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J. Biol. Chem., Vol. 281, Issue 26, 17827-17837, June 30, 2006

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ADAMTS1 Interacts with, Cleaves, and Modifies the Extracellular Location of the Matrix Inhibitor Tissue Factor Pathway Inhibitor-2^*

Antoni X. Torres-Collado, Walter Kisiel, Maria L. Iruela-Arispe^¶, and Juan C. Rodríguez-Manzaneque¹

From the Medical Oncology Research Program, Vall d'Hebron University Hospital Research Institute/Universitat Autònoma de Barcelona, Barcelona 08035, Spain, Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131, and ^¶Department of Molecular, Cellular, and Developmental Biology, University of California at Los Angeles, Los Angeles, California 90095

ADAMTS1 is an extracellular metalloproteinase known to participate in a variety of biological processes that includes inflammation, angiogenesis, and development of the urogenital system. Many of its functions rely on its catalytic activity, which thus far has been limited to the cleavage of the matrix proteoglycans aggrecan and versican. However, it is likely that other substrates exist. Using a yeast two-hybrid screen, we identified the Kunitz-type inhibitor, tissue factor pathway inhibitor-2 (TFPI-2), as a binding partner of ADAMTS1. The interaction was confirmed by several biochemical and cell-based assays. In addition, our studies revealed alterations in the pattern of TFPI-2-secreted isoforms and in its extracellular location caused by the specific action of ADAMTS1. Interestingly, we found that TFPI-2 is a novel substrate of ADAMTS1. The cleavage removes a protease-sensitive C-terminal region in TFPI-2, altering its binding properties. The proposed role of TFPI-2 as a maintenance factor of extracellular remodeling suggests the indirect function of ADAMTS1 as an additional homeostatic player by its ability to alter the extracellular location of TFPI-2 and, therefore, to disrupt the remodeling machinery, a phenomenon directly associated to pathologies such as atherosclerosis and tumor progression.

Received for publication, December 19, 2005 , and in revised form, April 20, 2006.

^* This work was supported by Ministerio de Educación y Ciencia Grants SAF2002-00575 and Fondo de Investigación Sanitaria (01/3009) (to J. C. R.-M.) and National Institutes of Health Grant HL64119 (to W. K.). 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 To whom correspondence should be addressed: Laboratori de Angiogènesi, Institut de Recerca Hospital Universitari Vall d'Hebron, Psg. Vall d'Hebron 119–129, Barcelona 08035, Spain. Tel.: 34-93-489-4167; Fax: 34-93-274-6026; E-mail: jcrodrig{at}ir.vhebron.net.

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