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

Abstract

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.

Skeletal Deficits in Male and Female down Syndrome Model Mice Arise Independent of Normalized Dyrk1a Expression in Osteoblasts

“…1.4. DYRK1A Gene Dosage Contributes to the Development of Skeletal Phenotypes in Ts21 DYRK1A, a gene found in three copies of most DS mouse models and individuals with DS, is a candidate gene for cognitive impairment, Alzheimer-like phenotypes, and skeletal abnormalities related to DS [36][37][38][39][40]. Transgenic mice overexpressing Dyrk1a displayed appendicular skeletal deficiencies and osteopenia [27].…”

Design and Microwave Synthesis of New (5Z) 5-Arylidene-2-thioxo-1,3-thiazolinidin-4-one and (5Z) 2-Amino-5-arylidene-1,3-thiazol-4(5H)-one as New Inhibitors of Protein Kinase DYRK1A

“…The Dyrk1A gene is located within the human chromosome 21 Down Syndrome Critical Region (DSCR) [3]. According to recent literature, DYRK1A appears to be involved in various diseases, including Alzheimer's disease (AD), Down syndrome (DS) [4], and cancer [5][6][7], and many efforts have evolved over the last five years toward the identification of potent and selective DYRK1A inhibitors [8,9]. Few potent and selective Dyrks inhibitors have been described (Figure 1).…”

Computer-Aided Drug Design (CADD) to De-Orphanize Marine Molecules: Finding Potential Therapeutic Agents for Neurodegenerative and Cardiovascular Diseases

“…Both belong to the so-called dual specificity kinases (EC 2.7.12.1) which include CLKs (1-4) and DYRKs (1A,1B, 2-4), among others. They are related to different diseases, including neurodegenerative disorders, cancer, or diabetes [116]. Meridianin-A binds to the orthosteric, ATP, binding site in both cases, establishing similar interactions as reported inhibitors.…”