Characterization of FIM-FGFR1, the fusion product of the myeloproliferative disorder-associated t(8;13) translocation.
The t(8;13) translocation found in a rare type of stem cell myeloproliferative disorder generates a constitutively activated tyrosine kinase containing N-terminal sequence encoded by the FIM gene linked to the FGFR1 kinase domain. Here we have further characterized FIM and FIM-FGFR1 proteins. Firstly, we have studied their respective subcellular localization. We show that FIM has nuclear and nucleolar localization, whereas FIM-FGFR1 is mainly cytoplasmic. Within the nucleolus, FIM colocalizes with the upstream binding factor in interphasic cells, indicating that FIM may be involved in the regulation of rRNA transcription. We demonstrate that the targetting of FIM to the nucleus depends upon its C-terminal region, which is absent in the cytoplasmic FIM-FGFR1 protein. Secondly, we demonstrate that FIM-FGFR1 has constitutive dimerization capability mediated by the FIM N-terminal sequences. Finally, we show that FIM-FGFR1 promotes survival of pro-B Ba/F3 cells after interleukin-3 withdrawal, whereas ligand-activated FGFR1 induced not only cell survival but also interleukin-3 independence. Taken together, these results indicate that FIM-FGFR1 is activated by dimerization as a cytoplasmic kinase and suggest that FIM-FGFR1 partially signals through the FGFR1 pathways.
Ollendorff
V
V
Laboratoire d'Oncologie Moléculaire, U119 INSERM, Institut de Cancérologie et d'Immunologie, 27 Boulevard Leï Roure, 13009 Marseille, France.
Guasch
G
G
Isnardon
D
D
Galindo
R
R
Birnbaum
D
D
Pébusque
M J
MJ
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D002478:Cells, Cultured; D002874:Chromosome Mapping; D002882:Chromosomes, Human, Pair 13; D002898:Chromosomes, Human, Pair 8; D004268:DNA-Binding Proteins / Q000235:genetics*; D019281:Dimerization; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D009196:Myeloproliferative Disorders / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D014157:Transcription Factors; D014162:Transfection; D014178:Translocation, Genetic
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D017468:Receptors, Fibroblast Growth Factor; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C111777:ZMYM2 protein, human; C498438:Zmym2 protein, mouse; D005346:Fibroblast Growth Factors; C496348:FGFR1 protein, human; C496349:Fgfr1 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1