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Published 3 March 2003. doi:10.1083/jcb.200212114
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© The Rockefeller University Press, 0021-9525/2003/3/753 $5.00
The Journal of Cell Biology, Volume 160, Number 5, 753-767

Article

 Differential regulation of cell motility and invasion by FAK

Datsun A. Hsia1, Satyajit K. Mitra1, Christof R. Hauck1,2, Daniel N. Streblow2, Jay A. Nelson2, Dusko Ilic3, Shuang Huang1, Erguang Li1, Glen R. Nemerow1, Jay Leng1, Kathryn S.R. Spencer1, David A. Cheresh1 and David D. Schlaepfer1

1 Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037
2 Department of Molecular Microbiology and Immunology, Oregon Health Sciences University, Portland, OR 97201
3 Department of Stomatology, University of California, San Francisco, CA 94143

Address correspondence to David D. Schlaepfer, The Scripps Research Institute, Dept. of Immunology, IMM26, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: (858) 784-8207. Fax: (858) 784-8227. E-mail: dschlaep{at}scripps.edu

Cell migration and invasion are fundamental components of tumor cell metastasis. Increased focal adhesion kinase (FAK) expression and tyrosine phosphorylation are connected with elevated tumorigenesis. Null mutation of FAK results in embryonic lethality, and FAK-/- fibroblasts exhibit cell migration defects in culture. Here we show that viral Src (v-Src) transformation of FAK-/- cells promotes integrin-stimulated motility equal to stable FAK reexpression. However, FAK-/- v-Src cells were not invasive, and FAK reexpression, Tyr-397 phosphorylation, and FAK kinase activity were required for the generation of an invasive cell phenotype. Cell invasion was linked to transient FAK accumulation at lamellipodia, formation of a FAK–Src-p130Cas–Dock180 signaling complex, elevated Rac and c-Jun NH2-terminal kinase activation, and increased matrix metalloproteinase expression and activity. Our studies support a dual role for FAK in promoting cell motility and invasion through the activation of distinct signaling pathways.

Key Words: motility; invasion; FAK; Src; JNK


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