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Science 289 (5483): 1360-1365

Copyright © 2000 by the American Association for the Advancement of Science

Regulated Cleavage of a Contact-Mediated Axon Repellent

Mitsuharu Hattori,* Miriam Osterfield, John G. Flanagandagger

Contact-mediated axon repulsion by ephrins raises an unresolved question: these cell surface ligands form a high-affinity multivalent complex with their receptors present on axons, yet rather than being bound, axons can be rapidly repelled. We show here that ephrin-A2 forms a stable complex with the metalloprotease Kuzbanian, involving interactions outside the cleavage region and the protease domain. Eph receptor binding triggered ephrin-A2 cleavage in a localized reaction specific to the cognate ligand. A cleavage-inhibiting mutation in ephrin-A2 delayed axon withdrawal. These studies reveal mechanisms for protease recognition and control of cell surface proteins, and, for ephrin-A2, they may provide a means for efficient axon detachment and termination of signaling.

Department of Cell Biology and Program in Neuroscience, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
*   Present address: Department of Molecular Neurobiology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.

dagger    To whom correspondence should be addressed. E-mail: flanagan{at}hms.harvard.edu

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The metalloprotease Kuzbanian (ADAM10) mediates the transactivation of EGF receptor by G protein-coupled receptors.
Y. Yan, K. Shirakabe, and Z. Werb (2002)
J. Cell Biol. 158, 221-226
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Intracellular Processing of Metalloprotease Disintegrin ADAM12.
Y. Cao, Q. Kang, Z. Zhao, and A. Zolkiewska (2002)
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Expression and Function of the Eph A Receptors and Their Ligands Ephrins A in the Rat Thymus.
J. J. Munoz, L. M. Alonso-C., R. Sacedon, T. Crompton, A. Vicente, E. Jimenez, A. Varas, and A. G. Zapata (2002)
J. Immunol. 169, 177-184
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Mice Lacking the Metalloprotease-Disintegrin MDC9 (ADAM9) Have No Evident Major Abnormalities during Development or Adult Life.
G. Weskamp, H. Cai, T. A. Brodie, S. Higashyama, K. Manova, T. Ludwig, and C. P. Blobel (2002)
Mol. Cell. Biol. 22, 1537-1544
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Ephrin-A5 induces rounding, blebbing and de-adhesion of EphA3-expressing 293T and melanoma cells by CrkII and Rho-mediated signalling.
I. D. Lawrenson, S. H. Wimmer-Kleikamp, P. Lock, S. M. Schoenwaelder, M. Down, A. W. Boyd, P. F. Alewood, and M. Lackmann (2002)
J. Cell Sci. 115, 1059-1072
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Phosphorylation-dependent Interactions between ADAM15 Cytoplasmic Domain and Src Family Protein-tyrosine Kinases.
Z. Poghosyan, S. M. Robbins, M. D. Houslay, A. Webster, G. Murphy, and D. R. Edwards (2002)
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kuzbanian-mediated cleavage of Drosophila Notch.
T. Lieber, S. Kidd, and M. W. Young (2002)
Genes & Dev. 16, 209-221
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The divergent C. elegans ephrin EFN-4 functions inembryonic morphogenesis in a pathway independent of the VAB-1 Eph receptor.
I. D. Chin-Sang, S. L. Moseley, M. Ding, R. J. Harrington, S. E. George, and A. D. Chisholm (2002)
Development 129, 5499-5510
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The Kallmann syndrome gene homolog in C. elegans is involved in epidermal morphogenesis and neurite branching.
E. I. Rugarli, E. Di Schiavi, M. A. Hilliard, S. Arbucci, C. Ghezzi, A. Facciolli, G. Coppola, A. Ballabio, and P. Bazzicalupo (2002)
Development 129, 1283-1294
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