title: An activating mutation in the ATP binding site of the ABL kinase domain.
abstract: A number of structural alterations have been shown to activate the leukemogenic potential of the ABL oncogene, but there is little understanding of the regulatory mechanisms that are subverted by such changes. We have used directed mutagenesis to examine a potential regulatory motif in cABL, which could directly influence ABL tyrosine kinase activity. A tyrosine to phenylalanine substitution within the ATP binding fold of the ABL kinase domain is sufficient to activate cABL enzymatic activity, and the mutant protein will alleviate growth factor dependence when expressed in the BA/F3 cell line. This growth promotion is dependent upon the structure of the amino terminus of the protein, and the ABL mutation will cooperate with certain BCR sequences in BCR/ABL fusion proteins to deregulate ABL kinase activity.
authors.affiliation: Leukaemia Research Fund Centre, Institute of Cancer Research, Chester Beatty Laboratories, Fulham Road, London, SW3 6JB United Kingdom.
authors.forename: P B
authors.initials: PB
authors.lastname: Allen
authors.forename: L M
authors.initials: LM
authors.lastname: Wiedemann
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000595:Amino Acid Sequence; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D004789:Enzyme Activation; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009838:Oligodeoxyribonucleotides; D015513:Oncogene Proteins / Q000235:genetics; D010449:Peptide Mapping; D010748:Phosphopeptides / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics* / Q000378:metabolism; D051562:Proto-Oncogene Proteins c-bcr; D016160:Retinoblastoma Protein / Q000378:metabolism
chemical_list: D009838:Oligodeoxyribonucleotides; D015513:Oncogene Proteins; D010748:Phosphopeptides; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D000255:Adenosine Triphosphate; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl; D051562:Proto-Oncogene Proteins c-bcr