Targeting DYRKs in Cardiovascular Diseases: From Biological Mechanisms to Therapeutic Translation

Figures

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  Figure 1. Structural Features of the DYRK Family. Class I DYRKs contain an NLS and a C-terminal PEST domain enriched in proline, glutamic acid, serine, and threonine residues, whereas Class II members harbor an NAPA domain. DYRK1A contains a bipartite N-terminal NLS and a second complex NLS within the catalytic domain. Compared with DYRK1A, DYRK1B has a shorter N-terminal region. DYRK2 contains two regulatory phosphorylation sites, Ser159 in the glycine-rich loop and Tyr309 in the activation loop. With the exception of DYRK3, all DYRK family members contain an NLS. NLS: Nuclear Localization Signal; DH Box: DEAD-box helicase domain; NAPA: N-terminal autophosphorylation accessory domain; PEST: Proline (P), Glutamic acid (E), Serine (S), Threonine (T) domain; MAPK: mitogen-activated protein kinase.

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  Figure 2. DYRK1A regulates the cardiomyocyte cell cycle following myocardial infarction. DYRK1A inhibits cell-cycle progression by promoting Cyclin D degradation and LIN52 Ser28 phosphorylation, thereby stabilizing the DREAM complex. DYRK1A deficiency elevates Cyclin D levels, disrupts DREAM assembly, promotes MMB complex formation and E2F release, and drives G1/S transition and cardiomyocyte proliferation. MuvB: Multi-vulval class B; DREAM complex: DP, RB-like, E2F, and MuvB complex; BMYB: MYB proto-oncogene like 2; MMB complex: Myb-MuvB complex.

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  Figure 3. DYRK1A-mediated Regulation of Cardiac Hypertrophy. (A) DYRK1A opposes PE- and ET-1-induced cardiomyocyte hypertrophy. (B) DYRK1A phosphorylates NFAT and cooperates with GSK3β to promote NFAT nuclear export, thereby suppressing hypertrophic gene expression. (C) Dysregulation of the DYRK1A-ASF-CaMKIIδ pathway contributes to hypertension-induced cardiac hypertrophy. NFAT: Nuclear Factor of Activated T cells; GSK3β: Glycogen Synthase Kinase 3 β; ASF: Alternative Splicing Factor; CaMKIIδ: Calmodulin-dependent Protein Kinase IIδ.

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  Figure 4. DYRK1A and DYRK2 regulate myocardial fibrosis. Inflammatory cell-derived TGF-β activates TRPA1, triggering Ca2+ influx and calcineurin activation. Cardiomyocyte-derived exosomal miR-199b-5p and miR-15a-5p suppress DYRK1A and DYRK2, respectively, leading to NFATc4 dephosphorylation and nuclear activation, induction of α-SMA and collagen I/III expression, and promotion of myocardial fibrosis. TGF-β: Transforming Growth Factor-β; NFATc4: Nuclear Factor of Activated T cells, cytoplasmic 4; TRPA1: Transient Receptor Potential Ankyrin 1; α-SMA: alpha-Smooth Muscle Actin.