The circadian regulatory proteins BMAL1 and cryptochromes are substrates of casein kinase Iepsilon

J Biol Chem. 2002 May 10;277(19):17248-54. doi: 10.1074/jbc.M111466200. Epub 2002 Mar 1.

Abstract

The serine/threonine protein kinase casein kinase I epsilon (CKIepsilon) is a key regulator of metazoan circadian rhythm. Genetic and biochemical data suggest that CKIepsilon binds to and phosphorylates the PERIOD proteins. However, the PERIOD proteins interact with a variety of circadian regulators, suggesting the possibility that CKIepsilon may interact with and phosphorylate additional clock components as well. We find that CRY1 and BMAL1 are phosphoproteins in cultured cells. Mammalian PERIOD proteins act as a scaffold with distinct domains that simultaneously bind CKIepsilon and mCRY1 and mCRY2 (mCRY). mCRY is phosphorylated by CKIepsilon only when both proteins are bound to mammalian PERIOD proteins. BMAL1 is also a substrate for CKIepsilon in vitro, and CKIepsilon kinase activity positively regulates BMAL1-dependent transcription from circadian promoters in reporter assays. We conclude that CKIepsilon phosphorylates multiple circadian substrates and may exert its effects on circadian rhythm in part by a direct effect on BMAL1-dependent transcription.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ARNTL Transcription Factors
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Binding Sites
  • Casein Kinases
  • Cell Line
  • Cryptochromes
  • Drosophila Proteins*
  • Eye Proteins*
  • Flavoproteins / metabolism*
  • Humans
  • Microscopy, Fluorescence
  • Phosphorylation
  • Photoreceptor Cells, Invertebrate*
  • Precipitin Tests
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Kinases / metabolism
  • Protein Kinases / physiology*
  • Protein Structure, Tertiary
  • Receptors, G-Protein-Coupled
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Transfection

Substances

  • ARNTL Transcription Factors
  • BMAL1 protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • CRY1 protein, human
  • Cryptochromes
  • Drosophila Proteins
  • Eye Proteins
  • Flavoproteins
  • Receptors, G-Protein-Coupled
  • Transcription Factors
  • cry protein, Drosophila
  • Protein Kinases
  • Casein Kinases