AN ACTIVATING MUTATION IN THE ATP BINDING-SITE OF THE ABL KINASE DOMAIN

A number of structural alterations have been shown to activate the leu kemogenic potential of the ABL oncogene, but there is little understan ding of the regulatory mechanisms that are subverted by such changes. We have used directed mutagenesis to examine a potential regulatory mo tif in cABL, which could directly influence ABL tyrosine kinase activi ty. A tyrosine to phenylalanine substitution within the ATP binding fo ld of the ABL kinase domain is sufficient to activate cABL enzymatic a ctivity, and the mutant protein will alleviate growth factor dependenc e when expressed in the BA/F3 cell line. This growth promotion is depe ndent upon the structure of the amino terminus of the protein, and the ABL mutation will cooperate with certain BCR sequences in BCR/ABL fus ion proteins to deregulate ABL kinase activity.