DYRK1A is a member of the bispecific tyrosine phosphorylation regulated kinase (DYRK) family. This member contains a nuclear targeting signal sequence, a protein kinase domain, a leucine zipper motif, and a highly conserved 13 consecutive histidine repeats. This gene is a homolog of the fruit fly mnb (minibrain) gene and the rat Dyrk gene. It plays a very important role not only in physiological processes such as nerve development, cell proliferation and differentiation, but also in the pathogenesis of neurodegenerative diseases. In addition, its function in other pathogenesis and signaling pathways is also important. It catalyzes its own phosphorylation on serine/threonine and tyrosine residues. It may play an important role in the signaling pathways that regulate cell proliferation and may be involved in brain development.

Figure 1. Protein structure of DYRK1A.

Study on the role of DYRK1A in tumor formation

The role of DYRK1A in tumors is not clear. Studies have found that adult DS patients have significantly lower cancer rates than normal adults. DYRK1A is underexpressed in the bone marrow of patients with acute myeloid leukemia (AML). Overexpression of DYRK1A can reduce the proliferation of AML cells by increasing the G0/G1 phase ratio. Relapsed patients have significantly lower expression of DYRK1A than newly diagnosed patients. It indicates that DYRK1A can be used as a tumor suppressor. However, other studies have shown that DYRK1A is highly expressed in glioblastoma (GBM), and its role is related to EGFR. Inhibition of DYRK1A in early GBM cells and neural progenitor cells will promote the degradation of EGFR, significantly reducing the self-renewal ability of normal and tumor-forming cells. Inhibition of DYRK1A makes EGFR unstable and reduces the growth of EGFR-dependent GBM. Other studies have shown that inactivation of nuclear factor of activated T cells (NFATc) through phosphorylation of DYRK1A can improve the migration ability of breast cancer cells and drug resistance of leukemia cells; DYRK1A can phosphorylate heterochromatin protein Thr45 and ser57 sites of 1 (heterochromatin protein 1, HP1), which caused abnormal activation of cytokine gene expression and caused DS-associated megakaryotic leukemia. It has been reported that DYRK1A can form a DREAM complex with several other proteins, and terminates cell division and enters the dormant phase by phosphorylating Ser28 of Protein LIN52. DREAM-deficient mice show defects in cartilage formation and postnatal death due to inhibition of cell proliferation.

Study on the role of DYRK1A in other diseases

There are many substrates for DYRK1A, most of which have been confirmed in in vitro kinase activity experiments, but only a small part has been confirmed in vivo, such as caspase-9 and Tau proteins. Human fetal and AD patients have similar levels of Tau protein phosphorylation, but fetal Tau protein does not appear in polymer form or Tau disease. Because there are many similarities between islet β cells and neuronal cells in gene expression and development, the role of DYRK1A in the development of islet β cells and the changes in the expression of DYRK1A on mouse β cells have also attracted attention. It is shown that insufficient single dose of DYRK1A reduces the number of islet β cells, the cell volume becomes smaller, and the cell proliferation is affected. This shows that the expression of DYRK1A is related to diabetes.

Conclusions

Since its discovery, the DYRK1A molecule has been considered to be a molecule related to the pathogenesis of DS. With the deepening of its functional research, it is found that it plays a key role in the occurrence of various diseases, and also plays an important role in the regulation of cell division and differentiation. It can be seen that the study of DYRK1A can not only provide a potential method for the treatment of neurological diseases such as DS and AD, but also clarify its role in intracellular signal transduction and explore other physiological and pathological functions of the molecule. Currently reported functions of DYRK1A are concentrated in its protein kinase part, and there are few reports on the function of its C-terminal special repeats and specific amino acid-rich regions, and the correlation between these special structures and the occurrence of disease is unclear. At the same time, DYRK1A is also highly expressed in some tumor cells, but it can also inhibit the occurrence of some tumors. Whether DYRK1 is involved in tumorigenesis and the corresponding regulatory pathways, and what role it has in the tumorigenesis, formation, and degree of deterioration needs further study.

Reference:

1. Park J; et al. Two key genes closely implicated with the neuropathological characteristics in Down syndrome: DYRK1A and RCAN1. BMB reports, 2009, 42(1):6-15.