Nikolic M, Chou M M, Lu W, Mayer B J, Tsai L H
Howard Hughes Medical Institute and Department of Pathology, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature. 1998 Sep 10;395(6698):194-8. doi: 10.1038/26034.
Cyclin-dependent kinase 5 (Cdk5) and its neuron-specific regulator p35 are essential for neuronal migration and for the laminar configuration of the cerebral cortex. In addition, p35/Cdk5 kinase concentrates at the leading edges of axonal growth cones and regulates neurite outgrowth in cortical neurons in culture. The Rho family of small GTPases is implicated in a range of cellular functions, including cell migration and neurite outgrowth. Here we show that the p35/Cdk5 kinase co-localizes with Rac in neuronal growth cones. Furthermore, p35 associates directly with Rac in a GTP-dependent manner. Another Rac effector, Pak1 kinase, is also present in the Rac-p35/Cdk5 complexes and co-localizes with p35/Cdk5 and Rac at neuronal peripheries. The active p35/Cdk5 kinase causes Pak1 hyperphosphorylation in a Rac-dependent manner, which results in down-regulation of Pak1 kinase activity. Because the Rho family of GTPases and the Pak kinases are implicated in actin polymerization, the modification of Pak1, imposed by the p35/Cdk5 kinase, is likely to have an impact on the dynamics of the reorganization of the actin cytoskeleton in neurons, thus promoting neuronal migration and neurite outgrowth.
细胞周期蛋白依赖性激酶5（Cdk5）及其神经元特异性调节因子p35对于神经元迁移和大脑皮质的分层结构至关重要。此外，p35/Cdk5激酶集中于轴突生长锥的前沿，并调节培养的皮质神经元中的神经突生长。小GTP酶的Rho家族参与一系列细胞功能，包括细胞迁移和神经突生长。在这里，我们表明p35/Cdk5激酶在神经元生长锥中与Rac共定位。此外，p35以GTP依赖的方式直接与Rac结合。另一种Rac效应器Pak1激酶也存在于Rac-p35/Cdk5复合物中，并在神经元周边与p35/Cdk5和Rac共定位。活性p35/Cdk5激酶以Rac依赖的方式导致Pak1过度磷酸化，从而导致Pak1激酶活性下调。由于GTP酶的Rho家族和Pak激酶参与肌动蛋白聚合，p35/Cdk5激酶对Pak1的修饰可能会影响神经元中肌动蛋白细胞骨架重组的动力学，从而促进神经元迁移和神经突生长。
