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J. Biol. Chem., Vol. 282, Issue 24, 17450-17459, June 15, 2007

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Tumor Necrosis Factor- Stimulates Focal Adhesion Kinase Activity Required for Mitogen-activated Kinase-associated Interleukin 6 Expression^*

From the Department of Immunology, The Scripps Research Institute, La Jolla, California 92037

Focal adhesion kinase (FAK) is a cytoplasmic protein-tyrosine kinase that promotes cell migration, survival, and gene expression. Here we show that FAK signaling is important for tumor necrosis factor- (TNF)-induced interleukin 6 (IL-6) mRNA and protein expression in breast (4T1), lung (A549), prostate (PC-3), and neural (NB-8) tumor cells by FAK short hairpin RNA knockdown and by comparisons of FAK-null (FAK^–/–) and FAK^+/+ mouse embryo fibroblasts. FAK promoted TNF-stimulated MAPK activation needed for maximal IL-6 production. FAK was not required for TNF-mediated nuclear factor-B or c-Jun N-terminal kinase activation. TNF-stimulated FAK catalytic activation and IL-6 production were inhibited by FAK N-terminal but not FAK C-terminal domain overexpression. Analysis of FAK^–/– fibroblasts stably reconstituted with wild type or various FAK point mutants showed that FAK catalytic activity, Tyr-397 phosphorylation, and the Pro-712/713 proline-rich region of FAK were required for TNF-stimulated MAPK activation and IL-6 production. Constitutively activated MAPK kinase-1 (MEK1) expression in FAK^–/– and A549 FAK short hairpin RNA-expressing cells rescued TNF-stimulated IL-6 production. Inhibition of Src protein-tyrosine kinase activity or mutation of Src phosphorylation sites on FAK (Tyr-861 or Tyr-925) did not affect TNF-stimulated IL-6 expression. Moreover, analyses of Src^–/–, Yes^–/–, and Fyn^–/– fibroblasts showed that Src expression was inhibitory to TNF-stimulated IL-6 production. These studies provide evidence for a novel Src-independent FAK to MAPK signaling pathway regulating IL-6 expression with potential importance to inflammation and tumor progression.

Received for publication, November 17, 2006 , and in revised form, March 30, 2007.

^* This work was supported in part by CA102310 [GenBank] and CA87038 from the National Institutes of Health. This is manuscript 18575-IMM from The Scripps Research Institute. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported in part by National Institutes of Health Grant CA75240 and American Heart Association Established Investigator Award 0540115N. To whom correspondence should be addressed: The Scripps Research Institute, Dept. of Immunology, IMM 21, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-784-8207; Fax: 858-784-8289; E-mail: dschlaep{at}scripps.edu.

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