Alternative titles; symbols
HGNC Approved Gene Symbol: CSNK1A1
Cytogenetic location: 5q32 Genomic coordinates (GRCh38): 5:149,492,982-149,551,439 (from NCBI)
Tapia et al. (1994) isolated a cDNA encoding human casein kinase I from a fetal brain library using PCR primers based on the bovine sequence. The cDNA was sequenced and shown to have a predicted amino acid sequence identical to the bovine protein except that it contains 12 additional amino acids at the carboxyl end.
Jia et al. (2004) showed that protein kinase A (PKA; see 188830) and casein kinase I (CKI) regulate Smo (601500) cell surface accumulation and activity in response to hedgehog (Hh; see 600725). Blocking PKA or CKI activity in the Drosophila wing disc prevented Hh-induced Smo accumulation and attenuated pathway activity, whereas increasing PKA activity promoted Smo accumulation and pathway activation. Jia et al. (2004) showed that PKA and CKI phosphorylate Smo at several sites, and that phosphorylation-deficient forms of Smo fail to accumulate on the cell surface and are unable to transduce the Hh signal. Conversely, phosphorylation-mimicking Smo variants showed constitutive cell surface expression and signaling activity. Furthermore, Jia et al. (2004) found that the levels of Smo cell surface expression and activity correlated with its levels of phosphorylation. Jia et al. (2004) concluded that Hh induces progressive Smo phosphorylation by PKA and CKI, leading to elevation of Smo cell surface levels and signaling activity.
Bidere et al. (2009) conducted parallel screens involving a mass spectrometry analysis of CARMA1 (607210) binding partners and an RNA interference screen for growth inhibition of the CBM-dependent 'activated B cell-like' (ABC) subtype of diffuse large B-cell lymphoma (DLBCL; see 605027). Bidere et al. (2009) reported that both screens identified CK1-alpha as a bifunctional regulator of NF-kappa-B (164011). CK1-alpha dynamically associates with the CBM complex on T cell receptor engagement to participate in cytokine production and lymphocyte proliferation. However, CK1-alpha kinase activity has a contrasting role by subsequently promoting the phosphorylation and inactivation of CARMA1. CK1-alpha has thus a dual 'gating' function which first promotes and then terminates receptor-induced NF-kappa-B. ABC DLBCL cells required CK1-alpha for constitutive NF-kappa-B activity, indicating that CK1-alpha functions as a conditionally essential malignancy gene.
Elyada et al. (2011) showed that casein kinase I-alpha, a component of the beta-catenin (116806) destruction complex, is a critical regulator of the Wnt signaling (see 164820) pathway. Inducing the ablation of Csnk1a1 in the gut triggers massive Wnt activation, surprisingly without causing tumorigenesis. CKI-alpha-deficient epithelium shows many of the features of human colorectal tumors in addition to Wnt activation, in particular the induction of the DNA damage response and cellular senescence, both of which are thought to provide a barrier against malignant transformation. The epithelial DNA damage response in mice is accompanied by substantial activation of p53 (191170), suggesting that the p53 pathway may counteract the protumorigenic effects of Wnt hyperactivation. Notably, the transition from benign adenomas to invasive colorectal cancer in humans is typically linked to p53 inactivation, underscoring the importance of p53 as a safeguard against malignant progression; however, the mechanism of p53-mediated tumor suppression is unknown. Elyada et al. (2011) showed that the maintenance of intestinal homeostasis in CKI-alpha-deficient gut requires p53-mediated growth control, because the combined ablation of Csnk1a1 and either p53 or its target gene p21 (116899) triggered high-grade dysplasia with extensive proliferation. Unexpectedly, these ablations also induced nonproliferating cells to invade the villous lamina propria rapidly, producing invasive carcinomas throughout the small bowel. Furthermore, in p53-deficient gut, loss of heterozygosity of the gene encoding CKI-alpha caused a highly invasive carcinoma, indicating that CKI-alpha caused a highly invasive carcinoma, indicating that CKI-alpha functions as a tumor suppressor when p53 is inactivated. Elyada et al. (2011) identified a set of genes (the p53-suppressed invasiveness signature, PSIS) that is activated by the loss of both p53 and CKI-alpha and which probably accounts for the brisk induction of invasiveness. PSIS transcription and tumor invasion were suppressed by p21, independently of cell cycle control. Restraining tissue invasion through suppressing PSIS expression is thus a novel tumor suppressor function of wildtype p53. PROX1 (601546), IFITM2 (605578), and IFITM3 (605579) are all PSIS genes.
Lenalidomide is a highly effective treatment for myelodysplastic disease with deletion of chromosome 5q (del(5q) MDS; 153550). Kronke et al. (2015) demonstrated that lenalidomide induces the ubiquitination of CK1-alpha by the E3 ubiquitin ligase CUL4 (see 603137)-RBX1 (603814)-DDB1 (600045)-CRBN (609262) (known as CUL4-CRBN), resulting in CK1-alpha degradation. CK1-alpha is encoded by a gene, CSNK1A1, within the common deleted region for del(5q) MDS, and haploinsufficient expression sensitizes cells to lenalidomide therapy, providing a mechanistic basis for the therapeutic window of lenalidomide in del(5q) MDS. Kronke et al. (2015) found that mouse cells are resistant to lenalidomide, but that changing a single amino acid in mouse Crbn to the corresponding human residue enables lenalidomide-dependent degradation of CK1-alpha. The authors further demonstrated that minor side-chain modifications in thalidomide and a novel analog, CC-122, can modulate the spectrum of substrates targeted by CRL4-CRBN.
Tapia et al. (1994) identified YAC genomic clones containing the human gene and used them to map CKI to chromosome 13q13. Fish et al. (1995) mapped the CSNK1A1 gene to chromosome 13q13.1-q14.1 by FISH. However, Gross (2011) mapped the CSNK1A1 gene to chromosome 5q32 based on an alignment of the CSNK1A1 sequence (GenBank BC008717) with the genomic sequence (GRCh37).
Bidere, N., Ngo, V. N., Lee, J., Collins, C., Zheng, L., Wan, F., Davis, R. E., Lenz, G., Anderson, D. E., Arnoult, D., Vazquez, A., Sakai, K., Zhang, J., Meng, Z., Veenstra, T. D., Staudt, L. M., Lenardo, M. J. Casein kinase 1-alpha governs antigen-receptor-induced NF-kappa-B activation and human lymphoma cell survival. Nature 458: 92-96, 2009. [PubMed: 19118383] [Full Text: https://doi.org/10.1038/nature07613]
Elyada, E., Pribluda, A., Goldstein, R. E., Morgenstern, Y., Brachya, G., Cojocaru, G., Snir-Alkalay, I., Burstain, I., Haffner-Krausz, R., Jung, S., Wiener, Z., Alitalo, K., Oren, M., Pikarsky, E., Ben-Neriah, Y. CKI-alpha ablation highlights a critical role for p53 in invasiveness control. Nature 470: 409-413, 2011. [PubMed: 21331045] [Full Text: https://doi.org/10.1038/nature09673]
Fish, K. J., Cegielska, A., Getman, M. E., Landes, G. M., Virshup, D. M. Isolation and characterization of human casein kinase I-epsilon (CKI), a novel member of the CKI gene family. J. Biol. Chem. 270: 14875-14883, 1995. [PubMed: 7797465] [Full Text: https://doi.org/10.1074/jbc.270.25.14875]
Gross, M. B. Personal Communication. Baltimore, Md. 2/9/2011.
Jia, J., Tong, C., Wang, B., Luo, L., Jiang, J. Hedgehog signalling activity of Smoothened requires phosphorylation by protein kinase A and casein kinase I. Nature 432: 1045-1050, 2004. [PubMed: 15616566] [Full Text: https://doi.org/10.1038/nature03179]
Kronke, J., Fink, E. C., Hollenbach, P. W., MacBeth, K. J., Hurst, S. N., Udeshi, N. D., Chamberlain, P. P., Mani, D. R., Man, H. W., Gandhi, A. K., Svinkina, T., Schneider, R. K., and 9 others. Lenalidomide induces ubiquitination and degradation of CK1-alpha in del(5q) MDS. Nature 523: 183-188, 2015. [PubMed: 26131937] [Full Text: https://doi.org/10.1038/nature14610]
Tapia, C., Featherstone, T., Gomez, C., Taillon-Miller, P., Allende, C. C., Allende, J. E. Cloning and chromosomal localization of the gene coding for human protein kinase CK1. FEBS Lett. 349: 307-312, 1994. [PubMed: 8050587] [Full Text: https://doi.org/10.1016/0014-5793(94)00679-2]