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Suppression of the Phosphorylation of Receptor Tyrosine Phosphatase- on the Src-Independent Site Tyrosine 789 by Reactive Oxygen Species

Department of Biochemistry, the University of Texas Health Center at Tyler, Tyler, Texas

Oxidation of receptor protein tyrosine phosphatase- (RPTP) is emerging as an important yet poorly characterized regulatory mechanism for RPTP signaling in cells. RPTP has been shown to be reversibly oxidized and inhibited by reactive oxygen species. However, it is not known whether oxidative stress could regulate the phosphorylation of Tyr789, a critical tyrosine residue for RPTP signaling that modulates the function of Grb2 and the activation of Src family kinases. In the present study, we have taken advantage of a phosphospecific antibody against Tyr789-phosphorylated RPTP and characterized the phosphorylation of RPTP Tyr789 in various cultured cells, including SYF cells lacking all three ubiquitously expressed members (Src, Yes, and Fyn) of Src family kinases. We have obtained substantial evidence indicating that the phosphorylation of RPTP Tyr789 is regulated predominantly by an Src kinase inhibitor, protein phosphatase 1 (PP1)-sensitive but Src/Yes/Fyn-independent tyrosine kinase, in cells. We further reported a novel finding that, besides the inhibition of RPTP's activity, H₂O₂ at low to moderate concentrations (50-250 µM) markedly suppressed the phosphorylation of RPTP Tyr789 and the association of RPTP with Grb2 in cultured cells, which may result from inhibition of such a PP1-sensitive but Src/Yes/Fyn-independent tyrosine kinase. Because Tyr789 plays an important role in RPTP signaling, our findings may provide new insights into the functional regulation of RPTP by oxidative stress in cells.

Address correspondence to: Dr. Hua Tang, Department of Biochemistry, The University of Texas Health Center at Tyler, 11937 US Highway 271, Tyler, TX 75708. E-mail: hua.tang{at}uthct.edu