DYRK1A Kinase Positively Regulates Angiogenic Responses in Endothelial Cells

Cell Rep. 2018 May 8;23(6):1867-1878. doi: 10.1016/j.celrep.2018.04.008.

Abstract

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 PLCγ1 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.

Keywords: DYRK1A; NFAT; VEGF; VEGFR2; angiogenesis; endothelial cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biocatalysis
  • Calcium / metabolism
  • Down-Regulation / genetics
  • Female
  • Heterozygote
  • Human Umbilical Vein Endothelial Cells / metabolism*
  • Humans
  • Mice, Inbred C57BL
  • NFATC Transcription Factors / metabolism
  • Neovascularization, Physiologic*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Signal Transduction
  • Transcriptional Activation / genetics
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • NFATC Transcription Factors
  • Vascular Endothelial Growth Factor A
  • Dyrk kinase
  • Protein-Tyrosine Kinases
  • Vascular Endothelial Growth Factor Receptor-2
  • Protein Serine-Threonine Kinases
  • Calcium