Molecular controls of lymphatic VEGFR3 signaling

Arterioscler Thromb Vasc Biol. 2015 Feb;35(2):421-9. doi: 10.1161/ATVBAHA.114.304881. Epub 2014 Dec 18.

Abstract

Objectives: Vascular endothelial growth factor receptor 3 (VEGFR3) plays important roles both in lymphangiogenesis and angiogenesis. On stimulation by its ligand VEGF-C, VEGFR3 is able to form both homodimers as well as heterodimers with VEGFR2 and activates several downstream signal pathways, including extracellular signal-regulated kinases (ERK)1/2 and protein kinase B (AKT). Despite certain similarities with VEGFR2, molecular features of VEGFR3 signaling are still largely unknown.

Approach and results: Human dermal lymphatic endothelial cells were used to examine VEGF-C-driven activation of signaling. Compared with VEGF-A activation of VEGFR2, VEGF-C-induced VEGFR3 activation led to a more extensive AKT activation, whereas activation of ERK1/2 displayed a distinctly different kinetics. Furthermore, VEGF-C, but not VEGF-A, induced formation of VEGFR3/VEGFR2 complexes. Silencing VEGFR2 or its partner neuropilin 1 specifically abolished VEGF-C-induced AKT but not ERK activation, whereas silencing of neuropilin 2 had little effect on either signaling pathway. Finally, suppression of vascular endothelial phosphotyrosine phosphatase but not other phosphotyrosine phosphatases enhanced VEGF-C-induced activation of both ERK and AKT pathways. Functionally, both ERK and AKT pathways are important for lymphatic endothelial cells migration.

Conclusions: VEGF-C activates AKT signaling via formation of VEGFR3/VEGFR2 complex, whereas ERK is activated by VEGFR3 homodimer. Neuropilin 1 and vascular endothelial phosphotyrosine phosphatase are involved in regulation of VEGFR3 signaling.

Keywords: NRP1; NRP2; VE-PTP; VEGF-C; VEGFR2; VEGFR3.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Movement
  • Cells, Cultured
  • Endocytosis
  • Endothelial Cells / metabolism*
  • Enzyme Activation
  • Humans
  • Kinetics
  • Ligands
  • Lymphangiogenesis*
  • Lymphatic Vessels / metabolism*
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Neuropilin-1 / genetics
  • Neuropilin-1 / metabolism
  • Neuropilin-2 / genetics
  • Neuropilin-2 / metabolism
  • Protein Multimerization
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • Receptor-Like Protein Tyrosine Phosphatases, Class 3 / metabolism
  • Signal Transduction*
  • Transfection
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor C / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism
  • Vascular Endothelial Growth Factor Receptor-3 / genetics
  • Vascular Endothelial Growth Factor Receptor-3 / metabolism*

Substances

  • Ligands
  • Neuropilin-2
  • VEGFA protein, human
  • VEGFC protein, human
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor C
  • neuropilin-2, human
  • Neuropilin-1
  • FLT4 protein, human
  • KDR protein, human
  • Vascular Endothelial Growth Factor Receptor-2
  • Vascular Endothelial Growth Factor Receptor-3
  • Proto-Oncogene Proteins c-akt
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Receptor-Like Protein Tyrosine Phosphatases, Class 3