c-Abl is activated by growth factors and Src family kinases and has a rolein the cellular response to PDGF

The c-Abl tyrosine kinase localizes to the cytoplasm and plasma membrane in addition to the nucleus. However, there is little information regarding a role for c-Abl in the cytoplasm/plasma membrane compartments. Here we repor t that a membrane pool of c-Abl is activated by the growth factors PDGF and EGF in fibroblasts. The pattern and kinetics of activation are similar to growth factor activation of Src family kinases. To determine whether a link existed between activation of c-Abl and members of the Src family, we exam ined c-Abl kinase activity in cells that expressed oncogenic Src proteins. We found that c-Abl kinase activity was increased by 10- to 20-fold in thes e cells, and that Src and Fyn kinases directly phosphorylated c-Abl in vitr o. Furthermore, overexpression of wild-type Src potentiated c-Abl activatio n by growth factors, and a kinase-inactive form of Src reduced this activat ion, showing that Abl activation by growth factors occurs at least in part via activation of Src kinases. Significantly, we show that c-Abl has a func tional role in the morphological response to PDGF. Whereas PDGF treatment o f serum-starved wild-type mouse embryo fibroblasts resulted in distinct lin ear or circular/dorsal membrane ruffling, c-Abl-null cells demonstrated dra matically reduced ruffling in response to PDGF, which was rescued by physio logical re-expression of c-Abl. These data identify c-Abl as a downstream t arget of activated receptor tyrosine kinases and Src family kinases, and sh ow for the first time that c-Abl functions in the cellular response to grow th factors.