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© The Rockefeller University Press, 0021-9525/1998//1087 $5.00
The Journal of Cell Biology, Volume 143, Number 4, , 1998 1087-1099

Regular Articles

The Transcription Factor AP-1 Is Required for EGF-induced Activation of Rho-like GTPases, Cytoskeletal Rearrangements, Motility, and In Vitro Invasion of A431 Cells



Angeliki Malliri*, Marc Symons{ddagger}, Robert F. Hennigan*, Adam F.L. Hurlstone*, Richard F. Lamb*, Tricia Wheeler*, and Bradford W. Ozanne*

* Beatson Institute for Cancer Research, Bearsden, Glasgow, G61 1BD, United Kingdom; and {ddagger} Onyx Pharmaceuticals, Richmond, California 94806

Human squamous cell carcinomas (SCC) frequently express elevated levels of epidermal growth factor receptor (EGFR). EGFR overexpression in SCC-derived cell lines correlates with their ability to invade in an in vitro invasion assay in response to EGF, whereas benign epidermal cells, which express low levels of EGFR, do not invade. EGF-induced invasion of SCC-derived A431 cells is inhibited by sustained expression of the dominant negative mutant of c-Jun, TAM67, suggesting a role for the transcription factor AP-1 (activator protein-1) in regulating invasion. Significantly, we establish that sustained TAM67 expression inhibits growth factor–induced cell motility and the reorganization of the cytoskeleton and cell-shape changes essential for this process: TAM67 expression inhibits EGF-induced membrane ruffling, lamellipodia formation, cortical actin polymerization and cell rounding. Introduction of a dominant negative mutant of Rac and of the Rho inhibitor C3 transferase into A431 cells indicates that EGF-induced membrane ruffling and lamellipodia formation are regulated by Rac, whereas EGF-induced cortical actin polymerization and cell rounding are controlled by Rho. Constitutively activated mutants of Rac or Rho introduced into A431 or A431 cells expressing TAM67 (TA cells) induce equivalent actin cytoskeletal rearrangements, suggesting that the effector pathways downstream of Rac and Rho required for these responses are unimpaired by sustained TAM67 expression. However, EGF-induced translocation of Rac to the cell membrane, which is associated with its activation, is defective in TA cells. Our data establish a novel link between AP-1 activity and EGFR activation of Rac and Rho, which in turn mediate the actin cytoskeletal rearrangements required for cell motility and invasion.

Key Words: AP-1 • Rho-like GTPases • invasion • motility • EGFR

Abbreviations used in this paper: AP-1, activator protein-1; CAT, chloramphenicol acetyl transferase; Col, collagenase; ECM, extracellular matrix; EGFR, epidermal growth factor receptor; GAP, GTPase-activating proteins; GDI, guanine nucleotide dissociation inhibitors; GEF, guanine nucleotide exchange factors; HEK, human epidermal keratinocytes; HGF/SF, hepatocyte growth factor/scatter factor; HPV, human papilloma virus; JNK, c-Jun NH2-terminal kinase; SRF, serum response factor; SCC, squamous cell carcinomas.

Address all correspondence to Prof. B.W. Ozanne, Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow, G61 1BD, UK. Tel.: 44 141 942 0855. Fax: 44 141 942 6521. E-mail: b.ozanne{at}beatson.gla.ac.uk

Robert F. Hennigan's present address is Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati College of Medicine, Cincinnati, OH 45267.

Richard F. Lamb's present address is MRC Laboratory of Molecular and Cellular Biology, University College London, Gower Street, London, C1E 6BT, UK.

Marc Symon's present address is Picower Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030.


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