Apoptosis of adherent cells by recruitment of caspase-8 to unligated integrins.
Integrin-mediated adhesion promotes cell survival in vitro, whereas integrin antagonists induce apoptosis of adherent cells in vivo. Here, we demonstrate that cells adherent within a three-dimensional extracellular matrix undergo apoptosis due to expression of unligated integrins, the beta subunit cytoplasmic 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. Surprisingly, unligated integrin or beta integrin tails recruit caspase-8 to the membrane, where it becomes activated in a death receptor-independent manner. Integrin ligation disrupts this integrin-caspase containing complex and increases survival, revealing an unexpected role for integrins in the regulation of apoptosis and tissue remodeling.
Stupack
D G
DG
Department of Immunology and Department of Vascular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Puente
X S
XS
Boutsaboualoy
S
S
Storgard
C M
CM
Cheresh
D A
DA
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D001665:Binding Sites; D019556:COS Cells; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002448:Cell Adhesion; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism; D039482:Integrin alpha5; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D039661:Integrin beta3; D010980:Platelet Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000378:metabolism
D015703:Antigens, CD; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D039482:Integrin alpha5; D019012:Integrin beta1; D039661:Integrin beta3; D010980:Platelet Membrane Glycoproteins; D015375:Receptors, Interleukin-2; D019030:Receptors, Vitronectin; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases