON WC1X 8RR, ENGLAND }}</ref>
* [[Extracellular signal-regulated kinases|Erk]]<ref name="Shp2 Erk PI3K">{{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}}</ref><ref name="B.G. Neel">{{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 }}</ref>
* [[FRS2]],<ref name=pmid10650943>{{vcite2 journal | vauthors = Delahaye L, Rocchi S, Van Obberghen E | title = Potential involvement of FRS2 in insulin signaling | journal = [[Endocrinology (journal)|Endocrinology]] | volume = 141 | issue = 2 | pages = 621–8 | date = Feb 2000 | pmid = 10650943 | doi = 10.1210/endo.141.2.7298 | authorlink = }}</ref><ref name=pmid11360177>{{vcite2 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 | authorlink = }}</ref><ref name=pmid9632781>{{vcite2 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 | authorlink = }}</ref>
* [[FRS2]],<ref name=pmid10650943>{{cite journal | vauthors = Delahaye L, Rocchi S, Van Obberghen E | title = Potential involvement of FRS2 in insulin signaling | journal = [[Endocrinology (journal)|Endocrinology]] | volume = 141 | issue = 2 | pages = 621–8 | date = Feb 2000 | pmid = 10650943 | doi = 10.1210/endo.141.2.7298 | doi-access = free }}</ref><ref name=pmid11360177>{{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 = }}</ref><ref name=pmid9632781>{{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 }}</ref>
* [[GAB1]],<ref name=pmid11940581>{{vcite2 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 | authorlink = }}</ref><ref name=pmid9658397>{{vcite2 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 | authorlink = }}</ref>
* [[GAB1]],<ref name=pmid11940581>{{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 }}</ref><ref name=pmid9658397>{{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 }}</ref>
* [[GAB2]],<ref name=pmid12135708/><ref name="pmid11782427">{{vcite2 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 }}</ref><ref name="pmid10391903">{{vcite2 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 }}</ref><ref name="pmid11334882">{{vcite2 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 }}</ref>
* [[GAB2]],<ref name=pmid12135708/><ref name="pmid11782427">{{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 }}</ref><ref name="pmid10391903">{{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 }}</ref><ref name="pmid11334882">{{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 }}</ref>
* [[GAB3]],<ref name="WolfJenkins2002">{{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}}</ref> <!-- SHP2 is a synonym for PTPN11 -->
* [[Glycoprotein 130]],<ref name=pmid12403768/><ref name=pmid10946280>{{vcite2 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 | authorlink = }}</ref><ref name=pmid9388212>{{vcite2 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 | authorlink = }}</ref>
* [[Grb2]],<ref name=pmid9632781/><ref name=pmid8995399/><ref name=pmid10747947>{{vcite2 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 | authorlink = }}</ref><ref name=pmid8041791>{{vcite2 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 = [[PNAS|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 | authorlink = }}</ref><ref name=pmid9824671>{{vcite2 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 | authorlink = }}</ref><ref name=pmid9362449>{{vcite2 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 | authorlink = }}</ref><ref name=pmid10212213>{{vcite2 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 | authorlink = }}</ref><ref name=pmid10080542>{{vcite2 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 | authorlink = }}</ref><ref name=pmid8702859>{{vcite2 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 | authorlink = }}</ref>
* [[Glycoprotein 130]],<ref name=pmid12403768/><ref name=pmid10946280>{{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 }}</ref><ref name=pmid9388212>{{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 }}</ref>
* [[Grb2]],<ref name=pmid9632781/><ref name=pmid8995399/><ref name=pmid10747947>{{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 }}</ref><ref name=pmid8041791>{{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 = [[PNAS|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 }}</ref><ref name=pmid9824671>{{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 }}</ref><ref name=pmid9362449>{{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 }}</ref><ref name=pmid10212213>{{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}}</ref><ref name=pmid10080542>{{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 }}</ref><ref name=pmid8702859>{{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 }}</ref>
* [[Growth hormone receptor]],<ref name="pmid10976913">{{vcite2 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/me.14.9.1338 }}</ref><ref name="pmid9632636">{{vcite2 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 }}</ref>
* [[Growth hormone receptor]],<ref name="pmid10976913">{{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 }}</ref><ref name="pmid9632636">{{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 }}</ref>
* [[HoxA10]],<ref name=pmid19022774>{{vcite2 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 | authorlink = }}</ref>
* [[HoxA10]],<ref name=pmid19022774>{{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 }}</ref>
* [[Insulin receptor]],<ref name=pmid8135823>{{vcite2 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 | authorlink = }}</ref><ref name=pmid7493946>{{vcite2 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 | authorlink = }}</ref>
* [[Insulin receptor]],<ref name=pmid8135823>{{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 }}</ref><ref name=pmid7493946>{{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 }}</ref>
* [[Insulin-like growth factor 1 receptor]],<ref name=pmid10082579>{{vcite2 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 | authorlink = }}</ref><ref name=pmid7642582>{{vcite2 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 | authorlink = }}</ref>
* [[Insulin-like growth factor 1 receptor]],<ref name=pmid10082579>{{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}}</ref><ref name=pmid7642582>{{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}}</ref>
* [[IRS1]],<ref name=pmid8505282>{{vcite2 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 | pmid = 8505282 | authorlink = }}</ref><ref name=pmid9756938>{{vcite2 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 | authorlink = }}</ref>
* [[IRS1]],<ref name=pmid8505282>{{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 }}</ref><ref name=pmid9756938>{{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 }}</ref>
* [[Janus kinase 1]],<ref name="pmid12403768">{{vcite2 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 }}</ref><ref name=pmid8995399/>
* [[Janus kinase 1]],<ref name="pmid12403768">{{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 }}</ref><ref name=pmid8995399/>
* [[Janus kinase 2]],<ref name="pmid8995399">{{vcite2 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 }}</ref><ref name="pmid8639815">{{vcite2 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 = }}</ref><ref name="pmid8912646">{{vcite2 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 }}</ref>
* [[Janus kinase 2]],<ref name="pmid8995399">{{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 }}</ref><ref name="pmid8639815">{{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 }}</ref><ref name="pmid8912646">{{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 }}</ref>
* [[LAIR1]],<ref name=pmid10903717>{{vcite2 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 | authorlink = }}</ref><ref name=pmid9285412>{{vcite2 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 = 283–90 | date = Aug 1997 | pmid = 9285412 | doi = 10.1016/S1074-7613(00)80530-0 | authorlink = }}</ref>
* [[LAIR1]],<ref name=pmid10903717>{{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 }}</ref><ref name=pmid9285412>{{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 }}</ref>
* [[LRP1]],<ref name="pmid18381291">{{vcite2 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 }}</ref>
* [[LRP1]],<ref name="pmid18381291">{{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 }}</ref>
* [[PDGFRB]],<ref name=pmid11266449>{{vcite2 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 | authorlink = }}</ref><ref name=pmid7691811>{{vcite2 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 | pmid = 7691811 | authorlink = }}</ref>
* [[PDGFRB]],<ref name=pmid11266449>{{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 }}</ref><ref name=pmid7691811>{{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 }}</ref>
* [[PI3K]] → [[Akt]] <ref name="Shp2 Erk PI3K"/>
* [[PI3K]] → [[Akt]]<ref name="Shp2 Erk PI3K"/>
* [[PLCG2]],<ref name="pmid12135708">{{vcite2 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 }}</ref>
* [[PLCG2]],<ref name="pmid12135708">{{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 }}</ref>
* [[PTK2B]],<ref name="pmid10880513">{{vcite2 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 }}</ref>
* [[PTK2B]],<ref name="pmid10880513">{{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 }}</ref>
* [[Ras subfamily|Ras]]<ref name="Shp2 Erk PI3K"/><ref name="B.G. Neel"/>
* [[Ras subfamily|Ras]]<ref name="Shp2 Erk PI3K"/><ref name="B.G. Neel"/>
* [[SLAMF1]],<ref name=pmid11806999>{{vcite2 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 | authorlink = }}</ref><ref name=pmid11689425>{{vcite2 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 | authorlink = }}</ref>
* [[SLAMF1]],<ref name=pmid11806999>{{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 }}</ref><ref name=pmid11689425>{{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 }}</ref>
* [[SOCS3]],<ref name=pmid12403768/>
* [[SOCS3]],<ref name=pmid12403768/>
* [[SOS1]],<ref name=pmid9632781/><ref name=pmid9344843>{{vcite2 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 | authorlink = }}</ref>
* [[SOS1]],<ref name=pmid9632781/><ref name=pmid9344843>{{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 }}</ref>
* [[STAT3]],<ref name="Gen-Sheng Feng"/>
* [[STAT3]],<ref name="Gen-Sheng Feng"/>
* [[STAT5A]],<ref name=pmid10617656>{{vcite2 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 | authorlink = }}</ref><ref name=pmid12060651>{{vcite2 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 | authorlink = }}</ref> and
* [[STAT5A]],<ref name=pmid10617656>{{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 }}</ref><ref name=pmid12060651>{{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 }}</ref> and
* [[STAT5B]].<ref name=pmid10617656/>
* [[STAT5B]].<ref name=pmid10617656/>
{{Div col end}}
{{Div col end}}


===H Pylori CagA virulence factor===
===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 [[stomach cancer|gastric carcinoma]].<ref name="pmid15343275">{{vcite2 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 }}</ref>
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.&nbsp;pylori'' in the development of [[atrophic gastritis]], [[peptic ulcer]] disease and [[stomach cancer|gastric carcinoma]].<ref name="pmid15343275">{{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 }}</ref>


== References ==
== References ==
{{Reflist|2}}
{{reflist}}


== Further reading ==
== Further reading ==
{{Refbegin| 2}}
{{Refbegin| 2}}
* {{vcite2 journal | vauthors = Marron MB, Hughes DP, McCarthy MJ, Beaumont ER, Brindle NP | title = Tie-1 receptor tyrosine kinase endodomain interaction with SHP2: potential signalling mechanisms and roles in angiogenesis. | journal = Adv. Exp. Med. Biol. | volume = 476 | issue = | pages = 35–46 | year = 2000 | pmid = 10949653 | doi = 10.1007/978-1-4615-4221-6_3 }}
* {{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 }}
* {{vcite2 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 Prog. Horm. Res. | volume = 55 | issue = | pages = 293–311 | year = 2000 | pmid = 11036942 | doi = }}
* {{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 Prog. Horm. Res. | volume = 55 | pages = 293–311 | year = 2000 | pmid = 11036942 }}
* {{vcite2 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 = Hum. Genet. | volume = 111 | issue = 4-5 | pages = 421–7 | year = 2002 | pmid = 12384786 | doi = 10.1007/s00439-002-0803-6 }}
* {{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 = Hum. Genet. | volume = 111 | issue = 4–5 | pages = 421–7 | year = 2002 | pmid = 12384786 | doi = 10.1007/s00439-002-0803-6 | s2cid = 27085702 }}
* {{vcite2 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 = 853–4 | year = 2006 | pmid = 15951301 | doi = }}
* {{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 = 853–4 | year = 2006 | pmid = 15951301 }}
* {{vcite2 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 = 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 }}
* {{vcite2 journal | vauthors = Ogata T, Yoshida R | title = PTPN11 mutations and genotype-phenotype correlations in Noonan and LEOPARD syndromes. | journal = Pediatric endocrinology reviews : PER | volume = 2 | issue = 4 | pages = 669–74 | year = 2006 | pmid = 16208280 | doi = }}
* {{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 = 669–74 | year = 2006 | pmid = 16208280 }}
* {{vcite2 journal | vauthors = Feng GS | title = Shp2-mediated molecular signaling in control of embryonic stem cell self-renewal and differentiation. | journal = Cell Res. | volume = 17 | issue = 1 | pages = 37–41 | year = 2007 | pmid = 17211446 | doi = 10.1038/sj.cr.7310140 }}
* {{cite journal | vauthors = Feng GS | title = Shp2-mediated molecular signaling in control of embryonic stem cell self-renewal and differentiation. | journal = Cell Res. | volume = 17 | issue = 1 | pages = 37–41 | year = 2007 | pmid = 17211446 | doi = 10.1038/sj.cr.7310140 | doi-access = free }}
* {{vcite2 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 = Cell. Mol. Life Sci. | volume = 64 | issue = 13 | pages = 1585–90 | year = 2007 | pmid = 17453145 | doi = 10.1007/s00018-007-6509-0 }}
* {{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 = Cell. Mol. Life Sci. | volume = 64 | issue = 13 | pages = 1585–90 | year = 2007 | pmid = 17453145 | doi = 10.1007/s00018-007-6509-0 | s2cid = 25934330 | pmc = 11136329 }}
{{Refend}}
{{Refend}}


== External links ==
== External links ==
* [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=noonan GeneReviews/NCBI/NIH/UW entry on Noonan syndrome]
* [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}}
{{PDB Gallery|geneid=5781}}
{{Protein tyrosine phosphatases}}
{{Protein tyrosine phosphatases}}
{{Esterases}}
⚫
{{Use dmy dates|date=September 2010}}
{{Enzymes}}
{{Portal bar|Biology|border=no}}


{{DEFAULTSORT:Ptpn11}}
{{DEFAULTSORT:Ptpn11}}
[[Category:Human genes]]
[[Category:EC 3.1.3]]
[[Category:EC 3.1.3]]

Latest revision as of 05:41, 17 June 2024

PTPN11
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPTPN11, BPTP3, CFC, JMML, METCDS, NS1, PTP-1D, PTP2C, SH-PTP2, SH-PTP3, SHP2, protein tyrosine phosphatase, non-receptor type 11, protein tyrosine phosphatase non-receptor type 11
External IDsOMIM: 176876; MGI: 99511; HomoloGene: 2122; GeneCards: PTPN11; OMA:PTPN11 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

5781

19247

Ensembl

ENSG00000179295

ENSMUSG00000043733

UniProt

Q06124

P35235

RefSeq (mRNA)

NM_002834
NM_080601
NM_001330437
NM_001374625
NM_018508

NM_001109992
NM_011202

RefSeq (protein)

NP_001317366
NP_002825
NP_542168
NP_001361554

NP_001103462
NP_035332

Location (UCSC)Chr 12: 112.42 – 112.51 MbChr 5: 121.27 – 121.33 Mb
PubMed search[3][4]
Wikidata
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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.[5][6]

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.[7]

Structure and function

[edit]

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

[edit]

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.[8]

It has also been associated with metachondromatosis.[9]

Noonan syndrome

[edit]

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.[10]

Leopard syndrome

[edit]

The mutations that cause Leopard syndrome are restricted regions affecting the catalytic core of the enzyme producing catalytically impaired Shp2 variants.[11] 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

[edit]

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.[12] 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,[13] 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.[14] 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.[14] 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.[15]

Interactions

[edit]

PTPN11 has been shown to interact with

H Pylori CagA virulence factor

[edit]

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.[71]

References

[edit]
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  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000043733 – Ensembl, May 2017
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Further reading

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