EGF-R signaling through Fyn kinase disrupts the function of integrin alpha6beta4 at hemidesmosomes: Role in epithelial cell migration and carcinoma invasion Journal Article


Authors: Mariotti, A.; Kedeshian, P. A.; Dans, M.; Curatola, A. M.; Gagnoux-Palacios, L.; Giancotti, F. G.
Article Title: EGF-R signaling through Fyn kinase disrupts the function of integrin alpha6beta4 at hemidesmosomes: Role in epithelial cell migration and carcinoma invasion
Abstract: 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 alpha6beta4 in both normal and neoplastic keratinocytes. Activation of the EGF-R causes tyrosine phosphorylation of the beta4 cytoplasmic domain and disruption of hemidesmosomes. The Src family kinase inhibitors PP1 and PP2 prevent tyrosine phosphorylation of beta4 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 alpha6beta4. By contrast, Src and Lck do not associate with alpha6beta4 to a significant extent. A dominant negative form of Fyn, but not Src, prevents tyrosine phosphorylation of beta4 and disassembly of hemidesmosomes. These observations suggest that the EGF-R causes disassembly of hemidesmosomes by activating Fyn, which in turn phosphorylates the beta4 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.
Keywords: signal transduction; oncoprotein; genetics; proto-oncogene proteins; mouse; animal; metabolism; animals; mice; metastasis; epidermal growth factor receptor; cell motion; receptor, epidermal growth factor; enzyme activation; pathology; tumor cell culture; tumor cells, cultured; protein tyrosine kinase; phosphorylation; physiology; membrane antigen; nude mouse; mice, nude; rat; neoplasm metastasis; neoplasms, experimental; cell movement; epithelium cell; epithelial cells; rats; neoplasm invasiveness; experimental neoplasm; src-family kinases; integrin; antigens, surface; integrins; hemidesmosomes; protein kinase fyn; proto-oncogene proteins c-fyn; fyn protein, mouse; tumor invasion; alpha6beta4 integrin; hemidesmosome; integrin alpha6beta4; humans; human; fyn protein, human; fyn protein, rat
Journal Title: Journal of Cell Biology
Volume: 155
Issue: 3
ISSN: 0021-9525
Publisher: Rockefeller University Press  
Date Published: 2001-10-29
Start Page: 447
End Page: 457
Language: English
PUBMED: 11684709
PROVIDER: scopus
PMCID: PMC2150849
DOI: 10.1083/jcb.200105017
DOI/URL:
Notes: Export Date: 21 May 2015 -- Source: Scopus
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  1. Michael J Dans
    9 Dans