SH1 domain autophosphorylation of P210 BCR/ABL is required for transformation but not growth factor independence.
P210 BCR/ABL is a chimeric oncogene implicated in the pathogenesis of chronic myelogenous leukemia. BCR sequences have been shown to be required for activation of the tyrosine kinase and transforming functions of BCR/ABL. In this work, we show that two other structural requirements for full transforming activity of P210 BCR/ABL include a functional tyrosine kinase and the presence of tyrosine 1294, a site of autophosphorylation within the tyrosine kinase domain. Replacement of tyrosine 1294 with phenylalanine (1294F) greatly diminishes the transforming activity of BCR/ABL without affecting the specific activity of the protein tyrosine kinase. Expression of an exogenous myc gene in fibroblasts partially complements the transforming capacity of mutant P210 BCR/ABL (1294F). Surprisingly, tyrosine 1294 is not required for efficient induction of growth factor-independence in hematopoietic cell lines by P210 BCR/ABL. These results suggest that autophosphorylation at tyrosine 1294 may be important for recognition and phosphorylation of cellular substrates in the pathway of transformation, but it is not critical for mediating the events which lead to growth factor independence.
Pendergast
A M
AM
Department of Microbiology and Molecular Genetics, University of California, Los Angeles 90024.
Gishizky
M L
ML
Havlik
M H
MH
Witte
O N
ON
D000818:Animals; D002471:Cell Transformation, Neoplastic; D005347:Fibroblasts / Q000502:physiology; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D016259:Genes, myc / Q000235:genetics; D005816:Genetic Complementation Test; D006133:Growth Substances / Q000378:metabolism*; D007951:Leukemia, Myeloid / Q000209:etiology; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D006133:Growth Substances; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl