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J. Biol. Chem., Vol. 279, Issue 21, 22377-22386, May 21, 2004

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Integrin ₅₁ and ADAM-17 Interact in Vitro and Co-localize in Migrating HeLa Cells^*

Daniel V. Bax¶, Anthea J. Messent, Jonathan Tart||, Mien van Hoang, Jane Kott, Rose A. Maciewicz||, and Martin J. Humphries**

From the Wellcome Trust Centre for Cell-Matrix Research, School of Biological Sciences, University of Manchester, The Michael Smith Building, Oxford Road, Manchester M13 9PT and the ^||Respiratory and Inflammation Research Department, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom

Tumor necrosis factor (TNF) -converting enzyme (TACE/ADAM-17) has diverse roles in the proteolytic processing of cell surface molecules and, due to its ability to process TNF, is a validated therapeutic target for anti-inflammatory therapies. Unlike a number of other ADAM proteins, which interact with integrin receptors via their disintegrin domains, there is currently no evidence for an ADAM-17-integrin association. By analyzing the adhesion of a series of cell lines with recombinant fragments of the extracellular domain of ADAM-17, we now demonstrate a functional interaction between ADAM-17 and ₅₁ integrin in a trans orientation. Because ADAM-17-mediated adhesion was sensitive to RGD peptides and EDTA, and the integrin-binding site within ADAM-17 was narrowed down to the disintegrin/cysteine-rich region, the two molecules appear to have a ligand-receptor relationship mediated by the ₅₁ ligand binding pocket. Intriguingly, ADAM-17 and ₅₁ were found to co-localize in both membrane ruffles and focal adhesions in HeLa cells. When confluent HeLa cell monolayers were wounded, ADAM-17 and ₅₁ redistributed to the leading edge and co-localized, which is suggestive of a cis orientation. We postulate that the interaction of ADAM-17 with ₅₁ may target or modulate its metalloproteolytic activity.

Received for publication, January 8, 2004 , and in revised form, February 11, 2004.

^* This work was supported in part by Programme Grant 045225 from the Wellcome Trust, by Biotechnology and Biological Sciences and Research Council Realizing Our Potential Award 34/97C08897, and by Wellcome Trust Centre for Cell-Matrix Research Core Grant 061149 (all to M. J. H.). 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.

Both authors contributed equally to this work.

^¶ Supported by a Medical Research Council Industrial Collaborative studentship award in conjunction with AstraZeneca.

^** To whom correspondence should be addressed. Tel.: 44-(0)161-275-5071; Fax: 44-(0)161-275-1505; E-mail: martin.humphries{at}man.ac.uk.

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