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The aryl hydrocarbon receptor regulates focal adhesion sites through a non-genomic FAK/Src pathway

Abstract

The aryl hydrocarbon receptor (AhR) is commonly described as a transcription factor, which regulates xenobiotic-metabolizing enzymes. Recent studies have suggested that the binding of ligands to the AhR also activates the Src kinase. In this manuscript, we show that the AhR, through the activation of Src, activates focal adhesion kinase (FAK) and promotes integrin clustering. These effects contribute to cell migration. Further, we show that the activation of the AhR increases the interaction of FAK with the metastatic marker, HEF1/NEDD9/CAS-L, and the expression of several integrins. Xenobiotic exposure, thus, may contribute to novel cell-migratory programs.

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Acknowledgements

This work was supported by the ANSES (Agence Nationale de SEcurité Sanitaire de l'alimentation, de l'environnement et du travail; all authors), ANR (Agence Nationale de la Recherche, 06SEST26, Oncopop; all authors), ARC (Association pour la Recherche sur le Cancer, 3927 and SFI20101201842; all authors), CNRS (Center Nationale de la recherche scientifique), Fondation pour la Recherche Médicale, ‘Ecole Doctorale du Médicament’, Hospitals Européen Georges Pompidou and Necker Enfants Malade, INSERM (Institut National de la Santé et de la Recherche Médicale; all authors), Ligue contre le Cancer (post-doctoral fellowship), Ministère de l'enseignement supérieur et de la recherché, Région Ile de France (doctoral fellowship) and Université Paris Descartes, Paris Sorbonne Cité. The FRNK-expressing vector is a generous gift of Dr Kenneth M Yamada (NIDCR, NIH, USA) and Dr Bernard Rothhut (CNRS UMR 6237, Reims). We warmly thank Dr Lawrence Aggerbeck for his critical reading of this manuscript.

Authors Contributions: Céline Tomkiewicz-Raulet performed most of the experiments and wrote a significant part of the manuscript. Linh-Chi Bui initiated several key experiments including the immunofluorescence staining. Laurence Herry set up the immunoprecipitation and the transfection experiments. Charles Métayer set up some of the Western blot experiments. Mathilde Bourdeloux set up some of the immunofluoresence and the immunoprecipitation experiments. Robert Barouki and Xavier Coumoul raised funds for the project, supervised all of the experiments and wrote most of the manuscript.

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Tomkiewicz, C., Herry, L., Bui, LC. et al. The aryl hydrocarbon receptor regulates focal adhesion sites through a non-genomic FAK/Src pathway. Oncogene 32, 1811–1820 (2013). https://doi.org/10.1038/onc.2012.197

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