Abstract
Neurite outgrowth is essential for the establishment of a functional nervous system. Brain-derived neurotrophic factor (BDNF) binds to its receptor TrkB and regulates axonal and dendritic morphology through signaling transduction and gene expression in neurons. SH2B1β, a signaling adaptor protein, has previously been shown to regulate several signaling pathways. Our preliminary results suggest that overexpression of SH2B1β promotes BDNF-induced neurite outgrowth in hippocampal neurons. However, little is known about the underlying mechanisms by which SH2B1β promotes BDNF-induced neurite outgrowth. In this study, we showed that SH2B1β promotes the number of dendrites in hippocampal neurons. To examine how SH2B1β promotes BDNF-induced neurite outgrowth, we have established PC12 cells stably expressing SH2B1β and TrkB to investigate its role in BDNF-induced signaling pathways. Our data demonstrated that overexpressing SH2B1β promotes BDNF-induced neurite outgrowth in PC12-SH2B1β+TrkB cells compared with the control cells. SH2B1β enhances BDNF-induced MEK-ERK1/2, PI3K-AKT and PLCγ1 signaling pathways. Inhibition of MEK-ERK1/2 and PI3K-AKT pathway by specific inhibitors further suggest that these two pathways are required for SH2B1β-promoted BDNF-induced neurite outgrowth. Moreover, SH2B1β enhances BDNF-stimulated signal transducer and activator of transcription 3 (STAT3) phosphorylation at serine 727. We further demonstrate that SH2 domain and tyrosine phosphorylation of SH2B1β are involved in BDNF-induced signaling pathways and neurite outgrowth. Taken together, our results demonstrate that SH2B1β promotes BDNF-induced neurite outgrowth through enhancing pathways involving MEK-ERK1/2, PI3K-AKT, PLCγ1 and phosphorylation of STAT3 at serine 727.