c-Abl is an effector of Src for growth factor-induced c-myc expression and DNA synthesis

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Abstract
The mechanism by which the ubiquitously expressed Src family kinases regulate mitogenesis is not well understood. Here we report that cytoplasmic tyrosine kinase c‐Abl is an important effector of c‐Src for PDGF‐ and serum‐induced DNA synthesis. Inactivation of cytoplasmic c‐Abl by the kinase‐ inactive Abl‐PP‐K− (AblP242E/P249E/K290M) or by microinjection of Abl neutralizing antibodies inhibited mitogenesis. The kinase‐inactive SrcK295M induced a G1 block that was overcome by the constitutively active Abl‐PP (AblP242E/P249E). Conversely, the inhibitory effect of Abl‐PP‐K− was not compensated by Src. c‐Src‐induced c‐Abl activation involves phosphorylation of Y245 and Y412, two residues required for c‐Abl mitogenic function. Finally, we found that p53 inactivation and c‐ myc expression, two cell cycle events regulated by Src during mitogenesis, also implied c‐Abl: c‐Abl function was dispensable in cells deficient in active p53 and inhibition of c‐Abl reduced mitogen‐induced c‐ myc expression. These data identify a novel function of cytoplasmic c‐Abl in the signalling pathways regulating growth factor‐induced c‐ myc expression and we propose the existence of a tyro sine kinase signalling cascade (PDGFR/c‐Src/c‐Abl) important for mitogenesis.