Inserm, U1016, Institut Cochin, Paris, 75014, France.
CNRS UMR 8104, Paris, 75014, France.
Nat Commun. 2018 Mar 23;9(1):1216. doi: 10.1038/s41467-018-03609-x.
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.
转化生长因子-β（TGFβ）信号由 I 型、II 型 TGFβ 受体（TβRI/TβRII）复合物起始。在这里，我们报告了 TβRI 与孤儿 G 蛋白偶联受体超家族成员 GPR50 之间形成替代复合物。GPR50 与 TβRI 的相互作用通过稳定活性 TβRI 构象并与 TβRI 结合的负调节剂 FKBP12 竞争，诱导自发的 TβRI 依赖性 Smad 和非 Smad 信号转导。MDA-MB-231 细胞中 GPR50 的过表达模拟了 TβRI 的抗增殖作用，并在异种移植小鼠模型中降低了肿瘤生长。相反，MMTV/Neu 自发性乳腺癌模型中 GPR50 的靶向缺失显示出肿瘤起始后生存率降低和肿瘤生长增加。无论乳腺癌亚型如何，人类乳腺癌中低 GPR50 表达与预后不良相关。这描述了 TβRI 的一种以前未被认识的自发 TGFβ 非依赖性激活模式，并将 GPR50 鉴定为具有潜在影响癌症发展的 TβRI 共受体。
