The orphan GPR50 receptor promotes constitutive TGF? receptor signaling and protects against cancer development.

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

SUBMITTER: Wojciech S 

PROVIDER: S-EPMC5865211 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature