Journal
CELLULAR SIGNALLING
Volume 22, Issue 5, Pages 848-856Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2009.12.012
Keywords
Bcr-Abl; Actin cytoskeleton; Adaptor proteins; GADS; Slp-76; Nck
Categories
Funding
- European Union [MRTN-CT-2004-512253]
- Cancer Research UK
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Bcr-Abl is the transforming principle underlying chronic myelogenous leukaemia (CML). Here, we use a functional interaction proteomics approach to map pathways by which Bcr-Abl regulates defined cellular processes. The results show that Bcr-Abl regulates the actin cytoskeleton and non-apoptotic membrane blebbing via a GADS/Slp-76/Nck1 adaptor protein pathway. The binding of GADS to Bcr-Abl requires Bcr-Abl tyrosine kinase activity and is sensitive to the Bcr-Abl inhibitor imatinib, while the GADS/Slp-76 and Slp-76/Nck interactions are tyrosine phosphorylation independent. All three adaptor proteins co-localize with cortical actin in membrane blebs. Downregulation of each adaptor protein disrupts the actin cytoskeleton and membrane blebbing in a similar fashion and similar to imatinib. These findings highlight the importance of protein interaction dependent adaptor protein pathways in oncogenic kinase signaling. (C) 2010 Elsevier Inc. All rights reserved.
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