Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known asprotein-tyrosine phosphatase 1D (PTP-1D),Src homology region 2 domain-containing phosphatase-2 (SHP-2), orprotein-tyrosine phosphatase 2C (PTP-2C) is anenzyme that in humans is encoded by thePTPN11gene. PTPN11 is aprotein 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 ofNoonan syndrome as well as acute myeloid leukemia.[7]
This phosphatase, along with its paralogue,Shp1, possesses a domain structure that consists of two tandemSH2 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.
Missense mutations in the PTPN11 locus are associated with bothNoonan syndrome andLeopard syndrome. At least 79 disease-causing mutations in this gene have been discovered.[8]
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]
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.
Patients with a subset of Noonan syndrome PTPN11 mutations also have a higher prevalence ofjuvenile myelomonocytic leukemias (JMML). Activating Shp2 mutations have also been detected inneuroblastoma,melanoma,acute myeloid leukemia,breast cancer,lung cancer,colorectal cancer.[12] Recently, a relatively high prevalence of PTPN11 mutations (24%) were detected bynext-generation sequencing in a cohort ofNPM1-mutatedacute myeloid leukemia patients,[13] although the prognostic significance of such associations has not been clarified. These data suggests that Shp2 may be aproto-oncogene. However, it has been reported that PTPN11/Shp2 can act as either tumorpromoter orsuppressor.[14] In aged mouse model, hepatocyte-specific deletion of PTPN11/Shp2 promotes inflammatory signaling through theSTAT3 pathway and hepatic inflammation/necrosis, resulting in regenerative hyperplasia and spontaneous development of tumors. Decreased PTPN11/Shp2 expression was detected in a subfraction of humanhepatocellular carcinoma (HCC) specimens.[14] The bacteriumHelicobacter pylori has been associated with gastric cancer, and this is thought to be mediated in part by the interaction of its virulence factorCagA with SHP2.[15]
CagA is a protein andvirulence factor inserted byHelicobacter 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 inapoptosis of the host cell. Epidemiological studies have shown roles of cagA- positiveH. pylori in the development ofatrophic gastritis,peptic ulcer disease andgastric carcinoma.[71]
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^Maegawa H, Ugi S, Adachi M, Hinoda Y, Kikkawa R, Yachi A, Shigeta Y, Kashiwagi A (March 1994). "Insulin receptor kinase phosphorylates protein tyrosine phosphatase containing Src homology 2 regions and modulates its PTPase activity in vitro".Biochem. Biophys. Res. Commun.199 (2):780–5.doi:10.1006/bbrc.1994.1297.PMID8135823.
^Maegawa H, Kashiwagi A, Fujita T, Ugi S, Hasegawa M, Obata T, Nishio Y, Kojima H, Hidaka H, Kikkawa R (November 1996). "SHPTP2 serves adapter protein linking between Janus kinase 2 and insulin receptor substrates".Biochem. Biophys. Res. Commun.228 (1):122–7.doi:10.1006/bbrc.1996.1626.PMID8912646.
^Chin H, Saito T, Arai A, Yamamoto K, Kamiyama R, Miyasaka N, Miura O (October 1997). "Erythropoietin and IL-3 induce tyrosine phosphorylation of CrkL and its association with Shc, SHP-2, and Cbl in hematopoietic cells".Biochem. Biophys. Res. Commun.239 (2):412–7.doi:10.1006/bbrc.1997.7480.PMID9344843.
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Hugues L, Cavé H, Philippe N, Pereira S, Fenaux P, Preudhomme C (2006). "Mutations of PTPN11 are rare in adult myeloid malignancies".Haematologica.90 (6):853–4.PMID15951301.
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