title: Repelling class discrimination: ephrin-A5 binds to and activates EphB2 receptor signaling.
abstract: The interactions between Eph receptor tyrosine kinases and their ephrin ligands regulate cell migration and axon pathfinding. The EphA receptors are generally thought to become activated by ephrin-A ligands, whereas the EphB receptors interact with ephrin-B ligands. Here we show that two of the most widely studied of these molecules, EphB2 and ephrin-A5, which have never been described to interact with each other, do in fact bind one another with high affinity. Exposure of EphB2-expressing cells to ephrin-A5 leads to receptor clustering, autophosphorylation and initiation of downstream signaling. Ephrin-A5 induces EphB2-mediated growth cone collapse and neurite retraction in a model system. We further show, using X-ray crystallography, that the ephrin-A5-EphB2 complex is a heterodimer and is architecturally distinct from the tetrameric EphB2-ephrin-B2 structure. The structural data reveal the molecular basis for EphB2-ephrin-A5 signaling and provide a framework for understanding the complexities of functional interactions and crosstalk between A- and B-subclass Eph receptors and ephrins.
authors.affiliation: Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
authors.forename: Juha-Pekka
authors.initials: JP
authors.lastname: Himanen
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Chumley
authors.forename: Martin
authors.initials: M
authors.lastname: Lackmann
authors.forename: Chen
authors.initials: C
authors.lastname: Li
authors.forename: William A
authors.initials: WA
authors.lastname: Barton
authors.forename: Phillip D
authors.initials: PD
authors.lastname: Jeffrey
authors.forename: Christopher
authors.initials: C
authors.lastname: Vearing
authors.forename: Detlef
authors.initials: D
authors.lastname: Geleick
authors.forename: David A
authors.initials: DA
authors.lastname: Feldheim
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Boyd
authors.forename: Mark
authors.initials: M
authors.lastname: Henkemeyer
authors.forename: Dimitar B
authors.initials: DB
authors.lastname: Nikolov
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002460:Cell Line; D002850:Chromatography, Gel / Q000379:methods; D002852:Chromatography, Ion Exchange / Q000379:methods; D006224:Cricetinae; D003412:Cricetulus; D003461:Crystallography / Q000379:methods; D004586:Electrophoresis / Q000379:methods; D036386:Ephrin-A5 / Q000737:chemistry / Q000378:metabolism*; D036388:Ephrin-B2 / Q000378:metabolism*; D005455:Fluorescent Antibody Technique / Q000379:methods; D049452:Green Fluorescent Proteins; D006801:Humans; D007239:Infections; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D016501:Neurites / Q000502:physiology; D009447:Neuroblastoma; D010766:Phosphorylation; D011485:Protein Binding / Q000502:physiology; D036121:Receptor, EphA3 / Q000378:metabolism; D036183:Receptor, EphB2 / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D012845:Sindbis Virus; D013050:Spectrometry, Fluorescence / Q000379:methods; D020349:Surface Plasmon Resonance / Q000379:methods; D013997:Time Factors; D014162:Transfection / Q000379:methods; D014741:Video Recording
chemical_list: D036386:Ephrin-A5; D036388:Ephrin-B2; D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins; D036121:Receptor, EphA3; D036183:Receptor, EphB2; D000469:Alkaline Phosphatase