Casein kinase 1 alpha (CSNK1A1) (CK1α)

Casein kinase 1 alpha (CK1α), encoded by the CSNK1A1 gene, is a ubiquitous serine/threonine kinase that acts as a key regulator of diverse cellular processes, including the Wnt/beta-catenin signaling pathway and the p53 tumor suppressor response (UniProt P48729). It has emerged as a critical therapeutic target in hematologic malignancies, specifically myelodysplastic syndrome (MDS) characterized by the deletion of chromosome 5q [del(5q)]. The therapeutic strategy utilizes lenalidomide, an immunomodulatory drug (IMiD) that functions as a molecular glue. Lenalidomide binds to Cereblon (CRBN), the substrate recognition component of the CRL4^CRBN E3 ubiquitin ligase complex, creating a neo-interface that recruits CK1α as a neosubstrate for polyubiquitination and subsequent proteasomal degradation (Kronke et al., 2015, Nature). Because the CSNK1A1 gene is located within the commonly deleted region of chromosome 5q, del(5q) MDS cells are haploinsufficient for CK1α and are uniquely sensitive to its further drug-induced depletion. This depletion triggers a p53-dependent apoptotic response that selectively eliminates the malignant clone while sparing normal hematopoietic cells (Fink et al., 2018, Blood). This mechanism represents a landmark example of using small molecules to induce the degradation of specific proteins to exploit genetic vulnerabilities in cancer.

Other names

CSNK1A1Casein kinase I isoform alphaCK1aCK1-alphaCK1alpha

Molecular glue-induced recruitment to the CRL4-CRBN E3 ubiquitin ligase complex, leading to polyubiquitination and proteasomal degradation.