Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
Neuron. 2011 Jan 13;69(1):106-19. doi: 10.1016/j.neuron.2010.12.004.
The cAMP responsive element-binding protein (CREB) functions in a broad array of biological and pathophysiological processes. We found that salt-inducible kinase 2 (SIK2) was abundantly expressed in neurons and suppressed CREB-mediated gene expression after oxygen-glucose deprivation (OGD). OGD induced the degradation of SIK2 protein concomitantly with the dephosphorylation of the CREB-specific coactivator transducer of regulated CREB activity 1 (TORC1), resulting in the activation of CREB and its downstream gene targets. Ca(2+)/calmodulin-dependent protein kinase I/IV are capable of phosphorylating SIK2 at Thr484, resulting in SIK2 degradation in cortical neurons. Neuronal survival after OGD was significantly increased in neurons isolated from sik2(-/-) mice, and ischemic neuronal injury was significantly reduced in the brains of sik2(-)(/-) mice subjected to transient focal ischemia. These findings suggest that SIK2 plays critical roles in neuronal survival, is modulated by CaMK I/IV, and regulates CREB via TORC1.
环磷酸腺苷反应元件结合蛋白（CREB）在广泛的生物和病理生理过程中发挥作用。我们发现盐诱导激酶 2（SIK2）在神经元中大量表达，并在氧葡萄糖剥夺（OGD）后抑制 CREB 介导的基因表达。OGD 诱导 SIK2 蛋白的降解，同时伴随着 CREB 特异性共激活剂调节 CREB 活性 1（TORC1）的去磷酸化，导致 CREB 及其下游基因靶标的激活。钙/钙调蛋白依赖性蛋白激酶 I/IV 能够在 Thr484 处磷酸化 SIK2，导致皮质神经元中 SIK2 的降解。从 sik2（-/-）小鼠中分离出的神经元中，OGD 后神经元的存活显著增加，而在短暂性局灶性缺血后接受 SIK2（-/-）处理的大脑中，缺血性神经元损伤显著减少。这些发现表明 SIK2 在神经元存活中发挥关键作用，受 CaMK I/IV 调节，并通过 TORC1 调节 CREB。
