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Published 29 October 2001. doi:10.1083/jcb.200105017
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© The Rockefeller University Press, 0021-9525/2001/10/447 $5.00
The Journal of Cell Biology, Volume 155, Number 3, October 29, 2001 447-458

Article

 EGF-R signaling through Fyn kinase disrupts the function of integrin {alpha}6ß4 at hemidesmosomes : role in epithelial cell migration and carcinoma invasion



Agnese Mariotti1, Paul A. Kedeshian1,2, Michael Dans1, Anna Maria Curatola3, Laurent Gagnoux-Palacios1 and Filippo G. Giancotti1

1 Cellular Biochemistry and Biophysics Program, Department of Surgery, Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
2 Head and Neck Service, Department of Surgery, Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
3 Department of Pediatrics, New York University School of Medicine, New York, New York 10016

Address correspondence to Filippo G. Giancotti Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, Box 216, 1275 York Ave., New York, NY 10021. Tel.: (212) 639-6998. Fax: (212) 794-6236. E-mail: f-giancotti{at}ski.mskcc.org

We have examined the mechanism and functional significance of hemidesmosome disassembly during normal epithelial cell migration and squamous carcinoma invasion. Our findings indicate that a fraction of EGF receptor (EGF-R) combines with the hemidesmosomal integrin {alpha}6ß4 in both normal and neoplastic keratinocytes. Activation of the EGF-R causes tyrosine phosphorylation of the ß4 cytoplasmic domain and disruption of hemidesmosomes. The Src family kinase inhibitors PP1 and PP2 prevent tyrosine phosphorylation of ß4 and disassembly of hemidesmosomes without interfering with the activation of EGF-R. Coimmunoprecipitation experiments indicate that Fyn and, to a lesser extent, Yes combine with {alpha}6ß4. By contrast, Src and Lck do not associate with {alpha}6ß4 to a significant extent. A dominant negative form of Fyn, but not Src, prevents tyrosine phosphorylation of ß4 and disassembly of hemidesmosomes. These observations suggest that the EGF-R causes disassembly of hemidesmosomes by activating Fyn, which in turn phosphorylates the ß4 cytoplasmic domain. Neoplastic cells expressing dominant negative Fyn display increased hemidesmosomes and migrate poorly in vitro in response to EGF. Furthermore, dominant negative Fyn decreases the ability of squamous carcinoma cells to invade through Matrigel in vitro and to form lung metastases following intravenous injection in nude mice. These results suggest that disruption of hemidesmosomes mediated by Fyn is a prerequisite for normal keratinocyte migration and squamous carcinoma invasion.

Key Words: {alpha}6ß4; fyn; EGF-R; hemidesmosomes; carcinoma invasion


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