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

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  • Ramona Schrage

    (Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn
    Pharmacology & Toxicology Section, Institute of Pharmacy, 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
    Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO))

  • 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
    Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST))

  • 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)

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.

Suggested Citation

  • 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 Shridh, 2015. "The experimental power of FR900359 to study Gq-regulated biological processes," Nature Communications, Nature, vol. 6(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms10156
    DOI: 10.1038/ncomms10156
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    Cited by:

    1. Takefumi Kimura & Sai P. Pydi & Lei Wang & Dhanush Haspula & Yinghong Cui & Huiyan Lu & Gabriele M. König & Evi Kostenis & Gregory R. Steinberg & Oksana Gavrilova & Jürgen Wess, 2022. "Adipocyte Gq signaling is a regulator of glucose and lipid homeostasis in mice," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Evi Kostenis & Jesus Gomeza & Elke Miess-Tanneberg & Nina Kathleen Blum & Tobias Benkel & Andy Chevigné & Carsten Hoffmann & Peter Kolb & Viacheslav Nikolaev & Maria Waldhoer & Martyna Szpakowska & As, 2023. "Reply to: How carvedilol does not activate β2-adrenoceptors," Nature Communications, Nature, vol. 14(1), pages 1-3, December.
    3. Ahmed Wagdi & Daniela Malan & Udhayabhaskar Sathyanarayanan & Janosch S. Beauchamp & Markus Vogt & David Zipf & Thomas Beiert & Berivan Mansuroglu & Vanessa Dusend & Mark Meininghaus & Linn Schneider , 2022. "Selective optogenetic control of Gq signaling using human Neuropsin," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    4. Sandra Schrenk & Lindsay J. Bischoff & Jillian Goines & Yuqi Cai & Shruti Vemaraju & Yoshinobu Odaka & Samantha R. Good & Joseph S. Palumbo & Sara Szabo & Damien Reynaud & Catherine D. Raamsdonk & Ric, 2023. "MEK inhibition reduced vascular tumor growth and coagulopathy in a mouse model with hyperactive GNAQ," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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