The circadian regulatory proteins BMAL1 and cryptochromes are substrates of casein kinase Iepsilon.
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.
Eide
Erik J
EJ
Department of Oncological Sciences, Huntsman Cancer Institute Center for Children, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA.
Vielhaber
Erica L
EL
Hinz
William A
WA
Virshup
David M
DM
D056930:ARNTL Transcription Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D001665:Binding Sites; D047388:Casein Kinases; D002460:Cell Line; D056931:Cryptochromes; D029721:Drosophila Proteins; D005136:Eye Proteins; D005420:Flavoproteins / Q000378:metabolism*; D006801:Humans; D008856:Microscopy, Fluorescence; D010766:Phosphorylation; D017956:Photoreceptor Cells, Invertebrate; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism / Q000502:physiology*; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D047388:Casein Kinases; D056931:Cryptochromes; D029721:Drosophila Proteins; D005136:Eye Proteins; D005420:Flavoproteins; D011494:Protein Kinases; D043562:Receptors, G-Protein-Coupled; D014157:Transcription Factors; C538960:BMAL1 protein, human; C538963:CRY1 protein, human; C119828:cry protein, Drosophila