Cleavage of Focal Adhesion Kinase by Caspases during Apoptosis*
- From the ‡Department of Pulmonary and Critical Care Medicine, Stanford University, Stanford, California 94305, the§Cancer Biology Laboratories, Department of Pathology, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, and the ¶Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109
Abstract
Apoptotic cells undergo characteristic morphological changes that include detachment of cell attachment from the substratum and loss of cell-cell interactions. Attachment of cells to the extracellular matrix and to other cells is mediated by integrins. The interactions of integrins with the extracellular matrix activates focal adhesion kinase (FAK) and suppresses apoptosis in diverse cell types. Members of the tumor necrosis family such as Fas and Apo-2L, also known as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), induce apoptosis in both suspension and adherent cells through the activation of caspases. These caspases, when activated, cleave substrates that are important for the maintenance of nuclear and membrane integrity. In this study, we show that FAK is sequentially cleaved into two different fragments early in Apo-2L-induced apoptosis. We also demonstrate that FAK cleavage is mediated by caspases and that FAK shows unique sensitivity to different caspases. Our results suggest that disruption of FAK may contribute to the morphological changes observed in apoptotic suspension and adherent cells.
Footnotes
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↵* This work was supported in part by a grant from the Program in Molecular and Genetic Medicine, Stanford University (to G. D. R.), and National Institutes of Health Grant GM52890 (to J.-L. G.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‖ To whom correspondence should be addressed: Stanford University Medical Center, Pulmonary and Critical Care Medicine, 300 Pasteur Dr., Stanford, CA 94305-5236. Tel.: 415-725-9536; Fax: 415-725-5489; E-mail: grosen{at}leland.stanford.edu.
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↵1 The abbreviations used are: ECM, extracellular matrix; FAK, focal adhesion kinase; PARP, poly(A)DP-ribose polymerase; mAb, monoclonal antibody; FMK, fluoromethyl ketone; ICE, interleukin-1β-converting enzyme.
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↵2 Guy Salvesen, personal communication.
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↵3 L. P. Wen, J.-L. Guan, and G. D. Rosen, unpublished results.
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- Received April 1, 1997.
- Revision received June 6, 1997.
