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.
Highlights
Tinct sequences are indicated: Activation loop and tyrosine residue that is autophosphorylated (Yn); nuclear localization signal domain (NB: a NLS sequence is only found in isoform 4 of DYRK4, not in the canonical homology box; His domain, 13 consecutive kinase quence); PEST, proline (P), glutamic acid (E), serine (S), and histidine threonineresidues (T)-richregion; domain; S/T,domain; serine, and thr nine-enriched domain; WDR68 binding domain
NAPA, N-terminal autophosphorylation accessory domain; NLS, nuclear localization signal domain (NB: a NLS sequence is only found in isoform 4 of DYRK4, not in the canonical sequence); PEST, proline (P), glutamic acid (E), serine (S), and threonine (T)-rich domain; S/T, serine, and threonineenriched domain; WDR68 binding domain
The gene encoding DYRK1A is located on chromosome 21, within the Down syndrome critical region (DSCR), the triploidy of which is responsible for most DS-associated deficiencies (Table 3 for more details)
Summary
Protein phosphorylation is probably one of the most important and most studied mechanism used by cells to regulate their proteins in terms of enzymatic activity, functions, localization, half-life, interactions with other proteins or other ligands, etc. It is a key mechanism for signal transduction between cells and within cells. Protein kinases catalyze the transfer of the of ATP to the the hydroxyl substituents of serine, threonine, or tyrosine residues in proteins, thereby altering hydroxyl substituents of serine, threonine, or tyrosine residues in proteins, thereby altering the the physiological properties of their protein substrates.
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