Tyrosine phosphorylation of rasGAP and associated proteins in chronic myelogenous leukemia cell lines

The Philadelphia chromosome (Ph1), detected in virtually all cases of chronic myelogenous leukemia, is formed by a reciprocal translocation between chromosomes 9 and 22 that fuses BCR encoded sequences upstream of exon 2 of c-ABL. This oncogene produces a fusion protein (p210BCR/ABL) in which the ABL tyrosine kinase activity is elevated. This elevated kinase activity is essential for transformation, but the mechanisms involved are unknown. We report here that p21ras GTPase activating protein (rasGAP) or rasGAP-associated proteins p190 and p62 are phosphorylated on tyrosine in Ph1 (+) cell lines. Further, rasGAP coimmunoprecipitates with p210BCR/ABL in these cell lines. These results suggest that rasGAP or associated proteins are potential substrates for p210BCR/ABL kinase and thus directly link p210BCR/ABL with a signal transduction pathway known to be activated by hematopoietic growth factors (p21ras).