v-fps causes transformation by inducing tyrosine phosphorylation and activation of the PDGFbeta receptor

Abstract

The v-fps oncogene encodes an activated tyrosine kinase which is capable of transforming fibroblasts. In this report, we provide evidence that within a few minutes of activation of the tyrosine kinase activity of v-Fps, tyrosine phosphorylation of the platelet derived growth factor (PDGF) beta receptor is observed. Further, sustained expression of activated v-Fps results in a down-regulation of the PDGF receptor both at the level of the mRNA (approximately 4-8-fold), but even more markedly at the level of the receptor protein (> 100-fold). The kinase activity of the v-Fps oncoprotein was found to be required for both the induction of PDGF receptor tyrosine phosphorylation and ultimately the reduced receptor protein levels. Tyrosine phosphorylation of a kinase inactive PDGF receptor was also demonstrated in cells which also express v-fps, but this was not sufficient to induce transformation. Only cells expressing both v-fps and a wild type PDGF receptor were able to form colonies in soft agar. These findings suggest that wild type v-fps may use tyrosine phosphorylation of the PDGFbeta receptor to constitutively activate the kinase activity of the receptor, resulting in a sustained proliferative signal and fibroblast transformation.