Tanaka Teruyuki, Serneo Finley F, Tseng Huang Chun, Kulkarni Ashok B, Tsai Li Huei, Gleeson Joseph G
Department of Neurosciences, University of California, San Diego, La Jolla, 92093, USA.
Neuron. 2004 Jan 22;41(2):215-27. doi: 10.1016/s0896-6273(03)00852-3.
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.
人类双皮质素（DCX）基因突变或小鼠中cdk5基因的靶向破坏会导致发育中的大脑出现类似的皮质分层缺陷。在此我们表明Dcx被Cdk5磷酸化。Dcx磷酸化受发育调控，并且与Cdk5的主要激活亚基p35的表达时间相对应。质谱和蛋白质印迹分析表明Dcx残基Ser297发生了磷酸化。在体外，Dcx的磷酸化降低了其对微管的亲和力，降低了其对聚合的影响，并使其从培养的神经元中的微管上脱离。Ser297突变以类似于Cdk5活性的药理学抑制的方式阻断了Dcx对迁移的影响。这些结果表明，Cdk5介导的Dcx磷酸化通过对微管的作用来调节其对迁移的作用。
