Repelling class discrimination: Ephrin-A5 binds to and activates EphB2 receptor signaling

Juha Pekka Himanen, Michael J. Chumley, Martin Lackmann, Chen Li, William A. Barton, Phillip D. Jeffrey, Christopher Vearing, Detlef Geleick, David A. Feldheim, Andrew W. Boyd, Mark Henkemeyer, Dimitar B. Nikolov

Research output: Contribution to journalArticle

337 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)501-509
Number of pages9
JournalNature neuroscience
Volume7
Issue number5
DOIs
StatePublished - May 2004

ASJC Scopus subject areas

  • Neuroscience(all)

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    Himanen, J. P., Chumley, M. J., Lackmann, M., Li, C., Barton, W. A., Jeffrey, P. D., Vearing, C., Geleick, D., Feldheim, D. A., Boyd, A. W., Henkemeyer, M., & Nikolov, D. B. (2004). Repelling class discrimination: Ephrin-A5 binds to and activates EphB2 receptor signaling. Nature neuroscience, 7(5), 501-509. https://doi.org/10.1038/nn1237