The interaction of the Bcr-Abl tyrosine kinase with the Src kinase Hck is mediated by multiple binding domains.
Bcr-Abl is found in more than 95% of cases with CML. The mechanism of Bcr-Abl-induced transformation is not fully understood. Bcr-Abl is a constitutively active tyrosine kinase with transforming capacity for hematopoietic cells. We demonstrated recently that the Src kinase Hck interacts directly with Bcr-Abl by a kinase-independent mechanism. Moreover, ... the inhibition of the Hck kinase seems to block some of the transforming effects of Bcr-Abl. To identify the binding domains mediating this interaction of Hck with Bcr-Abl, we co-expressed different plasmid and baculovirus vectors containing mutants or single domains of Bcr-Abl and/or Hck in COS7 and Sf9 cells. At least four independent binding regions for Hck were identified in Bcr-Abl, one in Bcr, one in the region comprising the SH3 and SH2 domain of Abl, one in the SH1 domain of Abl, and one in the C-terminal domain of Abl. In the Hck kinase, deletion of the SH2 and/or the SH3 region abolished binding to Bcr-Abl. In contrast, deletion of the Hck SH1 domain enhanced binding of Hck to Abl and Bcr-Abl. In conclusion, the results indicate that the interaction of Bcr-Abl with Hck is mediated by a novel, complex mechanism that involves multiple domains of Bcr-Abl and the SH2 and SH3 domains of Hck.
Mesh Terms:
Animals, Binding Sites, COS Cells, Cercopithecus aethiops, Cloning, Molecular, DNA Primers, Fusion Proteins, bcr-abl, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Mutagenesis, Site-Directed, Polymerase Chain Reaction, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-hck, Recombinant Proteins, Spodoptera, Transfection
Animals, Binding Sites, COS Cells, Cercopithecus aethiops, Cloning, Molecular, DNA Primers, Fusion Proteins, bcr-abl, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Mutagenesis, Site-Directed, Polymerase Chain Reaction, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-hck, Recombinant Proteins, Spodoptera, Transfection
Leukemia
Date: Feb. 01, 2003
PubMed ID: 12592324
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