title: Molecular controls of lymphatic VEGFR3 signaling.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: 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.
authors.forename: Yong
authors.initials: Y
authors.lastname: Deng
authors.affiliation: 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.
authors.forename: Xi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Simons
mesh_terms: D002465:Cell Movement; D002478:Cells, Cultured; D004705:Endocytosis; D042783:Endothelial Cells / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D007700:Kinetics; D008024:Ligands; D042583:Lymphangiogenesis; D042601:Lymphatic Vessels / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D039942:Neuropilin-1 / Q000235:genetics / Q000378:metabolism; D039943:Neuropilin-2 / Q000235:genetics / Q000378:metabolism; D055503:Protein Multimerization; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D008024:Ligands; D039943:Neuropilin-2; C467484:VEGFA protein, human; C467486:VEGFC protein, human; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; C581308:neuropilin-2, human; D039942:Neuropilin-1; C581309:FLT4 protein, human; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3; D051057:Proto-Oncogene Proteins c-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3
keywords: NRP1; NRP2; VE-PTP; VEGF-C; VEGFR2; VEGFR3