Format

Send to

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

Molecular controls of lymphatic VEGFR3 signaling.

Author information

1
From the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine (Y.D., X.Z., M.S.) and Department of Cell Biology (X.Z., M.S.), Yale University School of Medicine, New Haven, CT.
2
From the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine (Y.D., X.Z., M.S.) and Department of Cell Biology (X.Z., M.S.), Yale University School of Medicine, New Haven, CT. michael.simons@yale.edu.

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

PMID:
25524775
PMCID:
PMC4304921
DOI:
10.1161/ATVBAHA.114.304881
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center