Fu A K, Fu W Y, Cheung J, Tsim K W, Ip F C, Wang J H, Ip N Y
Department of Biochemistry, Biotechnology Research Institute, Molecular Neuroscience Center, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
Nat Neurosci. 2001 Apr;4(4):374-81. doi: 10.1038/86019.
Here we describe an important involvement of Cdk5/p35 in regulating the gene expression of acetylcholine receptor (AChR) at the neuromuscular synapse. Cdk5 and p35 were prominently expressed in embryonic muscle, and concentrated at the neuromuscular junction in adulthood. Neuregulin increased the p35-associated Cdk5 kinase activity in the membrane fraction of cultured C2C12 myotubes. Co-immunoprecipitation studies revealed the association between Cdk5, p35 and ErbB receptors in muscle and cultured myotubes. Inhibition of Cdk5 activity not only blocked the NRG-induced AChR transcription, but also attenuated ErbB activation in cultured myotubes. In light of our finding that overexpression of p35 alone led to an increase in AChR promoter activity in muscle, Cdk5 activation is sufficient to mediate the up-regulation of AChR gene expression. Taken together, these results reveal the unexpected involvement of Cdk5/p35 in neuregulin signaling at the neuromuscular synapse.
在此，我们描述了细胞周期蛋白依赖性激酶5（Cdk5）/p35在调节神经肌肉突触处乙酰胆碱受体（AChR）基因表达中的重要作用。Cdk5和p35在胚胎肌肉中显著表达，并在成年期集中于神经肌肉接头处。神经调节蛋白增加了培养的C2C12肌管膜组分中与p35相关的Cdk5激酶活性。免疫共沉淀研究揭示了肌肉和培养的肌管中Cdk5、p35与表皮生长因子受体（ErbB）之间的关联。抑制Cdk5活性不仅阻断了神经调节蛋白诱导的AChR转录，还减弱了培养肌管中ErbB的激活。鉴于我们发现单独过表达p35会导致肌肉中AChR启动子活性增加，Cdk5激活足以介导AChR基因表达的上调。综上所述，这些结果揭示了Cdk5/p35在神经肌肉突触处神经调节蛋白信号传导中的意外作用。
