title: EphB4 forward signalling regulates lymphatic valve development.
abstract: Bidirectional signalling is regarded as a notable hallmark of the Eph-ephrin signalling system: Eph-dependent forward signalling in Eph-expressing cells and ephrin-dependent reverse signalling in Ephrin-expressing cells. The notion of ephrin-dependent reverse signalling derives from genetic experiments utilizing mice carrying mutations in the intracellular region of ephrinBs. Here we show that EphB4-dependent forward signalling regulates lymphatic valve development, a process previously thought to be regulated by ephrinB2-dependent reverse signalling. We develop antibodies that selectively target EphB4 and ephrinB2. We find that mice bearing genetically altered cytoplasmic region of ephrinB2 have significantly altered EphB4-dependent forward signalling. Selective inhibition of EphB4 using a functional blocking antibody results in defective lymphatic valve development. Furthermore, a chemical genetic approach is used to unequivocally show that the kinase activity of EphB4 is essential for lymphatic valve development.
authors: Department of Molecular Oncology, Division of Research, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Gu
authors: G
authors: Zhang
authors: Department of Molecular Oncology, Division of Research, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: John
authors: J
authors: Brady
authors: Department of Antibody Engineering, Division of Research, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors: Wei-Ching
authors: WC
authors: Liang
authors: Department of Antibody Engineering, Division of Research, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors: Yan
authors: Y
authors: Wu
authors: Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: Mark
authors: M
authors: Henkemeyer
authors: Department of Molecular Oncology, Division of Research, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Minhong
authors: M
authors: Yan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D057134:Antibodies, Neutralizing / Q000096:biosynthesis / Q000737:chemistry; D036388:Ephrin-B2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D042601:Lymphatic Vessels / Q000033:anatomy & histology / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009024:Morphogenesis / Q000235:genetics; D041681:NIH 3T3 Cells; D019151:Peptide Library; D010770:Phosphotransferases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015202:Protein Engineering; D036224:Receptor, EphB4 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D057134:Antibodies, Neutralizing; C000601240:EFNB2 protein, mouse; D036388:Ephrin-B2; D019151:Peptide Library; D010770:Phosphotransferases; C086681:Ephb4 protein, mouse; D036224:Receptor, EphB4