Rin GTPase Couples Nerve Growth Factor Signaling to p38 and b-Raf/ERK Pathways to Promote Neuronal Differentiation

摘要: In neuronal precursor cells, the magnitude and longevity of mitogen-activated protein (MAP) kinase cascade activation contribute to nature cellular response, differentiation, or proliferation. However, mechanisms by which neurotrophins promote prolonged MAP signaling are not well understood. Here we defined Rin GTPase as a novel component regulatory machinery contributing selective integration development. is expressed exclusively in neurons activated neurotrophin signaling, loss-of-function analysis demonstrates that makes an essential contribution nerve growth factor (NGF)-mediated differentiation. Most surprisingly, although was unable stimulate activity NIH 3T3 it potently isoform-specific p38α weakly stimulated ERK pheochromocytoma (PC6) cells. This cell-type specificity explained part finding binds stimulates b-Raf but does activate c-Raf. Accordingly, down-regulation PC6 cells suppressed neurotrophin-elicited p38, without obvious effects on NGF-induced activation. Moreover, ability NGF neurite outgrowth inhibited knockdown. Together, these observations establish specific regulator required couple stimulation sustain p38 cascades for