Molecular controls of lymphatic VEGFR3 signaling

Y Deng, X Zhang, M Simons - Arteriosclerosis, thrombosis, and …, 2015 - Am Heart Assoc
Y Deng, X Zhang, M Simons
Arteriosclerosis, thrombosis, and vascular biology, 2015Am Heart Assoc
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 …
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.
Am Heart Assoc