The Orphan Gpr50 Receptor Promotes Constitutive Tgf Beta Receptor Signaling And Protects Against Cancer Development

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