Study of a novel signal transduction pathway mediated by fibroblast growth factor receptor(FGFR)

我们假设神经干细胞的生长、分化和趋化是由FGFR和Eph之间的分子相互作用调节的。我们的研究重点是通过FGFR-EphA4复合体阐明一种新的信号机制。我们的研究结果总结如下：(1)FGFR-EphA4相互作用的生理学意义同时表达FGFR和EphA4的已分化的P19细胞，经肾上腺素刺激后，促进FGFR-EphA4复合体的形成，进而激活EphA4反式磷酸化的FGFR。免疫细胞化学显示FGFR和EphA4在P19细胞和神经干细胞上共定位，表明FGFR与EphA4在生理上相互作用。(2)FGFR-EphA4复合体的形成通过FGFRFRS2促进FRS2-RAS-MAPK信号转导，FGFR是FGFR激活的下游分子。我们在小鼠神经干细胞中发现了FRS2-FGFR-EphA4的复合体，这种相互作用增加了Ras-MAPK信号。我们的结果表明，FGFR-EphA4相互作用对神经发生和再生具有重要作用。

We hypothesized that neural stem cell growth, differentiation and chemotaxsis are regulated by molecular interaction between FGFR and Eph. Our study is focused on elucidation of a novel signaling mechamism through FGFR-EphA4 complex. Our summary of findings are described bellow.(1)Physiological significance of FGFR-EphA4 interactionEphrin stimulation of differentiated P19 cellls expressing both FGFR and EphA4 promoted FGFR-EphA4 complex formation and then activated EphA4 trans-phosphorylated FGFR. Futhermore, colocalization of FGFR and EphA4 on P19 cells and neural stem cells was shown by immunocytochemical study, indicating that FGFR interacts with EphA4 phisiologically.(2)FGFR-EphA4 complex formation increased FRS2-Ras-MAPK signaling through FGFRFRS2 is well known as a down strem molecule activated by FGFR. We found a complex formation of FRS2-FGFR-EphA4 in mouse neural stem cells and this interaction increasesd Ras-MAPK signaling.Our results suggested that FGFR-EphA4 interaction was important for neurogenesis and regeneration.