RGD-independent binding of integrin α₉β₁ to the ADAM-12 and -15 disintegrin domains mediates cell-cell interaction

ADAMs (a disintegrin and metalloproteases) mediate several important processes (e.g. tumor necrosis factor-α release, fertilization, and myoblast fusion). The ADAM disintegrin domains generally lack RGD motifs, and their receptors are virtually unknown. Here we show that integrin α₉β₁ specifically interacts with the recombinant ADAMs-12 and -15 disintegrin domains in an RGD-independent manner. We also show that interaction between ADAM-12 or -15 and α₉β₁ supports cell-cell interaction. Interestingly, the cation requirement and integrin activation status required for α₉β₁/ADAM-mediated cell adhesion and cell-cell interaction is similar to those required for known integrin-extracellular matrix interaction. These results are quite different from recent reports that ADAM-2/α₆β₁ interaction during sperm/egg fusion requires an integrin activation status distinct from that for extracellular matrix interaction. These results suggest that α₉β₁ may be a major receptor for ADAMs that lack RGD motifs, and that, considering a wide distribution of ADAMs and α₉β₁, this interaction may be of potential biological and pathological significance.