DYRK2 kinase is an enzyme encoded by the DYRK2 gene in humans. DYRK2 is a member of the class II DYRK family of proteins and is a key regulator of p53, which can phosphorylate at Ser46, thereby inducing apoptosis in response to DNA damage. In addition, recent studies have found that DYRK2 regulates G1/S transition, epithelial-mesenchymal transition and stemness in human cancer cells. DYRK2 also appears to play a role in the tissue development of lower eukaryotes. DYRK2 belongs to a family of protein kinases, and its members may be involved in cell growth and development. This family is defined by the structural similarity of its kinase domains and their ability to autophosphorylate on tyrosine residues. DYRK2 has demonstrated in vitro autophosphorylation of tyrosine and catalytic phosphorylation of histones H3 and H2B. The two isoforms of DYRK2 have been separated. The main isoform, isoform 1, lacks a 5 'end insert.

Figure 1. Protein structure of DYRK2.

Regulation of cell differentiation

In DYRK, it is well known that DYRK1A plays an important role in promoting neuronal differentiation in the developing cerebral cortex. However, there are few reports on the spatiotemporal expression pattern and function of DYRK2 in mammalian development. Here, we attempt to summarize the evidence for DYRK2 in the development and cell differentiation of several species. Although the Dyrk2 ineffective fly is homozygous and has no visible phenotype, the mutant shows a molecular mechanism of damage in both olfactory behavior (response to aversion to odor) and the visual system (light transduction activity). DYRK2 reduces vision and olfactory responses remain unclear. However, this knockout-based analysis suggests that DYRK2 is certainly involved in tissue development.

Regulates the cell cycle as a promoter of GSK3

DYRK2 also acts as a starter kinase for GSK3, which is a serine/threonine kinase. In a hierarchical phosphorylation system, the efficiency of GSK3 substrate phosphorylation can be greatly improved by initiating phosphorylation. As a starter kinase, DYRK2 can directly phosphorylate c-Jun at Ser24 and c-Myc at Ser62, thereby regulating G1/S conversion to oncogenic transcription factors (Figure 2). These phosphorylation sites promote subsequent phosphorylation of GSK3. GSK3 phosphorylated c-Jun and c-Myc are recognized and ubiquitinated by Skp1-cullin-F-box-protein complex (SCF), a ubiquitin ligase-mediated degradation system. In the SCF system, two phosphorylation sites trigger and process kinases recognize F-box proteins (such as F-box and protein 7 (Fbw7) containing the WD-40 repeat domain) and are triggered by the ubiquitin proteasome system Protein degradation is essential. These evidences indicate that DYRK2 regulates the cell cycle by regulating the renewal of target proteins through the ubiquitin-proteasome degradation system.

Conclusions

Considering in vitro and xenograft studies and the down-regulation of DYRK2 in tumor specimens, DYRK2 is an important candidate drug for suppressing tumors and may have the potential for new anticancer genes. However, especially in breast tumor cells, whether DYRK2 functions as a tumor suppressor gene or oncogene is still controversial and needs further research. In contrast to tumor cells, little is known about the function of DYRK2 in mammalian development. However, some evidence supports that DYRK2 regulates the activation and rapid degradation of target proteins in several species. This evidence makes it possible to speculate that DYRK2 is also involved in mammalian rapid differentiation and cytoskeleton tissue. Further in vivo studies are needed, such as identifying the spatiotemporal expression patterns of Dyrk2 and methods using knockout animals, which will provide new insights into the mechanisms of DYRK2 in mammalian development and cancer progression.

References:

1. Becker W; et al. Sequence characteristics, subcellular localization, and substrate specificity of DYRK-related kinases, a novel family of dual specificity protein kinases. J Biol Chem. 1998, 273 (40): 25893–902.
2. Yoshida S; et al. Multiple functions of DYRK2 in cancer and tissue development. FEBS Letters. 2019.