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Published online 2 December 2002. doi:10.1083/jcb.200206023
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© The Rockefeller University Press, 0021-9525/2002/12/893 $5.00
The Journal of Cell Biology, Volume 159, Number 5, 893-902

Article

 The cysteine-rich domain regulates ADAM protease function in vivo

Katherine M. Smith1, Alban Gaultier1,2, Helene Cousin1, Dominique Alfandari1, Judith M. White1 and Douglas W. DeSimone1

1 Department of Cell Biology, University of Virginia, Health Sciences Center, Charlottesville, VA 22908
2 Laboratoire de Biologie Moléculaire et Cellulaire du Developpement, Université Pierre et Maire Curie, 75005 Paris, France

Address correspondence to Dr. Douglas W. DeSimone, Department of Cell Biology, University of Virginia, Health Sciences Center, P.O. Box 800732, Charlottesville, VA 22908. Tel.: (434) 924-2172. Fax: (434) 982-3912. E-mail: dwd3m{at}virginia.edu

ADAMs are membrane-anchored proteases that regulate cell behavior by proteolytically modifying the cell surface and ECM. Like other membrane-anchored proteases, ADAMs contain candidate "adhesive" domains downstream of their metalloprotease domains. The mechanism by which membrane-anchored cell surface proteases utilize these putative adhesive domains to regulate protease function in vivo is not well understood. We address this important question by analyzing the relative contributions of downstream extracellular domains (disintegrin, cysteine rich, and EGF-like repeat) of the ADAM13 metalloprotease during Xenopus laevis development. When expressed in embryos, ADAM13 induces hyperplasia of the cement gland, whereas ADAM10 does not. Using chimeric constructs, we find that the metalloprotease domain of ADAM10 can substitute for that of ADAM13, but that specificity for cement gland expansion requires a downstream extracellular domain of ADAM13. Analysis of finer resolution chimeras indicates an essential role for the cysteine-rich domain and a supporting role for the disintegrin domain. These and other results reveal that the cysteine-rich domain of ADAM13 cooperates intramolecularly with the ADAM13 metalloprotease domain to regulate its function in vivo. Our findings thus provide the first evidence that a downstream extracellular adhesive domain plays an active role in regulating ADAM protease function in vivo. These findings are likely relevant to other membrane-anchored cell surface proteases.

Key Words: ADAM; metalloprotease; disintegrin; cysteine rich; Xenopus


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