Charting the molecular network of the drug target Bcr-Abl

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...

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Bibliographic Details
Published in:	Proceedings of the National Academy of Sciences - PNAS 2009-05, Vol.106 (18), p.7414-7419
Main Authors:	Brehme, Marc, Hantschel, Oliver, Colinge, Jacques, Kaupe, Ines, Planyavsky, Melanie, Köcher, Thomas, Mechtler, Karl, Bennett, Keiryn L, Superti-Furga, Giulio
Format:	Article
Language:	eng
Subjects:	Antibodies Biological Sciences Cell Line Cell lines Chronic myeloid leukemia Drug interactions Fusion Proteins, bcr-abl - antagonists & inhibitors Fusion Proteins, bcr-abl - metabolism Humans K562 cells Kinases Lead Leukemia Molecular interactions Multienzyme Complexes - antagonists & inhibitors Multienzyme Complexes - metabolism Phosphatases Protein Interaction Mapping Protein Kinase Inhibitors - pharmacology Proteins Proteomics
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Summary:	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.
ISSN:	0027-8424 1091-6490