The tyrosine kinase Abl is requiered for Src-induced cell transformation implicating Rac and ERK5 pathways Free

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The cytoplasmic tyrosine kinase c-Src has been implicated in signal transduction induced by growth factors and integrins. Src also exhibits oncogenic activities when it is deregulated. Accumulating evidences indicate that the tyrosine kinase Abl is an important substrate for Src-mitogenic signaling in normal cells. Here we show that Abl is also required for Src-induced cell transformation in mouse fibroblasts. First, Abl does not mediate tyrosine phosphorylation of Stat3 and Shc, two important regulators of Src-oncogenic activity. In contrast, Abl controls the activation of the small GTPase Rac for Src-oncogenic signaling. Accordingly, an active form of Rac partly rescues Src transformation in cells expressing an inactive form of Abl. In addition, Abl also mediates Src-induced ERK5 activation for full cell transformation. Finally, we suggest that these Abl/Rac and Abl/ERK5 pathways also operate in human breast cancer cell lines with transforming capacity dependent on Src-like activities. Taken together our results indicate that Abl is an important regulator of Src-oncogenic activity both in mouse fibroblasts and human cancer cells. In line with this, targeting Abl-dependent signaling cascades may be of therapeutic values in Src-dependent breast cancers.