casein kinases


Summary: A group of protein-serine-threonine kinases that was originally identified as being responsible for the PHOSPHORYLATION of CASEINS. They are ubiquitous enzymes that have a preference for acidic proteins. Casein kinases play a role in SIGNAL TRANSDUCTION by phosphorylating a variety of regulatory cytoplasmic and regulatory nuclear proteins.

Top Publications

  1. Bontems S, Di Valentin E, Baudoux L, Rentier B, Sadzot Delvaux C, Piette J. Phosphorylation of varicella-zoster virus IE63 protein by casein kinases influences its cellular localization and gene regulation activity. J Biol Chem. 2002;277:21050-60 pubmed
    ..We demonstrate here that cellular casein kinases I and II are implicated in the in vitro and in vivo phosphorylation of IE63...
  2. Feng Y, Davis N. Akr1p and the type I casein kinases act prior to the ubiquitination step of yeast endocytosis: Akr1p is required for kinase localization to the plasma membrane. Mol Cell Biol. 2000;20:5350-9 pubmed
    ..ubiquitination, these being mutant either for the ankyrin repeat protein Akr1p or for the redundant type I casein kinases Yck1p and Yck2p...
  3. Sakanaka C, Leong P, Xu L, Harrison S, Williams L. Casein kinase iepsilon in the wnt pathway: regulation of beta-catenin function. Proc Natl Acad Sci U S A. 1999;96:12548-52 pubmed
    ..CKIepsilon appears to be a positive regulator of the pathway and a link between upstream signals and the complexes that regulate beta-catenin. ..
  4. Peters J, McKay R, McKay J, Graff J. Casein kinase I transduces Wnt signals. Nature. 1999;401:345-50 pubmed
    ..In addition, CKI bound to and increased the phosphorylation of dishevelled, a known component of the Wnt pathway. These data indicate that CKI may be a conserved component of the Wnt pathway. ..
  5. Desagher S, Osen Sand A, Montessuit S, Magnenat E, Vilbois F, Hochmann A, et al. Phosphorylation of bid by casein kinases I and II regulates its cleavage by caspase 8. Mol Cell. 2001;8:601-11 pubmed
    ..Moreover, a mutant of Bid that cannot be phosphorylated was found to be more toxic than wild-type Bid. Together, these data indicate that phosphorylation of Bid represents a new mechanism whereby cells control apoptosis. ..
  6. Lee C, Etchegaray J, Cagampang F, Loudon A, Reppert S. Posttranslational mechanisms regulate the mammalian circadian clock. Cell. 2001;107:855-67 pubmed
    ..We also provide in vivo evidence that casein kinase I delta is a second clock relevant kinase. ..
  7. Mikula M, Karczmarski J, Dzwonek A, Rubel T, Hennig E, Dadlez M, et al. Casein kinases phosphorylate multiple residues spanning the entire hnRNP K length. Biochim Biophys Acta. 2006;1764:299-306 pubmed
    ..Mass spectrometry of K protein isolated from proliferating cells and from cells under oxidative stress revealed the same pattern of phosphopeptides. The structural implications of phosphorylation are discussed. ..
  8. Huang G, Chen S, Li S, Cha J, Long C, Li L, et al. Protein kinase A and casein kinases mediate sequential phosphorylation events in the circadian negative feedback loop. Genes Dev. 2007;21:3283-95 pubmed
    ..negative feedback loop, FREQUENCY (FRQ) protein inhibits WHITE COLLAR (WC) complex activity by recruiting the casein kinases CKI and CKII to phosphorylate the WC proteins, resulting in the repression of frq transcription...
  9. Panek H, Stepp J, Engle H, Marks K, Tan P, Lemmon S, et al. Suppressors of YCK-encoded yeast casein kinase 1 deficiency define the four subunits of a novel clathrin AP-like complex. EMBO J. 1997;16:4194-204 pubmed
    ..These results suggest that vesicle trafficking at the plasma membrane requires the activity of Yck protein kinases, and that the new AP-related complex may participate in this process. ..

More Information


  1. Tiffert T, Lew V, Ginsburg H, Krugliak M, Croisille L, Mohandas N. The hydration state of human red blood cells and their susceptibility to invasion by Plasmodium falciparum. Blood. 2005;105:4853-60 pubmed
    ..These results suggest that the presence of dense RBCs is a protective factor, additional to any other protection mechanism prevailing in each of the different pathologies. ..
  2. Okochi M, Walter J, Koyama A, Nakajo S, Baba M, Iwatsubo T, et al. Constitutive phosphorylation of the Parkinson's disease associated alpha-synuclein. J Biol Chem. 2000;275:390-7 pubmed
    ..These data demonstrate that alpha-synuclein is constitutively phosphorylated within its C terminus and may indicate that the function of alpha-synuclein is regulated by phosphorylation/dephosphorylation. ..
  3. Guo L, Jiang M, Ma Y, Cheng H, Ni X, Ma Y, et al. Molecular cloning, mapping and characterization of a human CK1gamma1 gene. Int J Mol Med. 2002;10:227-30 pubmed
    ..Furthermore, the human CK1gamma1 gene was mapped to chromosome 15q22 between STS marker D15S159 and D15S125 by polymerase chain reaction analysis of human/rodent hybrid cell panels. ..
  4. Dhillon N, Hoekstra M. Characterization of two protein kinases from Schizosaccharomyces pombe involved in the regulation of DNA repair. EMBO J. 1994;13:2777-88 pubmed
    ..We suggest that Hhp1 and Hhp2 are involved in the regulation of distinct and overlapping DNA repair pathways in S. pombe. ..
  5. Choi E, Miller J, Zaidi N, Salih E, Buxbaum J, Wasco W. Phosphorylation of calsenilin at Ser63 regulates its cleavage by caspase-3. Mol Cell Neurosci. 2003;23:495-506 pubmed
    ..Given that the N-terminal domain of calsenilin is not conserved in the larger NCS family including other KChIP/CALP proteins, phosphorylation of calsenilin may regulate a functional role that is unique to this member of the superfamily. ..
  6. Datta N, Schell M, Roux S. Spermine stimulation of a nuclear NII kinase from pea plumules and its role in the phosphorylation of a nuclear polypeptide. Plant Physiol. 1987;84:1397-401 pubmed
    ..Using [gamma-32P]GTP, we have shown that spermine promotes the phosphorylation of the 47 kilodalton polypeptide(s) in isolated nuclei, at least in part by stimulating an NII kinase. ..
  7. Dubois T, Kerai P, Zemlickova E, Howell S, Jackson T, Venkateswarlu K, et al. Casein kinase I associates with members of the centaurin-alpha family of phosphatidylinositol 3,4,5-trisphosphate-binding proteins. J Biol Chem. 2001;276:18757-64 pubmed
    Mammalian casein kinases I (CKI) belong to a family of serine/threonine protein kinases involved in diverse cellular processes including cell cycle progression, membrane trafficking, circadian rhythms, and Wnt signaling...
  8. Okamura A, Iwata N, Nagata A, Tamekane A, Shimoyama M, Gomyo H, et al. Involvement of casein kinase Iepsilon in cytokine-induced granulocytic differentiation. Blood. 2004;103:2997-3004 pubmed
  9. Kishida M, Hino Si -, Michiue T, Yamamoto H, Kishida S, Fukui A, et al. Synergistic activation of the Wnt signaling pathway by Dvl and casein kinase Iepsilon. J Biol Chem. 2001;276:33147-55 pubmed
    ..These results indicate that Dvl and CKIepsilon synergistically activated the Wnt signaling pathway and that the binding of the complex of Dvl and CKIepsilon to Axin is necessary for their synergistic action. ..
  10. Litchfield D, Lozeman F, Cicirelli M, Harrylock M, Ericsson L, Piening C, et al. Phosphorylation of the beta subunit of casein kinase II in human A431 cells. Identification of the autophosphorylation site and a site phosphorylated by p34cdc2. J Biol Chem. 1991;266:20380-9 pubmed
    ..This residue, which is near the carboxyl terminus of the protein, can be phosphorylated in vitro by p34cdc2. ..
  11. Tobin A, Totty N, Sterlin A, Nahorski S. Stimulus-dependent phosphorylation of G-protein-coupled receptors by casein kinase 1alpha. J Biol Chem. 1997;272:20844-9 pubmed
  12. Maritzen T, Löhler J, Deppert W, Knippschild U. Casein kinase I delta (CKIdelta) is involved in lymphocyte physiology. Eur J Cell Biol. 2003;82:369-78 pubmed
    ..In addition, we observed an increased immunostaining in cells of hyperplastic B follicles and advanced B-cell lymphomas in p53-deficient mice. Thus, our results indicate that CKIdelta plays several roles in lymphocyte physiology...
  13. Graves P, Haas D, Hagedorn C, DePaoli Roach A, Roach P. Molecular cloning, expression, and characterization of a 49-kilodalton casein kinase I isoform from rat testis. J Biol Chem. 1993;268:6394-401 pubmed
    ..Casein kinase I delta therefore represents a separate member of the casein kinase I family distinguished by its larger size and unique kinetic behavior with respect to heparin. ..
  14. Manak J, Prywes R. Mutation of serum response factor phosphorylation sites and the mechanism by which its DNA-binding activity is increased by casein kinase II. Mol Cell Biol. 1991;11:3652-9 pubmed
    ..Rather, using partial proteolysis to probe SRF's structure, we find that the conformation of SRF's DNA-binding domain is altered by phosphorylation. ..
  15. Lincoln G, Messager S, Andersson H, Hazlerigg D. Temporal expression of seven clock genes in the suprachiasmatic nucleus and the pars tuberalis of the sheep: evidence for an internal coincidence timer. Proc Natl Acad Sci U S A. 2002;99:13890-5 pubmed
  16. Klimczak L, Farini D, Lin C, Ponti D, Cashmore A, Giuliano G. Multiple isoforms of Arabidopsis casein kinase I combine conserved catalytic domains with variable carboxyl-terminal extensions. Plant Physiol. 1995;109:687-96 pubmed
    ..Like several recombinant CKI isoforms from yeast, CKI1 was able to phosphorylate tyrosine-containing acidic polymers. ..
  17. Donella Deana A, Monti E, Pinna L. Inhibition of tyrosine protein kinases by the antineoplastic agent adriamycin. Biochem Biophys Res Commun. 1989;160:1309-15 pubmed
    ..Unlike tyrosine protein kinases most serine/threonine specific protein kinases, with the notable exception of protein kinase-C, appear to be relatively insensitive to adriamycin. ..
  18. Mohan M, Ryder S, Claypool P, Geisert R, Malayer J. Analysis of gene expression in the bovine blastocyst produced in vitro using suppression-subtractive hybridization. Biol Reprod. 2002;67:447-53 pubmed
    ..These results show that construction of subtracted cDNA libraries from small numbers of embryos is feasible and can provide information on gene expression patterns during preattachment embryogenesis. ..
  19. Muhlrad P, Ward S. Spermiogenesis initiation in Caenorhabditis elegans involves a casein kinase 1 encoded by the spe-6 gene. Genetics. 2002;161:143-55 pubmed
    ..The activation signal is transduced through SPE-8, SPE-12, SPE-27, and SPE-29 to relieve SPE-6 repression, thus triggering the formation of crawling spermatozoa. ..
  20. Lussier G, Larose L. A casein kinase I activity is constitutively associated with Nck. J Biol Chem. 1997;272:2688-94 pubmed
    ..These results support an in vivo interaction between Nck and CKI-gamma2 and suggest that CKI-gamma2 could be involved in signaling pathways downstream of RTKs. ..
  21. Corbett A, Fernald A, Osheroff N. Protein kinase C modulates the catalytic activity of topoisomerase II by enhancing the rate of ATP hydrolysis: evidence for a common mechanism of regulation by phosphorylation. Biochemistry. 1993;32:2090-7 pubmed
    ..abstract truncated at 250 words) ..
  22. Vancura A, Sessler A, Leichus B, Kuret J. A prenylation motif is required for plasma membrane localization and biochemical function of casein kinase I in budding yeast. J Biol Chem. 1994;269:19271-8 pubmed
    ..These data suggest that members of the casein kinase I family have distinct but partially overlapping distributions in the cell that are mediated by their unique C-terminal regions. ..
  23. Nagata Y, Todokoro K. Activation of helix-loop-helix proteins Id1, Id2 and Id3 during neural differentiation. Biochem Biophys Res Commun. 1994;199:1355-62 pubmed
    ..These results indicate that Id family members may function as immediate-early gene products, and that the expression of the Id family may play an important role in the early stage of neural differentiation. ..
  24. Takano A, HOE H, Isojima Y, Nagai K. Analysis of the expression, localization and activity of rat casein kinase 1epsilon-3. Neuroreport. 2004;15:1461-4 pubmed
    ..Moreover, the kinase activity of the rCK1epsilon-3 protein differed from that of rCK1epsilon-1. These data suggest that rCK1epsilon-1 and rCK1epsilon-3 may play different functional roles. ..
  25. Flotow H, Graves P, Wang A, Fiol C, Roeske R, Roach P. Phosphate groups as substrate determinants for casein kinase I action. J Biol Chem. 1990;265:14264-9 pubmed
    ..Thus, casein kinase I may be involved in hierarchal substrate phosphorylation schemes in which its activity is controlled by the phosphorylation state of its substrates. ..
  26. Jirage D, Keenan S, Waters N. Exploring novel targets for antimalarial drug discovery: plasmodial protein kinases. Infect Disord Drug Targets. 2010;10:134-46 pubmed
    ..With wide spread malaria drug resistance, coupled by a parasite that can develop resistance quickly to new drugs, the development of multi-kinase inhibitors may be extremely efficacious and reduce the likelihood for resistance. ..
  27. Milne D, Palmer R, Campbell D, Meek D. Phosphorylation of the p53 tumour-suppressor protein at three N-terminal sites by a novel casein kinase I-like enzyme. Oncogene. 1992;7:1361-9 pubmed
    ..Moreover, phosphopeptide analyses of p53 phosphorylated by CKI or by PK270 gave similar results, indicating that these two kinases phosphorylate the same sites in p53. ..
  28. Couzin J. RNA interference. New screen nets 'Hedgehog' genes. Science. 2003;299:1961 pubmed
  29. Babu P, Bryan J, Panek H, Jordan S, Forbrich B, Kelley S, et al. Plasma membrane localization of the Yck2p yeast casein kinase 1 isoform requires the C-terminal extension and secretory pathway function. J Cell Sci. 2002;115:4957-68 pubmed
    ..Deletion analysis within the 185 residue C-terminus indicates that the final 28 residues are critical for membrane association, and additional sequences just upstream are required for proper plasma membrane targeting. ..
  30. Okamura H, Garcia Rodriguez C, Martinson H, Qin J, Virshup D, Rao A. A conserved docking motif for CK1 binding controls the nuclear localization of NFAT1. Mol Cell Biol. 2004;24:4184-95 pubmed
    ..The CK1 docking motif is present in proteins of the Wnt, Hedgehog, and circadian-rhythm pathways, which also integrate the activities of CK1 and GSK3. ..
  31. Chan H, Mai L, Oikonomopoulou A, Chan H, Richardson A, Wang S, et al. Altered enamelin phosphorylation site causes amelogenesis imperfecta. J Dent Res. 2010;89:695-9 pubmed publisher
    ..Ser(216) is one of two serines on the 32-kDa enamelin that is phosphorylated by Golgi casein kinase and is thought to mediate calcium binding. We propose that phosphorylation of enamelin is critical for its function. ..
  32. Hummel T, Attix S, Gunning D, Zipursky S. Temporal control of glial cell migration in the Drosophila eye requires gilgamesh, hedgehog, and eye specification genes. Neuron. 2002;33:193-203 pubmed
    ..We propose that the spatiotemporal control of glial cell migration plays a critical role in determining the directionality of R cell axon outgrowth. ..
  33. Liu F, Ma X, Ule J, Bibb J, Nishi A, DeMaggio A, et al. Regulation of cyclin-dependent kinase 5 and casein kinase 1 by metabotropic glutamate receptors. Proc Natl Acad Sci U S A. 2001;98:11062-8 pubmed
    ..Together these results indicate that a CK1-Cdk5-DARPP-32 cascade may be involved in the regulation by mGluR agonists of Ca(2+) channels. ..
  34. Knippschild U, Milne D, Campbell L, DeMaggio A, Christenson E, Hoekstra M, et al. p53 is phosphorylated in vitro and in vivo by the delta and epsilon isoforms of casein kinase 1 and enhances the level of casein kinase 1 delta in response to topoisomerase-directed drugs. Oncogene. 1997;15:1727-36 pubmed
    ..These data suggest that p53 is phosphorylated by CK1delta and CK1epsilon and additionally that there may be a regulatory feedback loop involving p53 and CK1delta. ..
  35. Lozeman F, Litchfield D, Piening C, Takio K, Walsh K, Krebs E. Isolation and characterization of human cDNA clones encoding the alpha and the alpha' subunits of casein kinase II. Biochemistry. 1990;29:8436-47 pubmed
    ..1 encoded the alpha' subunit. These studies show that there are two distinct catalytic subunits for casein kinase II (alpha and alpha') and that the sequence of these subunits is largely conserved between the bovine and the human. ..
  36. Link W, Dosemeci A, Floyd C, Pant H. Bovine neurofilament-enriched preparations contain kinase activity similar to casein kinase I--neurofilament phosphorylation by casein kinase I (CKI). Neurosci Lett. 1993;151:89-93 pubmed
    ..These studies suggest that the major independent kinase activity associated with NFs is CKI. ..
  37. Luscher B, Kuenzel E, Krebs E, Eisenman R. Myc oncoproteins are phosphorylated by casein kinase II. EMBO J. 1989;8:1111-9 pubmed
    ..Since CK-II can be rapidly activated after mitogen treatment we postulate that CK-II mediated phosphorylation of Myc plays a role in signal transduction to the nucleus. ..
  38. Bidère N, Ngo V, Lee J, Collins C, Zheng L, Wan F, et al. Casein kinase 1alpha governs antigen-receptor-induced NF-kappaB activation and human lymphoma cell survival. Nature. 2009;458:92-6 pubmed publisher
    ..ABC DLBCL cells required CK1alpha for constitutive NF-kappaB activity, indicating that CK1alpha functions as a conditionally essential malignancy gene-a member of a new class of potential cancer therapeutic targets. ..
  39. Marchal C, Haguenauer Tsapis R, Urban Grimal D. Casein kinase I-dependent phosphorylation within a PEST sequence and ubiquitination at nearby lysines signal endocytosis of yeast uracil permease. J Biol Chem. 2000;275:23608-14 pubmed
    ..This may be due to CK1 having a second counteracting role in endocytosis as shown by the higher turnover of variant permeases with unphosphorylatable versions of the PEST sequence. ..
  40. Yang Y, Cheng P, He Q, Wang L, Liu Y. Phosphorylation of FREQUENCY protein by casein kinase II is necessary for the function of the Neurospora circadian clock. Mol Cell Biol. 2003;23:6221-8 pubmed
    ..Together, these data indicate that CKII is an important component of the Neurospora circadian clock...
  41. Moriya H, Johnston M. Glucose sensing and signaling in Saccharomyces cerevisiae through the Rgt2 glucose sensor and casein kinase I. Proc Natl Acad Sci U S A. 2004;101:1572-7 pubmed
    ..Our results add nutrient sensing to the growing list of processes in which casein kinase I is involved. ..
  42. Pulgar V, Tapia C, Vignolo P, Santos J, Sunkel C, Allende C, et al. The recombinant alpha isoform of protein kinase CK1 from Xenopus laevis can phosphorylate tyrosine in synthetic substrates. Eur J Biochem. 1996;242:519-28 pubmed
    ..CK1 alpha can phosphorylate the tyrosine residues of poly(Glu80:Tyr20) and the tyrosine residue in the synthetic peptide RRREEEYEEEE. This kinase preparation also autophosphorylates in serine, threonine and weakly in tyrosine. ..
  43. Doi M, Okano T, Yujnovsky I, Sassone Corsi P, Fukada Y. Negative control of circadian clock regulator E4BP4 by casein kinase Iepsilon-mediated phosphorylation. Curr Biol. 2004;14:975-80 pubmed
    ..These results not only demonstrate a phosphorylation-dependent regulatory mechanism for E4BP4 function but also highlight the role of CK1epsilon as a negative regulator for E4BP4-mediated repression of cPer2. ..
  44. Donella Deana A, Krinks M, Ruzzene M, Klee C, Pinna L. Dephosphorylation of phosphopeptides by calcineurin (protein phosphatase 2B). Eur J Biochem. 1994;219:109-17 pubmed
  45. Dobrowolska G, Boldyreff B, Issinger O. Cloning and sequencing of the casein kinase 2 alpha subunit from Zea mays. Biochim Biophys Acta. 1991;1129:139-40 pubmed
    ..The primary amino acid sequence exhibits 75% identity to the alpha subunit and 71% identity to the alpha' subunit of human casein kinase 2. ..
  46. Voss H, Wirkner U, Jakobi R, Hewitt N, Schwager C, Zimmermann J, et al. Structure of the gene encoding human casein kinase II subunit beta. J Biol Chem. 1991;266:13706-11 pubmed
    ..The CKII beta gene promoter shares common features with that of mammalian protein kinases and is closely related to the regulatory subunit gene promoter of cAMP-dependent protein kinase. ..
  47. Boldyreff B, Piontek K, Schmidt Spaniol I, Issinger O. The beta subunit of casein kinase II: cloning of cDNAs from murine and porcine origin and expression of the porcine sequence as a fusion protein. Biochim Biophys Acta. 1991;1088:439-41 pubmed
    ..cDNAs encoding the beta subunit of pig and mouse CKII were isolated. The porcine cDNA was expressed as a fusion protein in Escherichia coli and used for the production of anti-CKII-beta subunit specific antibodies. ..
  48. Zemlickova E, Johannes F, Aitken A, Dubois T. Association of CPI-17 with protein kinase C and casein kinase I. Biochem Biophys Res Commun. 2004;316:39-47 pubmed
    ..We previously found that CPI-17 co-purified with casein kinase I in brain suggesting they are part of a complex and we now show that CPI-17 associates with the kinase domain of CKI isoforms. ..
  49. Monroy A, Labbe E, Dhindsa R. Low temperature perception in plants: effects of cold on protein phosphorylation in cell-free extracts. FEBS Lett. 1997;410:206-9 pubmed
  50. Sedelnikova A, Weiss D. Phosphorylation of the recombinant rho1 GABA receptor. Int J Dev Neurosci. 2002;20:237-46 pubmed
    ..This study is a first and necessary step towards elucidating the regulation of rho1 GABA receptors by phosphorylation. ..
  51. Bordin L, Vargiu C, Clari G, Brunati A, Colombatto S, Salvi M, et al. Phosphorylation of recombinant human spermidine/spermine N(1)-acetyltransferase by CK1 and modulation of its binding to mitochondria: a comparison with CK2. Biochem Biophys Res Commun. 2002;290:463-8 pubmed
  52. Shanware N, Trinh A, Williams L, Tibbetts R. Coregulated ataxia telangiectasia-mutated and casein kinase sites modulate cAMP-response element-binding protein-coactivator interactions in response to DNA damage. J Biol Chem. 2007;282:6283-91 pubmed
    ..The coregulated ATM and CK sites identified in CREB may constitute a signaling motif that is common to other DNA damage-regulated substrates. ..
  53. Tanaka K, Petersen J, Maciver F, Mulvihill D, Glover D, Hagan I. The role of Plo1 kinase in mitotic commitment and septation in Schizosaccharomyces pombe. EMBO J. 2001;20:1259-70 pubmed
    ..The ability of plo1(+) overexpression to induce septation was severely compromised by SIN inactivation. We propose that Plo1 acts before the SIN to control septation. ..