Inactivation of protein-tyrosine phosphatases as mechanism of UV-induced signal transduction

UV irradiation of cells causes ligand-independent activation of receptor ty rosine kinases. On the basis of dephosphorylation kinetics, UV-induced inac tivation of receptor-directed tyrosine phosphatases (PTP) has been proposed as the mechanism of receptor activation (Knebel, A., Rahmsdorf, H. J., Ull rich, A., and Herrlich, P. (1996) EMBO J, 15, 5314-5325), Here we show that four defined protein-tyrosine phosphatases (PTPs), SHP-1, RPTP alpha, RPTP sigma and DEP-1, are partially inactivated upon UV irradiation of PTP-over expressing cells. The dephosphorylation of coexpressed platelet-derived gro wth factor beta (PDGF beta) receptor by RPTP alpha is inhibited upon UV irr adiation. UV converts RPTP alpha into a substrate-trapping enzyme which can coprecipitate PDGF beta receptor, similarly to the PTP mutant at the activ e-center cysteine: C433S. In agreement with the proposed mechanism that ina ctivation of PTPs accounts for receptor tyrosine kinase activation, no evid ence for a UV-induced receptor cross-linking could be obtained in PDGF beta receptor-enriched membrane micelle preparations and in PDGF beta receptor overexpressing 293 cells. The intrinsic activity of PDGF beta receptor kina se was required for the UV-induced enhancement of receptor phosphorylation, but was not changed upon UV irradiation. The data support a mechanism of U V-induced signal transduction involving inactivation of PTPs through an unk nown reactive intermediate that oxidizes the conserved cysteine in the acti ve sites of PTPs.