Ollendorff V, Guasch G, Isnardon D, Galindo R, Birnbaum D, Pébusque M J
Laboratoire d'Oncologie Moléculaire, U119 INSERM, Institut de Cancérologie et d'Immunologie, 27 Boulevard Leï Roure, 13009 Marseille, France.
J Biol Chem. 1999 Sep 17;274(38):26922-30. doi: 10.1074/jbc.274.38.26922.
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.
在一种罕见类型的干细胞骨髓增殖性疾病中发现的t(8;13)易位产生了一种组成型激活的酪氨酸激酶，该激酶包含由与FGFR1激酶结构域相连的FIM基因编码的N端序列。在此，我们进一步对FIM和FIM-FGFR1蛋白进行了表征。首先，我们研究了它们各自的亚细胞定位。我们发现FIM定位于细胞核和核仁，而FIM-FGFR1主要位于细胞质。在核仁内，FIM在间期细胞中与上游结合因子共定位，这表明FIM可能参与rRNA转录的调控。我们证明FIM靶向细胞核取决于其C端区域，而细胞质中的FIM-FGFR1蛋白缺乏该区域。其次，我们证明FIM-FGFR1具有由FIM N端序列介导的组成型二聚化能力。最后，我们表明FIM-FGFR1在白细胞介素-3撤除后促进前B细胞Ba/F3的存活，而配体激活的FGFR1不仅诱导细胞存活，还诱导白细胞介素-3非依赖性。综上所述，这些结果表明FIM-FGFR1作为一种细胞质激酶通过二聚化被激活，并提示FIM-FGFR1部分通过FGFR1途径发出信号。
