Autoinhibition of Bcr-Abl through its SH3 domain

Mol Cell. 2003 Jul;12(1):27-37. doi: 10.1016/s1097-2765(03)00274-0.

Abstract

Bcr-Abl is a dysregulated tyrosine kinase whose mechanism of activation is unclear. Here, we demonstrate that, like c-Abl, Bcr-Abl is negatively regulated through its SH3 domain. Kinase activity, transformation, and leukemogenesis by Bcr-Abl are greatly impaired by mutations of the Bcr coiled-coil domain that disrupt oligomerization, but restored by an SH3 point mutation that blocks ligand binding or a complementary mutation at the intramolecular SH3 binding site defined in c-Abl. Phosphorylation of tyrosines in the activation loop of the catalytic domain and the linker between the SH2 and catalytic domains (SH2-CD linker) is dependent on oligomerization and required for leukemogenesis. These results suggest that Bcr-Abl has a monomeric, unphosphorylated state with the SH3 domain engaged intramolecularly to Pro1124 in the SH2-CD linker, the form that is sensitive to the inhibitor imatinib (STI-571). The sole function of the coiled-coil domain is to disrupt the autoinhibited conformation through oligomerization and intermolecular autophosphorylation.

Publication types

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

MeSH terms

  • 3T3 Cells
  • Alanine / genetics
  • Alanine / metabolism
  • Amino Acid Sequence / genetics
  • Animals
  • Binding Sites / genetics
  • Catalytic Domain / drug effects
  • Catalytic Domain / genetics
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Eukaryotic Cells / enzymology*
  • Feedback, Physiological / drug effects
  • Feedback, Physiological / genetics*
  • Fusion Proteins, bcr-abl
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Mice
  • Mice, Inbred BALB C
  • Models, Molecular
  • Mutation / drug effects
  • Mutation / genetics
  • Phosphorylation / drug effects
  • Proline / genetics
  • Proline / metabolism
  • Protein Binding / drug effects
  • Protein Binding / genetics
  • Protein Structure, Tertiary / drug effects
  • Protein Structure, Tertiary / genetics
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Tyrosine / metabolism

Substances

  • Enzyme Inhibitors
  • Tyrosine
  • Proline
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl
  • Alanine