Selective modulation of integrin-mediated cell migration by distinct ADAM family members

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 (alpha 4 beta 1, alpha 5 beta 1, or both), and cell migration on full-length fibronectin or on its alpha 4 beta 1 or alpha 5 beta 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 alpha 4 beta 1 but not the alpha 5 beta 1 integrin. ADAM17 had the reciprocal effect; it inhibited alpha 5 beta 1- but not alpha 4 beta 1-mediated cell migration. ADAM19 and ADAM33 inhibited migration mediated by both alpha 4 beta 1 and alpha 5 beta 1 integrins. A point mutation in the ADAM12 disintegrin loop partially reduced the inhibitory effect of ADAM12 on cell migration on the alpha 4 beta 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.