title: Charting the molecular network of the drug target Bcr-Abl.
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.
authors.affiliation: Research Center for Molecular Medicine, Austrian Academy of Sciences, Lazarettgasse 19, 1090 Vienna, Austria.
authors.forename: Marc
authors.initials: M
authors.lastname: Brehme
authors.forename: Oliver
authors.initials: O
authors.lastname: Hantschel
authors.forename: Jacques
authors.initials: J
authors.lastname: Colinge
authors.forename: Ines
authors.initials: I
authors.lastname: Kaupe
authors.forename: Melanie
authors.initials: M
authors.lastname: Planyavsky
authors.forename: Thomas
authors.initials: T
authors.lastname: Köcher
authors.forename: Karl
authors.initials: K
authors.lastname: Mechtler
authors.forename: Keiryn L
authors.initials: KL
authors.lastname: Bennett
authors.forename: Giulio
authors.initials: G
authors.lastname: Superti-Furga
mesh_terms: D002460:Cell Line; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D025941:Protein Interaction Mapping; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D040901:Proteomics
chemical_list: D009097:Multienzyme Complexes; D047428:Protein Kinase Inhibitors; D016044:Fusion Proteins, bcr-abl