title: The experimental power of FR900359 to study Gq-regulated biological processes.
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.
authors.affiliation: Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, 53115 Bonn, Germany.|Pharmacology &Toxicology Section, Institute of Pharmacy, University of Bonn, 53121 Bonn, Germany.
authors.forename: Ramona
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authors.lastname: Schrage
authors.affiliation: Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, 53115 Bonn, Germany.
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Schmitz
authors.affiliation: Department of Dermatology and Allergy, Laboratory of Experimental Dermatology, University of Bonn, 53105 Bonn, Germany.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Gaffal
authors.affiliation: Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, 53115 Bonn, Germany.
authors.forename: Suvi
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authors.lastname: Annala
authors.affiliation: Institute of Pharmaceutical Biology, University of Bonn, 53115 Bonn, Germany.
authors.forename: Stefan
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authors.affiliation: Institute of Physiology I, Life and Brain Center, University of Bonn, 53105 Bonn, Germany.
authors.forename: Daniela
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authors.lastname: Wenzel
authors.affiliation: Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, 53115 Bonn, Germany.
authors.forename: Katrin M
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authors.affiliation: Department of Dermatology and Allergy, Laboratory of Experimental Dermatology, University of Bonn, 53105 Bonn, Germany.
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authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai City 980-0065, Japan.|Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.
authors.forename: Asuka
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authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai City 980-0065, Japan.
authors.forename: Yuji
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authors.lastname: Shinjo
authors.affiliation: Institut des Maladies Métaboliques et Cardiovasculaires, Institut Nataional de la Santé et de la Recherche Médicale, Université Toulouse III Paul Sabatier, 31432 Toulouse, France.
authors.forename: Ségolène
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authors.affiliation: Department of Dermatology and Allergy, Laboratory of Experimental Dermatology, University of Bonn, 53105 Bonn, Germany.
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authors.affiliation: Institute of Physiology I, Life and Brain Center, University of Bonn, 53105 Bonn, Germany.
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authors.affiliation: Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, 53115 Bonn, Germany.
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authors.affiliation: Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, 53115 Bonn, Germany.
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authors.affiliation: Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA.
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authors.affiliation: Medical Research Council Toxicology Unit, University of Leicester, Hodgkin building, Leicester LE1 9HN, UK.
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authors.affiliation: Department of Dermatology and Allergy, Laboratory of Experimental Dermatology, University of Bonn, 53105 Bonn, Germany.
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authors.affiliation: Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, 53105 Bonn, Germany.
authors.forename: Maike
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authors.forename: Yoon
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authors.affiliation: Molecular Pharmacology Group, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland G12 8QQ, UK.
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authors.initials: L
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authors.affiliation: Eduard-Zintl-Institute of Inorganic and Physical Chemistry, Technische Universität Darmstadt, 64287 Darmstadt, Germany.
authors.forename: Velten
authors.initials: V
authors.lastname: Horn
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, 53121 Bonn, Germany.
authors.forename: Anne
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authors.affiliation: Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, 53115 Bonn, Germany.
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authors.affiliation: Eduard-Zintl-Institute of Inorganic and Physical Chemistry, Technische Universität Darmstadt, 64287 Darmstadt, Germany.
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authors.affiliation: Pharmaceutical Chemistry I, Institute of Pharmacy, University of Bonn, 53121 Bonn, Germany.
authors.forename: Diana
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authors.affiliation: Institut des Maladies Métaboliques et Cardiovasculaires, Institut Nataional de la Santé et de la Recherche Médicale, Université Toulouse III Paul Sabatier, 31432 Toulouse, France.
authors.forename: Céline
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authors.affiliation: Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, 53115 Bonn, Germany.
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authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, 53121 Bonn, Germany.
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authors.initials: CE
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authors.identifier: http://orcid.org/0000-0003-1128-0100
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authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai City 980-0065, Japan.|Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), 1-7-1 Otemachi, Chiyoda, Tokyo 100-0004, Japan.
authors.forename: Junken
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authors.affiliation: Institute of Pharmaceutical Biology, University of Bonn, 53115 Bonn, Germany.
authors.forename: Gabriele M
authors.initials: GM
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authors.lastname: Tüting
authors.affiliation: Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, 53115 Bonn, Germany.
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mesh_terms: D000818:Animals; D031644:Ardisia / Q000737:chemistry; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000737:chemistry / Q000494:pharmacology*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008545:Melanoma / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D020033:Protein Isoforms; D015398:Signal Transduction; D013623:Tail / Q000098:blood supply; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D047630:Depsipeptides; C000607068:FR900359; D020033:Protein Isoforms; D043802:GTP-Binding Protein alpha Subunits, Gq-G11