Inactivation of Protein-tyrosine Phosphatases as Mechanism of UV-induced Signal Transduction

UV irradiation of cells causes ligand-independent activation of receptor tyrosine kinases. On the basis of dephosphorylation kinetics, UV-induced inactivation of receptor-directed tyrosine phosphatases (PTP) has been proposed as the mechanism of receptor activation (Knebel, A., Rahmsdorf, H. J., Ullrich, A., and Herrlich, P. (1996) EMBO J. 15, 5314–5325). Here we show that four defined protein-tyrosine phosphatases (PTPs), SHP-1, RPTPα, RPTPς, and DEP-1, are partially inactivated upon UV irradiation of PTP-overexpressing cells. The dephosphorylation of coexpressed platelet-derived growth factor β (PDGFβ) receptor by RPTPα is inhibited upon UV irradiation. UV converts RPTPα into a substrate-trapping enzyme which can coprecipitate PDGFβ receptor, similarly to the PTP mutant at the active-center cysteine: C433S. In agreement with the proposed mechanism that inactivation of PTPs accounts for receptor tyrosine kinase activation, no evidence for a UV-induced receptor cross-linking could be obtained in PDGFβ receptor-enriched membrane micelle preparations and in PDGFβ receptor overexpressing 293 cells. The intrinsic activity of PDGFβ receptor kinase was required for the UV-induced enhancement of receptor phosphorylation, but was not changed upon UV irradiation. The data support a mechanism of UV-induced signal transduction involving inactivation of PTPs through an unknown reactive intermediate that oxidizes the conserved cysteine in the active sites of PTPs.