Reelin-mediated signaling locally regulates protein kinase B/Akt and glycogen synthase kinase 3β
Reelin-mediated signaling locally regulates protein kinase B/Akt and glycogen synthase kinase 3β
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DOI：
10.1074/jbc.m209205200
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发表时间：
2002-12-20
影响因子：
4.8
通讯作者：
Herz, J
中科院分区：
文献类型：
--
作者：
Beffert, U;Morfini, G;Herz, J
Reelin是一种大的分泌蛋白，其通过经由极低密度脂蛋白受体和载脂蛋白E受体2的信号传导来控制皮质分层，从而诱导衔接蛋白Disabled-1（Dab 1）的酪氨酸磷酸化并抑制体内tau磷酸化。在这里，我们表明，这些受体的结合Reelin刺激磷脂酰肌醇3-激酶，导致激活蛋白激酶B和抑制糖原合成酶激酶3 β。我们目前的遗传证据表明，这级联依赖于载脂蛋白E受体2，极低密度脂蛋白受体，和Dab 1。在轴突生长锥中富含Reelin信号传导成分，其中Dab 1的酪氨酸磷酸化响应于Reelin而增加。这些发现表明，在神经元生长锥中，Reelin介导的磷脂酰肌醇3-激酶信号通过局部调节蛋白激酶B（糖原合酶激酶3，6激酶）活性，有助于最终神经元在哺乳动物脑中的定位。
Reelin is a large secreted protein that controls cortical layering by signaling through the very low density lipoprotein receptor and apolipoprotein E receptor 2, thereby inducing tyrosine phosphorylation of the adaptor protein Disabled-1 (Dab1) and suppressing tau phosphorylation in vivo. Here we show that binding of Reelin to these receptors stimulates phosphatidylinositol 3-kinase, resulting in activation of protein kinase B and inhibition of glycogen synthase kinase 3beta. We present genetic evidence that this cascade is dependent on apolipoprotein E receptor 2, very low density lipoprotein receptor, and Dab1. Reelin-signaling components are enriched in axonal growth cones, where tyrosine phosphorylation of Dab1 is increased in response to Reelin. These findings suggest that Reelin-mediated phosphatidylinositol 3-kinase signaling in neuronal growth cones contributes to final neuron positioning in the mammalian brain by local modulation of protein kinase B an glycogen synthase kinase 3,6 kinase activities.