A myristoyl/phosphotyrosine switch regulates c-Abl

Oliver Hantschel, Bhushan Nagar, Sebastian Guettler, Jana Kretzschmar, Karel Dorey, John Kuriyan, Giulio Superti-Furga

    Research output: Contribution to journalArticlepeer-review


    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.
    Original languageEnglish
    Pages (from-to)845-857
    Number of pages12
    Issue number6
    Publication statusPublished - 21 Mar 2003


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