Cytoplasmic c-Abl provides a molecular 'Rheostat' controlling carcinoma cell survival and invasion.
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.
Kain
Kristin H
KH
Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, SP 231, La Jolla, CA 92037, USA.
Gooch
Stacy
S
Klemke
Richard L
RL
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D029563:Cellular Apoptosis Susceptibility Protein / Q000235:genetics / Q000378:metabolism; D002642:Chick Embryo; D003593:Cytoplasm / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D050737:Proto-Oncogene Proteins c-crk
D029563:Cellular Apoptosis Susceptibility Protein; D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D016315:Proto-Oncogene Proteins c-abl