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

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Abstract
Oxidation of receptor protein tyrosine phosphatase-α (RPTPα) is emerging as an important yet poorly characterized regulatory mechanism for RPTPα signaling in cells. RPTPα 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 RPTPα 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 RPTPα and characterized the phosphorylation of RPTPα 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 RPTPα 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 RPTPα9s activity, H2O2 at low to moderate concentrations (50-250 μM) markedly suppressed the phosphorylation of RPTPα Tyr789 and the association of RPTPα 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 RPTPα signaling, our findings may provide new insights into the functional regulation of RPTPα by oxidative stress in cells.