Cyclin-dependent kinase 5 (Cdk5) regulates the function of CLOCK protein by direct phosphorylation

J Biol Chem. 2013 Dec 27;288(52):36878-89. doi: 10.1074/jbc.M113.494856. Epub 2013 Nov 14.

Abstract

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.

Keywords: CDK (Cyclin-dependent Kinase); CLOCK; Cdk5; Circadian Rhythms; Clock Genes; Molecular Clock; Neuroscience; Protein Phosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CLOCK Proteins / genetics
  • CLOCK Proteins / metabolism*
  • Cyclin-Dependent Kinase 5 / genetics
  • Cyclin-Dependent Kinase 5 / metabolism*
  • HEK293 Cells
  • Humans
  • Mice
  • NIH 3T3 Cells
  • Phosphorylation / physiology
  • Protein Processing, Post-Translational / physiology*
  • Protein Stability
  • Protein Transport / physiology
  • Threonine / genetics
  • Threonine / metabolism
  • Transcriptional Activation / physiology*

Substances

  • Threonine
  • CLOCK Proteins
  • CLOCK protein, human
  • Clock protein, mouse
  • Cyclin-Dependent Kinase 5
  • CDK5 protein, human
  • Cdk5 protein, mouse