Casein kinase 1 alpha 1 (CK1α)

Casein kinase 1 alpha 1 (CK1α) is a ubiquitous serine/threonine protein kinase that serves as a master regulator of diverse cellular processes, including signal transduction, cell cycle progression, and DNA repair (UniProt P48729). It is a key component of the β-catenin destruction complex, where it phosphorylates β-catenin at Ser45 to prime it for further phosphorylation and subsequent proteasomal degradation, thereby acting as a negative regulator of the Wnt signaling pathway (J. Biol. Chem. 2011 286:10). CK1α also regulates the tumor suppressor p53 by phosphorylating its regulators MDM2 and MDMX, and its loss can trigger a p53-dependent apoptotic response (Cancer Cell 2014 26:4). In the treatment of myelodysplastic syndrome (MDS) with a deletion of chromosome 5q (del(5q)), CK1α is the primary target of the drug lenalidomide. Lenalidomide acts as a molecular glue that recruits CK1α to the CRL4-CRBN E3 ubiquitin ligase complex, leading to its selective degradation (Nature 2015 523:7559). Because del(5q) MDS cells are haploinsufficient for the CSNK1A1 gene, they are uniquely sensitive to this degradation, which provides a therapeutic window for the drug to eliminate malignant clones while sparing normal hematopoietic cells (Blood 2015 126:21).

Other names

CSNK1A1CK1aCKIaCasein kinase I isoform alphaClock regulator kinaseHEL-S-77p

Lenalidomide and related immunomodulatory drugs (IMiDs) act as molecular glues that bind to the cereblon (CRBN) subunit of the CRL4-CRBN E3 ubiquitin ligase complex. This binding alters the substrate specificity of the ligase, inducing the recruitment, ubiquitination, and subsequent proteasomal degradation of Casein kinase 1 alpha 1 (CK1α). In del(5q) myelodysplastic syndrome, this degradation leads to p53-mediated apoptosis of malignant cells.