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J. Biol. Chem., Vol. 283, Issue 46, 31920-31932, November 14, 2008

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Heparan Sulfate Regulates ADAM12 through a Molecular Switch Mechanism^*

Hans Peter Sørensen, Romain R. Vivès, Christina Manetopoulos, Reidar Albrechtsen, Magnus C. Lydolph, Jonas Jacobsen, John R. Couchman¹, and Ulla M. Wewer²

From the Department of Biomedicine and Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark and Institut de Biologie Structurale, CNRS-Commissariat à l'Energie Atomique-Université Joseph Fourier, UMR 5075, 41 Rue Horowitz, 38027 Grenoble, France

The disintegrin and metalloproteases (ADAMs) are emerging as therapeutic targets in human disease, but specific drug design is hampered by potential redundancy. Unlike other metzincins, ADAM prodomains remain bound to the mature enzyme to regulate activity. Here ADAM12, a protease that promotes tumor progression and chondrocyte proliferation in osteoarthritic cartilage, is shown to possess a prodomain/catalytic domain cationic molecular switch, regulated by exogenous heparan sulfate and heparin but also endogenous cell surface proteoglycans and the polyanion, calcium pentosan polysulfate. Sheddase functions of ADAM12 are regulated by the switch, as are proteolytic functions in placental tissue and sera of pregnant women. Moreover, human heparanase, an enzyme also linked to tumorigenesis, can promote ADAM12 sheddase activity at the cell surface through cleavage of the inhibitory heparan sulfate. These data present a novel concept that might allow targeting of ADAM12 and suggest that other ADAMs may have specific regulatory activity embedded in their prodomain and catalytic domain structures.

Received for publication, May 29, 2008 , and in revised form, August 14, 2008.

^* This work was supported by Danish Cancer Society Grants DP06052 and DP05076, the Lundbeck Foundation, the Novo Nordisk Foundation, the Danish Medical Research Council, the Carlsberg Foundation, the Munksholm Foundation, and the Hartmann Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1 and Figs. 1-6.

¹ Supported by the Danish National Research Foundation.

² To whom correspondence should be addressed. Tel.: 45-35326081; Fax: 45-35325669; E-mail: ullaw{at}pai.ku.dk.

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