Experimental Medicine II, Nikolaus-Fiebiger-Center, Friedrich-Alexander University Erlangen-Nürnberg, 91054, Erlangen, Germany.
Department of Cell Physiology and Metabolism, Centre Médical Universitaire, University of Geneva, 1211, Geneva 4, Geneva, Switzerland.
Nat Commun. 2022 Feb 3;13(1):674. doi: 10.1038/s41467-022-28286-9.
Conductin/axin2 is a scaffold protein negatively regulating the pro-proliferative Wnt/β-catenin signaling pathway. Accumulation of scaffold proteins in condensates frequently increases their activity, but whether condensation contributes to Wnt pathway inhibition by conductin remains unclear. Here, we show that the Gαi2 subunit of trimeric G-proteins induces conductin condensation by targeting a polymerization-inhibiting aggregon in its RGS domain, thereby promoting conductin-mediated β-catenin degradation. Consistently, transient Gαi2 expression inhibited, whereas knockdown activated Wnt signaling via conductin. Colorectal cancers appear to evade Gαi2-induced Wnt pathway suppression by decreased Gαi2 expression and inactivating mutations, associated with shorter patient survival. Notably, the Gαi2-activating drug guanabenz inhibited Wnt signaling via conductin, consequently reducing colorectal cancer growth in vitro and in mouse models. In summary, we demonstrate Wnt pathway inhibition via Gαi2-triggered conductin condensation, suggesting a tumor suppressor function for Gαi2 in colorectal cancer, and pointing to the FDA-approved drug guanabenz for targeted cancer therapy.
连接蛋白/轴突生长诱向因子 2 是一种支架蛋白，可负向调节促增殖的 Wnt/β-连环蛋白信号通路。支架蛋白在凝聚物中的积累常常会增加其活性，但凝聚物是否有助于连接蛋白抑制 Wnt 途径尚不清楚。在这里，我们表明三聚体 G 蛋白的 Gαi2 亚基通过靶向其 RGS 结构域中的聚合抑制聚集物来诱导连接蛋白凝聚，从而促进连接蛋白介导的β-连环蛋白降解。一致地，瞬时 Gαi2 表达抑制，而通过连接蛋白敲低则激活了 Wnt 信号。结直肠癌似乎通过降低 Gαi2 表达和失活突变来逃避 Gαi2 诱导的 Wnt 通路抑制，与患者生存时间缩短相关。值得注意的是，Gαi2 激活药物胍那苄通过连接蛋白抑制 Wnt 信号，从而减少体外和小鼠模型中的结直肠癌细胞生长。总之，我们通过 Gαi2 触发的连接蛋白凝聚来证明 Wnt 途径抑制，提示 Gαi2 在结直肠癌中具有肿瘤抑制功能，并指出已获得 FDA 批准的胍那苄可用于靶向癌症治疗。
