The Omnipresence of DYRK1A in Human Diseases

Abstract

The increasing population will challenge healthcare, particularly because the worldwide population has never been older. Therapeutic solutions to age-related disease will be increasingly critical. Kinases are key regulators of human health and represent promising therapeutic targets for novel drug candidates. The dual-specificity tyrosine-regulated kinase (DYRKs) family is of particular interest and, among them, DYRK1A has been implicated ubiquitously in varied human diseases. Herein, we focus on the characteristics of DYRK1A, its regulation and functional role in different human diseases, which leads us to an overview of future research on this protein of promising therapeutic potential.

Keywords: DYRK1A; cancers; diabetes; heart diseases; neurodegenerative diseases; protein kinase; viral infections.

Figure 1

DYRK family of proteins origins and specificities in humans (based on [10,14,15,16,17,18,19,20]). The percentage of conservation at the protein level between orthologues is indicated above the arrows and between two paralogues is indicated in parentheses within the boxes.

Figure 2

Schematic representation of the protein sequences of the 5 human DYRKs (from uniport.org and based on [10,24]). The different protein motifs identified are indicated: NLS, nuclear localization signal; DH, DYRK-homology box; NAPA, N-terminal autophosphorylation accessory region; kinase, kinase domain; PEST, motif rich in proline, glutamic acid, serine, and threonine residues; His, polyhistidine domain; S/T, serine and threonine-enriched domain; and Y, tyrosine residue autophosphorylated by DYRKs within the activation loop. Turquoise lines indicate protein regions affected by alternative splicing events.

Figure 3

Schematic representation of the spectrum of action of a DYRK1A activator or inhibitor on the development of neurological (in green) and other diseases (in brown) in humans. Pathologies are labeled with a green cross if DYRK1A activation is a potential therapeutic solution and with a red line if DYRK1A inhibition is a potential solution.