Cdk5 regulates differentiation of oligodendrocyte precursor cells through the direct phosphorylation of paxillin
Cdk5 regulates differentiation of oligodendrocyte precursor cells through the direct phosphorylation of paxillin
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DOI：
10.1242/jcs.018218
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发表时间：
2007-12-15
影响因子：
4
通讯作者：
Tanoue, Akito
中科院分区：
文献类型：
--
作者：
Miyamoto, Yuki;Yamauchi, Junji;Tanoue, Akito
少突胶质细胞前体细胞（OPCs）分化成少突胶质细胞（OLs）以形成髓鞘，髓鞘是脊椎动物神经系统中动作电位快速传播所需的。尽管髓鞘形成具有相当大的临床重要性，但对OL分化和髓鞘形成的基本分子机制知之甚少。在这里，我们表明，细胞周期蛋白依赖性激酶（Cdk）5激活分化诱导后，和Cdk5抑制剂roscovitine抑制OL分化。在使用RNAi敲低内源性Cdk5后，OL过程的复杂性也降低。我们还表明，粘着斑蛋白桩蛋白直接磷酸化的Ser244 Cdk5。携带Ser244至Ala突变的桩蛋白构建体的转染显著抑制其形态学效应。重要的是，桩蛋白在Ser244处的磷酸化降低了其与粘着斑激酶（FAK）的相互作用。综上所述，这些结果表明，桩蛋白的Cdk5磷酸化是OL分化的关键机制，并可能最终调节髓鞘形成。
Oligodendrocyte precursor cells (OPCs) differentiate into oligodendrocytes (OLs) in order to form myelin, which is required for the rapid propagation of action potentials in the vertebrate nervous system. In spite of the considerable clinical importance of myelination, little is known about the basic molecular mechanisms underlying OL differentiation and myelination. Here, we show that cyclin-dependent kinase (Cdk) 5 is activated following the induction of differentiation, and that the Cdk5 inhibitor roscovitine inhibits OL differentiation. The complexity of the OL processes is also diminished after knocking down endogenous Cdk5 using RNAi. We also show that the focal adhesion protein paxillin is directly phosphorylated at Ser244 by Cdk5. Transfection of a paxillin construct harboring a Ser244 to Ala mutation dramatically inhibits its morphological effects. Importantly, phosphorylation of paxillin at Ser244 reduces its interaction with focal adhesion kinase (FAK). Taken together, these results suggest that phosphorylation of paxillin by Cdk5 is a key mechanism in OL differentiation and may ultimately regulate myelination.