Extracellular Redox Regulation of α7β Integrin-Mediated Cell Migration Is Signaled via a Dominant Thiol-Switch
| Autor: | Christoph Westerhausen, Michele F. Caliandro, Lukas Bergerhausen, Juliane Meißner, Gereon Poschmann, Julius Grosche, Matthias Mörgelin, Maryam Rezaei, Andrej Kamenac, Dietmar Vestweber, Eva-Maria Hanschmann, Johannes A. Eble, Christina Hecker |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
cell migration Physiology Clinical Biochemistry Integrin Biochemistry Redox Article Extracellular matrix redox regulation 03 medical and health sciences 0302 clinical medicine Extracellular ddc:610 extracellular thioredoxin-1 Laminin binding Cell adhesion redox signaling Molecular Biology thiol-switch biology Chemistry lcsh:RM1-950 Cell migration Cell Biology laminin binding 030104 developmental biology lcsh:Therapeutics. Pharmacology 030220 oncology & carcinogenesis biology.protein Biophysics integrin α7β1 Cysteine |
| Zdroj: | Antioxidants, Vol 9, Iss 3, p 227 (2020) Antioxidants Volume 9 Issue 3 |
| ISSN: | 2076-3921 |
| Popis: | While adhering to extracellular matrix (ECM) proteins, such as laminin-111, cells temporarily produce hydrogen peroxide at adhesion sites. To study the redox regulation of &alpha 7&beta 1 integrin-mediated cell adhesion to laminin-111, a conserved cysteine pair within the &alpha subunit hinge region was replaced for alanines. The molecular and cellular effects were analyzed by electron and atomic force microscopy, impedance-based migration assays, flow cytometry and live cell imaging. This cysteine pair constitutes a thiol-switch, which redox-dependently governs the equilibrium between an extended and a bent integrin conformation with high and low ligand binding activity, respectively. Hydrogen peroxide oxidizes the cysteines to a disulfide bond, increases ligand binding and promotes cell migration toward laminin-111. Inversely, extracellular thioredoxin-1 reduces the disulfide, thereby decreasing laminin binding. Mutation of this cysteine pair into the non-oxidizable hinge-mutant shows molecular and cellular effects similar to the reduced wild-type integrin, but lacks redox regulation. This proves the existence of a dominant thiol-switch within the &alpha subunit hinge of &alpha 1 integrin, which is sufficient to implement activity regulation by extracellular redox agents in a redox-regulatory circuit. Our data reveal a novel and physiologically relevant thiol-based regulatory mechanism of integrin-mediated cell-ECM interactions, which employs short-lived hydrogen peroxide and extracellular thioredoxin-1 as signaling mediators. |
| Databáze: | OpenAIRE |
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