CSNK1E,CSNK1D phosphorylate CRY and PER proteins

Stable Identifier
R-HSA-9909369
Type
Reaction [transition]
Species
Homo sapiens
Compartment
cytosol
ReviewStatus
5/5
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CSNK1E,CSNK1D phosphorylate CRY and PER proteins
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In the cytosol the kinases casein kinase I delta (CSNK1D) and casein kinase I epsilon (CSNK1E) phosphorylate PER1 (Keesler et al. 2000, Camacho et al. 2001, Miyazaki et al. 2001, and inferred from mouse homologs), PER2 (Camacho et al. 2001, Toh et al. 2001, Isojima et al. 2009, Narasimamurthy et al. 2018, and inferred from mouse homologs), PER3 (inferred from mouse homologs), and CRY2 (inferred from mouse homologs) at multiple sites when the CRY, PER, and kinase proteins are in a complex together (reviewed in Virshup et al. 2007). Mouse Per2 is observed to be phosphorylatable at 21 residues (Vanselow et al. 2006). Evidence indicates that PER:CRY complexes form a stable ternary complex with either CSNK1E or CSNK1D (inferred from mouse homologs).
PER1 protein contains a nuclear localization sequence (inferred from the mouse homolog) and PER proteins contain nuclear export sequences (inferred from mouse homologs) allowing their movement into and out of the nucleus. Phosphorylation is required for transit of PER:CRY:kinase complexes into the nucleus and for interaction of PER proteins with the ubiquitin-mediated degradation process in the cytoplasm (Shirogane et al. 2005).
A S662G mutation in PER2 causes hypophosphorylation of PER2 and is responsible for familial advanced phase sleep syndrome (FASPS), an advancement of the circadian clock, however the particular kinase responsible for phosphorylating serine-662 is unknown (Toh et al. 2001, human PER2 assayed in mouse cells in Xu et al. 2007). The T44A mutation in CSNK1D causes decreases kinase activity, which also results in FASPS (Xu et al. 2005).
In mouse cells, the kinase CK2 interacts with Csnk1e and enhances Csnk1e-dependent degradation of Per2 (Tsuchiya et al. 2009). In mouse cells, inhibition of the protein phosphatase PP1 by calyculinA or RNA interference causes hyperphosphorylation and increased nuclear accumulation of Per1 and Per2, indicating that PP1 negatively regulates phosphorylation of Per1 and Per2 (Lee et al. 2011, Schmutz et al. 2011)
Literature References
PubMed ID Title Journal Year
29784789 CK1δ/ε protein kinase primes the PER2 circadian phosphoswitch

Narasimamurthy, R, Hunt, SR, Lu, Y, Fustin, JM, Okamura, H, Partch, CL, Forger, DB, Kim, JK, Virshup, DM

Proc Natl Acad Sci U S A 2018
10790862 Phosphorylation and destabilization of human period I clock protein by human casein kinase I epsilon

Keesler, GA, Camacho, F, Guo, Y, Virshup, D, Mondadori, C, Yao, Z

Neuroreport 2000
11232563 An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome

Toh, KL, Jones, CR, He, Y, Eide, EJ, Hinz, WA, Virshup, DM, Ptácek, LJ, Fu, YH

Science 2001
15800623 Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome

Xu, Y, Padiath, QS, Shapiro, RE, Jones, CR, Wu, SC, Saigoh, N, Saigoh, K, Ptácek, LJ, Fu, YH

Nature 2005
11165242 Human casein kinase Idelta phosphorylation of human circadian clock proteins period 1 and 2

Camacho, F, Cilio, M, Guo, Y, Virshup, DM, Patel, K, Khorkova, O, Styren, S, Morse, B, Yao, Z, Keesler, GA

FEBS Lett 2001
19805222 CKIepsilon/delta-dependent phosphorylation is a temperature-insensitive, period-determining process in the mammalian circadian clock

Isojima, Y, Nakajima, M, Ukai, H, Fujishima, H, Yamada, RG, Masumoto, KH, Kiuchi, R, Ishida, M, Ukai-Tadenuma, M, Minami, Y, Kito, R, Nakao, K, Kishimoto, W, Yoo, SH, Shimomura, K, Takao, T, Takano, A, Kojima, T, Nagai, K, Sakaki, Y, Takahashi, JS, Ueda, HR

Proc Natl Acad Sci U S A 2009
14750904 Phosphorylation of clock protein PER1 regulates its circadian degradation in normal human fibroblasts

Miyazaki, K, Nagase, T, Mesaki, M, Narukawa, J, Ohara, O, Ishida, N

Biochem J 2004
Participants
Input
Output
Participates
as an event of
Catalyst Activity

protein serine/threonine kinase activity of CRY1:CRY2:PER1:p-S396-PER2:PER3:CSNK1E,CSNK1D [cytosol]

Physical Entity
CRY1:CRY2:PER1:p-S396-PER2:PER3:CSNK1E,CSNK1D [cytosol] (Homo sapiens)
Activity
protein serine/threonine kinase activity (GO:0004674)
This event is regulated
Negatively by
Regulator
PP1 catalytic subunit [cytosol] (Homo sapiens)
Positively by
Regulator
Casein kinase II [cytosol] (Homo sapiens)
Inferred From
Csnk1e,Csnk1d phosphorylate Cry and Per proteins (Mus musculus)
Authored
May, B  (2024-05-11)
Reviewed
Sancar, A  (2025-02-14)
Albrecht, U  (2025-02-18)
Created
May, B  (2024-05-13)
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