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 Armando; Maike 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

doi:10.1038/ncomms10156

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

PHA - Life and Pharmaceutical Science

Research output: Contribution to journal › Article › peer-review

232 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 language	English
Article number	10156
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms10156
Publication status	Published - 2015

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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, Article 10156. https://doi.org/10.1038/ncomms10156

@article{b447aa67d3174136a249045c9e0a4160,

title = "The experimental power of FR900359 to study Gq-regulated biological processes",

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.",

author = "Ramona Schrage and Schmitz, {Anna Lena} and Evelyn Gaffal and Suvi Annala and Stefan Kehraus and Daniela Wenzel and B{\"u}llesbach, {Katrin M.} and Tobias Bald and Asuka Inoue and Yuji Shinjo and S{\'e}gol{\`e}ne Galandrin and Naveen Shridhar and Michael Hesse and Manuel Grundmann and Nicole Merten and Charpentier, {Thomas H.} and Matthew Martz and Butcher, {Adrian J.} and Tanja Slodczyk and Sylvain Armando and Maike Effern and Yoon Namkung and Laura Jenkins and Velten Horn and Anne St{\"o}{\ss}el and Harald Dargatz and Daniel Tietze and Diana Imhof and C{\'e}line Gales and Christel Drewke and M{\"u}ller, {Christa E.} and Michael H{\"o}lzel and Graeme Milligan and Tobin, {Andrew B.} and Jesus Gomeza and Dohlman, {Henrik G.} and John Sondek and Harden, {T. Kendall} and Michel Bouvier and Laporte, {St{\'e}phane A.} and Junken Aoki and Fleischmann, {Bernd K.} and Klaus Mohr and K{\"o}nig, {Gabriele M.} and Thomas T{\"u}ting and Evi Kostenis",

note = "Funding Information: We thank Nina Heycke, Ulrike Rick and Dr Irene Loef for expert technical assistance on DMR and IP1 assays, Dr Marion Schneider for assistance with LC-MS analytics and recording of mass spectra, and Drs Jun Ishiguro and Kumiko Makide at Tohoku University for technical assistance of FACS and cell maintenance. We are grateful to Corning Inc., PerkinElmer and Molecular Devices for their support on label-free DMR (Corning Epic BT System, PerkinElmer EnSight) as well as cellular dielectric spectroscopy (CellKey) biosensors. We thank Dr Girolamo Calo (Pharmacology Section, University of Ferrara) for the ORL1 cDNA. This research was supported by the National Institutes of Health grant no. R01 GM059167 to H.G.D., the training grant no. T32 CA009156-40 to M.M./H.G.D., the Danish Council for Strategic Research grant no. 11-116196 to E.K./M.G., the Medical Research Council UK (A.B.T. and A.J.B.) as well as PRESTO, JST (A.I.) and AMED-CREST (J.A.). K.M.B. was supported by the Deutsche Forschungsgemeinschaft-funded research training group RTG1873 {\textquoteleft}Pharmacology of 7TM-receptors and downstream signalling pathways{\textquoteright}.",

year = "2015",

doi = "10.1038/ncomms10156",

language = "English",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Schrage, R, Schmitz, AL, Gaffal, E, Annala, S, Kehraus, S, Wenzel, D, Büllesbach, KM, Bald, T, Inoue, A, Shinjo, Y, Galandrin, S, Shridhar, N, Hesse, M, Grundmann, M, Merten, N, Charpentier, TH, Martz, M, Butcher, AJ, Slodczyk, T, Armando, S, Effern, M, Namkung, Y, Jenkins, L, Horn, V, Stößel, A, Dargatz, H, Tietze, D, Imhof, D, Gales, C, Drewke, C, Müller, CE, Hölzel, M, Milligan, G, Tobin, AB, Gomeza, J, Dohlman, HG, Sondek, J, Harden, TK, Bouvier, M, Laporte, SA, Aoki, J, Fleischmann, BK, Mohr, K, König, GM, Tüting, T & Kostenis, E 2015, 'The experimental power of FR900359 to study Gq-regulated biological processes', Nature Communications, vol. 6, 10156. https://doi.org/10.1038/ncomms10156

TY - JOUR

T1 - The experimental power of FR900359 to study Gq-regulated biological processes

AU - Schrage, Ramona

AU - Schmitz, Anna Lena

AU - Gaffal, Evelyn

AU - Annala, Suvi

AU - Kehraus, Stefan

AU - Wenzel, Daniela

AU - Büllesbach, Katrin M.

AU - Bald, Tobias

AU - Inoue, Asuka

AU - Shinjo, Yuji

AU - Galandrin, Ségolène

AU - Shridhar, Naveen

AU - Hesse, Michael

AU - Grundmann, Manuel

AU - Merten, Nicole

AU - Charpentier, Thomas H.

AU - Martz, Matthew

AU - Butcher, Adrian J.

AU - Slodczyk, Tanja

AU - Armando, Sylvain

AU - Effern, Maike

AU - Namkung, Yoon

AU - Jenkins, Laura

AU - Horn, Velten

AU - Stößel, Anne

AU - Dargatz, Harald

AU - Tietze, Daniel

AU - Imhof, Diana

AU - Gales, Céline

AU - Drewke, Christel

AU - Müller, Christa E.

AU - Hölzel, Michael

AU - Milligan, Graeme

AU - Tobin, Andrew B.

AU - Gomeza, Jesus

AU - Dohlman, Henrik G.

AU - Sondek, John

AU - Harden, T. Kendall

AU - Bouvier, Michel

AU - Laporte, Stéphane A.

AU - Aoki, Junken

AU - Fleischmann, Bernd K.

AU - Mohr, Klaus

AU - König, Gabriele M.

AU - Tüting, Thomas

AU - Kostenis, Evi

N1 - Funding Information: We thank Nina Heycke, Ulrike Rick and Dr Irene Loef for expert technical assistance on DMR and IP1 assays, Dr Marion Schneider for assistance with LC-MS analytics and recording of mass spectra, and Drs Jun Ishiguro and Kumiko Makide at Tohoku University for technical assistance of FACS and cell maintenance. We are grateful to Corning Inc., PerkinElmer and Molecular Devices for their support on label-free DMR (Corning Epic BT System, PerkinElmer EnSight) as well as cellular dielectric spectroscopy (CellKey) biosensors. We thank Dr Girolamo Calo (Pharmacology Section, University of Ferrara) for the ORL1 cDNA. This research was supported by the National Institutes of Health grant no. R01 GM059167 to H.G.D., the training grant no. T32 CA009156-40 to M.M./H.G.D., the Danish Council for Strategic Research grant no. 11-116196 to E.K./M.G., the Medical Research Council UK (A.B.T. and A.J.B.) as well as PRESTO, JST (A.I.) and AMED-CREST (J.A.). K.M.B. was supported by the Deutsche Forschungsgemeinschaft-funded research training group RTG1873 ‘Pharmacology of 7TM-receptors and downstream signalling pathways’.

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

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UR - http://www.scopus.com/inward/citedby.url?scp=84984911801&partnerID=8YFLogxK

U2 - 10.1038/ncomms10156

DO - 10.1038/ncomms10156

M3 - Article

C2 - 26658454

AN - SCOPUS:84984911801

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 10156

ER -

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

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