CELL-TRANSFORMATION AND ACTIVATION OF PP60(C-SRC) BY OVEREXPRESSION OF A PROTEIN TYROSINE PHOSPHATASE

THE kinase activity of pp60c-src is specifically and transiently increased during mitosis and repressed during interphase1. Loss of cell-cycle control of pp60c-src occurs on mutation of Tyr 527 to Phe or when pp60c-src is associated with polyoma middle-T-antigen, and these conditions result in cell transformation or tumorigenesis2,3. In both cases, pp60c-src has elevated kinase activity which is maintained throughout the cell cycle and accompanied by dephosphorylation of the carboxy-terminal negative regulatory4-7 Tyr 527 site, or mimicry of Tyr 527 dephosphorylation in the case of the mutant. Here we report that overexpression of the receptor-like protein tyrosine phosphatase PTP-alpha-8-10 results in persistent activation of pp60c-src kinase, with concomitant cell transformation and tumorigenesis. In PTP-alpha-overexpressing cells the pp60c-src kinase activation is accompanied by dephosphorylation at Tyr 527, and direct dephosphorylation of this site by purified PTP-alpha occurs in vitro. Our results suggest that PTP-alpha is involved in the regulation of cell proliferation, exerting at least some of its effects through pp60c-src kinase, and has oncogenic capability when overexpressed.