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J. Cell Biol. 155 (3): 459-470

Copyright © 2001 by the Rockefeller University Press.


Article

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

Dwayne G. Stupack, Xose S. Puente, Souphaphone Boutsaboualoy, Chris M. Storgard, and David A. Cheresh

Department of Immunology and Department of Vascular Biology, The Scripps Research Institute, La Jolla, CA 92037

Address correspondence to David Cheresh, The Scripps Research Institute, Department of Immunology, IMM24 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: (858) 784-8281. Fax: (858) 784-8926. E-mail: cheresh{at}scripps.edu

Abstract: 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 ß 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 ß 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.

Key Words: cell adhesion; apoptosis; caspase; integrin; ligands

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R. Pankov, E. Cukierman, K. Clark, K. Matsumoto, C. Hahn, B. Poulin, and K. M. Yamada (2003)
J. Biol. Chem. 278, 18671-18681
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The Cell Adhesion Molecule CEACAM1-L Is a Substrate of Caspase-3-mediated Cleavage in Apoptotic Mouse Intestinal Cells.
C. Houde, S. Roy, N. Leung, D. W. Nicholson, and N. Beauchemin (2003)
J. Biol. Chem. 278, 16929-16935
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Vascular morphogenesis: tales of two syndromes.
D. A. Marchuk, S. Srinivasan, T. L. Squire, and J. S. Zawistowski (2003)
Hum. Mol. Genet. 12, R97-112
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The Mechanism of CD47-Dependent Killing of T Cells: Heterotrimeric Gi-Dependent Inhibition of Protein Kinase A.
P. P. Manna and W. A. Frazier (2003)
J. Immunol. 170, 3544-3553
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Apoptotic Susceptibility of Cancer Cells Selected for Camptothecin Resistance: Gene Expression Profiling, Functional Analysis, and Molecular Interaction Mapping.
W. C. Reinhold, H. Kouros-Mehr, K. W. Kohn, A. K. Maunakea, S. Lababidi, A. Roschke, K. Stover, J. Alexander, P. Pantazis, L. Miller, et al. (2003)
Cancer Res. 63, 1000-1011
   Abstract »    Full Text »    PDF »
Transendothelial migration leads to protection from starvation-induced apoptosis in CD34+CD14+ circulating precursors: evidence for PECAM-1 involvement through Akt/PKB activation.
E. Ferrero, D. Belloni, P. Contini, C. Foglieni, M. E. Ferrero, M. Fabbri, A. Poggi, and M. R. Zocchi (2003)
Blood 101, 186-193
   Abstract »    Full Text »    PDF »
Fas Activation Induces Renal Tubular Epithelial Cell beta 8 Integrin Expression and Function in the Absence of Apoptosis.
G. Jarad, B. Wang, S. Khan, J. DeVore, H. Miao, K. Wu, S. L. Nishimura, B. A. Wible, M. Konieczkowski, J. R. Sedor, et al. (2002)
J. Biol. Chem. 277, 47826-47833
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Restoration of Transforming Growth Factor {beta} Signaling by Functional Expression of Smad4 Induces Anoikis.
M. Ramachandra, I. Atencio, A. Rahman, M. Vaillancourt, A. Zou, J. Avanzini, K. Wills, R. Bookstein, and P. Shabram (2002)
Cancer Res. 62, 6045-6051
   Abstract »    Full Text »    PDF »
Integrin alpha V beta 3 as a target for treatment of rheumatoid arthritis and related rheumatic diseases.
R L Wilder (2002)
Ann Rheum Dis 61, ii96-99
   Abstract »    Full Text »    PDF »
Get a ligand, get a life: integrins, signaling and cell survival.
D. G. Stupack and D. A. Cheresh (2002)
J. Cell Sci. 115, 3729-3738
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Autocrine Stimulation by Osteopontin Contributes to Antiapoptotic Signalling of Melanocytes in Dermal Collagen.
E. Geissinger, C. Weisser, P. Fischer, M. Schartl, and C. Wellbrock (2002)
Cancer Res. 62, 4820-4828
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Role of integrins in regulating epidermal adhesion, growth and differentiation.
F. M. Watt (2002)
EMBO J. 21, 3919-3926
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