| Protein tyrosine phosphatase SHP-2: a proto-oncogene product that promotes Ras activation. | |
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MedLine Citation:
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PMID: 19622105 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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SHP-2 is a cytoplasmic protein tyrosine phosphatase (PTP) that contains two Src homology 2 (SH2) domains. Although PTPs are generally considered to be negative regulators on the basis of their ability to oppose the effects of protein tyrosine kinases, SHP-2 is unusual in that it promotes the activation of the Ras-MAPK signaling pathway by receptors for various growth factors and cytokines. The molecular basis for the activation of SHP-2 is also unique: In the basal state, the NH(2)-terminal SH2 domain of SHP-2 interacts with the PTP domain, resulting in autoinhibition of PTP activity; the binding of SHP-2 via its SH2 domains to tyrosine-phosphorylated growth factor receptors or docking proteins, however, results in disruption of this intramolecular interaction, leading to exposure of the PTP domain and catalytic activation. Indeed, SHP-2 proteins with artificial mutations in the NH(2)-terminal SH2 domain have been shown to act as dominant active mutants in vitro. Such activating mutations of PTPN11 (human SHP-2 gene) were subsequently identified in individuals with Noonan syndrome, a human developmental disorder that is sometimes associated with juvenile myelomonocytic leukemia. Furthermore, somatic mutations of PTPN11 were found to be associated with pediatric leukemia. SHP-2 is also thought to participate in the development of other malignant disorders, but in a manner independent of such activating mutations. Biochemical and functional studies of SHP-2 and genetic analysis of PTPN11 in human disorders have thus converged to provide new insight into the pathogenesis of cancer as well as potential new targets for cancer treatment. |
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Authors:
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Takashi Matozaki; Yoji Murata; Yasuyuki Saito; Hideki Okazawa; Hiroshi Ohnishi |
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Publication Detail:
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Type: Journal Article; Review Date: 2009-06-23 |
Journal Detail:
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Title: Cancer science Volume: 100 ISSN: 1349-7006 ISO Abbreviation: Cancer Sci. Publication Date: 2009 Oct |
Date Detail:
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Created Date: 2009-09-21 Completed Date: 2009-10-09 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101168776 Medline TA: Cancer Sci Country: England |
Other Details:
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Languages: eng Pagination: 1786-93 Citation Subset: IM |
Affiliation:
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Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan. matozaki@showa.gunma-u.ac.jp |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Enzyme Activation / physiology Humans Neoplasms / genetics, metabolism* Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics, metabolism* Signal Transduction / physiology* ras Proteins / metabolism* |
| Chemical | |
Reg. No./Substance:
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EC 3.1.3.48/Protein Tyrosine Phosphatase, Non-Receptor Type 11; EC 3.6.5.2/ras Proteins |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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