The DYRK1A kinase positively regulates angiogenic responses in endothelial cells
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ABSTRACT:
PROVIDER: PRJNA443148 | ENA |
REPOSITORIES: ENA
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Project description:Angiogenesis is a highly regulated process essential for organ development and maintenance, and its deregulation contributes to inflammation, cardiac disorders and cancer. The Ca2+/Nuclear Factor of Activated T-cells (NFAT) signaling pathway is central to endothelial cell angiogenic responses, and it is activated by stimuli like the vascular endothelial growth factor A (VEGF). NFAT phosphorylation by dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) is thought to be an inactivating event. Contrary to expectations, we show that the DYRK family member DYRK1A positively regulates VEGF-dependent NFAT transcriptional responses in primary endothelial cells. DYRK1A silencing reduces intracellular Ca2+ influx in response to VEGF, which dampens NFAT activation. The effect is exerted at the level of VEGFR2 accumulation leading to impairment in PLCg1 activation. Notably, Dyrk1a heterozygous mice show defects in developmental retinal vascularization. Our data establish a regulatory circuit, DYRK1A/ Ca2+/NFAT, to fine-tune endothelial cell proliferation and angiogenesis.
2018-03-22 | GSE112172 | GEO
Project description:DYRK1A is a dosage-sensitive protein kinase that fulfills key roles during development and in tissue homeostasis, and its dysregulation results in human pathologies. DYRK1A is present in both the nucleus and cytoplasm of mammalian cells, although its nuclear function remains unclear. Genome-wide analysis of DYRK1A-associated loci reveals that the kinase is recruited preferentially to promoters of genes actively transcribed by RNA polymerase II (RNAPII), which are functionally associated with translation, RNA processing and cell cycle. DYRK1A-bound promoter sequences are highly enriched in a conserved palindromic motif, which is necessary to drive DYRK1A-dependent transcriptional activation. DYRK1A phosphorylates the carboxy-terminal domain (CTD) of RNAPII at Ser2 and Ser5. Depletion of DYRK1A results in reduced association of RNAPII at the target promoters as well as hypophosphorylation of the CTD of RNAPII along the target gene bodies. Accordingly, we propose that DYRK1A acts as a transcriptional regulator by acting as a novel CTD kinase. Occupancy of the kinase DYRK1A in two different cell lines and in two different growing conditions.
2015-03-11 | E-GEOD-63712 | biostudies-arrayexpress
Project description:DYRK1A is a protein kinase with several roles in brain development. This kinase is involved in two intellectual disability syndromes: Down syndrome and DYRK1A haploinsufficiency syndrome. The Dyrk1a+/- mouse is a model for DYRK1A haploinsufficiency syndrome. We used microarray to evaluate the impact of DYRK1A haploinsufficiency in the development of the cerebral cortex.
2019-03-06 | GSE127707 | GEO
Project description:DYRK1A is a dosage-sensitive protein kinase that fulfills key roles during development and in tissue homeostasis, and its dysregulation results in human pathologies. DYRK1A is present in both the nucleus and cytoplasm of mammalian cells, although its nuclear function remains unclear. Genome-wide analysis of DYRK1A-associated loci reveals that the kinase is recruited preferentially to promoters of genes actively transcribed by RNA polymerase II (RNAPII), which are functionally associated with translation, RNA processing and cell cycle. DYRK1A-bound promoter sequences are highly enriched in a conserved palindromic motif, which is necessary to drive DYRK1A-dependent transcriptional activation. DYRK1A phosphorylates the carboxy-terminal domain (CTD) of RNAPII at Ser2 and Ser5. Depletion of DYRK1A results in reduced association of RNAPII at the target promoters as well as hypophosphorylation of the CTD of RNAPII along the target gene bodies. Accordingly, we propose that DYRK1A acts as a transcriptional regulator by acting as a novel CTD kinase.
2015-03-11 | GSE63712 | GEO
Project description:Type 1 conventional dendritic cells (cDC1s) play an integral role in mediating immune responses and maintaining homeostasis, yet the molecular mechanisms underlying their functions remain poorly understood. In this study, we identify dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) as a key kinase that responds to TLR and growth factor stimulation, acting as an essential regulator of cDC1 function. Genetic ablation of Dyrk1a specifically in cDC1s impairs antitumor immunity and accelerates tumor progression in murine models. Mechanistically, DYRK1A mediates the phosphorylation of the mTORC1 inhibitor TSC2 at serine 540, triggering the degradation of TSC2 and promoting the mTORC1 signaling in cDC1s. Notably, Tsc2 deletion in Dyrk1a-deficient cDC1s remarkably restores their antitumor immune functions. Furthermore, DYRK1A-mediated mTORC1 signaling in cDC1s positively correlates with effector T-cell responses across multiple human cancers. Our findings highlight a critical role for the DYRK1A-TSC2-mTORC1 signaling pathway in regulating cDC1 functions in antitumor immunity, offering potential strategies to improve cancer immunotherapy.
2026-04-01 | GSE281370 | GEO
Project description:We demonstrate that DYRK1A regulates ACE2 and DPP4 transcription independent of its catalytic kinase function to support SARS-CoV, SARS-CoV-2, and MERS-CoV entry. We show that DYRK1A promotes DNA accessibility at the ACE2 promoter and a putative distal enhancer, facilitating transcription and gene expression. Finally, we validate that the proviral activity of DYRK1A is conserved across species using cells of monkey and human origin and an in vivo mouse model.
2023-04-02 | GSE213998 | GEO
Project description:We demonstrate that DYRK1A regulates ACE2 and DPP4 transcription independent of its catalytic kinase function to support SARS-CoV, SARS-CoV-2, and MERS-CoV entry. We show that DYRK1A promotes DNA accessibility at the ACE2 promoter and a putative distal enhancer, facilitating transcription and gene expression. Finally, we validate that the proviral activity of DYRK1A is conserved across species using cells of monkey and human origin and an in vivo mouse model.
2023-04-02 | GSE213997 | GEO
Project description:Type 1 conventional dendritic cells (cDC1s) play an integral role in mediating immune responses and maintaining homeostasis, yet the molecular mechanisms underlying their functions remain poorly understood. In this study, we identified dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) as a key kinase that responded to TLR and growth factor stimulation and acted as an essential regulator of cDC1 function. Genetic ablation of Dyrk1a specifically in cDC1s impaired antitumor immunity and accelerated tumor progression in murine models. Mechanistically, DYRK1A mediated the phosphorylation of the mTORC1 inhibitor TSC2 at serine 540, triggering the degradation of TSC2 and promoting the mTORC1 signaling in cDC1s. Notably, Tsc2 deletion in Dyrk1a-deficient cDC1s remarkably restored their antitumor immune functions. Furthermore, DYRK1A-mediated mTORC1 signaling in cDC1s positively correlated with effector T-cell responses across multiple human cancers. Our findings highlight a critical role for the DYRK1A-TSC2-mTORC1 signaling pathway in regulating cDC1 functions in antitumor immunity, offering potential strategies to improve cancer immunotherapy.
2026-04-10 | GSE327455 | GEO
Project description:Pro-angiogenic transcriptome of zebrafish endothelial cells
| PRJNA541913 | ENA
Project description:Dendritic cells (DCs) play an integral role in mediating immune responses and homeostasis, but the molecular mechanism underlying the functions of DCs remains elusive. Here, we identified dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) as a kinase that responds to TLR and growth factor stimulation and acts as an important regulator of DC function. DC-specific DYRK1A deletion blunted antitumor immune responses, rendering mice sensitive to tumor progression. Mechanistically, DYRK1A mediates the phosphorylation of the mTORC1 inhibitor TSC2 at S540 site, thereby facilitating the degradation of TSC complex and promoting the mTORC1 signaling in DCs. Deletion of TSC2 in DCs can restore the defected immune function of DYRK1A-deficient DCs. Importantly, DYRK1A-mediated mTORC1 signaling in DCs positively correlated with the better survival probabilities of melanoma and bladder cancer patients. Thus, our data suggest a pivotal role for the DYRK1A signaling axis in regulating DC functions in antitumor immunity and can be harnessed to improve cancer immunotherapies.
2024-11-12 | PXD057775 |