Repelling class discrimination: ephrin-A5 binds to and activates EphB2 receptor signaling.
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.
Himanen
Juha-Pekka
JP
Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Chumley
Michael J
MJ
Lackmann
Martin
M
Li
Chen
C
Barton
William A
WA
Jeffrey
Phillip D
PD
Vearing
Christopher
C
Geleick
Detlef
D
Feldheim
David A
DA
Boyd
Andrew W
AW
Henkemeyer
Mark
M
Nikolov
Dimitar B
DB
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
D036386:Ephrin-A5; D036388:Ephrin-B2; D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins; D036121:Receptor, EphA3; D036183:Receptor, EphB2; D000469:Alkaline Phosphatase