G alpha i2-induced conductin/axin2 condensates inhibit Wnt/beta-catenin signaling and suppress cancer growth

Conductin/axin2 is a scaffold protein negatively regulating the pro-proliferative Wnt/beta-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 G alpha i2 subunit of trimeric G-proteins induces conductin condensation by targeting a polymerization-inhibiting aggregon in its RGS domain, thereby promoting conductin-mediated beta-catenin degradation. Consistently, transient G alpha i2 expression inhibited, whereas knockdown activated Wnt signaling via conductin. Colorectal cancers appear to evade G alpha i2-induced Wnt pathway suppression by decreased G alpha i2 expression and inactivating mutations, associated with shorter patient survival. Notably, the G alpha i2-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 G alpha i2-triggered conductin condensation, suggesting a tumor suppressor function for G alpha i2 in colorectal cancer, and pointing to the FDA-approved drug guanabenz for targeted cancer therapy. Wnt/beta-catenin signalling is frequently hyperactivated in colorectal carcinoma (CRC). Here the authors show that G alpha i2 inhibits this signalling pathway by promoting the condensation of conductin/axin2 and beta-catenin degradation, and consequently suppresses CRC growth.