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

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 integrinmediated cell migration. ADAMs were expressed in Chinese hamster ovary cells that express defined integrins ( 4 1, 5 1, or both), and cell migration on full-length fibronectin or on its 4 1 or 5 1 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 4 1 but not the 5 1 integrin. ADAM17 had the reciprocal effect; it inhibited 5 1but not 4 1-mediated cell migration. ADAM19 and ADAM33 inhibited migration mediated by both 4 1 and 5 1 integrins. A point mutation in the ADAM12 disintegrin loop partially reduced the inhibitory effect of ADAM12 on cell migration on the 4 1 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.