Alternative signals to RAS for hematopoietic transformation by the BCR-ABL oncogene.
Biological function of the BCR-ABL oncogene is dependent on its activated tyrosine kinase. Mutations that inactivate the SRC homology 2 (SH2) domain, the GRB2-binding site in BCR, or the major autophosphorylation site of the kinase domain selectively disrupt downstream signaling but not tyrosine kinase activity. Despite a loss of fibroblast transformation activity, all three mutants retain the ability to render hematopoietic cell lines growth factor independent and transform primary bone marrow cells in vitro. In vivo tests of malignant potential reveal a most critical role for signals dependent on the BCR-ABL SH2 domain. The efficiency of both fibroblast and hematopoietic transformation by BCR-ABL is strongly affected by increased dosage of the SHC adapter protein, which can connect tyrosine kinase signals to RAS. The BCR-ABL oncogene activates multiple alternative pathways to RAS for hematopoietic transformation.
Goga
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Department of Microbiology and Molecular Genetics, University of California, Los Angeles 90095, USA.
McLaughlin
J
J
Afar
D E
DE
Saffran
D C
DC
Witte
O N
ON
D000818:Animals; D001854:Bone Marrow Cells; D002461:Cell Line, Transformed / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005347:Fibroblasts / Q000502:physiology; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D006098:Granulocytes / Q000166:cytology; D016298:Hematopoietic Cell Growth Factors / Q000502:physiology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D008214:Lymphocytes / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009154:Mutation / Q000502:physiology; D009857:Oncogenes / Q000502:physiology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D018631:ras Proteins / Q000502:physiology; D018909:src Homology Domains / Q000502:physiology
D016298:Hematopoietic Cell Growth Factors; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D018631:ras Proteins