Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan, Republic of China.
PLoS One. 2013 Nov 15;8(11):e79619. doi: 10.1371/journal.pone.0079619. eCollection 2013.
Neurite outgrowth is an essential process for the establishment of the nervous system. Brain-derived neurotrophic factor (BDNF) binds to its receptor TrkB and regulates axonal and dendritic morphology of neurons through signal transduction and gene expression. SH2B1 is a signaling adaptor protein that regulates cellular signaling in various physiological processes. The purpose of this study is to investigate the role of SH2B1 in the development of the central nervous system. In this study, we show that knocking down SH2B1 reduces neurite formation of cortical neurons whereas overexpression of SH2B1β promotes the development of hippocampal neurons. We further demonstrate that SH2B1β promotes BDNF-induced neurite outgrowth and signaling using the established PC12 cells stably expressing TrkB, SH2B1β or SH2B1β mutants. Our data indicate that overexpressing SH2B1β enhances BDNF-induced MEK-ERK1/2, and PI3K-AKT signaling pathways. Inhibition of MEK-ERK1/2 and PI3K-AKT pathways by specific inhibitors suggest that these two pathways are required for SH2B1β-promoted BDNF-induced neurite outgrowth. Moreover, SH2B1β enhances BDNF-stimulated phosphorylation of signal transducer and activator of transcription 3 at serine 727. Finally, our data indicate that the SH2 domain and tyrosine phosphorylation of SH2B1β contribute to BDNF-induced signaling pathways and neurite outgrowth. Taken together, these findings demonstrate that SH2B1β promotes BDNF-induced neurite outgrowth through enhancing pathways involved MEK-ERK1/2 and PI3K-AKT.
神经突生长是神经系统建立的一个必要过程。脑源性神经营养因子（BDNF）与它的受体 TrkB 结合，通过信号转导和基因表达来调节神经元的轴突和树突形态。SH2B1 是一种信号衔接蛋白，在各种生理过程中调节细胞信号。本研究的目的是研究 SH2B1 在中枢神经系统发育中的作用。在这项研究中，我们表明敲低 SH2B1 会减少皮质神经元的神经突形成，而过表达 SH2B1β 则促进海马神经元的发育。我们进一步证明，SH2B1β 通过稳定表达 TrkB、SH2B1β 或 SH2B1β 突变体的 PC12 细胞，促进 BDNF 诱导的神经突生长和信号。我们的数据表明，过表达 SH2B1β 增强了 BDNF 诱导的 MEK-ERK1/2 和 PI3K-AKT 信号通路。通过特定抑制剂抑制 MEK-ERK1/2 和 PI3K-AKT 通路表明，这两条通路是 SH2B1β 促进 BDNF 诱导的神经突生长所必需的。此外，SH2B1β 增强了 BDNF 刺激的信号转导和转录激活因子 3 丝氨酸 727 的磷酸化。最后，我们的数据表明，SH2B1β 的 SH2 结构域和酪氨酸磷酸化有助于 BDNF 诱导的信号通路和神经突生长。总之，这些发现表明，SH2B1β 通过增强 MEK-ERK1/2 和 PI3K-AKT 途径促进 BDNF 诱导的神经突生长。
