title: A myristoyl/phosphotyrosine switch regulates c-Abl.
abstract: The c-Abl tyrosine kinase is inhibited by mechanisms that are poorly understood. Disruption of these mechanisms in the Bcr-Abl oncoprotein leads to several forms of human leukemia. We found that like Src kinases, c-Abl 1b is activated by phosphotyrosine ligands. Ligand-activated c-Abl is particularly sensitive to the anti-cancer drug STI-571/Gleevec/imatinib (STI-571). The SH2 domain-phosphorylated tail interaction in Src kinases is functionally replaced in c-Abl by an intramolecular engagement of the N-terminal myristoyl modification with the kinase domain. Functional studies coupled with structural analysis define a myristoyl/phosphotyrosine switch in c-Abl that regulates docking and accessibility of the SH2 domain. This mechanism offers an explanation for the observed cellular activation of c-Abl by tyrosine-phosphorylated proteins, the intracellular mobility of c-Abl, and it provides new insights into the mechanism of action of STI-571.
authors.affiliation: Developmental Biology Programme, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Hantschel
authors.forename: Bhushan
authors.initials: B
authors.lastname: Nagar
authors.forename: Sebastian
authors.initials: S
authors.lastname: Guettler
authors.forename: Jana
authors.initials: J
authors.lastname: Kretzschmar
authors.forename: Karel
authors.initials: K
authors.lastname: Dorey
authors.forename: John
authors.initials: J
authors.lastname: Kuriyan
authors.forename: Giulio
authors.initials: G
authors.lastname: Superti-Furga
mesh_terms: D000818:Animals; D001549:Benzamides; D002384:Catalysis; D002460:Cell Line; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate; D008024:Ligands; D008954:Models, Biological; D008958:Models, Molecular; D009154:Mutation; D010766:Phosphorylation; D019000:Phosphotyrosine; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D014709:Vero Cells; D018909:src Homology Domains
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; D008024:Ligands; D010879:Piperazines; D011743:Pyrimidines; D019000:Phosphotyrosine; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl