ZNF198-FGFR1 transforms Ba/F3 cells to growth factor independence and results in high level tyrosine phosphorylation of STATS 1 and 5.
The ZNF198- FGFR1 fusion gene arises as a result of the t(8;13)(p11;q12) in the 8p11 myeloproliferative syndrome. To determine the transforming properties of this chimeric protein we transfected ZNF198-FGFR1 into the interleukin (IL)-3 dependent cell line Ba/F3. Growth factor independent subclones were obtained in which ZNF198-FGFR1, STAT1, and STAT5 were ... constitutively tyrosine phosphorylated, as determined by immunoprecipitation and Western blot analysis. To test the hypothesis that constitutive activation of ZNF198-FGFR1 tyrosine kinase activity is a result of self-association of the fusion protein, we in vitro transcribed and translated ZNF198-FGFR1 and a derivative construct, ZNF198- FGFR1deltaC-myc, in which the C-terminal FGFR1 epitope was replaced by a c-myc tag. As expected, an anti-FGFR1 antibody immunoprecipitated ZNF198-FGFR1 but not ZNF198-FGFRdeltaC-myc. However when both products were translated together, both were coimmunoprecipitated by anti-FGFR1 antisera. Similar results were obtained by using an anti-myc antibody and demonstrated a physical interaction between the two proteins. Analysis of COS-7 cells transfected with ZNF198-FGFR1 demonstrated that the fusion gene, in contrast to normal FGFR1, is located in the cytoplasm. We conclude that ZNF198-FGFR1 is a cytoplasmic protein that self-associates and has constitutive transformation activity. These data suggest that ZNF198-FGFR1 plays a primary role in the pathogenesis of the t(8;13) myeloproliferative syndrome and is the first report to implicate STAT proteins in FGFR1-mediated signaling.
Mesh Terms:
Animals, Blotting, Western, COS Cells, Cell Line, Cytoplasm, DNA-Binding Proteins, Fluorescent Antibody Technique, Growth Substances, Humans, Interleukin-3, Mice, Milk Proteins, Myeloproliferative Disorders, Phosphorylation, Precipitin Tests, Protein Biosynthesis, Proto-Oncogene Proteins c-myc, Receptor Protein-Tyrosine Kinases, Receptor, Fibroblast Growth Factor, Type 1, Receptors, Fibroblast Growth Factor, Recombinant Fusion Proteins, Recombination, Genetic, STAT1 Transcription Factor, STAT5 Transcription Factor, Signal Transduction, Time Factors, Trans-Activators, Transcription, Genetic, Transfection, Tyrosine
Animals, Blotting, Western, COS Cells, Cell Line, Cytoplasm, DNA-Binding Proteins, Fluorescent Antibody Technique, Growth Substances, Humans, Interleukin-3, Mice, Milk Proteins, Myeloproliferative Disorders, Phosphorylation, Precipitin Tests, Protein Biosynthesis, Proto-Oncogene Proteins c-myc, Receptor Protein-Tyrosine Kinases, Receptor, Fibroblast Growth Factor, Type 1, Receptors, Fibroblast Growth Factor, Recombinant Fusion Proteins, Recombination, Genetic, STAT1 Transcription Factor, STAT5 Transcription Factor, Signal Transduction, Time Factors, Trans-Activators, Transcription, Genetic, Transfection, Tyrosine
Neoplasia
Date: Oct. 01, 1999
PubMed ID: 10935490
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