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: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:Pro-angiogenic transcriptome of zebrafish endothelial cells
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Project description:Effective protection from viral infections depends on the antibody-specific isotype. Here, we found that the protein kinase, DYRK1A, is essential for B cell-mediated protection from viral infection and vaccination through regulation of class switch recombination (CSR). Dyrk1a-deficient B cells were impaired in CSR activity in vivo and in vitro. Phospho-proteomic screens and kinase-activity assays identified MSH6, a DNA mismatch repair protein, as a direct substrate for DYRK1A, and deletion of a single phosphorylation site attenuated CSR. After CSR and germinal center seeding, DYRK1A was required for proper clonal expansion of antigen-specific B cells through attenuation of proliferation. These findings reveal DYRK1A-mediated biological mechanisms of antibody-mediated immune responses that may be used for manipulation in antibody-mediated autoimmunity
2022-11-27 | GSE206146 | GEO
Project description:Ribosomal protein genes (RPGs) coding sequences are highly conserved along evolution; however, promoter features and the machinery involved in their transcriptional regulation are not. In eukaryotes, the main genomic elements and players involved in RPG transcriptional regulation have been mostly characterized in Saccharomyces cerevisiae. However, given the lack of evolutionary conservation of the yeast factors, studies in higher eukaryotes have focused on searching for differential enrichment of transcription factor-binding motifs within the RPG promoters. Among them, the palindromic motif TCTCGCGAGA, which is currently acknowledged as a ZBTB33/KAISO motif, also matches the genomic sequence bound by the protein kinase DYRK1A. DYRK1A, a member of the human family of DYRK kinases, fulfills many diverse functions by phosphorylating a broad set of proteins involved in different cellular processes. One of such functions is to be a chromatin-associated kinase capable of regulating gene expression. Here, we analyze in-depth the presence of DYRK1A at the promoters of human and mouse RPGs and explore its functional consequences. Our results indicate that DYRK1A is a positive regulator of RPGs’ expression at the transcriptional level, and further expand the functional spectrum of the kinase as a contributor to the regulation of cell growth in mammalian cells.
2023-08-01 | GSE155807 | GEO
Project description:Ribosomal protein genes (RPGs) coding sequences are highly conserved along evolution; however, promoter features and the machinery involved in their transcriptional regulation are not. In eukaryotes, the main genomic elements and players involved in RPG transcriptional regulation have been mostly characterized in Saccharomyces cerevisiae. However, given the lack of evolutionary conservation of the yeast factors, studies in higher eukaryotes have focused on searching for differential enrichment of transcription factor-binding motifs within the RPG promoters. Among them, the palindromic motif TCTCGCGAGA, which is currently acknowledged as a ZBTB33/KAISO motif, also matches the genomic sequence bound by the protein kinase DYRK1A. DYRK1A, a member of the human family of DYRK kinases, fulfills many diverse functions by phosphorylating a broad set of proteins involved in different cellular processes. One of such functions is to be a chromatin-associated kinase capable of regulating gene expression. Here, we analyze in-depth the presence of DYRK1A at the promoters of human and mouse RPGs and explore its functional consequences. Our results indicate that DYRK1A is a positive regulator of RPGs’ expression at the transcriptional level, and further expand the functional spectrum of the kinase as a contributor to the regulation of cell growth in mammalian cells.
2023-08-01 | GSE155808 | GEO