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

Stefanie Wojciech, Raise Ahmad, Zakia Belaid-Choucair, Anne-Sophie Journé, Sarah Gallet, Julie Dam, Avais Daulat, Delphine Ndiaye-Lobry, Olivier Lahuna, Angeliki Karamitri, Jean-Luc Guillaume, Marcio Do Cruzeiro, François Guillonneau, Anastasia Saade, Nathalie Clément, Thomas Courivaud, Nawel Kaabi, Kenjiro Tadagaki, Philippe Delagrange, Vincent Prévot, Olivier Hermine, Céline Prunier and Ralf Jockers ()
Additional contact information
Stefanie Wojciech: Institut Cochin
Raise Ahmad: Institut Cochin
Zakia Belaid-Choucair: Université Sorbonne Paris Cité
Anne-Sophie Journé: Institut Cochin
Sarah Gallet: Jean-Pierre Aubert Research Center
Julie Dam: Institut Cochin
Avais Daulat: Institut Cochin
Delphine Ndiaye-Lobry: Institut Cochin
Olivier Lahuna: Institut Cochin
Angeliki Karamitri: Institut Cochin
Jean-Luc Guillaume: Institut Cochin
Marcio Do Cruzeiro: Institut Cochin
François Guillonneau: Institut Cochin
Anastasia Saade: Institut Cochin
Nathalie Clément: Institut Cochin
Thomas Courivaud: Centre de Recherche Saint-Antoine (CRSA)
Nawel Kaabi: Centre de Recherche Saint-Antoine (CRSA)
Kenjiro Tadagaki: Institut Cochin
Philippe Delagrange: Institut de Recherches SERVIER
Vincent Prévot: Jean-Pierre Aubert Research Center
Olivier Hermine: Université Sorbonne Paris Cité
Céline Prunier: Centre de Recherche Saint-Antoine (CRSA)
Ralf Jockers: Institut Cochin

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-03609-x

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