Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan.
PLoS One. 2011;6(10):e26433. doi: 10.1371/journal.pone.0026433. Epub 2011 Oct 18.
SH2B adaptor protein family members (SH2B1-3) regulate various physiological responses through affecting signaling, gene expression, and cell adhesion. SH2B1 and SH2B2 were reported to enhance nerve growth factor (NGF)-induced neuronal differentiation in PC12 cells, a well-established neuronal model system. In contrast, SH2B3 was reported to inhibit cell proliferation during the development of immune system. No study so far addresses the role of SH2B3 in the nervous system. In this study, we provide evidence suggesting that SH2B3 is expressed in the cortex of embryonic rat brain. Overexpression of SH2B3 not only inhibits NGF-induced differentiation of PC12 cells but also reduces neurite outgrowth of primary cortical neurons. SH2B3 does so by repressing NGF-induced activation of PLCγ, MEK-ERK1/2 and PI3K-AKT pathways and the expression of Egr-1. SH2B3 is capable of binding to phosphorylated NGF receptor, TrkA, as well as SH2B1β. Our data further demonstrate that overexpression of SH2B3 reduces the interaction between SH2B1β and TrkA. Consistent with this finding, overexpressing the SH2 domain of SH2B3 is sufficient to inhibit NGF-induced neurite outgrowth. Together, our data demonstrate that SH2B3, unlike the other two family members, inhibits neuronal differentiation of PC12 cells and primary cortical neurons. Its inhibitory mechanism is likely through the competition of TrkA binding with the positive-acting SH2B1 and SH2B2.
SH2B 衔接蛋白家族成员（SH2B1-3）通过影响信号转导、基因表达和细胞黏附来调节各种生理反应。已有报道称，SH2B1 和 SH2B2 可增强 PC12 细胞（一种成熟的神经元模型系统）中神经生长因子（NGF）诱导的神经元分化。相比之下，SH2B3 被报道可在免疫系统发育过程中抑制细胞增殖。目前尚无研究涉及 SH2B3 在神经系统中的作用。在这项研究中，我们提供了证据表明，SH2B3 在胚胎大鼠大脑皮质中表达。SH2B3 的过表达不仅抑制 NGF 诱导的 PC12 细胞分化，还减少原代皮质神经元的突起生长。SH2B3 通过抑制 NGF 诱导的 PLCγ、MEK-ERK1/2 和 PI3K-AKT 通路的激活以及 Egr-1 的表达来实现这一点。SH2B3 能够与磷酸化的 NGF 受体 TrkA 以及 SH2B1β 结合。我们的数据进一步表明，SH2B3 的过表达减少了 SH2B1β 与 TrkA 之间的相互作用。与这一发现一致的是，过表达 SH2B3 的 SH2 结构域足以抑制 NGF 诱导的突起生长。总之，我们的数据表明，SH2B3 与其他两个家族成员不同，可抑制 PC12 细胞和原代皮质神经元的神经元分化。其抑制机制可能是通过与正向作用的 SH2B1 和 SH2B2 竞争 TrkA 结合。
