Abstract
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.
Highlights
Transforming growth factor-β (TGFβ) signaling is initiated by the type I, II TGFβ receptor (TβRI/TβRII) complex
When searching for GPR50interacting partners by tandem affinity purification coupled to mass spectrometry, we identified five unique peptides corresponding to the TβRI in HEK293T cells expressing the frequent GPR50Δ4 variant but not in naive HEK293T cells (Fig. 1a)
Colocalization between GPR50 and TβRI was observed in mouse brain slices of tanycytes, tanycyte primary cultures, human lung carcinoma NCI-H520 cells expressing endogenous GPR50, and in transfected HeLa cells as revealed by immunofluorescence microscopy and proximity ligation assay (PLA, Fig. 1b–d; Supplementary Fig. 1a-c)
Summary
Transforming growth factor-β (TGFβ) signaling is initiated by the type I, II TGFβ receptor (TβRI/TβRII) complex. 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 TGFβindependent activation mode of TβRI and identifies GPR50 as a TβRI co-receptor with potential impact on cancer development. The constitutively active TβRII kinase activates TβRI by phosphorylating several Ser/Thr residues in the highly conserved GS region (185TTSGSGSG192) located N-terminal to the kinase domain of TβRI7 This induces the so-called “inhibitor to substrate” activatory switch, which consists in the dissociation of the FKBP12 inhibitor and the subsequent binding of Smad2/3 proteins[8]. GPCRs have the potential to interact with themselves (homomers) or with other receptors (heteromers)[15] Within these heteromeric complexes, allosteric regulation of one protomer by the other is often observed. This includes the allosteric regulation of the function of other GPCRs in heteromeric protein complexes
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