Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinases (DYRKs) and cdc2-Like Kinases (CLKs) in Human Disease, an Overview

Int J Mol Sci. 2021 Jun 3;22(11):6047. doi: 10.3390/ijms22116047.


Dual-specificity tyrosine phosphorylation-regulated kinases (DYRK1A, 1B, 2-4) and cdc2-like kinases (CLK1-4) belong to the CMGC group of serine/threonine kinases. These protein kinases are involved in multiple cellular functions, including intracellular signaling, mRNA splicing, chromatin transcription, DNA damage repair, cell survival, cell cycle control, differentiation, homocysteine/methionine/folate regulation, body temperature regulation, endocytosis, neuronal development, synaptic plasticity, etc. Abnormal expression and/or activity of some of these kinases, DYRK1A in particular, is seen in many human nervous system diseases, such as cognitive deficits associated with Down syndrome, Alzheimer's disease and related diseases, tauopathies, dementia, Pick's disease, Parkinson's disease and other neurodegenerative diseases, Phelan-McDermid syndrome, autism, and CDKL5 deficiency disorder. DYRKs and CLKs are also involved in diabetes, abnormal folate/methionine metabolism, osteoarthritis, several solid cancers (glioblastoma, breast, and pancreatic cancers) and leukemias (acute lymphoblastic leukemia, acute megakaryoblastic leukemia), viral infections (influenza, HIV-1, HCMV, HCV, CMV, HPV), as well as infections caused by unicellular parasites (Leishmania, Trypanosoma, Plasmodium). This variety of pathological implications calls for (1) a better understanding of the regulations and substrates of DYRKs and CLKs and (2) the development of potent and selective inhibitors of these kinases and their evaluation as therapeutic drugs. This article briefly reviews the current knowledge about DYRK/CLK kinases and their implications in human disease.

Keywords: Alzheimer’s disease; CLKs; DYRKs; Down syndrome; acute lymphoblastic leukemia; kinase; kinase inhibitor; type 1 diabetes; type 2 diabetes; viral infections.

Publication types

  • Review

MeSH terms

  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / genetics*
  • CDC2-CDC28 Kinases / genetics*
  • Cell Differentiation / genetics
  • Diabetes Mellitus / drug therapy
  • Diabetes Mellitus / genetics
  • Down Syndrome / drug therapy
  • Down Syndrome / genetics*
  • Dyrk Kinases
  • Humans
  • Phosphorylation / genetics
  • Protein Kinase Inhibitors / therapeutic use
  • Protein Serine-Threonine Kinases / genetics*
  • Protein-Tyrosine Kinases / genetics*
  • Signal Transduction / drug effects


  • Protein Kinase Inhibitors
  • DYRK3 protein, human
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • CDC2-CDC28 Kinases