Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-05850-w
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Funding
- Spemann Graduate School of Biology and Medicine (SGBM) - Excellence Initiative of the German Federal and State Governments [GSC-4]
- German Research Foundation (DFG) [FOR2036]
- Collaborative Research Centre - DFG [SFB1140]
- Centre for Biological Signalling Studies (BIOSS) [EXC-294]
- Excellence Cluster Inflammation at Interfaces [EXC-306]
- Excellence Initiative, Germany
- DFG [SCHI 871/5, SCHI 871/6, GR 1748/6, INST 39/900-1, SFB850]
- European Research Council [ERC-2011-StG 282111-ProteaSys]
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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 alpha V/beta 3 with Cilengitide. Thus, GT can target integrins to induce anoikis on lung epithelial cells.
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