Tyrosine phosphorylation of p62 dok by p210 bcr-abl inhibits RasGAP activity

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Abstract
The t(9;22) chromosomal translocation is found in almost all patients with chronic myelogenous leukemia. The resultant Bcr-Abl fusion gene expresses a chimeric fusion protein p210 bcr-abl with increased tyrosine kinase activity. Hematopoietic progenitors isolated from chronic myelogenous leukemia patients in the chronic phase contain constitutively tyrosine-phosphorylated p62 dok protein. p62 dok associates with the Ras GTPase-activating protein (RasGAP), but only when p62 dok is tyrosine phosphorylated. Here we have investigated the interaction between p62 dok and RasGAP and the consequences of p62 dok tyrosine phosphorylation on the activity of RasGAP. We have found that p62 dok is directly tyrosine phosphorylated by p210 bcr-abl , and the sites of phosphorylation are located in the C-terminal half of the p62 dok molecule. We have identified five tyrosine residues that are involved in in vitro RasGAP binding and have found that tyrosine-phosphorylated p62 dok inhibits RasGAP activity. Our results suggest that p210 bcr-abl might lead to the activation of the Ras signaling pathway by inhibiting a key down-regulator of Ras signaling.