Casein kinase 1 alpha (CK1α) (CK1α)

Casein kinase 1 alpha (CK1α) is a ubiquitous serine/threonine protein kinase that plays a central role in regulating the Wnt/beta-catenin signaling pathway and the p53-mediated DNA damage response (UniProt P48729). It is encoded by the CSNK1A1 gene, which is located on chromosome 5q; its haploinsufficiency is a defining feature of myelodysplastic syndrome (MDS) with del(5q) (Kronke et al., Nature 2015). CK1α is recognized as a "neo-substrate" because it is not a natural substrate of the cereblon (CRBN) E3 ubiquitin ligase but is recruited to it in the presence of thalidomide analogs like lenalidomide. This drug-induced proximity leads to the polyubiquitination and subsequent proteasomal degradation of CK1α. Because del(5q) MDS cells already possess reduced levels of CK1α, further degradation by lenalidomide drives the protein below a survival threshold, inducing p53-dependent cell cycle arrest and apoptosis (Fink et al., Blood 2018). This mechanism explains the high sensitivity of del(5q) MDS to lenalidomide compared to other hematologic conditions.

Other names

CSNK1A1Casein kinase I isoform alphaCK1aCKI-alphaHCKP1

Molecular glue-mediated targeted protein degradation via the CRL4-CRBN E3 ubiquitin ligase complex (Kronke et al., Nature 2015).