Journal Article

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

Courivaud, Thomas, Ahmad, Raise, Delagrange, Philippe, Clément, Nathalie, Journé, Anne-Sophie, Tadagaki, Kenjiro, Prévot, Vincent, Ndiaye-Lobry, Delphine, Prunier, Céline, Jockers, Ralf, Hermine, Olivier, Guillaume, Jean-Luc, Belaid-Choucair, Zakia, Lahuna, Olivier, Saade, Anastasia, Daulat, Avais, Do Cruzeiro, Marcio, Wojciech, Stefanie, Karamitri, Angeliki, Gallet, Sarah, Guillonneau, François, Dam, Julie, Kaabi, Nawel

2018

Overview

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. Transforming growth factor-β (TGFβ) regulates many cellular processes. Here the authors show that the orphan G-protein coupled receptor GPR50 can activate the TGFβ receptor I, in the absence of TGFβ, by stabilizing its active conformation and show antitumor activity in a mouse model of breast cancer.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 14 / 14/19 / 14/33 / 38 / 631/67/1347 / 631/80/86 / 82/80 / 96 / 96/109 / 96/95 / Animals / Breast cancer / Breast Neoplasms - metabolism / Cancer / Cell Line, Tumor / Cell Proliferation / Clonal deletion / Endosomes - metabolism / ErbB-2 protein / Female / Gene deletion / Gene Expression Profiling / HEK293 Cells / HeLa Cells / Humanities and Social Sciences / Humans / Life Sciences / Mammary Neoplasms, Animal - metabolism / Mammary Neoplasms, Animal - prevention & control / Medical prognosis / Mice / Mice, Inbred C57BL / multidisciplinary / Neoplasm Transplantation / Nerve Tissue Proteins - genetics / Nerve Tissue Proteins - physiology / Oligonucleotide Array Sequence Analysis / Receptor, Transforming Growth Factor-beta Type I - physiology / Receptors, G-Protein-Coupled - genetics / Receptors, G-Protein-Coupled - physiology / Science / Science (multidisciplinary) / Signal Transduction / Signaling / Smad protein / Smad Proteins - metabolism / Survival / Tacrolimus Binding Protein 1A - metabolism / Transforming growth factor / Transforming growth factor-b / Xenografts / Xenotransplantation