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

Author

Listed:
  • Stefanie Wojciech

    (Institut Cochin
    CNRS UMR 8104
    Université Sorbonne Paris Cité)

  • Raise Ahmad

    (Institut Cochin
    CNRS UMR 8104
    Université Sorbonne Paris Cité)

  • Zakia Belaid-Choucair

    (Université Sorbonne Paris Cité
    Hôpital Necker)

  • Anne-Sophie Journé

    (Institut Cochin
    CNRS UMR 8104
    Université Sorbonne Paris Cité)

  • Sarah Gallet

    (Jean-Pierre Aubert Research Center)

  • Julie Dam

    (Institut Cochin
    CNRS UMR 8104
    Université Sorbonne Paris Cité)

  • Avais Daulat

    (Institut Cochin
    CNRS UMR 8104
    Université Sorbonne Paris Cité)

  • Delphine Ndiaye-Lobry

    (Institut Cochin
    CNRS UMR 8104
    Université Sorbonne Paris Cité)

  • Olivier Lahuna

    (Institut Cochin
    CNRS UMR 8104
    Université Sorbonne Paris Cité)

  • Angeliki Karamitri

    (Institut Cochin
    CNRS UMR 8104
    Université Sorbonne Paris Cité)

  • Jean-Luc Guillaume

    (Institut Cochin
    CNRS UMR 8104
    Université Sorbonne Paris Cité)

  • Marcio Do Cruzeiro

    (Institut Cochin
    CNRS UMR 8104
    Université Sorbonne Paris Cité)

  • François Guillonneau

    (Institut Cochin
    CNRS UMR 8104
    Université Sorbonne Paris Cité
    Plateforme Proteomique 3P5 de l’Université Paris Descartes)

  • Anastasia Saade

    (Institut Cochin
    CNRS UMR 8104
    Université Sorbonne Paris Cité)

  • Nathalie Clément

    (Institut Cochin
    CNRS UMR 8104
    Université Sorbonne Paris Cité)

  • Thomas Courivaud

    (Centre de Recherche Saint-Antoine (CRSA))

  • Nawel Kaabi

    (Centre de Recherche Saint-Antoine (CRSA))

  • Kenjiro Tadagaki

    (Institut Cochin
    CNRS UMR 8104
    Université Sorbonne Paris Cité)

  • Philippe Delagrange

    (Institut de Recherches SERVIER)

  • Vincent Prévot

    (Jean-Pierre Aubert Research Center)

  • Olivier Hermine

    (Université Sorbonne Paris Cité
    Hôpital Necker)

  • Céline Prunier

    (Centre de Recherche Saint-Antoine (CRSA))

  • Ralf Jockers

    (Institut Cochin
    CNRS UMR 8104
    Université Sorbonne Paris Cité)

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.

Suggested Citation

  • 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 Guillaum, 2018. "The orphan GPR50 receptor promotes constitutive TGFβ receptor signaling and protects against cancer development," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03609-x
    DOI: 10.1038/s41467-018-03609-x
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    Cited by:

    1. Lucia Balazova & Miroslav Balaz & Carla Horvath & Áron Horváth & Caroline Moser & Zuzana Kovanicova & Adhideb Ghosh & Umesh Ghoshdastider & Vissarion Efthymiou & Elke Kiehlmann & Wenfei Sun & Hua Dong, 2021. "GPR180 is a component of TGFβ signalling that promotes thermogenic adipocyte function and mediates the metabolic effects of the adipocyte-secreted factor CTHRC1," Nature Communications, Nature, vol. 12(1), pages 1-18, December.

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