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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}

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Distinct Roles of Ephrin-B2 Forward and EphB4 Reverse Signaling in Endothelial Cells.
K. Hamada, Y. Oike, Y. Ito, H. Maekawa, K. Miyata, T. Shimomura, and T. Suda (2003)
Arterioscler Thromb Vasc Biol 23, 190-197
   Abstract »    Full Text »    PDF »
The ADAMs family of metalloproteases: multidomain proteins with multiple functions.
D. F. Seals and S. A. Courtneidge (2003)
Genes & Dev. 17, 7-30
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Autolytic Processing at Glu586-Ser587within the Cysteine-rich Domain of Human Adamalysin 19/Disintegrin-Metalloproteinase 19 Is Necessary for Its Proteolytic Activity.
T. Kang, H. I. Park, Y. Suh, Y.-G. Zhao, H. Tschesche, and Q.-X. A. Sang (2002)
J. Biol. Chem. 277, 48514-48522
   Abstract »    Full Text »    PDF »
Cis and trans interactions of L1 with neuropilin-1 control axonal responses to semaphorin 3A.
V. Castellani, E. De Angelis, S. Kenwrick, and G. Rougon (2002)
EMBO J. 21, 6348-6357
   Abstract »    Full Text »    PDF »
EphB1 Associates with Grb7 and Regulates Cell Migration.
D. C. Han, T.-L. Shen, H. Miao, B. Wang, and J.-L. Guan (2002)
J. Biol. Chem. 277, 45655-45661
   Abstract »    Full Text »    PDF »
Evidence for Regulation of the Tumor Necrosis Factor alpha -Convertase (TACE) by Protein-tyrosine Phosphatase PTPH1.
Y. Zheng, J. Schlondorff, and C. P. Blobel (2002)
J. Biol. Chem. 277, 42463-42470
   Abstract »    Full Text »    PDF »
Metalloproteases and Guidance of Retinal Axons in the Developing Visual System.
C. A. Webber, J. C. Hocking, V. W. Yong, C. L. Stange, and S. McFarlane (2002)
J. Neurosci. 22, 8091-8100
   Abstract »    Full Text »    PDF »
Ephrin-B ligands play a dual role in the control of neural crest cell migration.
A. Santiago and C. A. Erickson (2002)
Development 129, 3621-3632
   Abstract »    Full Text »    PDF »
Regulation of vasculogenesis and angiogenesis by EphB/ephrin-B2 signaling between endothelial cells and surrounding mesenchymal cells.
Y. Oike, Y. Ito, K. Hamada, X.-Q. Zhang, K. Miyata, F. Arai, T. Inada, K. Araki, N. Nakagata, M. Takeya, et al. (2002)
Blood 100, 1326-1333
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »

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