Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology
Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology
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DOI：
10.1038/nature04976
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发表时间：
2006-08-17
期刊：
影响因子：
64.8
通讯作者：
Greengard, Paul
中科院分区：
文献类型：
--
作者：
Kim, Yong;Sung, Jee Young;Greengard, Paul
WAVE1 - Wiskott-Aldrich 综合征蛋白 (WASP) - 维普林同源蛋白 1 家族 - 通过其激活肌动蛋白相关蛋白 (Arp2/3) 复合物的能力，成为哺乳动物中肌动蛋白依赖性形态过程 (1) 的关键调节因子。在这里，我们表明，在体外和完整的小鼠神经元中，WAVE1 在多个位点被细胞周期蛋白依赖性激酶 5 (Cdk5) 磷酸化。 Cdk5 磷酸化 WAVE1 会抑制其调节 Arp2/3 复合物依赖性肌动蛋白聚合的能力。体内或培养神经元中 WAVE1 功能的丧失会导致成熟树突棘的减少。 WAVE1 去磷酸化模拟突变体的表达可以逆转 WAVE1 在脊柱形态中功能的丧失，但磷酸化模拟突变体的表达则不能。环 AMP ( cAMP) 信号传导可减少 WAVE1 中 Cdk5 位点的磷酸化，并以 WAVE1 依赖性方式增加树突棘密度。我们的数据表明，神经元中 WAVE1 的磷酸化/去磷酸化在丝状肌动蛋白细胞骨架的形成中具有重要作用，因此在树突棘形态的调节中具有重要作用。
WAVE1 - the Wiskott - Aldrich syndrome protein ( WASP)- family verprolin homologous protein 1 - is a key regulator of actin-dependent morphological processes(1) in mammals, through its ability to activate the actin-related protein (Arp2/3) complex. Here we show that WAVE1 is phosphorylated at multiple sites by cyclin-dependent kinase 5 (Cdk5) both in vitro and in intact mouse neurons. Phosphorylation of WAVE1 by Cdk5 inhibits its ability to regulate Arp2/3 complex-dependent actin polymerization. Loss of WAVE1 function in vivo or in cultured neurons results in a decrease in mature dendritic spines. Expression of a dephosphorylation-mimic mutant of WAVE1 reverses this loss of WAVE1 function in spine morphology, but expression of a phosphorylation-mimic mutant does not. Cyclic AMP ( cAMP) signalling reduces phosphorylation of the Cdk5 sites in WAVE1, and increases spine density in a WAVE1-dependent manner. Our data suggest that phosphorylation/dephosphorylation of WAVE1 in neurons has an important role in the formation of the filamentous actin cytoskeleton, and thus in the regulation of dendritic spine morphology.