Molecular Controls of Lymphatic VEGFR3 Signaling

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 35; no. 2; pp. 421 - 429
• Main Authors: Deng, Yong, Zhang, Xi, Simons, Michael
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.02.2015
• Subjects: 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; Receptor-Like Protein Tyrosine Phosphatases, Class 3 - metabolism; RNA Interference; 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; VEGFR2; NRP1; VEGFR3; NRP2; VEGF-C; VE-PTP
• DOI: 10.1161/ATVBAHA.114.304881
• ISSN: 1079-5642; 1524-4636

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.