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A widely expressed human protein-tyrosine phosphatase containing src homology 2 domains.

ABSTRACT: A cDNA encoding a nontransmembrane protein-tyrosine phosphatase (PTP; EC 3.1.3.48), termed PTP2C, was isolated from a human umbilical cord cDNA library. The enzyme contains a single phosphatase domain and two adjacent copies of the src homology 2 (SH2) domain at its amino terminus. A variant of PTP2C (PTP2Ci) which has four extra amino acid residues within the catalytic domain has been identified also. PTP2C is widely expressed in human tissues and is particularly abundant in heart, brain, and skeletal muscle. The catalytic domain of PTP2C was expressed as a recombinant enzyme in Escherichia coli and purified to near homogeneity by two chromatographic steps. The recombinant enzyme was totally specific toward phosphotyrosine residues. The structural similarity between PTP2C and the previously described PTP1C suggests the existence of a subfamily of SH2-containing PTPs; these may play an important role in signal transduction through interaction of their SH2 domains with phosphotyrosine-containing proteins.

SUBMITTER: Ahmad S

PROVIDER: S-EPMC46053 | biostudies-other | 1993 Mar

REPOSITORIES: biostudies-other

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A widely expressed human protein-tyrosine phosphatase containing src homology 2 domains.

Ahmad S S Banville D D Zhao Z Z Fischer E H EH Shen S H SH

Proceedings of the National Academy of Sciences of the United States of America 19930301 6

A cDNA encoding a nontransmembrane protein-tyrosine phosphatase (PTP; EC 3.1.3.48), termed PTP2C, was isolated from a human umbilical cord cDNA library. The enzyme contains a single phosphatase domain and two adjacent copies of the src homology 2 (SH2) domain at its amino terminus. A variant of PTP2C (PTP2Ci) which has four extra amino acid residues within the catalytic domain has been identified also. PTP2C is widely expressed in human tissues and is particularly abundant in heart, brain, and s ...[more]

PMID: 7681589

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Project description:Tumor invasion and metastasis represent a major unsolved problem in cancer pathogenesis. Recent studies have indicated the involvement of Src-homology 2 domain-containing tyrosine phosphatase 2 (SHP2) in multiple malignancies; however, the role of SHP2 in oral cancer progression has yet to be elucidated. We propose that SHP2 is involved in the progression of oral cancer toward metastasis.SHP2 expression was evaluated in paired oral cancer tissues by using immunohistochemical staining and real-time reverse transcription polymerase chain reaction. Isogenic highly invasive oral cancer cell lines from their respective low invasive parental lines were established using a Boyden chamber assay, and changes in the hallmarks of the epithelial-mesenchymal transition (EMT) were assessed to evaluate SHP2 function. SHP2 activity in oral cancer cells was reduced using si-RNA knockdown or enforced expression of a catalytically deficient mutant to analyze migratory and invasive ability in vitro and metastasis toward the lung in mice in vivo.We observed the significant upregulation of SHP2 in oral cancer tissues and cell lines. Following SHP2 knockdown, the oral cancer cells markedly attenuated migratory and invasion ability. We observed similar results in phosphatase-dead SHP2 C459S mutant expressing cells. Enhanced invasiveness was associated with significant upregulation of E-cadherin, vimentin, Snail/Twist1, and matrix metalloproteinase-2 in the highly invasive clones. In addition, we determined that SHP2 activity is required for the downregulation of phosphorylated ERK1/2, which modulates the downstream effectors, Snail and Twist1 at a transcript level. In lung tissue sections of mice, we observed that HSC3 tumors with SHP2 deletion exhibited significantly reduced metastatic capacity, compared with tumors administered control si-RNA.Our data suggest that SHP2 promotes the invasion and metastasis of oral cancer cells. These results provide a rationale for further investigating the effects of small-molecule SHP2 inhibitors on the progression of oral cancer, and indicate a previously unrecognized SHP2-ERK1/2-Snail/Twist1 pathway that is likely to play a crucial role in oral cancer invasion and metastasis.

Dataset Information

A widely expressed human protein-tyrosine phosphatase containing src homology 2 domains.

Publications

A widely expressed human protein-tyrosine phosphatase containing src homology 2 domains.

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