The role of protein-tyrosine phosphatase 1B in integrin signaling

Fubo Liang, Seung Yub Lee, Jiao Liang, David S. Lawrence, Zhong Yin Zhang

Research output: Contribution to journalArticle

79 Scopus citations

Abstract

Protein-tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin and leptin signaling and a novel therapeutic target for the treatment of type 2 diabetes, obesity, and other associated metabolic syndromes. Because PTP1B regulates multiple signal pathways and it can both enhance and antagonize a cellular event, it is important to establish the physiological relevance of PTP1B in these processes. In this study, we utilize potent and selective PTP1B inhibitors to delineate the role of PTP1B in integrin signaling. We show that down-regulation of PTP1B activity with small molecule inhibitors suppresses cell spreading and migration to fibronectin, increases Tyr527 phosphorylation in Src, and decreases phosphorylation of FAK, p130 Cas, and ERK1/2. In addition, PTP1B "substrate-trapping" mutants bind Tyr527-phosphorylated Src and protect it from dephosphorylation by endogenous PTP1B. These results establish that PTP1B promotes integrin-mediated responses in fibroblasts by dephosphorylating the inhibitory pTyr527 and thereby activating the Src kinase. We also show that PTP1B forms a complex with Src and p130Cas, and that the proline-rich motif PPRPPK (residues 309-314) in PTP1B is essential for the complex formation. We suggest that the specificity of PTP1B for Src pTyr 527 is mediated by protein-protein interactions involving the docking protein p130Cas with both Src and PTP1B in addition to the interactions between the PTP1B active site and the pTyr527 motif.

Original languageEnglish (US)
Pages (from-to)24857-24863
Number of pages7
JournalJournal of Biological Chemistry
Volume280
Issue number26
DOIs
StatePublished - Jul 1 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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