SIRPα negatively regulates differentiation of PC12 cell

Signal regulatory protein α (SIRPα) is an Ig superfamily protein whose cytoplasmic region contains immunoreceptor tyrosine-based inhibitory motif (ITIM), which when tyrosine phosphorylated binds the SH2-domain containing phosphatase 2 (SHP-2). Both SIRPα and SHP-2 are highly expressed in brain. Murine cerebellar cells cultured on SIRPα-coated surface exhibit enhanced neurite outgrowth and SIRPα is localized at sites of synaptogenesis in postnatal mouse brain. In this study, we show that nerve growth factor (NGF) stimulation resulted in elevated SIRPα expression during PC12 differentiation. We also show that NGF-induced morphological differentiation, but not growth arrest response, was inhibited by ectopic SIRPα expression. PC12 cells stably expressing SIRPα proliferated more rapidly than mock-transfected cells. The activity of c-jun N-terminal kinase (JNK) decreased in SIRPα-transfected PC12 cells, whereas nuclear factor-κB (NF-κB) activity increased. Collectively, our results suggest that SIRPα may stabilize synaptic connections by inhibiting improper neurite outgrowth and might realize its neuronal function, at least in part, by modulating JNK and NF-κB activity.