Ohkubo Nobutaka, Vitek Michael P, Morishima Atsuyuki, Suzuki Yoji, Miki Tetsuro, Maeda Nobuji, Mitsuda Noriaki
Department of Physiology, Graduate School of Medicine, Ehime University, Shitsukawa, Toon, Ehime, Japan.
J Neurochem. 2007 Oct;103(2):820-30. doi: 10.1111/j.1471-4159.2007.04804.x. Epub 2007 Aug 13.
Reelin plays an important role in the migration of embryonic neurons, but its continuing presence suggests additional functions in the brain. We now report a novel function where reelin protects P19 embryonal cells from apoptosis during retinoic acid-induced neuronal differentiation. This increased survival is associated with reelin activation of the phosphatidyl-inositol-3-kinase (PI3 K)/Akt pathway. When PI3 K was inhibited with LY294002, reelin failed to protect against this retinoic acid-induced apoptosis. The protective effect of reelin includes activating the Src-family kinases/PI3 K/Akt pathway which then led to selective phosphorylation of Bcl-2/Bcl-XL associated death promoter (BAD) at serine-136, while the phosphorylation-incompetent mutation of BAD (S136A) suppressed this protection. These and additional studies define a novel pathway where reelin binds apoE receptors, significantly activates the PI3 K/Akt pathway causing phosphorylation of BAD which helps to protect cells from apoptosing, thus serving an important role in promoting the survival of maturing neurons in the brain.
Reelin在胚胎神经元迁移中起重要作用，但其持续存在表明在大脑中还有其他功能。我们现在报告一种新功能，即Reelin在视黄酸诱导的神经元分化过程中保护P19胚胎细胞免于凋亡。这种存活率的提高与Reelin激活磷脂酰肌醇-3-激酶（PI3K）/Akt信号通路有关。当用LY294002抑制PI3K时，Reelin无法防止这种视黄酸诱导的凋亡。Reelin的保护作用包括激活Src家族激酶/PI3K/Akt信号通路，进而导致Bcl-2/Bcl-XL相关死亡促进因子（BAD）在丝氨酸136处发生选择性磷酸化，而BAD的磷酸化无能力突变（S136A）则抑制了这种保护作用。这些及其他研究确定了一条新途径，即Reelin与载脂蛋白E受体结合，显著激活PI3K/Akt信号通路，导致BAD磷酸化，从而有助于保护细胞免于凋亡，因此在促进大脑中成熟神经元的存活中发挥重要作用。
