Dual substrate specific tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is an important protein kinase that is closely related to the development of Down syndrome and is very conservative in evolution. DYRK1A is involved in physiological processes such as neurodevelopment, cell proliferation and differentiation, and tumorigenesis, as well as in the pathogenesis of neurodegenerative diseases. In addition, DYRK1A also plays an important role in the pathogenesis and signaling pathway regulation of other diseases.
Figure 1. Protein structure of DYRK1A.
DYRK1A belongs to the DYRK family. DYRK1A is highly conservative in evolution. There are five different subtypes of the DYRK family in mammals. In the family, only DYRK1A is located in the DSCR region of human chromosome 21. DYRK1A is expressed by the gene dyrk1a, and the encoded mature protein is composed of 763 amino acids, including a protein kinase domain (Protein Kinase Domain) and some other special structures, including Poly-Ser, Poly-Hi, Ser/Thr-rich. DYRK1A can autophosphorylate a tyrosine residue in the molecule, or directly recognize a specific sequence acting on an exogenous substrate and phosphorylate the substrate.
DYRK1A has a high expression level in the early stages of embryonic development, but its expression decreases in the later stages of embryo development. The expression distribution of DYRK1A in tissues is very extensive, but it is most abundant in the cerebellum, olfactory bulb, and hippocampus, and the nucleus is the most abundant in cells. It is a very conservatively evolved nuclear protein.
As a protein kinase, DYRK1A has a very wide range of substrates. According to reports, the substrates of DYRK1A are both nuclear and cytoplasmic proteins, including: transcription factor (NFAT), splicing factor (cyclin L2), translation factor (eIF2Be), junction protein (dynamin I), and some other effects Protein (caspase-9) and so on. The diversity of substrates reflects the diversity of physiological functions of the protein. There is evidence that DYRK1A plays an important role in multiple signaling pathways (Wnt, Notch). Studies have shown that there are many important proteins that can be used as substrates for DYRK1A and are regulated by them to participate in a variety of biological processes in cells. For example, DYRK1A can directly phosphorylate the Ser-10 site of the cycle-dependent kinase inhibitor p27kip1 and stabilize p27 to increase its intracellular content. P27 is encoded by cdkn1b (cyclin-dependent kinase inhibitor 1B), which is the cell cycle. Regulatory protein, which can terminate the cell cycle after activation; DYRK1A can directly phosphorylate the Thr-286 site of Cyclin D1 and promote the degradation of Cyclin D1 to reduce its intracellular content. Cyclin D1 is a positive regulator of cell division and participates in NOTCH The pathway regulates the cell cycle. DYRK1A can regulate cell proliferation and differentiation by phosphorylation of substrates related to the cell cycle.
In recent years, great progress has been made in the functional research and mechanism of DYRK1A molecule. However, there are still many problems to be solved: Does DYRK1A play a direct or indirect role in the signaling pathway? Is the role of DYRK1A in the formation of different tumors determined solely by its substrate or involves more other signaling pathways? How the special terminal structure affects the activity of protein kinases, the solution of these problems may play an important role in elucidating the molecular mechanism of molecular biological function. The elucidation of the molecular mechanism of DYRK1A has profound significance for the prevention and treatment of tumor-related diseases.
