The orphan GPR50 receptor promotes constitutive TGFbeta receptor signaling and protects against cancer development (Équipe Prunier)

Nat Commun. 2018;9(1):1216

Transforming growth factor-beta (TGFbeta) signaling is initiated by the type I, II TGFbeta receptor (TbetaRI/TbetaRII) complex. Here we report the formation of an alternative complex between TbetaRI and the orphan GPR50, belonging to the G protein-coupled receptor super-family. The interaction of GPR50 with TbetaRI induces spontaneous TbetaRI-dependent Smad and non-Smad signaling by stabilizing the active TbetaRI conformation and competing for the binding of the negative regulator FKBP12 to TbetaRI. GPR50 overexpression in MDA-MB-231 cells mimics the anti-proliferative effect of TbetaRI 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 TGFbeta-independent activation mode of TbetaRI and identifies GPR50 as a TbetaRI co-receptor with potential impact on cancer development.