Insights from the protein interaction Universe of the multifunctional "Goldilocks" kinase DYRK1A

Abstract

Human Dual specificity tyrosine (Y)-Regulated Kinase 1A (DYRK1A) is encoded by a dosage-dependent gene located in the Down syndrome critical region of human chromosome 21. The known substrates of DYRK1A include proteins involved in transcription, cell cycle control, DNA repair and other processes. However, the function and regulation of this kinase is not fully understood, and the current knowledge does not fully explain the dosage-dependent function of this kinase. Several recent proteomic studies identified DYRK1A interacting proteins in several human cell lines. Interestingly, several of known protein substrates of DYRK1A were undetectable in these studies, likely due to a transient nature of the kinase-substrate interaction. It is possible that the stronger-binding DYRK1A interacting proteins, many of which are poorly characterized, are involved in regulatory functions by recruiting DYRK1A to the specific subcellular compartments or distinct signaling pathways. Better understanding of these DYRK1A-interacting proteins could help to decode the cellular processes regulated by this important protein kinase during embryonic development and in the adult organism. Here, we review the current knowledge of the biochemical and functional characterization of the DYRK1A protein-protein interaction network and discuss its involvement in human disease.

Keywords: DCAF7; FAM117B; FAM53C; GLCCI1; RNF169; TROAP; development; proteomic analysis.

FIGURE 1

Schema of the motifs found in DYRK family of protein kinases. This family is characterized by autophosphorylation of a key tyrosine (pY) residue within the activation loop, and by the presence of the DYRK-homology box (DH). Most DYRK proteins have a recognizable nuclear localization signal (NLS). The Class I kinases DYRK1A and DYRK1B share a DCAF7-binding domain and the motif rich in proline, glutamic acid, serine, and threonine residues (PEST), while the Class II kinases are characterized by the N-terminal autophosphorylation accessory region (NAPA). DYRK1A also contains several unique motifs, including a second NLS within the kinase domain, a histidine-rich domain (HIS) and a regulatory serine and threonine-rich motif (S/T).

FIGURE 2

Comparison of the DYRK1A proteomic studies reveals the most reproducible interactors. The lists of the protein hits from the four independent studies using DYRK1A as a bait (Varjosalo et al., 2013; Guard et al., 2019; Menon et al., 2019; Roewenstrunk et al., 2019) were obtained from the BioGrid, and compared using publicly available web tool (http://bioinformatics.psb.ugent.be/cgi-bin/liste/Venn/calculate_venn.htpl). Proteins detected in at least three independent studies (shown in bold) are discussed in detail here.

FIGURE 3

Schematic presentation of the DYRK1A interaction network in the context of human disease. Both gains or losses of DYRK1A during the development or in the adult organism could deregulate various biological processes mediated by multitude of its substrates and binding partners. Characterization of distinct DYRK1A functional networks in specific cell types or stages of development could inform the future therapeutic development for a precise fine-tuning of its activity. Created with http://www.BioRender.com.