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)

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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
Glasgow Author(s) Enlighten ID:Milligan, Professor Graeme and Tobin, Andrew and Jenkins, Mrs Laura
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 > Institute of Molecular Cell and Systems Biology
Journal Name:Nature Communications
Publisher:Nature Publishing Group
Copyright Holders:Copyright © 2015 The Authors
First Published:First published in Nature Communications 6:10156
Publisher Policy:Reproduced under a Creative Commons License

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