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Proc Natl Acad Sci U S A. 2009 May 5;106(18):7414-9. doi: 10.1073/pnas.0900653106. Epub 2009 Apr 20.

Charting the molecular network of the drug target Bcr-Abl.

Author information

1
Research Center for Molecular Medicine, Austrian Academy of Sciences, Lazarettgasse 19, 1090 Vienna, Austria.

Abstract

The tyrosine kinase Bcr-Abl causes chronic myeloid leukemia and is the cognate target of tyrosine kinase inhibitors like imatinib. We have charted the protein-protein interaction network of Bcr-Abl by a 2-pronged approach. Using a monoclonal antibody we have first purified endogenous Bcr-Abl protein complexes from the CML K562 cell line and characterized the set of most tightly-associated interactors by MS. Nine interactors were subsequently subjected to tandem affinity purifications/MS analysis to obtain a molecular interaction network of some hundred cellular proteins. The resulting network revealed a high degree of interconnection of 7 "core" components around Bcr-Abl (Grb2, Shc1, Crk-I, c-Cbl, p85, Sts-1, and SHIP-2), and their links to different signaling pathways. Quantitative proteomics analysis showed that tyrosine kinase inhibitors lead to a disruption of this network. Certain components still appear to interact with Bcr-Abl in a phosphotyrosine-independent manner. We propose that Bcr-Abl and other drug targets, rather than being considered as single polypeptides, can be considered as complex protein assemblies that remodel upon drug action.

PMID:
19380743
PMCID:
PMC2670881
DOI:
10.1073/pnas.0900653106
[Indexed for MEDLINE]
Free PMC Article

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