BCR/abl leads to the constitutive activation of Stat proteins, and shares an epitope with tyrosine phosphorylated Stats.
The mechanism by which BCR/abl leads to the transformation of hematopoietic cells is not understood. The introduction of BCR/abl into BaF3 cells, an IL-3-dependent pro-lymphocytic cell line, abrogates the requirement of IL-3 for growth. Given that IL-3 leads to the phosphorylation of Stat proteins, we tested the hypothesis that BCR/abl transformation of hematopoietic cells induces the phosphorylation of Stats. We found that BaF3 cells transformed by either the p190 or p210 forms of BCR/abl possess constitutively phosphorylated Stat1 and Stat5. Phosphorylation of Stat proteins was greater in cells transformed by p190 BCR/abl than in cells transformed by p210 BCR/abl, suggesting that the magnitude of phosphorylation of Stat proteins may play a role in the biological effects of BCR/abl. Expression of BCR/abl containing a mutation (Y177F) that prevents its interaction with GRB2 led to a decrease in the phosphorylation of Stat1 and Stat5. This suggested that GRB2, or its binding site on BCR/abl, may participate in the phosphorylation of Stat proteins. We also observed that the anti-phospho-Stat antibody directly recognized both the p190 and p210 forms of BCR/abl. This indicated that a tyrosine residue that becomes phosphorylated in BCR/abl may share homology with the tyrosine phosphorylation site of Stat1 and Stat5. These findings may have implications for the mechanisms by which BCR/abl interacts with signaling pathways to confer growth factor independence and induce transformation of hematopoietic cells.
Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
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Varticovski
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism*; D018604:Epitope Mapping; D000939:Epitopes / Q000276:immunology; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D008894:Milk Proteins; D009154:Mutation; D010766:Phosphorylation; D050794:STAT1 Transcription Factor; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000276:immunology / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
D004268:DNA-Binding Proteins; D000939:Epitopes; D008894:Milk Proteins; D050794:STAT1 Transcription Factor; D050799:STAT5 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D014443:Tyrosine; D016044:Fusion Proteins, bcr-abl