Updating dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2): molecular basis, functions and role in diseases

Abstract

Members of the dual-specificity tyrosine-regulated kinase (DYRKs) subfamily possess a distinctive capacity to phosphorylate tyrosine, serine, and threonine residues. Among the DYRK class II members, DYRK2 is considered a unique protein due to its role in disease. According to the post-transcriptional and post-translational modifications, DYRK2 expression greatly differs among human tissues. Regarding its mechanism of action, this kinase performs direct phosphorylation on its substrates or acts as a priming kinase, enabling subsequent substrate phosphorylation by GSK3β. Moreover, DYRK2 acts as a scaffold for the EDVP E3 ligase complex during the G2/M phase of cell cycle. DYRK2 functions such as cell survival, cell development, cell differentiation, proteasome regulation, and microtubules were studied in complete detail in this review. We have also gathered available information from different bioinformatic resources to show DYRK2 interactome, normal and tumoral tissue expression, and recurrent cancer mutations. Then, here we present an innovative approach to clarify DYRK2 functionality and importance. DYRK2 roles in diseases have been studied in detail, highlighting this kinase as a key protein in cancer development. First, DYRK2 regulation of c-Jun, c-Myc, Rpt3, TERT, and katanin p60 reveals the implication of this kinase in cell-cycle-mediated cancer development. Additionally, depletion of this kinase correlated with reduced apoptosis, with consequences on cancer patient response to chemotherapy. Other functions like cancer stem cell formation and epithelial-mesenchymal transition regulation are also controlled by DYRK2. Furthermore, the pharmacological modulation of this protein by different inhibitors (harmine, curcumine, LDN192960, and ID-8) has enabled to clarify DYRK2 functionality.

The DYRK Family of Kinases in Cancer: Molecular Functions and Therapeutic Opportunities

“…DYRK2 is a class II DYRK that has been more intensely studied in terms of its involvement in the events associated with tumor progression. The biochemistry and biology of DYRK2 was covered in recent reviews [ 126 , 127 ], and thus, here, we will center on the activity of this kinase in the context of tumor biology.…”

“…Several clues have been obtained regarding the putative molecular mechanisms responsible for DYRK2-mediated tumor development/progression. Thus, DYRK2 activity appears to affect crucial processes like the cell cycle, DDR, epithelial-to-mesenchymal transition (EMT), the xenobiotic response system and cellular proteostasis [ 127 ]. The activity of DYRK2 has often been linked to its ability to negatively regulate the stability of its target proteins—in particular, through its interaction with the UBR5/EDD-DNA damage-binding protein 1 (DDB1)-DDB1- and cullin 4-associated factor homolog 1 (DCAF1/VPRBP) (EDVP) E3 ubiquitin ligase complex [ 38 ] ( Figure 5 A).…”

Emerging roles of DYRK2 in cancer

“…3 ). Recent review articles mentioned the conflicting literature on DYRK2 ( 8 , 28 ) and reported that mRNA expression data show that DYRK2 levels are higher in invasive breast carcinoma and lung adenocarcinoma than normal/adjacent tissue control ( 8 , 26 ). However, others maintain that DYRK2 is a major tumor suppressor across all breast cancer subtypes and that DYRK2 depletion promotes proliferation ( 27 ).…”

“…Some of the cancer mutations in Figure 1 B are thought to affect efficient EDVP complex formation ( 3 ). Thus, over the past few decades, many groups have identified various molecular mechanism and substrates for DYRK2 playing diverse roles in cellular growth, proliferation, and developmental processes with a focal point being its role in cancer ( 10 , 25 , 26 , 27 , 28 ).…”

Regulation of the SIAH2-HIF-1 Axis by Protein Kinases and Its Implication in Cancer Therapy

“…Dual-specificity tyrosine-regulated kinase 2 (DYRK2) is a member of the DYRK family protein kinases containing 4 members in mammals: DYRK1A, DYRK1B, DYRK2, DYRK3, and DYRK4 ( Becker and Joost, 1999 ; Aranda et al, 2011 ; Soppa and Becker, 2015 ; Correa-Saez et al, 2020 ). DYRK2 functions in the DNA damage response by phosphorylating p53 at serine 46, thereby promoting cell apoptosis in response to genotoxic stress ( Taira et al, 2007 ).…”