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

Schrage, R. et al. (2015) The experimental power of FR900359 to study Gq-regulated biological processes. Nature Communications, 6, p. 10156. (doi: 10.1038/ncomms10156) (PMID:26658454) (PMCID:PMC4682109)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Jenkins, Mrs Laura and Milligan, Professor Graeme and Tobin, Andrew
• Authors: 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., Armando, S., Effern, M., Namkung, Y., Jenkins, L., Horn, V., Stößel, A., Dargatz, H., Tietze, D., Imhof, D., Galés, C., Drewke, C., Müller, C. E., Hölzel, M., Milligan, G., Tobin, A. B., Gomeza, J., Dohlman, H. G., Sondek, J., Harden, T. K., Bouvier, M., Laporte, S. A., Aoki, J., Fleischmann, B. K., Mohr, K., König, G. M., Tüting, T., and Kostenis, E.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Nature Communications
• Publisher: Nature Publishing Group
• ISSN: 2041-1723
• Copyright Holders: Copyright © 2015 The Authors
• First Published: First published in Nature Communications 6:10156
• Publisher Policy: Reproduced under a Creative Commons License