Cytoplasmic c-Abl provides a molecular ‘Rheostat’ controlling carcinoma cell survival and invasion

Abstract

Tumor cell metastasis involves the coordinated activation of migration and survival mechanisms necessary for cell invasion of foreign tissues. Here, we report that cytoplasmic c-Abl tyrosine kinase determines whether a cell invades the ECM or commits suicide. c-Abl phosphorylates the cytoskeleton-associated adaptor protein, Crk, at tyrosine 221, causing disassociation of Crk from the Crk-associated substrate (CAS) and disassembly of Crk/CAS complexes. c-Abl-induced disruption of Crk/CAS complexes inhibits cell migration and promotes apoptosis in normal cells, and is deregulated in highly invasive carcinoma cells. c-Abl-mediated disassembly of Crk/CAS complexes and induction of death occur via disruption of the cytoskeleton, which is distinct from nuclear c-Abl-induced apoptosis in response to DNA-damaging agents. Inhibition of c-Abl kinase activity or Crk binding to Abl's polyproline region prevents Crk phosphorylation and apoptosis, leading to increased cell survival and invasion of the extracellular matrix. Together, these data illustrate that c-Abl prevents aberrant motility and survival through Crk 221 phosphorylation and modulation of Crk/CAS complexes, and that deregulation of this pathway contributes to cell metastasis.