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

325 Citations (Scopus)

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

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EphB2 Receptors
Ephrin-A5
Eph Family Receptors
Ephrins
Ligands
Ephrin-B2
Growth Cones
X Ray Crystallography
Neurites
Cell Movement
Cluster Analysis

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Himanen, J. P., Chumley, M. J., Lackmann, M., Li, C., Barton, W. A., Jeffrey, P. D., ... 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

Repelling class discrimination : Ephrin-A5 binds to and activates EphB2 receptor signaling. / Himanen, Juha Pekka; Chumley, Michael J.; Lackmann, Martin; Li, Chen; Barton, William A.; Jeffrey, Phillip D.; Vearing, Christopher; Geleick, Detlef; Feldheim, David A.; Boyd, Andrew W.; Henkemeyer, Mark; Nikolov, Dimitar B.

In: Nature Neuroscience, Vol. 7, No. 5, 05.2004, p. 501-509.

Research output: Contribution to journalArticle

Himanen, JP, Chumley, MJ, Lackmann, M, Li, C, Barton, WA, Jeffrey, PD, Vearing, C, Geleick, D, Feldheim, DA, Boyd, AW, Henkemeyer, M & Nikolov, DB 2004, 'Repelling class discrimination: Ephrin-A5 binds to and activates EphB2 receptor signaling', Nature Neuroscience, vol. 7, no. 5, pp. 501-509. https://doi.org/10.1038/nn1237
Himanen JP, Chumley MJ, Lackmann M, Li C, Barton WA, Jeffrey PD et al. Repelling class discrimination: Ephrin-A5 binds to and activates EphB2 receptor signaling. Nature Neuroscience. 2004 May;7(5):501-509. https://doi.org/10.1038/nn1237
Himanen, Juha Pekka ; Chumley, Michael J. ; Lackmann, Martin ; Li, Chen ; Barton, William A. ; Jeffrey, Phillip D. ; Vearing, Christopher ; Geleick, Detlef ; Feldheim, David A. ; Boyd, Andrew W. ; Henkemeyer, Mark ; Nikolov, Dimitar B. / Repelling class discrimination : Ephrin-A5 binds to and activates EphB2 receptor signaling. In: Nature Neuroscience. 2004 ; Vol. 7, No. 5. pp. 501-509.
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