CDC-like kinase 1-4 (CLK1-4) and Dual-specificity tyrosine-phosphorylation-regulated kinase 1-4 (DYRK1-4) (CLK1-4 and DYRK1-4)

The CDC-like kinase (CLK) and Dual-specificity tyrosine-phosphorylation-regulated kinase (DYRK) families are closely related groups of enzymes within the CMGC kinase superfamily that serve as critical regulators of cellular homeostasis (UniProt P23292, Q13627). CLKs (CLK1, CLK2, CLK3, and CLK4) are primarily localized in the nucleus where they phosphorylate serine/arginine-rich (SR) proteins, essential components of the spliceosome that dictate alternative pre-mRNA splicing (PMID: 30241112). DYRKs (DYRK1A, DYRK1B, DYRK2, DYRK3, and DYRK4) are dual-specificity kinases that autophosphorylate on tyrosine residues for activation but phosphorylate substrates on serine/threonine residues, influencing cell proliferation, differentiation, and survival (PMID: 25708155). Dysregulation of these kinases is a hallmark of several major diseases; for instance, DYRK1A overactivity is linked to the cognitive deficits of Down syndrome and the hyperphosphorylation of tau in Alzheimer's disease, while CLKs are frequently overexpressed in various cancers to promote pro-tumorigenic splicing variants (PMID: 29153509, PMID: 31439716). Therapeutic targeting of these families often involves small-molecule inhibitors, such as Lorecivivint for osteoarthritis or Silmitasertib for oncology, which aim to restore normal splicing and signaling patterns (ClinicalTrials.gov NCT03122860).

Other names

CLKsDYRKsCDC-like kinasesDual-specificity tyrosine-phosphorylation-regulated kinasesCMGC kinasesLAMMER kinases

ATP-competitive inhibition of kinase activity to prevent the phosphorylation of substrate proteins, such as serine/arginine-rich (SR) proteins for CLKs and Tau or MAP proteins for DYRKs, thereby modulating alternative splicing and intracellular signaling pathways (PMID: 29153509, PMID: 30241112).