Apoptosis of adherent cells by recruitment of caspase-8 to unligated integrins

Integrin-mediated adhesion promotes cell survival in vitro, whereas integri n antagonists induce apoptosis of adherent cells in vivo. Here, we demonstr ate that cells adherent within a three-dimensional extracellular matrix und ergo apoptosis due to expression of unligated integrins, the beta subunit c ytoplasmic domain, or its membrane proximal sequence KLLITIHDRKEF. Integrin -mediated death requires initiator, but not stress, caspase activity and is distinct from anoikis, which is caused by the loss of adhesion per se. Sur prisingly, unligated integrin or beta integrin tails recruit caspase-8 to t he membrane, where it becomes activated in a death receptor-independent man ner. Integrin ligation disrupts this integrin-caspase containing complex an d increases survival, revealing an unexpected role for integrins in the reg ulation of apoptosis and tissue remodeling.