A myristoyl/phosphotyrosine switch regulates c-Abl

Cell. 2003 Mar 21;112(6):845-57. doi: 10.1016/s0092-8674(03)00191-0.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Benzamides
  • Catalysis
  • Cell Line
  • Chlorocebus aethiops
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation, Enzymologic*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Imatinib Mesylate
  • Ligands
  • Models, Biological
  • Models, Molecular
  • Mutation
  • Phosphorylation
  • Phosphotyrosine
  • Piperazines / pharmacology
  • Protein Binding
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins c-abl / antagonists & inhibitors
  • Proto-Oncogene Proteins c-abl / chemistry
  • Proto-Oncogene Proteins c-abl / genetics
  • Proto-Oncogene Proteins c-abl / metabolism*
  • Pyrimidines / pharmacology
  • Vero Cells
  • src Homology Domains


  • Benzamides
  • Enzyme Inhibitors
  • Ligands
  • Piperazines
  • Pyrimidines
  • Phosphotyrosine
  • Imatinib Mesylate
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-abl