Abstract：
Wnt/Wingless (Wg) signaling is critical in development and disease, including cancer. Canonical Wnt signaling is mediated by β-catenin/Armadillo (Arm in Drosophila) transducing signals to the nucleus, with IFT-A/Kinesin 2 complexes promoting nuclear translocation of β-catenin/Arm. Here, we demonstrate that a conserved small N-terminal Arm34-87/β-catenin peptide binds to IFT140, acting as a dominant interference tool to attenuate Wg/Wnt signaling in vivo. Arm34-87 expression antagonizes endogenous Wnt/Wg signaling, resulting in the reduction of its target expression. Arm34-87 inhibits Wg/Wnt signaling by interfering with nuclear translocation of endogenous Arm/β-catenin, and this can be modulated by levels of wild-type β-catenin or IFT140, with the Arm34-87 effect being enhanced or suppressed. Importantly, this mechanism is conserved in mammals with the equivalent β-catenin24-79 peptide blocking nuclear translocation and pathway activation, including in cancer cells. Our work indicates that Wnt signaling can be regulated by a defined N-terminal β-catenin peptide and thus might serve as an entry point for therapeutic applications to attenuate Wnt/β-catenin signaling.
摘要：
Wnt/无翼（Wg）信号在发育和疾病中至关重要，包括癌症.典型的Wnt信号是由β-catenin/Armadillo（果蝇中的手臂）介导的，用IFT-A/Kinesin2复合物促进β-catenin/Arm的核易位。这里,我们证明了保守的小N末端Arm34-87/β-catenin肽与IFT140结合,作为减弱体内Wg/Wnt信号传导的主要干扰工具。Arm34-87表达拮抗内源性Wnt/Wg信号,导致其靶表达的减少。Arm34-87通过干扰内源性Arm/β-catenin的核易位抑制Wg/Wnt信号,并且这可以通过野生型β-连环蛋白或IFT140的水平来调节,其中Arm34-87效应被增强或抑制。重要的是,这种机制在哺乳动物中保守，等价的β-catenin24-79肽阻断核易位和途径激活，包括癌细胞。我们的工作表明，Wnt信号传导可以由确定的N末端β-联蛋白肽调节，因此可能作为治疗应用的切入点以减弱Wnt/β-联蛋白信号传导。
