The Src family kinase Hck interacts with Bcr-Abl by a kinase-independent mechanism and phosphorylates the Grb2-binding site of Bcr

J Biol Chem. 1997 Dec 26;272(52):33260-70. doi: 10.1074/jbc.272.52.33260.


bcr-abl, the oncogene causing chronic myeloid leukemia, encodes a fusion protein with constitutively active tyrosine kinase and transforming capacity in hematopoietic cells. Various intracellular signaling intermediates become activated and/or associate by/with Bcr-Abl, including the Src family kinase Hck. To elucidate some of the structural requirements and functional consequences of the association of Bcr-Abl with Hck, their interaction was investigated in transiently transfected COS7 cells. Neither the complex formation of Hck kinase with Bcr-Abl nor the activation of Hck by Bcr-Abl was dependent on the Abl kinase activity. Both inactivating point mutations of Hck and dephosphorylation of Hck enhanced its complex formation with Bcr-Abl, indicating that their physical interaction was negatively regulated by Hck (auto)phosphorylation. Finally, experiments with a series of kinase negative Bcr-Abl mutants showed that Hck phosphorylated Bcr-Abl and induced the binding of Grb2 to Tyr177 of Bcr-Abl. Taken together, our results suggest that Bcr-Abl preferentially binds inactive forms of Hck by an Abl kinase-independent mechanism. This physical interaction stimulates the Hck tyrosine kinase, which may then phosphorylate the Grb2-binding site in Bcr-Abl.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Animals
  • Binding Sites
  • COS Cells
  • ErbB Receptors / metabolism*
  • Fusion Proteins, bcr-abl / metabolism*
  • GRB2 Adaptor Protein
  • Humans
  • Phosphorylation
  • Point Mutation
  • Protein-Tyrosine Kinases / metabolism*
  • Proteins / genetics
  • Proteins / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-hck
  • Proto-Oncogene Proteins pp60(c-src) / metabolism


  • Adaptor Proteins, Signal Transducing
  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • Proteins
  • Proto-Oncogene Proteins
  • ErbB Receptors
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl
  • HCK protein, human
  • Proto-Oncogene Proteins c-hck
  • Proto-Oncogene Proteins pp60(c-src)