A myristoyl/phosphotyrosine switch regulates c-Abl.
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.
Mesh Terms:
Animals, Catalysis, Cell Line, Cercopithecus aethiops, Enzyme Inhibitors, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Humans, Ligands, Models, Biological, Models, Molecular, Mutation, Phosphorylation, Phosphotyrosine, Piperazines, Protein Binding, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-abl, Pyrimidines, Vero Cells, src Homology Domains
Animals, Catalysis, Cell Line, Cercopithecus aethiops, Enzyme Inhibitors, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Humans, Ligands, Models, Biological, Models, Molecular, Mutation, Phosphorylation, Phosphotyrosine, Piperazines, Protein Binding, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-abl, Pyrimidines, Vero Cells, src Homology Domains
Cell
Date: Mar. 21, 2003
PubMed ID: 12654250
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