Understanding the molecular mechanism of neuronal differentiation is important to overcome the incurable diseases caused by nervous system damage. Neurite outgrowth is prerequisite for neuronal differentiation and regeneration, and cAMP response element-binding protein (CREB) is one of the major transcriptional factors positively regulating this process. Neuronal differentiation stimuli activate mammalian target of rapamycin (mTOR) complex 2 (mTORC2)/Akt signalling to phosphorylate CREB; however, the precise molecular mechanism of this event has not been fully understood. In this manuscript, we show that neuronal differentiation stimuli increased a protein level of protein phosphatase 6 (PP6), a member of type 2A Ser/Thr protein phosphatases. PP6 knockdown suppressed mTORC2/Akt/CREB signalling and results in failure of neurite outgrowth. SIN1 is a unique component of mTORC2 that enhances mTORC2 activity towards Akt when it is in dephosphorylated form. We found PP6 knockdown increased SIN1 phosphorylation. These data suggest that PP6 may positively regulate neurite outgrowth by dephosphorylating SIN1 to activate mTORC2/Akt/CREB signalling.

中文翻译：

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蛋白磷酸酶 6 通过促进 N2a 细胞中的 mTORC2 活性促进神经突生长

了解神经元分化的分子机制对于克服由神经系统损伤引起的不治之症具有重要意义。神经突的生长是神经元分化和再生的先决条件，而 cAMP 反应元件结合蛋白 (CREB) 是正向调节这一过程的主要转录因子之一。神经元分化刺激激活哺乳动物雷帕霉素靶蛋白 (mTOR) 复合物 2 (mTORC2)/Akt 信号传导以磷酸化 CREB；然而，这一事件的确切分子机制尚未完全清楚。在这份手稿中，我们表明神经元分化刺激增加了蛋白磷酸酶 6 (PP6) 的蛋白水平，这是 2A 型丝氨酸/苏氨酸蛋白磷酸酶的成员。PP6 敲低抑制了 mTORC2/Akt/CREB ​​信号传导并导致神经突生长失败。SIN1 是 mTORC2 的一个独特成分，当它处于去磷酸化形式时，它会增强 mTORC2 对 Akt 的活性。我们发现 PP6 敲低增加了 SIN1 磷酸化。这些数据表明，PP6 可以通过使 SIN1 去磷酸化以激活 mTORC2/Akt/CREB ​​信号传导来正向调节神经突的生长。