Article abstract
Nature Neuroscience 7, 501 - 509 (2004)
Published online: 25 April 2004 | doi:10.1038/nn1237
Repelling class discrimination: ephrin-A5 binds to and activates EphB2 receptor signaling
Juha-Pekka Himanen1,7, Michael J Chumley2,7, Martin Lackmann3,6, Chen Li1, William A Barton1, Phillip D Jeffrey1, Christopher Vearing3,6, Detlef Geleick3, David A Feldheim4, Andrew W Boyd5, Mark Henkemeyer2 & Dimitar B Nikolov1
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.
- Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
- Center for Developmental Biology and Kent Waldrep Center for Basic Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9133, USA.
- Ludwig Institute for Cancer Research, P.O. Royal Melbourne Hospital, Victoria, 3050 Victoria, Australia.
- Department of Molecular, Cellular, and Developmental Biology, University of California at Santa Cruz, Santa Cruz, California 95064, USA.
- Queensland Institute of Medical Research, PO Royal Brisbane Hospital 4029, Queensland, Australia.
- Present address: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Melbourne, Victoria 3168, Australia.
- These authors contributed equally to this work.
Correspondence to: Dimitar B Nikolov1 e-mail: dimitar@ximpact3.ski.mskcc.org
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