Cdk5 phosphorylation of doublecortin ser297 regulates its effect on neuronal migration
Cdk5 phosphorylation of doublecortin ser297 regulates its effect on neuronal migration
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DOI：
10.1016/s0896-6273(03)00852-3
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发表时间：
2004-01-22
期刊：
影响因子：
16.2
通讯作者：
Gleeson, JG
中科院分区：
文献类型：
--
作者：
Tanaka, T;Serneo, FF;Gleeson, JG
人类双皮质素（DCX）基因的突变或小鼠cdk5基因的靶向破坏导致发育中大脑中类似的皮质分层缺陷。在这里，我们表明，Dcx被Cdk5磷酸化。Dcx磷酸化是发育调节的，对应于Cdk5的主要活化亚基p35表达的时间。质谱和蛋白质印迹分析表明Dcx残基Ser297磷酸化。Dcx的磷酸化降低了其对体外微管的亲和力，降低了其对聚合的影响，并将其从培养的神经元中的微管中置换出来。Ser297的突变以类似于Cdk 5活性的药理学抑制的方式阻断Dcx对迁移的影响。这些结果表明，Dcx的磷酸化Cdk5调节其行动的迁移通过对微管的影响。
Mutations in the doublecortin (DCX) gene in human or targeted disruption of the cdk5 gene in mouse lead to similar cortical lamination defects in the developing brain. Here we show that Dcx is phosphorylated by Cdk5. Dcx phosphorylation is developmentally regulated and corresponds to the timing of expression of p35, the major activating subunit for Cdk5. Mass spectrometry and Western blot analysis indicate phosphorylation at Dcx residue Ser297. Phosphorylation of Dcx lowers its affinity to microtubules in vitro, reduces its effect on polymerization, and displaces it from microtubules in cultured neurons. Mutation of Ser297 blocks the effect of Dcx on migration in a fashion similar to pharmacological inhibition of Cdk5 activity. These results suggest that Dcx phosphorylation by Cdk5 regulates its actions on migration through an effect on microtubules.