GSK-3β regulates phosphorylation of CRMP-2 and neuronal polarity
GSK-3β regulates phosphorylation of CRMP-2 and neuronal polarity
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DOI：
10.1016/j.cell.2004.11.012
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发表时间：
2005-01-14
期刊：
影响因子：
64.5
通讯作者：
Kaibuchi, K
中科院分区：
文献类型：
--
作者：
Yoshimura, T;Kawano, Y;Kaibuchi, K
神经元是高度极化的，由结构和功能上不同的两个部分组成，即轴突和树突。我们先前的研究表明，崩溃素反应介体蛋白-2(CRMP-2)对于决定轴突/树突的命运至关重要，可能是通过微管组装促进轴突的伸长。在这里，我们发现糖原合成酶激酶-3β(GSK-3β)在Thr-514处使CRMP-2磷酸化并使其失活。非磷酸化CRMP-2的表达或抑制GSK-3β可诱导海马神经元形成多个轴突样突起。GSK-3β的表达减弱了神经元的极化，而非磷酸化形式的CRMP-2抵消了GSK-3β的抑制作用，表明GSK-3β是通过CRMP-2的磷酸化来调节神经元的极化的。神经营养素-3(NT-3)处理海马神经元可诱导GSK-3β失活和CRMP-2去磷酸化。抑制CRMP-2基因表达可抑制NT-3诱导的轴突生长。这些结果表明，NT-3减少了磷酸化CRMP-2，增加了非磷酸化活性CRMP-2，从而促进了轴突的生长。
Neurons are highly polarized and comprised of two structurally and functionally distinct parts, an axon and dendrites. We previously showed that collapsin response mediator protein-2 (CRMP-2) is critical for specifying axon/dendrite fate, possibly by promoting neurite elongation via microtubule assembly. Here, we showed that glycogen synthase kinase-3beta (GSK-3beta) phosphorylated CRMP-2 at Thr-514 and inactivated it. The expression of the nonphosphorylated form of CRMP-2 or inhibition of GSK-3beta induced the formation of multiple axon-like neurites in hippocampal neurons. The expression of constitutively active GSK-3beta impaired neuronal polarization, whereas the nonphosphorylated form of CRMP-2 counteracted the inhibitory effects of GSK-3beta, indicating that GSK-3beta regulates neuronal polarity through the phosphorylation of CRMP-2. Treatment of hippocampal neurons with neurotrophin-3 (NT-3) induced inactivation of GSK-3beta and dephosphorylation of CRMP-2. Knockdown of CRMP-2 inhibited NT-3-induced axon outgrowth. These results suggest that NT-3 decreases phosphorylated CRMP-2 and increases nonphosphorylated active CRMP-2, thereby promoting axon outgrowth.