The tetramerization domain-independent Ras activation by BCR-ABL oncoprotein in hematopoietic cells.
BCR-ABL is a chimeric oncoprotein that exhibits deregulated tyrosine kinase activity and is implicated in the pathogenesis of Philadelphia chromosome-positive human leukemias. We have previously shown that BCR-ABL activates Ras signaling pathways required for transformation. To elucidate the mechanisms whereby BCR-ABL induced transformation in hematopoietic cells, we examined the biological effects of expression of a series of BCR-ABL mutants. We found that the Grb2 binding site-deleted BCR-ABL and the SH2 domain-deleted BCR-ABL, as well as the tetramerization domain-deleted BCR-ABL do not diminish the transforming properties of BCR-ABL in hematopoietic cells, although these mutations were previously shown to drastically reduce the transforming activity of BCR-ABL in fibroblasts. The tetramerization domain-deleted BCR-ABL did not induce tyrosine phosphorylation of CrkL, SHP-2, Vav and the interactions of BCR-ABL and Shc. However, Ras is activated, Shc is tyrosine phosphorylated and binds to Grb2 in the tetramerization domain-deleted BCR-ABL expressing hematopoietic cells. These results suggest that the tetramerization domain-independent Ras activation is mediated by Shc proteins and induces the transformation of hematopoietic cells.
Tauchi
T
T
First Department of Internal Medicine, Tokyo Medical College, Tokyo 160, Japan.
Okabe
S
S
Miyazawa
K
K
Ohyashiki
K
K
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D019281:Dimerization; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry / Q000235:genetics*; D015870:Gene Expression / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D011905:Genes, ras / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics / Q000502:physiology; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000494:pharmacology; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains / Q000187:drug effects
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D011506:Proteins; D011994:Recombinant Proteins; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014443:Tyrosine; D016044:Fusion Proteins, bcr-abl