Cdk5 phosphorylation of WAVE2 regulates oligodendrocyte precursor cell migration through nonreceptor tyrosine kinase Fyn
Cdk5 phosphorylation of WAVE2 regulates oligodendrocyte precursor cell migration through nonreceptor tyrosine kinase Fyn
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DOI：
10.1523/jneurosci.1482-08.2008
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发表时间：
2008-08-13
影响因子：
5.3
通讯作者：
Tanoue, Akito
中科院分区：
文献类型：
--
作者：
Miyamoto, Yuki;Yamauchi, Junji;Tanoue, Akito
中枢神经系统的髓鞘形成是一个复杂的动态过程。在髓鞘形成开始之前，少突胶质细胞（Oligodendrocytes，OL），CNS的髓鞘形成胶质细胞，增殖并沿沿着迁移。关于早期髓鞘形成过程的分子机制知之甚少。在这里，我们表明，血小板衍生生长因子（PDGF），在早期OL发展的重要生理配体，控制少突胶质细胞前体细胞（OPCs）通过细胞周期蛋白依赖性激酶5（Cdk 5）的迁移。PDGF以时间依赖性方式刺激Cdk 5活性，而特异性抑制剂roscovitine或编码Cdk 5短发夹RNA的逆转录病毒抑制Cdk 5则损害PDGF依赖性OPC迁移。PDGF对Cdk 5的激活是由非受体酪氨酸激酶Fyn的磷酸化介导的，Fyn的抑制降低了PDGF依赖的OPC迁移。此外，Cdk 5通过直接磷酸化WASP（Wiskott-Aldrich综合征蛋白）-家族verprolin-同源蛋白2（WAVE 2）来调节PDGF依赖性OPC迁移。Cdk 5在体外磷酸化WAVE 2的Ser-137。感染携带Ser-137-to-Ala的WAVE 2构建体可减少PDGF-dependent迁移。总之，PDGF通过一个尚未鉴定的信号级联将Fyn激酶偶联到WAVE 2的Cdk 5磷酸化来调节OPC迁移。这些结果为Cdk 5在胶质细胞中的作用和控制OLs早期发育阶段的分子机制提供了新的见解。
Myelin formation of the CNS is a complex and dynamic process. Before the onset of myelination, oligodendrocytes (OLs), the myelinforming glia of the CNS, proliferate and migrate along axons. Little is known about the molecular mechanisms underlying the early myelination processes. Here, we show that platelet-derived growth factor (PDGF), the crucial physiological ligand in early OL development, controls the migration of oligodendrocyte precursor cells (OPCs) through cyclin-dependent kinase 5 (Cdk5). PDGF stimulates Cdk5 activity in a time-dependent manner, whereas suppression of Cdk5 by the specific inhibitor roscovitine or by the retrovirus encoding short-hairpin RNA for Cdk5 impairs PDGF-dependent OPC migration. The activation of Cdk5 by PDGF is mediated by the phosphorylation of the nonreceptor tyrosine kinase, Fyn, whose inhibition reduces PDGF-dependent OPC migration. Furthermore, Cdk5 regulates PDGF-dependent OPC migration through the direct phosphorylation of WASP (Wiskott-Aldrich syndrome protein)-family verprolin-homologous protein 2 (WAVE2). Cdk5 phosphorylates WAVE2 at Ser-137 in vitro. Infection of the WAVE2 construct harboring the Ser-137-to-Ala reduces PDGF-dependent migration. Together, PDGF regulates OPC migration through an as-yet-unidentified signaling cascade coupling Fyn kinase to Cdk5 phosphorylation of WAVE2. These results provide new insights into both the role of Cdk5 in glial cells and the molecular mechanisms controlling the early developmental stage of OLs.