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.
Highlights
Tyrosine phosphorylation plays a key role in mediating cellular responses to various extracellular stimuli, including those that modulate cell growth and proliferation [1, 2]
These mutated ABL proteins display an elevated level of tyrosine kinase activity, which is thought to be central to the disease process, but much is known concerning their transforming potential in various systems, the mechanism of oncogenic activation is unclear and very little is understood about the mode of the regulation of ABL kinase
Overexpression of cABL 1b in the BA/F3 cell line will not relieve the strict requirement these cells display for added growth factor
Summary
Tyrosine phosphorylation plays a key role in mediating cellular responses to various extracellular stimuli, including those that modulate cell growth and proliferation [1, 2]. These observations suggested that a regulatory mechanism similar to that of CDC2 may operate for cABL, in that phosphorylation of a tyrosine in the ATP binding site could down-regulate ABL kinase activity. VABL p160 expressing BA/F3 cells did not always give rise to factor-independent progeny in bulk culture, and for those clones that did so the conversion frequency was lower than that seen for the BCR/ABL constructs.
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