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    A new duo for the protection of breast cancer: the heterodimer complex GRP50 – TβRI

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    A study directed by Ralf Jockers

    G protein-coupled receptors (GPCRs) are involved in many physiological and pathophysiological processes. However, many functions of these receptors remain unknown, especially for the orphan GPCRs that do not have an identified ligand.

    This study, conducted by Dr. R. Jockers (Cochin Institute, Inserm / CNRS / Paris Descartes University) in collaboration with the teams of C. Prunier, O. Hermine and P. Delagrange demonstrates, for the first time, the anti-tumor properties of an orphan GPCR, GRP50. Indeed, in mammary tumors, the formation of heterodimers between GRP50 and the type I TGFβ receptor (TβRI) activates the antiproliferative effect of the TGFβ receptor which results in a lower tumor growth. Moreover, in women with breast cancer, low expression of GPR50 has been associated with poor survival prognosis regardless of the subtype of breast cancer. These new results make GRP50 a very promising diagnostic tool and therapeutic target for breast cancer. Published on March 23, 2018 in Nature Communications.

    G protein-coupled receptors (GPCRs) composed of 7 transmembrane domains represent the largest family of cell surface proteins. These membrane receptors are involved in many physiological and pathophysiological processes and nearly 30% of currently prescribed drugs target GPCRs. Two factors are known to modulate the function of GPCRs: ligand binding and/or the nature of the dimerization partner. Indeed, GPCRs recognize a wide variety of external (odors, light, molecules of taste, etc.) and internal (hormones, neurotransmitters etc.) signals. However, for almost hundred or so of these receptors, called orphans, the ligand is not known yet. In addition, GPCRs can interact with themselves (formation of homodimers) or with other receptors of the same family or other families (heterodimers). Unraveling the function of orphan GPCRs is of high interest since they constitute promising future drug targets. The Ralf Jockers team has been interested for several years in exploring the function of the orphan GPR50.

    In this study, the authors demonstrate that GRP50 form a heterodimer complex with the TGFβ receptor type I, TβRI, and activates the antiproliferative effect of this receptor independently of TGFβ. Thus, the formation of the GRP50-TβRI heterodimer leads to the phosphorylation and activation of TβRI and induces intracellular TGFβ mediated canonical/non-canonical signaling pathways. GRP50 stabilizes the active conformation of TβRI and competes with the negative regulator FKBP12. The researchers also showed that the overexpression of GPR50 mimics the anti-proliferative effect of TβRI and decreases tumor growth in a xenograft mouse model. Conversely, the targeted elimination of GPR50 in a mouse model of breast cancer increases tumor growth and decreases the chances of survival of the animal. Finally, in women with breast cancer, the authors have shown that low expression of breast GPR50 is associated with a poor survival prognosis regardless of the subtype of breast cancer.

    All of this research revealed the protective role of GRP50 in breast cancer, a result that opens up new diagnostic and therapeutic opportunities. On one hand, the measurement of GRP50 expression could be an early diagnostic test for breast cancer and on the other hand, a pharmacological approach for activating GRP50 or increasing its expression could be used to repress tumors.

     

    Bibliography

    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 & Ralf Jockers. Nature Communications volume 9, Article number: 1216 (2018) doi:10.1038/s41467-018-03609-x