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

Oncogene volume 22, pages 6071–6080 (2003)Cite this article

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.

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Acknowledgements

We thank Anthony Koleske, Michiyuki Matsuda, Jean Wang, Tomoyuki Shishido, Hidesaburo Hanafusa, Martin Schwartz, Larry Gerace, and Tony Hunter for valuable reagents. We are grateful to Pamela Woodring for her technical assistance and helpful discussion. This work was supported by grants to RLK (NIH CA78493, CA97022 and ACS RPG-99-180), and KHK (PHS Grant #5-T32-HL07195-26). This is manuscript number 15530-IMM from The Scripps Research Institute.

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  1. Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, SP 231, La Jolla, 92037, CA, USA

    Kristin H Kain, Stacy Gooch & Richard L Klemke

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Correspondence to Richard L Klemke.

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Kain, K., Gooch, S. & Klemke, R. Cytoplasmic c-Abl provides a molecular ‘Rheostat’ controlling carcinoma cell survival and invasion. Oncogene 22, 6071–6080 (2003). https://doi.org/10.1038/sj.onc.1206930

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