Program in Molecular Medicine; Davis Lab
Bacterial Infections and Mycoses | Cell Biology | Cells | Cellular and Molecular Physiology | Enzymes and Coenzymes | Fungi
Anoikis is a form of apoptosis induced by cell detachment. Integrin inactivation plays a major role in the process but the exact signalling pathway is ill-defined. Here we identify an anoikis pathway using gliotoxin (GT), a virulence factor of the fungus Aspergillus fumigatus, which causes invasive aspergillosis in humans. GT prevents integrin binding to RGD-containing extracellular matrix components by covalently modifying cysteines in the binding pocket. As a consequence, focal adhesion kinase (FAK) is inhibited resulting in dephosphorylation of p190RhoGAP, allowing activation of RhoA. Sequential activation of ROCK, MKK4/MKK7 and JNK then triggers pro-apoptotic phosphorylation of Bim. Cells in suspension or lacking integrin surface expression are insensitive to GT but are sensitised to ROCK-MKK4/MKK7-JNK-dependent anoikis upon attachment to fibronectin or integrin upregulation. The same signalling pathway is triggered by FAK inhibition or inhibiting integrin alphaV/beta3 with Cilengitide. Thus, GT can target integrins to induce anoikis on lung epithelial cells.
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Copyright © The Author(s) 2018. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
DOI of Published Version
Nat Commun. 2018 Aug 30;9(1):3524. doi: 10.1038/s41467-018-05850-w. Link to article on publisher's site
Haun, Florian; Neumann, Simon; Peintner, Lukas; Wieland, Katrin; Habicht, Juri; Schwan, Carsten; Ostevold, Kristine; Koczorowska, Maria Magdalena; Biniossek, Martin; Kist, Matthias; Busch, Hauke; Boerries, Melanie; Davis, Roger J.; Maurer, Ulrich; Schilling, Oliver; Aktories, Klaus; and Borner, Christoph, "Identification of a novel anoikis signalling pathway using the fungal virulence factor gliotoxin" (2018). Open Access Articles. 3560.
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This work is licensed under a Creative Commons Attribution 4.0 License.