Identification of a novel anoikis signalling pathway using the fungal virulence factor gliotoxin

Abstract: 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 αV/β3 with Cilengitide. Thus, GT can target integrins to induce anoikis on lung epithelial cells

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch
• Notes: Nature communications. - 9, 1 (2018) , 3524, ISSN: 2041-1723

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2019
• Creator: Haun, Florian ; Neumann, Simon ; Peintner, Lukas ; Wieland, Katrin ; Habicht, Jüri ; Schwan, Carsten ; Østevold, Kristine ; Koczorowska, Maria Magdalena ; Biniossek, Martin Lothar ; Kist, Matthias ; Busch, Hauke ; Börries, Melanie ; Davis, Roger J. ; Maurer, Ulrich ; Schilling, Oliver ; Aktories, Klaus ; Borner, Christoph
• Contributor: Zentrum für Biochemie und Molekulare Zellforschung ; Albert-Ludwigs-Universität Freiburg. Abteilung Pharmakologie I

Further information

• DOI: 10.1038/s41467-018-05850-w
• URN: urn:nbn:de:bsz:25-freidok-1459630
• Rights: Kein Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 25.03.2025, 1:45 PM CET