The orphan GPR50 receptor promotes constitutive TGFβ receptor signaling and protects against cancer development

Transforming growth factor-β (TGFβ) signaling is initiated by the type I, II TGFβ receptor (TβRI/TβRII) complex. Here we report the formation of an alternative complex between TβRI and the orphan GPR50, belonging to the G protein-coupled receptor super-family. The interaction of GPR50 with TβRI indu...

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Autores principales: Wojciech, Stefanie, Ahmad, Raise, Belaid-Choucair, Zakia, Journé, Anne-Sophie, Gallet, Sarah, Dam, Julie, Daulat, Avais, Ndiaye-Lobry, Delphine, Lahuna, Olivier, Karamitri, Angeliki, Guillaume, Jean-Luc, Do Cruzeiro, Marcio, Guillonneau, François, Saade, Anastasia, Clément, Nathalie, Courivaud, Thomas, Kaabi, Nawel, Tadagaki, Kenjiro, Delagrange, Philippe, Prévot, Vincent, Hermine, Olivier, Prunier, Céline, Jockers, Ralf
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865211/
https://www.ncbi.nlm.nih.gov/pubmed/29572483
http://dx.doi.org/10.1038/s41467-018-03609-x
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author Wojciech, Stefanie
Ahmad, Raise
Belaid-Choucair, Zakia
Journé, Anne-Sophie
Gallet, Sarah
Dam, Julie
Daulat, Avais
Ndiaye-Lobry, Delphine
Lahuna, Olivier
Karamitri, Angeliki
Guillaume, Jean-Luc
Do Cruzeiro, Marcio
Guillonneau, François
Saade, Anastasia
Clément, Nathalie
Courivaud, Thomas
Kaabi, Nawel
Tadagaki, Kenjiro
Delagrange, Philippe
Prévot, Vincent
Hermine, Olivier
Prunier, Céline
Jockers, Ralf
author_facet Wojciech, Stefanie
Ahmad, Raise
Belaid-Choucair, Zakia
Journé, Anne-Sophie
Gallet, Sarah
Dam, Julie
Daulat, Avais
Ndiaye-Lobry, Delphine
Lahuna, Olivier
Karamitri, Angeliki
Guillaume, Jean-Luc
Do Cruzeiro, Marcio
Guillonneau, François
Saade, Anastasia
Clément, Nathalie
Courivaud, Thomas
Kaabi, Nawel
Tadagaki, Kenjiro
Delagrange, Philippe
Prévot, Vincent
Hermine, Olivier
Prunier, Céline
Jockers, Ralf
author_sort Wojciech, Stefanie
collection PubMed
description Transforming growth factor-β (TGFβ) signaling is initiated by the type I, II TGFβ receptor (TβRI/TβRII) complex. Here we report the formation of an alternative complex between TβRI and the orphan GPR50, belonging to the G protein-coupled receptor super-family. The interaction of GPR50 with TβRI induces spontaneous TβRI-dependent Smad and non-Smad signaling by stabilizing the active TβRI conformation and competing for the binding of the negative regulator FKBP12 to TβRI. GPR50 overexpression in MDA-MB-231 cells mimics the anti-proliferative effect of TβRI and decreases tumor growth in a xenograft mouse model. Inversely, targeted deletion of GPR50 in the MMTV/Neu spontaneous mammary cancer model shows decreased survival after tumor onset and increased tumor growth. Low GPR50 expression is associated with poor survival prognosis in human breast cancer irrespective of the breast cancer subtype. This describes a previously unappreciated spontaneous TGFβ-independent activation mode of TβRI and identifies GPR50 as a TβRI co-receptor with potential impact on cancer development.
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spelling pubmed-58652112018-03-28 The orphan GPR50 receptor promotes constitutive TGFβ receptor signaling and protects against cancer development Wojciech, Stefanie Ahmad, Raise Belaid-Choucair, Zakia Journé, Anne-Sophie Gallet, Sarah Dam, Julie Daulat, Avais Ndiaye-Lobry, Delphine Lahuna, Olivier Karamitri, Angeliki Guillaume, Jean-Luc Do Cruzeiro, Marcio Guillonneau, François Saade, Anastasia Clément, Nathalie Courivaud, Thomas Kaabi, Nawel Tadagaki, Kenjiro Delagrange, Philippe Prévot, Vincent Hermine, Olivier Prunier, Céline Jockers, Ralf Nat Commun Article Transforming growth factor-β (TGFβ) signaling is initiated by the type I, II TGFβ receptor (TβRI/TβRII) complex. Here we report the formation of an alternative complex between TβRI and the orphan GPR50, belonging to the G protein-coupled receptor super-family. The interaction of GPR50 with TβRI induces spontaneous TβRI-dependent Smad and non-Smad signaling by stabilizing the active TβRI conformation and competing for the binding of the negative regulator FKBP12 to TβRI. GPR50 overexpression in MDA-MB-231 cells mimics the anti-proliferative effect of TβRI and decreases tumor growth in a xenograft mouse model. Inversely, targeted deletion of GPR50 in the MMTV/Neu spontaneous mammary cancer model shows decreased survival after tumor onset and increased tumor growth. Low GPR50 expression is associated with poor survival prognosis in human breast cancer irrespective of the breast cancer subtype. This describes a previously unappreciated spontaneous TGFβ-independent activation mode of TβRI and identifies GPR50 as a TβRI co-receptor with potential impact on cancer development. Nature Publishing Group UK 2018-03-23 /pmc/articles/PMC5865211/ /pubmed/29572483 http://dx.doi.org/10.1038/s41467-018-03609-x Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Wojciech, Stefanie
Ahmad, Raise
Belaid-Choucair, Zakia
Journé, Anne-Sophie
Gallet, Sarah
Dam, Julie
Daulat, Avais
Ndiaye-Lobry, Delphine
Lahuna, Olivier
Karamitri, Angeliki
Guillaume, Jean-Luc
Do Cruzeiro, Marcio
Guillonneau, François
Saade, Anastasia
Clément, Nathalie
Courivaud, Thomas
Kaabi, Nawel
Tadagaki, Kenjiro
Delagrange, Philippe
Prévot, Vincent
Hermine, Olivier
Prunier, Céline
Jockers, Ralf
The orphan GPR50 receptor promotes constitutive TGFβ receptor signaling and protects against cancer development
title The orphan GPR50 receptor promotes constitutive TGFβ receptor signaling and protects against cancer development
title_full The orphan GPR50 receptor promotes constitutive TGFβ receptor signaling and protects against cancer development
title_fullStr The orphan GPR50 receptor promotes constitutive TGFβ receptor signaling and protects against cancer development
title_full_unstemmed The orphan GPR50 receptor promotes constitutive TGFβ receptor signaling and protects against cancer development
title_short The orphan GPR50 receptor promotes constitutive TGFβ receptor signaling and protects against cancer development
title_sort orphan gpr50 receptor promotes constitutive tgfβ receptor signaling and protects against cancer development
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865211/
https://www.ncbi.nlm.nih.gov/pubmed/29572483
http://dx.doi.org/10.1038/s41467-018-03609-x
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