title: A coiled-coil tetramerization domain of BCR-ABL is essential for the interactions of SH2-containing signal transduction molecules.
abstract: BCR-ABL is a chimeric oncoprotein that exhibits deregulated tyrosine kinase activity and is implicated in the pathogenesis of Philadelphia chromosome (ph1)-positive leukemia. We have previously shown SH2-containing phosphotyrosine phosphatase SHP-2 forms stable complexes with BCR-ABL and Grb2 in BCR-ABL transformed cells (T., Tauchi, et al. J. Biol. Chem. 269, 15381, 1994). To elucidate the structural requirement of BCR-ABL for the interactions with SH2-containing signaling molecules, we examined a series of BCR-ABL mutants which include the Grb2 binding site deleted BCR-ABL (1-63 BCR/ABL), the tetramerization domain deleted BCR-ABL (64-509 BCR/ABL), and the SH2 domain deleted BCR-ABL (BCR/ABL delta SH2). These BCR-ABL mutants were previously shown to reduce the transforming activity in fibroblasts. We found that the tetramerization domain deleted BCR-ABL did not induce the tyrosine phosphorylation of SHP-2 and the interactions of BCR-ABL, SHP-2, and Grb2. In vitro kinase assays have also shown the tetramerization domain deleted BCR-ABL mutant did not phosphorylate GST-SHP-2 in vitro. SHP-2 was co-immunoprecipitated with P13Kinase in BCR/ABL p210 transformed cells, however this interaction was not observed in the tetramerization domain deleted BCR-ABL mutant. Therefore the tetramerization domain of BCR-ABL is essential for interactions of these downstream molecules.
authors.affiliation: Department of Internal Medicine, Tokyo Medical College.
authors.forename: T
authors.initials: T
authors.lastname: Tauchi
authors.forename: K
authors.initials: K
authors.lastname: Miyazawa
authors.forename: K
authors.initials: K
authors.lastname: Ohyashiki
authors.forename: K
authors.initials: K
authors.lastname: Toyama
mesh_terms: D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl