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Molecular and Cellular Biology, May 2004, p. 4361-4371, Vol. 24, No. 10
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.10.4361-4371.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Focal Adhesion Kinase Suppresses Apoptosis by Binding to the Death Domain of Receptor-Interacting Protein

Elena Kurenova,1 Li-Hui Xu,2 Xihui Yang,2 Albert S. Baldwin Jr.,2 Rolf J. Craven,3 Steven K. Hanks,4 Zheng-gang Liu,5 and William G. Cance1*

Departments of Surgery, Biochemistry, and Molecular Biology, University of Florida, Gainesville, Florida 32610,1 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599,2 Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington, Kentucky 40536,3 Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232,4 Department of Cell and Cancer Biology, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 208925

Received 8 September 2003/ Returned for modification 21 October 2003/ Accepted 11 February 2004

Tumor cells resist the apoptotic stimuli associated with invasion and metastasis by activating survival signals that suppress apoptosis. Focal adhesion kinase (FAK), a tyrosine kinase that is overexpressed in a variety of human tumors, mediates one of these survival signals. Attenuation of FAK expression in tumor cells results in apoptosis that is mediated by caspase 8- and FADD-dependent pathways, suggesting that death receptor pathways are involved in the process. Here, we report a functional link between FAK and death receptors. We have demonstrated that FAK binds to the death domain kinase receptor-interacting protein (RIP). RIP is a major component of the death receptor complex and has been shown to interact with Fas and tumor necrosis factor receptor 1 through its binding to adapter proteins. We have shown that RIP provides proapoptotic signals that are suppressed by its binding to FAK. We thus propose that FAK overexpression in human tumors provides a survival signal function by binding to RIP and inhibiting its interaction with the death receptor complex.

* Corresponding author. Mailing address: Health Science Center, P.O. Box 100286, 1600 SW Archer Rd., Gainesville FL 32610. Phone: (352) 265-0622. Fax: (352) 338-9809. E-mail: cance{at}surgery.ufl.edu.

Molecular and Cellular Biology, May 2004, p. 4361-4371, Vol. 24, No. 10
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.10.4361-4371.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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