The experimental power of FR900359 to study Gq-regulated biological processes

Ramona Schrage, Anna-Lena Schmitz, Evelyn Gaffal, Suvi Annala, Stefan Kehraus, Daniela Wenzel, Katrin M. Büllesbach, Tobias Bald, Asuka Inoue, Yuji Shinjo, Ségolène Galandrin, Naveen Shridhar, Michael Hesse, Manuel Grundmann, Nicole Merten, Thomas H. Charpentier, Matthew Martz, Adrian J. Butcher, Tanja Slodczyk, Sylvain Armando, Maike Effern, Yoon Namkung, Laura Jenkins, Velten Horn, Anne Stößel, Harald Dargatz, Daniel Tietze, Diana Imhof, Céline Galés, Christel Drewke, Christa E. Müller, Michael Hölzel, Graeme Milligan, Andrew B. Tobin, Jesús Gomeza, Henrik G. Dohlman, John Sondek, T. Kendall Harden, Michel Bouvier, Stéphane A. Laporte, Junken Aoki, Bernd K. Fleischmann, Klaus Mohr, Gabriele M. König, Thomas Tüting () and Evi Kostenis ()
Additional contact information
Ramona Schrage: Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn
Anna-Lena Schmitz: Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn
Evelyn Gaffal: Laboratory of Experimental Dermatology, University of Bonn
Suvi Annala: Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn
Stefan Kehraus: Institute of Pharmaceutical Biology, University of Bonn
Daniela Wenzel: Institute of Physiology I, Life and Brain Center, University of Bonn
Katrin M. Büllesbach: Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn
Tobias Bald: Laboratory of Experimental Dermatology, University of Bonn
Asuka Inoue: Graduate School of Pharmaceutical Sciences, Tohoku University
Yuji Shinjo: Graduate School of Pharmaceutical Sciences, Tohoku University
Ségolène Galandrin: Institut des Maladies Métaboliques et Cardiovasculaires, Institut Nataional de la Santé et de la Recherche Médicale, Université Toulouse III Paul Sabatier
Naveen Shridhar: Laboratory of Experimental Dermatology, University of Bonn
Michael Hesse: Institute of Physiology I, Life and Brain Center, University of Bonn
Manuel Grundmann: Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn
Nicole Merten: Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn
Thomas H. Charpentier: University of North Carolina School of Medicine
Matthew Martz: University of North Carolina School of Medicine
Adrian J. Butcher: Medical Research Council Toxicology Unit, University of Leicester, Hodgkin building
Tanja Slodczyk: Laboratory of Experimental Dermatology, University of Bonn
Sylvain Armando: McGill University, and the Research Institute of the McGill University Health Centre
Maike Effern: University of Bonn
Yoon Namkung: McGill University, and the Research Institute of the McGill University Health Centre
Laura Jenkins: Molecular Pharmacology Group, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow
Velten Horn: Eduard-Zintl-Institute of Inorganic and Physical Chemistry, Technische Universität Darmstadt
Anne Stößel: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn
Harald Dargatz: Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn
Daniel Tietze: Eduard-Zintl-Institute of Inorganic and Physical Chemistry, Technische Universität Darmstadt
Diana Imhof: Pharmaceutical Chemistry I, Institute of Pharmacy, University of Bonn
Céline Galés: Institut des Maladies Métaboliques et Cardiovasculaires, Institut Nataional de la Santé et de la Recherche Médicale, Université Toulouse III Paul Sabatier
Christel Drewke: Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn
Christa E. Müller: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn
Michael Hölzel: University of Bonn
Graeme Milligan: Molecular Pharmacology Group, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow
Andrew B. Tobin: Medical Research Council Toxicology Unit, University of Leicester, Hodgkin building
Jesús Gomeza: Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn
Henrik G. Dohlman: University of North Carolina School of Medicine
John Sondek: University of North Carolina School of Medicine
T. Kendall Harden: University of North Carolina School of Medicine
Michel Bouvier: Université de Montréal
Stéphane A. Laporte: McGill University, and the Research Institute of the McGill University Health Centre
Junken Aoki: Graduate School of Pharmaceutical Sciences, Tohoku University
Bernd K. Fleischmann: Institute of Physiology I, Life and Brain Center, University of Bonn
Klaus Mohr: Pharmacology & Toxicology Section, Institute of Pharmacy, University of Bonn
Gabriele M. König: Institute of Pharmaceutical Biology, University of Bonn
Thomas Tüting: Laboratory of Experimental Dermatology, University of Bonn
Evi Kostenis: Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn

Nature Communications, 2015, vol. 6, issue 1, 1-17

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms10156

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