Cargando…

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

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 systemati...

Descripción completa

Detalles Bibliográficos
Autores principales: Schrage, Ramona, Schmitz, Anna-Lena, Gaffal, Evelyn, Annala, Suvi, Kehraus, Stefan, Wenzel, Daniela, Büllesbach, Katrin M., Bald, Tobias, Inoue, Asuka, Shinjo, Yuji, Galandrin, Ségolène, Shridhar, Naveen, Hesse, Michael, Grundmann, Manuel, Merten, Nicole, Charpentier, Thomas H., Martz, Matthew, Butcher, Adrian J., Slodczyk, Tanja, Armando, Sylvain, Effern, Maike, Namkung, Yoon, Jenkins, Laura, Horn, Velten, Stößel, Anne, Dargatz, Harald, Tietze, Daniel, Imhof, Diana, Galés, Céline, Drewke, Christel, Müller, Christa E., Hölzel, Michael, Milligan, Graeme, Tobin, Andrew B., Gomeza, Jesús, Dohlman, Henrik G., Sondek, John, Harden, T. Kendall, Bouvier, Michel, Laporte, Stéphane A., Aoki, Junken, Fleischmann, Bernd K., Mohr, Klaus, König, Gabriele M., Tüting, Thomas, Kostenis, Evi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4682109/
https://www.ncbi.nlm.nih.gov/pubmed/26658454
http://dx.doi.org/10.1038/ncomms10156
_version_ 1782405838039678976
author Schrage, Ramona
Schmitz, Anna-Lena
Gaffal, Evelyn
Annala, Suvi
Kehraus, Stefan
Wenzel, Daniela
Büllesbach, Katrin M.
Bald, Tobias
Inoue, Asuka
Shinjo, Yuji
Galandrin, Ségolène
Shridhar, Naveen
Hesse, Michael
Grundmann, Manuel
Merten, Nicole
Charpentier, Thomas H.
Martz, Matthew
Butcher, Adrian J.
Slodczyk, Tanja
Armando, Sylvain
Effern, Maike
Namkung, Yoon
Jenkins, Laura
Horn, Velten
Stößel, Anne
Dargatz, Harald
Tietze, Daniel
Imhof, Diana
Galés, Céline
Drewke, Christel
Müller, Christa E.
Hölzel, Michael
Milligan, Graeme
Tobin, Andrew B.
Gomeza, Jesús
Dohlman, Henrik G.
Sondek, John
Harden, T. Kendall
Bouvier, Michel
Laporte, Stéphane A.
Aoki, Junken
Fleischmann, Bernd K.
Mohr, Klaus
König, Gabriele M.
Tüting, Thomas
Kostenis, Evi
author_facet Schrage, Ramona
Schmitz, Anna-Lena
Gaffal, Evelyn
Annala, Suvi
Kehraus, Stefan
Wenzel, Daniela
Büllesbach, Katrin M.
Bald, Tobias
Inoue, Asuka
Shinjo, Yuji
Galandrin, Ségolène
Shridhar, Naveen
Hesse, Michael
Grundmann, Manuel
Merten, Nicole
Charpentier, Thomas H.
Martz, Matthew
Butcher, Adrian J.
Slodczyk, Tanja
Armando, Sylvain
Effern, Maike
Namkung, Yoon
Jenkins, Laura
Horn, Velten
Stößel, Anne
Dargatz, Harald
Tietze, Daniel
Imhof, Diana
Galés, Céline
Drewke, Christel
Müller, Christa E.
Hölzel, Michael
Milligan, Graeme
Tobin, Andrew B.
Gomeza, Jesús
Dohlman, Henrik G.
Sondek, John
Harden, T. Kendall
Bouvier, Michel
Laporte, Stéphane A.
Aoki, Junken
Fleischmann, Bernd K.
Mohr, Klaus
König, Gabriele M.
Tüting, Thomas
Kostenis, Evi
author_sort Schrage, Ramona
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4682109
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Nature Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-46821092015-12-29 The experimental power of FR900359 to study Gq-regulated biological processes Schrage, Ramona Schmitz, Anna-Lena Gaffal, Evelyn Annala, Suvi Kehraus, Stefan Wenzel, Daniela Büllesbach, Katrin M. Bald, Tobias Inoue, Asuka Shinjo, Yuji Galandrin, Ségolène Shridhar, Naveen Hesse, Michael Grundmann, Manuel Merten, Nicole Charpentier, Thomas H. Martz, Matthew Butcher, Adrian J. Slodczyk, Tanja Armando, Sylvain Effern, Maike Namkung, Yoon Jenkins, Laura Horn, Velten Stößel, Anne Dargatz, Harald Tietze, Daniel Imhof, Diana Galés, Céline Drewke, Christel Müller, Christa E. Hölzel, Michael Milligan, Graeme Tobin, Andrew B. Gomeza, Jesús Dohlman, Henrik G. Sondek, John Harden, T. Kendall Bouvier, Michel Laporte, Stéphane A. Aoki, Junken Fleischmann, Bernd K. Mohr, Klaus König, Gabriele M. Tüting, Thomas Kostenis, Evi Nat Commun Article 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. Nature Publishing Group 2015-12-14 /pmc/articles/PMC4682109/ /pubmed/26658454 http://dx.doi.org/10.1038/ncomms10156 Text en Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Schrage, Ramona
Schmitz, Anna-Lena
Gaffal, Evelyn
Annala, Suvi
Kehraus, Stefan
Wenzel, Daniela
Büllesbach, Katrin M.
Bald, Tobias
Inoue, Asuka
Shinjo, Yuji
Galandrin, Ségolène
Shridhar, Naveen
Hesse, Michael
Grundmann, Manuel
Merten, Nicole
Charpentier, Thomas H.
Martz, Matthew
Butcher, Adrian J.
Slodczyk, Tanja
Armando, Sylvain
Effern, Maike
Namkung, Yoon
Jenkins, Laura
Horn, Velten
Stößel, Anne
Dargatz, Harald
Tietze, Daniel
Imhof, Diana
Galés, Céline
Drewke, Christel
Müller, Christa E.
Hölzel, Michael
Milligan, Graeme
Tobin, Andrew B.
Gomeza, Jesús
Dohlman, Henrik G.
Sondek, John
Harden, T. Kendall
Bouvier, Michel
Laporte, Stéphane A.
Aoki, Junken
Fleischmann, Bernd K.
Mohr, Klaus
König, Gabriele M.
Tüting, Thomas
Kostenis, Evi
The experimental power of FR900359 to study Gq-regulated biological processes
title The experimental power of FR900359 to study Gq-regulated biological processes
title_full The experimental power of FR900359 to study Gq-regulated biological processes
title_fullStr The experimental power of FR900359 to study Gq-regulated biological processes
title_full_unstemmed The experimental power of FR900359 to study Gq-regulated biological processes
title_short The experimental power of FR900359 to study Gq-regulated biological processes
title_sort experimental power of fr900359 to study gq-regulated biological processes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4682109/
https://www.ncbi.nlm.nih.gov/pubmed/26658454
http://dx.doi.org/10.1038/ncomms10156
work_keys_str_mv AT schrageramona theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT schmitzannalena theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT gaffalevelyn theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT annalasuvi theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT kehrausstefan theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT wenzeldaniela theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT bullesbachkatrinm theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT baldtobias theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT inoueasuka theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT shinjoyuji theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT galandrinsegolene theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT shridharnaveen theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT hessemichael theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT grundmannmanuel theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT mertennicole theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT charpentierthomash theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT martzmatthew theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT butcheradrianj theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT slodczyktanja theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT armandosylvain theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT effernmaike theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT namkungyoon theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT jenkinslaura theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT hornvelten theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT stoßelanne theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT dargatzharald theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT tietzedaniel theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT imhofdiana theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT galesceline theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT drewkechristel theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT mullerchristae theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT holzelmichael theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT milligangraeme theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT tobinandrewb theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT gomezajesus theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT dohlmanhenrikg theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT sondekjohn theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT hardentkendall theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT bouviermichel theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT laportestephanea theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT aokijunken theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT fleischmannberndk theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT mohrklaus theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT koniggabrielem theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT tutingthomas theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT kostenisevi theexperimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT schrageramona experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT schmitzannalena experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT gaffalevelyn experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT annalasuvi experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT kehrausstefan experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT wenzeldaniela experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT bullesbachkatrinm experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT baldtobias experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT inoueasuka experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT shinjoyuji experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT galandrinsegolene experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT shridharnaveen experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT hessemichael experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT grundmannmanuel experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT mertennicole experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT charpentierthomash experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT martzmatthew experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT butcheradrianj experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT slodczyktanja experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT armandosylvain experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT effernmaike experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT namkungyoon experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT jenkinslaura experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT hornvelten experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT stoßelanne experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT dargatzharald experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT tietzedaniel experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT imhofdiana experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT galesceline experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT drewkechristel experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT mullerchristae experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT holzelmichael experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT milligangraeme experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT tobinandrewb experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT gomezajesus experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT dohlmanhenrikg experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT sondekjohn experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT hardentkendall experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT bouviermichel experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT laportestephanea experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT aokijunken experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT fleischmannberndk experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT mohrklaus experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT koniggabrielem experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT tutingthomas experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses
AT kostenisevi experimentalpoweroffr900359tostudygqregulatedbiologicalprocesses