Casein kinase I isoform alpha (CK1α) (CK1α)

Casein kinase I isoform alpha (CK1α), encoded by the CSNK1A1 gene, is a ubiquitous serine/threonine kinase that serves as a central regulator of various signaling pathways, including the Wnt/beta-catenin and p53 pathways (UniProt P48729). It plays a critical role in maintaining cellular homeostasis by phosphorylating key substrates involved in cell cycle progression and DNA damage responses (Kronke et al., 2015, Nature). In the context of hematology, CK1α is a validated therapeutic target for myelodysplastic syndrome (MDS) characterized by the deletion of chromosome 5q [del(5q)], a condition where the CSNK1A1 gene is haploinsufficient (Schneider et al., 2014, Cancer Cell). The immunomodulatory drug lenalidomide functions as a molecular glue that facilitates a de novo interaction between CK1α and the cereblon (CRBN) E3 ubiquitin ligase complex, leading to the selective ubiquitination and proteasomal degradation of CK1α (Petzold et al., 2016, Nature). This degradation triggers a p53-dependent apoptotic response that is particularly lethal to del(5q) MDS cells due to their reduced baseline dosage of the enzyme, providing a mechanism for the clinical efficacy of lenalidomide in this patient population (Fink et al., 2018, Blood).

Other names

CSNK1A1CK1aCasein kinase 1 alphaCKI-alphaHCK1A

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