Etk, a Btk family tyrosine kinase, mediates cellular transformation by linking Src to STAT3 activation

Etk (also called Bmx) is a member of the Btk tyrosine kinase family and is expressed in a variety of hematopoietic, epithelial, and endothelial cells. We have explored biological functions, regulators, and effecters of Etk Co expression of v-Src and Etk led to a transphosphorylation on tyrosine 566 o f Etk and subsequent autophosphorylation, These events correlated with a su bstantial increase in the kinase activity of Etk. STAT3, which was previous ly shown to be activated by Etk, associated with Etk in vivo. To investigat e whether Etk could mediate v-Src-induced activation of STAT3 and cell tran sformation, we overexpressed a dominant-negative mutant of Etk in an immort alized, untransformed rat liver epithelial cell line, WE, which contains en dogenous Etk Dominant-negative inactivation of Etk not only blocked v-Src-i nduced tyrosine phosphorylation and activation of STAT3 but also caused a g reat reduction in the transforming activity of v-Src. In NIH3T3 cells, alth ough Etk did not itself induce transformation, it effectively enhanced the transforming ability of a partially active c-Src mutant (c-Src378G). Furthe rmore, Etk activated STAT3-mediated gene expression in synergy with this Sr c mutant. Our findings thus indicate that Etk is a critical mediator of Src -induced cell transformation and STAT3 activation. The role of STAT3 in Etk -mediated transformation was also examined. Expression of Etk in a human he patoma cell line Hep3B resulted in a significant increase in its transformi ng ability, and this effect was abrogated by dominant-negative inhibition o f STAT3, These data strongly suggest that Etk links Src to STAT3 activation . Furthermore, Src-Etk-STAT3 is an important pathway in cellular transforma tion.