Journal
CELL REPORTS
Volume 23, Issue 6, Pages 1867-1878Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2018.04.008
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Funding
- Spanish Ministry of Economy and Competitiveness (MINECO) [BFU2013-44513, BFU2016-76141-P, SAF2015-69762R, SAF2014-59950-P, BIO2014-57716-C2-R, SAF2016-77971-R]
- La Marato de TV3''
- Instituto de Salud Carlos III [IIS10/00014, RD12/0042/0014]
- FEDER
- Secretariat of Universities and Research-Generalitat de Catalunya [2014SGR674]
- European Commission [317250, 675392]
- CIBERER
- MINECO Centro de Excelencia Severo Ochoa
- Maria de Maeztu Programme
- CERCA Programme/Generalitat de Catalunya
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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 vascular endothelial growth factor (VEGF) A. 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 PLC gamma 1 activation. Notably, Dyrk1 alpha heterozygous mice show defects in developmental retinal vascularization. Our data establish a regulatory circuit, DYRK1A/C-a2+/NFAT, to fine-tune endothelial cell proliferation and angiogenesis.
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