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J. Biol. Chem., Vol. 281, Issue 18, 12485-12494, May 5, 2006

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Cell-surface Processing of Pro-ADAMTS9 by Furin^*

Bon-Hun Koo, Jean-Michel Longpré¹, Robert P. T. Somerville, J. Preston Alexander^¶, Richard Leduc², and Suneel S. Apte³

From the Department of Biomedical Engineering and Orthopaedic Research Center, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, the Department of Pharmacology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada, and ^¶Triple Point Biologics, Portland, Oregon 97116

Processing of polypeptide precursors by proprotein convertases (PCs) such as furin typically occurs within the trans-Golgi network. Here, we show in a variety of cell types that the propeptide of ADAMTS9 is not excised intracellularly. Pulse-chase analysis in HEK293F cells indicated that the intact zymogen was secreted to the cell surface and was subsequently processed there before release into the medium. The processing occurred via a furin-dependent mechanism as shown using PC inhibitors, lack of processing in furin-deficient cells, and rescue by furin in these cells. Moreover, down-regulation of furin by small interference RNA reduced ADAMTS9 processing in HEK293F cells. PC5A could also process pro-ADAMTS9, but similarly to furin, processed forms were absent intracellularly. Cell-surface, furin-dependent processing of pro-ADAMTS9 creates a precedent for extracellular maturation of endogenously produced secreted proproteins. It also indicates the existence of a variety of mechanisms for processing of ADAMTS proteases.

Received for publication, October 12, 2005 , and in revised form, March 13, 2006.

^* This work was supported in part by National Institutes of Health Grant AR49930 (to S. S. A.) and a grant from the Canadian Institutes of Health Research (to R. L.). 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.

¹ A recipient of a Ph.D. studentship of the Fonds de la Recherche en Sante du Quebec (FRSQ).

² An FRSQ Chercheur National.

³ To whom correspondence should be addressed: Dept. of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic Foundation (ND20), 9500 Euclid Ave., Cleveland OH 44195. Tel.: 216-445-3278; Fax: 216-444-9198; E-mail: aptes{at}ccf.org.

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