casein kinase ialpha


Summary: A casein kinase I isoenzyme that plays a role in intracellular signaling pathways including the WNT SIGNALING PATHWAY, the CELL CYCLE, membrane trafficking, and RNA processing. Multiple isoforms of casein kinase I alpha exist and are due to ALTERNATIVE SPLICING.

Top Publications

  1. Chen L, Li C, Pan Y, Chen J. Regulation of p53-MDMX interaction by casein kinase 1 alpha. Mol Cell Biol. 2005;25:6509-20 pubmed
    ..These results suggest that CK1alpha is a functionally relevant MDMX-binding protein and plays an important role in regulating p53 activity in the absence or presence of stress. ..
  2. Venerando A, Marin O, Cozza G, Bustos V, Sarno S, Pinna L. Isoform specific phosphorylation of p53 by protein kinase CK1. Cell Mol Life Sci. 2010;67:1105-18 pubmed publisher
  3. Clokie S, Falconer H, Mackie S, Dubois T, Aitken A. The interaction between casein kinase Ialpha and 14-3-3 is phosphorylation dependent. FEBS J. 2009;276:6971-84 pubmed publisher
    ..We also show that both fission and budding yeast CKI kinase homologues phosphorylate mammalian and budding yeast (BMH1 and BMH2) 14-3-3 at the equivalent site. ..
  4. Dahlberg C, Nguyen E, Goodlett D, Kimelman D. Interactions between Casein kinase Iepsilon (CKIepsilon) and two substrates from disparate signaling pathways reveal mechanisms for substrate-kinase specificity. PLoS ONE. 2009;4:e4766 pubmed publisher
    ..The biochemical interactions between CKIepsilon and Disheveled, Period, and its own C-terminus lead to models that explain CKIepsilon's specificity and regulation. ..
  5. Budini M, Jacob G, Jedlicki A, Perez C, Allende C, Allende J. Autophosphorylation of carboxy-terminal residues inhibits the activity of protein kinase CK1alpha. J Cell Biochem. 2009;106:399-408 pubmed publisher
    ..This work demonstrates that CK1alpha and its splice variants can be regulated by their autophosphorylation status. ..
  6. Garcia Fuster M, Ramos Miguel A, Miralles A, Garcia Sevilla J. Opioid receptor agonists enhance the phosphorylation state of Fas-associated death domain (FADD) protein in the rat brain: functional interactions with casein kinase Ialpha, Galpha(i) proteins, and ERK1/2 signaling. Neuropharmacology. 2008;55:886-99 pubmed publisher
    ..Neuropsychopharmacology 32, 399-411]. FADD phosphorylation by casein kinase Ialpha (CKIalpha) appears to regulate its non-apoptotic activity...
  7. Zhang L, Jia J, Wang B, Amanai K, Wharton K, Jiang J. Regulation of wingless signaling by the CKI family in Drosophila limb development. Dev Biol. 2006;299:221-37 pubmed
    ..Finally, we provide evidence that several CKI isoforms including CKIalpha and Gish/CKIgamma can phosphorylate the Wg coreceptor Arrow (Arr), which may account, at least in part, for their positive roles in the Wg pathway. ..
  8. Kucherenko Y, Zelenak C, Eberhard M, Qadri S, Lang F. Effect of casein kinase 1? activator pyrvinium pamoate on erythrocyte ion channels. Cell Physiol Biochem. 2012;30:407-17 pubmed publisher
  9. Banerjee D, Chen X, Lin S, Slack F. kin-19/casein kinase I? has dual functions in regulating asymmetric division and terminal differentiation in C. elegans epidermal stem cells. Cell Cycle. 2010;9:4748-65 pubmed

More Information


  1. Thorne C, Hanson A, Schneider J, Tahinci E, Orton D, Cselenyi C, et al. Small-molecule inhibition of Wnt signaling through activation of casein kinase 1?. Nat Chem Biol. 2010;6:829-36 pubmed publisher
    ..Our findings reveal allosteric activation of CK1? as an effective mechanism to inhibit Wnt signaling and highlight a new strategy for targeted therapeutics directed against the Wnt pathway. ..
  2. Sinnberg T, Menzel M, Kaesler S, Biedermann T, Sauer B, Nahnsen S, et al. Suppression of casein kinase 1alpha in melanoma cells induces a switch in beta-catenin signaling to promote metastasis. Cancer Res. 2010;70:6999-7009 pubmed publisher
    ..These results show that melanoma cells developed an efficient new mechanism to activate the beta-catenin signaling pathway and define CK1alpha as a novel tumor suppressor. ..
  3. Saraswati S, Alfaro M, Thorne C, Atkinson J, Lee E, Young P. Pyrvinium, a potent small molecule Wnt inhibitor, promotes wound repair and post-MI cardiac remodeling. PLoS ONE. 2010;5:e15521 pubmed publisher
    ..These results need to be further followed-up to determine if therapeutic inhibition of canonical Wnt may avert adverse remodeling after ischemic injury and its impact on myocardial repair and regeneration. ..
  4. Elyada E, Pribluda A, Goldstein R, Morgenstern Y, Brachya G, Cojocaru G, et al. CKI? ablation highlights a critical role for p53 in invasiveness control. Nature. 2011;470:409-13 pubmed publisher
    ..PSIS transcription and tumour invasion were suppressed by p21, independently of cell cycle control. Restraining tissue invasion through suppressing PSIS expression is thus a novel tumour-suppressor function of wild-type p53. ..
  5. Liu J, Carvalho L, Bhattacharya S, Carbone C, Kumar K, Leu N, et al. Mammalian casein kinase 1alpha and its leishmanial ortholog regulate stability of IFNAR1 and type I interferon signaling. Mol Cell Biol. 2009;29:6401-12 pubmed publisher
    ..major modestly decreased IFNAR1 levels and attenuated cellular responses to IFN-alpha in vitro. We propose a role for mammalian and parasite CK1 enzymes in regulating IFNAR1 stability and type I IFN signaling. ..
  6. Zelenak C, Eberhard M, Jilani K, Qadri S, Macek B, Lang F. Protein kinase CK1? regulates erythrocyte survival. Cell Physiol Biochem. 2012;29:171-80 pubmed publisher
    ..In conclusion, CK1 isoform ? participates in the regulation of erythrocyte programmed cell death by modulating cytosolic Ca(2+) activity...
  7. Gonzales M, Mellman D, Anderson R. CKIalpha is associated with and phosphorylates star-PAP and is also required for expression of select star-PAP target messenger RNAs. J Biol Chem. 2008;283:12665-73 pubmed publisher
    ..We identify the PI-4,5-P(2)-sensitive casein kinase Ialpha (CKIalpha) as a protein kinase responsible for this activity and further show that CKIalpha is capable of ..
  8. Strutt H, Price M, Strutt D. Planar polarity is positively regulated by casein kinase Iepsilon in Drosophila. Curr Biol. 2006;16:1329-36 pubmed
    ..Finally, we also find that dco function in polarity is partially redundant with CKIalpha. ..
  9. Quintavalle M, Sambucini S, Summa V, Orsatti L, Talamo F, De Francesco R, et al. Hepatitis C virus NS5A is a direct substrate of casein kinase I-alpha, a cellular kinase identified by inhibitor affinity chromatography using specific NS5A hyperphosphorylation inhibitors. J Biol Chem. 2007;282:5536-44 pubmed
    ..In vitro kinase reactions performed with NS5A peptides show that Ser-2204 is a preferred substrate residue for CKI-alpha after pre-phosphorylation of Ser-2201. ..
  10. Järås M, Miller P, Chu L, Puram R, Fink E, Schneider R, et al. Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia. J Exp Med. 2014;211:605-12 pubmed publisher
  11. Huart A, MacLaine N, Narayan V, Hupp T. Exploiting the MDM2-CK1? protein-protein interface to develop novel biologics that induce UBL-kinase-modification and inhibit cell growth. PLoS ONE. 2012;7:e43391 pubmed publisher
  12. Dejmek J, Säfholm A, Kamp Nielsen C, Andersson T, Leandersson K. Wnt-5a/Ca2+-induced NFAT activity is counteracted by Wnt-5a/Yes-Cdc42-casein kinase 1alpha signaling in human mammary epithelial cells. Mol Cell Biol. 2006;26:6024-36 pubmed
  13. Lin L, Peng S. Coordination of NF-kappaB and NFAT antagonism by the forkhead transcription factor Foxd1. J Immunol. 2006;176:4793-803 pubmed
    ..These findings indicate the presence of a general network of forkhead proteins that enforce T cell quiescence. ..
  14. Chen Y, Sasai N, Ma G, Yue T, Jia J, Briscoe J, et al. Sonic Hedgehog dependent phosphorylation by CK1? and GRK2 is required for ciliary accumulation and activation of smoothened. PLoS Biol. 2011;9:e1001083 pubmed publisher
    ..Hence, despite divergence in their primary sequences and their subcellular trafficking, mSmo and dSmo employ analogous mechanisms for their activation. ..
  15. Wu S, Chen L, Becker A, Schonbrunn E, Chen J. Casein kinase 1? regulates an MDMX intramolecular interaction to stimulate p53 binding. Mol Cell Biol. 2012;32:4821-32 pubmed publisher
    ..Therefore, CK1? is an important functional partner of MDMX. DNA damage activates p53 in part by disrupting CK1?-MDMX interaction and reducing MDMX-p53 binding affinity. ..
  16. Bao X, Siprashvili Z, Zarnegar B, Shenoy R, Rios E, Nady N, et al. CSNK1a1 Regulates PRMT1 to Maintain the Progenitor State in Self-Renewing Somatic Tissue. Dev Cell. 2017;43:227-239.e5 pubmed publisher
    ..Maintenance of the progenitors thus requires cooperation by PRMT1 and CSNK1a1 to sustain proliferation gene expression and suppress premature differentiation driven by GRHL3. ..
  17. Panchenko M, Siddiquee Z, Dombkowski D, Alekseyev Y, Lenburg M, Walker J, et al. Protein kinase CK1alphaLS promotes vascular cell proliferation and intimal hyperplasia. Am J Pathol. 2010;177:1562-72 pubmed publisher
    ..Our results indicate that the nuclear form of CK1alpha in humans, CK1alphaLS, plays a critical role in vascular cell proliferation, cellular activation, and hydrogen peroxide-mediated mitogenic signal transduction. ..
  18. Jia J, Zhang L, Zhang Q, Tong C, Wang B, Hou F, et al. Phosphorylation by double-time/CKIepsilon and CKIalpha targets cubitus interruptus for Slimb/beta-TRCP-mediated proteolytic processing. Dev Cell. 2005;9:819-30 pubmed
    ..We propose that phosphorylation of Ci by CKI creates multiple Slimb/beta-TRCP binding sites that act cooperatively to recruit SCF(Slimb/beta-TRCP). ..
  19. Wang H, Albadawi H, Siddiquee Z, Stone J, Panchenko M, Watkins M, et al. Altered vascular activation due to deficiency of the NADPH oxidase component p22phox. Cardiovasc Pathol. 2014;23:35-42 pubmed publisher
    ..Furthermore, these findings suggest that the effects of NADPH oxidase on vascular activation are mediated in part by protein kinase CK1?LS. ..
  20. Vaid M, Prasad R, Sun Q, Katiyar S. Silymarin targets ?-catenin signaling in blocking migration/invasion of human melanoma cells. PLoS ONE. 2011;6:e23000 pubmed publisher
    ..However, this effect of silymarin and FH535 was not found in Mel 1011 melanoma cells. These results indicate for the first time that silymarin inhibits melanoma cell migration by targeting ?-catenin signaling pathway. ..
  21. Borgal L, Rinschen M, Dafinger C, Liebrecht V, Abken H, Benzing T, et al. Jade-1S phosphorylation induced by CK1α contributes to cell cycle progression. Cell Cycle. 2016;15:1034-45 pubmed publisher
    ..As Jade-1S protein expression in the kidney is altered upon renal injury, this could contribute to understanding mechanisms underlying epithelial injury repair. ..
  22. Galletti M, Riccardo S, Parisi F, Lora C, Saqcena M, Rivas L, et al. Identification of domains responsible for ubiquitin-dependent degradation of dMyc by glycogen synthase kinase 3beta and casein kinase 1 kinases. Mol Cell Biol. 2009;29:3424-34 pubmed publisher
    ..Expression of the dMyc mutants in the compound eye of the adult fly results in a visible defect that is attributed to the effect of dMyc on growth, cell death, and inhibition of ommatidial differentiation. ..
  23. Tillement V, Lajoie Mazenc I, Casanova A, Froment C, Penary M, Tovar D, et al. Phosphorylation of RhoB by CK1 impedes actin stress fiber organization and epidermal growth factor receptor stabilization. Exp Cell Res. 2008;314:2811-21 pubmed publisher
    ..Our data provide the first demonstration of RhoB phosphorylation and indicate that this post-translational maturation would be a novel critical mechanism to control the RhoB functions. ..
  24. Sobrado P, Jedlicki A, Bustos V, Allende C, Allende J. Basic region of residues 228-231 of protein kinase CK1alpha is involved in its interaction with axin: binding to axin does not affect the kinase activity. J Cell Biochem. 2005;94:217-24 pubmed
    ..Binding of CK1alpha to axin is not required for the phosphorylation of axin itself and, likewise, axin does not affect the kinetic parameters of the CK1alpha towards casein or a specific peptide substrate. ..
  25. Laishram R, Barlow C, Anderson R. CKI isoforms ? and ? regulate Star-PAP target messages by controlling Star-PAP poly(A) polymerase activity and phosphoinositide stimulation. Nucleic Acids Res. 2011;39:7961-73 pubmed publisher
    ..Our results demonstrate that CKI isoforms ? and ? modulate Star-PAP activity and regulates Star-PAP target messages. ..
  26. Pasini F, Maistro S, Snitcovsky I, Barbeta L, Rotea Mangone F, Lehn C, et al. Four-gene expression model predictive of lymph node metastases in oral squamous cell carcinoma. Acta Oncol. 2012;51:77-85 pubmed publisher
    ..The genes identified here that integrate our "Nodal Index" model are predictive of lymph node metastasis in OSCC. ..
  27. Kuga T, Kume H, Kawasaki N, Sato M, Adachi J, Shiromizu T, et al. A novel mechanism of keratin cytoskeleton organization through casein kinase I? and FAM83H in colorectal cancer. J Cell Sci. 2013;126:4721-31 pubmed publisher
  28. Xue B, Dunker A, Uversky V. The roles of intrinsic disorder in orchestrating the Wnt-pathway. J Biomol Struct Dyn. 2012;29:843-61 pubmed
    ..Intrinsically disordered APC helps the collection of ?-catenin from cytoplasm, facilitates the b-catenin delivery to the binding sites on Axin, and controls the final detachment of ?-catenin from Axin. ..
  29. Kattapuram T, Yang S, Maki J, Stone J. Protein kinase CK1alpha regulates mRNA binding by heterogeneous nuclear ribonucleoprotein C in response to physiologic levels of hydrogen peroxide. J Biol Chem. 2005;280:15340-7 pubmed
    ..In contrast, hnRNP-C1 that was also modified at the CK1alpha phosphorylation sites exhibited a 14-500-fold decrease in binding affinity, demonstrating that CK1alpha-mediated phosphorylation modulates the mRNA binding ability of hnRNP-C. ..
  30. Medrek C, Landberg G, Andersson T, Leandersson K. Wnt-5a-CKI{alpha} signaling promotes {beta}-catenin/E-cadherin complex formation and intercellular adhesion in human breast epithelial cells. J Biol Chem. 2009;284:10968-79 pubmed publisher
    ..Furthermore, Wnt-5a/casein kinase Ialpha (CKIalpha)-specific Ser-45 phosphorylation of beta-catenin is associated with an increased complex ..
  31. Papoff G, Trivieri N, Crielesi R, Ruberti F, Marsilio S, Ruberti G. FADD-calmodulin interaction: a novel player in cell cycle regulation. Biochim Biophys Acta. 2010;1803:898-911 pubmed publisher
    ..We suggest that the interplay of FADD, CaM and CKIalpha may have an important role in the regulation of cell fate. ..
  32. Ahn J, Lee H, Kim S, Ha T. Curcumin-induced suppression of adipogenic differentiation is accompanied by activation of Wnt/beta-catenin signaling. Am J Physiol Cell Physiol. 2010;298:C1510-6 pubmed publisher
    ..Curcumin also increased mRNA levels of c-Myc and cyclin D1, well-known Wnt targets. These results suggest that the Wnt signaling pathway participates in curcumin-induced suppression of adipogenesis in 3T3-L1 cells. ..
  33. Horiguchi R, Yoshikuni M, Tokumoto M, Nagahama Y, Tokumoto T. Identification of a protein kinase which phosphorylates a subunit of the 26S proteasome and changes in its activity during meiotic cell cycle in goldfish oocytes. Cell Signal. 2005;17:205-15 pubmed
    ..A protein band which well corresponded to the kinase activity was identified as casein kinase Ialpha (CKIalpha)...
  34. Magliozzi R, Low T, Weijts B, Cheng T, Spanjaard E, Mohammed S, et al. Control of epithelial cell migration and invasion by the IKK?- and CK1?-mediated degradation of RAPGEF2. Dev Cell. 2013;27:574-85 pubmed publisher
    ..These findings reveal a molecular mechanism regulating migration and invasion of epithelial cells and establish a key direct link between IKK? and cell motility controlled by Rap-integrin signaling...
  35. Wang L, Lu A, Zhou H, Sun R, Zhao J, Zhou C, et al. Casein kinase 1 alpha regulates chromosome congression and separation during mouse oocyte meiotic maturation and early embryo development. PLoS ONE. 2013;8:e63173 pubmed publisher
    ..Taken together, our study for the first time demonstrates that CK1? is required for chromosome alignment and segregation during oocyte meiotic maturation and early embryo development. ..
  36. Legent K, Steinhauer J, Richard M, Treisman J. A screen for X-linked mutations affecting Drosophila photoreceptor differentiation identifies Casein kinase 1? as an essential negative regulator of wingless signaling. Genetics. 2012;190:601-16 pubmed publisher
    ..We thus propose that Casein kinase 1? is essential to allow ?-Catenin degradation and prevent inappropriate Wingless signaling, but its effects on the Hedgehog pathway are redundant with other Casein kinase 1 family members. ..
  37. Honaker Y, Piwnica Worms H. Casein kinase 1 functions as both penultimate and ultimate kinase in regulating Cdc25A destruction. Oncogene. 2010;29:3324-34 pubmed publisher
    ..The priming of Cdc25A by at least three kinases (Chk1, GSK-3beta, CK1alpha), some of which also require priming, ensures diverse extra- and intracellular signals interface with Cdc25A to precisely control cell division. ..
  38. Mennella V, Tan D, Buster D, Asenjo A, Rath U, Ma A, et al. Motor domain phosphorylation and regulation of the Drosophila kinesin 13, KLP10A. J Cell Biol. 2009;186:481-90 pubmed publisher
    ..We propose a model in which phosphorylation of the KLP10A motor domain provides a regulatory switch controlling the time and place of MT depolymerization. ..
  39. Campagna M, Budini M, Arnoldi F, Desselberger U, Allende J, Burrone O. Impaired hyperphosphorylation of rotavirus NSP5 in cells depleted of casein kinase 1alpha is associated with the formation of viroplasms with altered morphology and a moderate decrease in virus replication. J Gen Virol. 2007;88:2800-10 pubmed
    ..These data show that CK1alpha is the kinase that phosphorylates NSP5 in virus-infected cells and contribute to further understanding of the role of NSP5 in RV infection. ..
  40. Sudha G, Yamunadevi S, Tyagi N, Das S, Srinivasan N. Structural and molecular basis of interaction of HCV non-structural protein 5A with human casein kinase 1? and PKR. BMC Struct Biol. 2012;12:28 pubmed publisher
    ..Designing inhibitors to prevent this interaction could enable the HCV genotype 1 infected patients respond well to interferon therapy. ..
  41. Donald R, Zhong T, Meijer L, Liberator P. Characterization of two T. gondii CK1 isoforms. Mol Biochem Parasitol. 2005;141:15-27 pubmed
    ..Since the more cell-permeable aminopurvalanol also inhibits parasite growth, these results provide further impetus to investigate inhibitors of CK1 as anti-parasitic agents. ..
  42. Duan S, Skaar J, Kuchay S, Toschi A, Kanarek N, Ben Neriah Y, et al. mTOR generates an auto-amplification loop by triggering the ?TrCP- and CK1?-dependent degradation of DEPTOR. Mol Cell. 2011;44:317-24 pubmed publisher
    ..Moreover, our results suggest that pharmacologic inhibition of CK1 may be a viable therapeutic option for the treatment of cancers characterized by activation of mTOR-signaling pathways. ..
  43. Li L, Ren C, Yang G, Fattah E, Goltsov A, Kim S, et al. GLIPR1 suppresses prostate cancer development through targeted oncoprotein destruction. Cancer Res. 2011;71:7694-704 pubmed publisher
    ..Furthermore, they reveal parallel mechanisms of c-myc downregulation by GLIPR1 that when ablated in the prostate are sufficient to drive c-Myc expression and malignant development. ..
  44. Jones D, Domingues P, Targett Adams P, McLauchlan J. Comparison of U2OS and Huh-7 cells for identifying host factors that affect hepatitis C virus RNA replication. J Gen Virol. 2010;91:2238-48 pubmed publisher
    ..Therefore, this study provides an important framework for future detailed analyses of these and other cellular proteins. ..
  45. Parkinson E, Ettelaie R, Dickinson E. Using self-consistent-field theory to understand enhanced steric stabilization by casein-like copolymers at low surface coverage in mixed protein layers. Biomacromolecules. 2005;6:3018-29 pubmed
  46. Carvalho G, Le Guelte A, Demian C, Vazquez A, Gavard J, Bidere N. Interplay between BCL10, MALT1 and IkappaBalpha during T-cell-receptor-mediated NFkappaB activation. J Cell Sci. 2010;123:2375-80 pubmed publisher
    ..Altogether, our data suggest a two-step mechanism to connect active IKK to IkappaBalpha, and further unveil a potential role for IkappaBalpha in resetting TCR-mediated signalling. ..
  47. Alappat E, Feig C, Boyerinas B, Volkland J, Samuels M, Murmann A, et al. Phosphorylation of FADD at serine 194 by CKIalpha regulates its nonapoptotic activities. Mol Cell. 2005;19:321-32 pubmed
    ..We now demonstrate that casein kinase Ialpha (CKIalpha) phosphorylates FADD at Ser194 both in vitro and in vivo...
  48. Chergui K, Svenningsson P, Greengard P. Physiological role for casein kinase 1 in glutamatergic synaptic transmission. J Neurosci. 2005;25:6601-9 pubmed
    ..These results provide the first evidence for a role of CK1 in the regulation of synaptic transmission in the brain. ..
  49. Eisenmann D. C. elegans seam cells as stem cells: Wnt signaling and casein kinase I? regulate asymmetric cell divisions in an epidermal progenitor cell type. Cell Cycle. 2011;10:20-1 pubmed
  50. Bjorklund C, Ma W, Wang Z, Davis R, Kuhn D, Kornblau S, et al. Evidence of a role for activation of Wnt/beta-catenin signaling in the resistance of plasma cells to lenalidomide. J Biol Chem. 2011;286:11009-20 pubmed publisher
  51. Quintavalle M, Sambucini S, Di Pietro C, De Francesco R, Neddermann P. The alpha isoform of protein kinase CKI is responsible for hepatitis C virus NS5A hyperphosphorylation. J Virol. 2006;80:11305-12 pubmed
    ..Finally, we showed that down-regulation of CKI-alpha attenuates HCV RNA replication. ..
  52. Nyati S, Ranga R, Ross B, Rehemtulla A, Bhojani M. Molecular imaging of glycogen synthase kinase-3beta and casein kinase-1alpha kinases. Anal Biochem. 2010;405:246-54 pubmed publisher