Cyclin-dependent kinase 5 (Cdk5) regulates the function of CLOCK protein by direct phosphorylation.
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.
From the Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Korea.
Yongdo
Y
Kwak
Jaehoon
J
Jeong
Saebom
S
Lee
Young-Un
YU
Park
Seol-Ae
SA
Lee
Dong-Hee
DH
Han
Joung-Hun
JH
Kim
Toshio
T
Ohshima
Katsuhiko
K
Mikoshiba
Yoo-Hun
YH
Suh
Sehyung
S
Cho
Sang Ki
SK
Park
D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism*; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D055550:Protein Stability; D021381:Protein Transport / Q000502:physiology; D013912:Threonine / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000502:physiology*
D013912:Threonine; D056926:CLOCK Proteins; C538943:CLOCK protein, human; C538944:Clock protein, mouse; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; C495906:Cdk5 protein, mouse
CDK (Cyclin-dependent Kinase); CLOCK; Cdk5; Circadian Rhythms; Clock Genes; Molecular Clock; Neuroscience; Protein Phosphorylation