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Cyclin-dependent Kinase 5 (Cdk5) Regulates the Function of CLOCK Protein by Direct Phosphorylation
Kwak, Yongdo,Jeong, Jaehoon,Lee, Saebom,Park, Young-Un,Lee, Seol-Ae,Han, Dong-Hee,Kim, Joung-Hun,Ohshima, Toshio,Mikoshiba, Katsuhiko,Suh, Yoo-Hun,Cho, Sehyung,Park, Sang Ki American Society for Biochemistry and Molecular Bi 2013 The Journal of biological chemistry Vol.288 No.52
<P>Circadian rhythm is a biological rhythm governing physiology and behavior with a period of ∼24 h. At the molecular level, circadian output is controlled by a molecular clock composed of positive and negative feedback loops in transcriptional and post-translational processes. CLOCK is a transcription factor known as a central component of the molecular clock feedback loops generating circadian oscillation. Although CLOCK is known to undergo multiple post-translational modifications, the knowledge of their entities remains limited. Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine-threonine kinase that is involved in various neuronal processes. Here, we report that Cdk5 is a novel regulator of CLOCK protein. Cdk5 phosphorylates CLOCK at the Thr-451 and Thr-461 residues in association with transcriptional activation of CLOCK. The Cdk5-dependent regulation of CLOCK function is mediated by alterations of its stability and subcellular distribution. These results suggest that Cdk5 is a novel regulatory component of the core molecular clock machinery.</P>