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Vol. 16, Issue 10, 4982-4991, October 2005

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Selective Modulation of Integrin-mediated Cell Migration by Distinct ADAM Family Members

Department of Cell Biology, School of Medicine, University of Virginia Health System, Charlottesville, VA 22908

Submitted March 28, 2005; Revised July 21, 2005; Accepted July 25, 2005
Monitoring Editor: Jean Schwarzbauer

A disintegrin and a metalloprotease (ADAM) family members have been implicated in many biological processes. Although it is recognized that recombinant ADAM disintegrin domains can interact with integrins, little is known about ADAM-integrin interactions in cellular context. Here, we tested whether ADAMs can selectively regulate integrin-mediated cell migration. ADAMs were expressed in Chinese hamster ovary cells that express defined integrins (41, 51, or both), and cell migration on full-length fibronectin or on its 41 or 51 binding fragments was studied. We found that ADAMs inhibit integrin-mediated cell migration in patterns dictated by the integrin binding profiles of their isolated disintegrin domains. ADAM12 inhibited cell migration mediated by the 41 but not the 51 integrin. ADAM17 had the reciprocal effect; it inhibited 51- but not 41-mediated cell migration. ADAM19 and ADAM33 inhibited migration mediated by both 41 and 51 integrins. A point mutation in the ADAM12 disintegrin loop partially reduced the inhibitory effect of ADAM12 on cell migration on the 41 binding fragment of fibronectin, whereas mutations that block metalloprotease activity had no effect. Our results indicate that distinct ADAMs can modulate cell migration mediated by specific integrins in a pattern dictated, at least in part, by their disintegrin domains.

Abbreviations used: ADAM, a disintegrin and metalloprotease; CCBD, central cell binding domain; CHO, Chinese hamster ovary; CNC, cranial neural crest; FBS, fetal bovine serum; GFP, green fluorescence protein; FN, fibronectin; PBS, phosphate buffered saline.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Judith M. White (jw7g{at}virginia.edu).

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