v-Src suppresses SHPS-1 expression via the Ras-MAP kinase pathway to promote the oncogenic growth of cells

We investigated the effect of cell transformation by v-src on the expressio n and tyrosine phosphorylation of SHPS-1, a putative docking protein for SH P-1 and SHP-2. We found that transformation by v-sle virtually inhibited th e SHPS-1 expression at mRNA level. While nontransforming Src kinases includ ing c-Src, nonmyristoylated forms of v-Src had no inhibitory effect on SHPS -1 expression, transforming Src kinases including wild-type v-Src and chime ric mutant of c-Src bearing v-Src SH3 substantially suppressed the SHPS-1 e xpression. In cells expressing temperature sensitive mutant of v-Src, suppr ession of the SHPS-1 expression was temperature-dependent. In contrast, tyr osine phosphorylation of SHPS-1 was rather activated in cells expressing c- Src or nonmyristoylated forms of v-Src, SHPS-1 expression in SR3Y1 was rest ored by treatment with herbimycin A, a potent inhibitor of tyrosine kinase, or by the expression of dominant negative form of Ras. Contrary, active fo rm of Mek1 markedly suppressed SHPS-1 expression. Finally, overexpression o f SHPS-1 in SR3Y1 led to the drastic reduction of anchorage independent gro wth of the cells. Taken together, our results suggest that the suppression of SHPS-1 expression is a pivotal event for cell transformation by v-src, a nd the Ras-MAP kinase cascade plays a critical role in the suppression.