Tyrosine Phosphatase- Activates Src and Supports the Transformed Phenotype of Neu-induced Mammary Tumor Cells*

Few tyrosine phosphatases support, rather than inhibit, survival of tumor cells. We present genetic evidence that receptor-type protein-tyrosine phosphatase (RPTP)performs such a function, as cells from mammary epithelial tumors induced by activated Neu in mice genetically lacking RPTP appeared morphologically less transformed and exhibited reduced proliferation. We show that at the molecular level, RPTP activates Src, a known collaborator of Neu in mammary tumorigenesis. Lack of RPTP reduced Src activity and altered Src phosphorylation in tumor cells; RPTP dephosphorylated and activated Src; and Src bound a substrate-trapping mutant of RPTP . The altered morphology of tumor cells lacking RPTP was corrected by exogenous Src and exogenous RPTP or RPTP ; exogenous activated Src corrected also the growth rate phenotype. Together, these results suggest that the altered morphology of RPTP -deficient tumor cells is caused by reduced Src activity, caused, in turn, by lack of RPTP . Unexpectedly, the phenotype of RPTP -deficient tumor cells occurs despite expression of the related RPTP , indicating that endogenous RPTP does not compensate for the absence of RPTP in this case. We conclude that RPTP is a physiological activator of Src in Neuinduced mammary tumors and suggest that pharmacological inhibition of phosphatases that activate Src may be useful to augment direct pharmacological inhibition of Src.