The experimental power of FR900359 to study Gq-regulated biological processes
| Autor: | Klaus Mohr, Michael Hölzel, John Sondek, Evelyn Gaffal, Thomas H. Charpentier, Graeme Milligan, Céline Galés, Tanja Slodczyk, Harald Dargatz, Tobias Bald, Junken Aoki, Yuji Shinjo, Daniel Tietze, Maike Effern, Anna Lena Schmitz, Asuka Inoue, Sylvain Armando, Henrik G. Dohlman, Anne Stößel, Ramona Schrage, Ségolène Galandrin, Gabriele M. König, Michael Hesse, Katrin M. Büllesbach, Christa E. Müller, Manuel Grundmann, Christel Drewke, Stefan Kehraus, Andrew B. Tobin, Diana Imhof, T. Kendall Harden, Suvi Annala, Stéphane A. Laporte, Jesus Gomeza, Thomas Tüting, Velten Horn, Naveen Shridhar, Nicole Merten, Yoon Namkung, Adrian J. Butcher, Daniela Wenzel, Laura Jenkins, Evi Kostenis, Michel Bouvier, Bernd K. Fleischmann, Matthew K. Martz |
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| Přispěvatelé: | Bouvier, Michel [0000-0003-1128-0100], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Gene isoform
Models Molecular Tail G protein Protein Conformation General Physics and Astronomy Biology Bioinformatics Pertussis toxin Article General Biochemistry Genetics and Molecular Biology Ardisia Mice Protein structure Heterotrimeric G protein Cell Line Tumor Depsipeptides Animals Humans Protein Isoforms Melanoma Depsipeptide Multidisciplinary Molecular Structure General Chemistry 3. Good health Cell biology Gene Expression Regulation Neoplastic Signalling Vasoconstriction GTP-Binding Protein alpha Subunits Gq-G11 Signal transduction Signal Transduction |
| Zdroj: | Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | Despite the discovery of heterotrimeric αβγ G proteins ∼25 years ago, their selective perturbation by cell-permeable inhibitors remains a fundamental challenge. Here we report that the plant-derived depsipeptide FR900359 (FR) is ideally suited to this task. Using a multifaceted approach we systematically characterize FR as a selective inhibitor of Gq/11/14 over all other mammalian Gα isoforms and elaborate its molecular mechanism of action. We also use FR to investigate whether inhibition of Gq proteins is an effective post-receptor strategy to target oncogenic signalling, using melanoma as a model system. FR suppresses many of the hallmark features that are central to the malignancy of melanoma cells, thereby providing new opportunities for therapeutic intervention. Just as pertussis toxin is used extensively to probe and inhibit the signalling of Gi/o proteins, we anticipate that FR will at least be its equivalent for investigating the biological relevance of Gq. Pertussis toxin is used extensively for perturbing Gαi/o pathways in the study of physiology and disease, but an equivalent inhibitor of Gαq signalling is not currently available to the research community. Here the authors characterize FR900359 as a specific Gq inhibitor and demonstrate its utility to dissect GPCR signalling and its potential to inhibit melanoma cells. |
| Databáze: | OpenAIRE |
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