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EphB–ephrinB bi-directional endocytosis terminates adhesion allowing contact mediated repulsion

Nature Cell Biology volume 5, pages 869–878 (2003)Cite this article

Abstract

Eph receptors and their membrane-associated ephrin ligands mediate cell–cell repulsion to guide migrating cells and axons. Repulsion requires that the ligand–receptor complex be removed from the cell surface, for example by proteolytic processing of the ephrin ectodomain. Here we show that cell contact-induced EphB–ephrinB complexes are rapidly endocytosed during the retraction of cells and neuronal growth cones. Endocytosis occurs in a bi-directional manner that comprises of full-length receptor and ligand complexes. Endocytosis is sufficient to promote cell detachment and seems necessary for axon withdrawal during growth cone collapse. Here, we show a mechanism for the termination of adhesion and the promotion of cell repulsion after intercellular (trans) interaction between two transmembrane proteins.

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Figure 1: Endocytosis of EphB2–Fc and ephrinB1–Fc.
Figure 2: Endocytosis of EphB2–Fc and ephrinB1–Fc in primary telencephalic neurons.
Figure 3: EphB2 and ephrinB1 cluster and endocytose at sites of cell–cell contact.
Figure 4: EphrinB1 and EphB2 uptake and transport by primary neurons.
Figure 5: Endocytosis requires cytoplasmic determinants.
Figure 6: Bi-directional endocytosis regulates the cell repulsion response and cell detachment.
Figure 7: EphB2 C-terminal truncation impairs growth cone detachment.

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Acknowledgements

We thank A. Weiss, T. Schwickert, L. Peters and C. König for experimental help. We also thank M. Osterfield, J.G. Flanagan, M. Dalva and M.E. Greenberg for providing reagents, and I.C. Grunwald, G.A. Wilkinson, F. Helmbacher and F. Bradke for critically reading the manuscript. We thank M. Zerial for helpful discussions. This work was funded in part by grants from the Deutsche Forschungsgemeinschaft.

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  1. Max-Planck Institute of Neurobiology, Am Klopferspitz 18A, Martinsried, D-82152, Germany

    Manuel Zimmer, Amparo Palmer, Jenny Köhler & Rüdiger Klein

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Correspondence to Rüdiger Klein.

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Zimmer, M., Palmer, A., Köhler, J. et al. EphB–ephrinB bi-directional endocytosis terminates adhesion allowing contact mediated repulsion. Nat Cell Biol 5, 869–878 (2003). https://doi.org/10.1038/ncb1045

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