Structural and signaling requirements for BCR-ABL-mediated transformation and inhibition of apoptosis.

摘要: BCR-ABL is a deregulated tyrosine kinase expressed in Philadelphia chromosome-positive human leukemias. Prolongation of hematopoietic cell survival by inhibition apoptosis has been proposed to be an integral component BCR-ABL-induced chronic myelogenous leukemia. elicits transformation both fibroblast and cells blocks following cytokine deprivation various factor-dependent cells. To elucidate the mechanisms whereby induces cells, we examined biological effects expression series mutants. Single amino acid substitutions GRB2 binding site (Y177F), Src homology 2 domain (R552L), or autophosphorylation (Y793F) do not diminish antiapoptotic transforming properties although these mutations were previously shown drastically reduce activity fibroblasts. A molecule containing all three (Y177F/R552L/Y793F) exhibits severe decrease activities compared with wild-type protein 32D myeloid progenitor Ras activated, SHC adapter phosphorylated binds GRB2, myc mRNA levels are increased active proteins exception Y177F/R552L/Y793F mutant We propose that uses multiple pathways activate this activation necessary for BCR-ABL. However, sufficient BCR-ABL-mediated transformation. deletion (delta 176-427) activates but severely impaired ability identified. These data suggest requires additional signaling components elicit tumorigenic growth which distinct from those required block apoptosis.