title: EphB ligand, ephrinB2, suppresses the VEGF- and angiopoietin 1-induced Ras/mitogen-activated protein kinase pathway in venous endothelial cells.
abstract: Interaction between ephrinB2 and EphB4 in endothelial cells at the arterial-venous capillary interface is critical for proper embryonic capillary morphogenesis. However, the intracellular downstream signaling of ephrinB2-EphB in vascular endothelial cells is unknown. This study examined the effect of ephrinB2-induced activation of EphB kinases on vascular endothelial growth factor (VEGF)- and angiopoietin-1 (Ang1)-induced Ras/mitogen-activated protein kinase (MAPK) signaling cascades in human umbilical vein endothelial cells (HUVECs). Reverse transcriptase-polymer chain reaction results showed that HUVECs expressed three kinds of EphB kinases known to bind to ephrinB2: EphB2, EphB3, and EphB4. EphrinB2 not only increased the phosphorylation of EphB2 and EphB4 in a time-dependent manner but also increased recruitment of p120-Ras-GTPase-activating protein (p120-RasGAP) to EphB2 and EphB4. Accordingly, ephrinB2 inhibited VEGF- and Ang1-induced Ras-MAPK activities, whereas ephrinB2 did not alter VEGF-induced Flk phosphorylation or Ang1-induced Tie2 phosphorylation. Furthermore, ephrinB2 suppressed VEGF- and Ang1-induced proliferation and/or migration, which are mediated mainly through Ras/MAPK signaling cascades. From these results, we propose that ephrinB2-EphB, signaling through Ras/MAPK cascade, may be critical for proper morphogenesis of capillary endothelium through the arrest of endothelial cell proliferation and migration at the arterial-venous interface.
authors.affiliation: National Creative Research Initiatives Center for Endothelial Cells and Department of Life Science, Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, 790-784, Republic of Korea.
authors.forename: Injune
authors.initials: I
authors.lastname: Kim
authors.forename: Young Shin
authors.initials: YS
authors.lastname: Ryu
authors.forename: Hee Jin
authors.initials: HJ
authors.lastname: Kwak
authors.forename: So Young
authors.initials: SY
authors.lastname: Ahn
authors.forename: Jong-Lark
authors.initials: JL
authors.lastname: Oh
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Gale
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
mesh_terms: D042683:Angiopoietin-1; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D036388:Ephrin-B2; D006801:Humans; D008024:Ligands; D008222:Lymphokines / Q000037:antagonists & inhibitors*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D008565:Membrane Proteins / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D010766:Phosphorylation; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D036183:Receptor, EphB2; D036224:Receptor, EphB4; D036081:Receptors, Eph Family; D014471:Umbilical Veins / Q000166:cytology / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020729:p120 GTPase Activating Protein / Q000378:metabolism
chemical_list: C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D016228:Endothelial Growth Factors; D036388:Ephrin-B2; D008024:Ligands; D008222:Lymphokines; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020729:p120 GTPase Activating Protein; D020794:Receptor Protein-Tyrosine Kinases; D036183:Receptor, EphB2; D036224:Receptor, EphB4; D036081:Receptors, Eph Family; D020928:Mitogen-Activated Protein Kinases; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)