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 ArmandoMaike Effern, Yoon Namkung, Laura Jenkins, Velten Horn, Anne Stößel, Harald Dargatz, Daniel Tietze, Diana Imhof, Céline Gales, Christel Drewke, Christa E. Müller, Michael Hölzel, Graeme Milligan, Andrew B. Tobin, Jesus 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, Evi Kostenis

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117 Citations (Scopus)

Abstract

Despite the discovery of heterotrimeric abg G proteins B25 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 Ga 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.

Original languageEnglish
Article number10156
JournalNature communications
Volume6
DOIs
Publication statusPublished - 2015

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Schrage, R., Schmitz, A. L., Gaffal, E., Annala, S., Kehraus, S., Wenzel, D., Büllesbach, K. M., Bald, T., Inoue, A., Shinjo, Y., Galandrin, S., Shridhar, N., Hesse, M., Grundmann, M., Merten, N., Charpentier, T. H., Martz, M., Butcher, A. J., Slodczyk, T., ... Kostenis, E. (2015). The experimental power of FR900359 to study Gq-regulated biological processes. Nature communications, 6, [10156]. https://doi.org/10.1038/ncomms10156