Department of Cancer Targets, Genentech Inc., South San Francisco, California 94080, USA.
J Biol Chem. 2013 Feb 8;288(6):3753-67. doi: 10.1074/jbc.M112.415240. Epub 2012 Dec 31.
The adenomatous polyposis coli (APC) protein functions as a negative regulator of the Wnt signaling pathway. In this capacity, APC forms a "destruction complex" with Axin, CK1α, and GSK3β to foster phosphorylation of the Wnt effector β-catenin earmarking it for Lys-48-linked polyubiquitylation and proteasomal degradation. APC is conjugated with Lys-63-linked ubiquitin chains when it is bound to Axin, but it is unclear whether this modification promotes the APC-Axin interaction or confers upon APC an alternative function in the destruction complex. Here we identify HectD1 as a candidate E3 ubiquitin ligase that modifies APC with Lys-63 polyubiquitin. Knockdown of HectD1 diminished APC ubiquitylation, disrupted the APC-Axin interaction, and augmented Wnt3a-induced β-catenin stabilization and signaling. These results indicate that HectD1 promotes the APC-Axin interaction to negatively regulate Wnt signaling.
腺瘤性结肠息肉蛋白（APC）作为 Wnt 信号通路的负调控因子发挥作用。在这种功能下，APC 与 Axin、CK1α 和 GSK3β 形成“破坏复合物”，促进 Wnt 效应物β-连环蛋白的磷酸化，使其成为 Lys-48 连接的多泛素化和蛋白酶体降解的标记。当 APC 与 Axin 结合时，它被连接到 Lys-63 连接的泛素链上，但尚不清楚这种修饰是促进 APC-Axin 相互作用，还是赋予 APC 在破坏复合物中的替代功能。在这里，我们鉴定出 HectD1 是一种候选 E3 泛素连接酶，它用 Lys-63 多泛素修饰 APC。HectD1 的敲低减少了 APC 的泛素化，破坏了 APC-Axin 相互作用，并增强了 Wnt3a 诱导的β-连环蛋白稳定和信号转导。这些结果表明，HectD1 促进 APC-Axin 相互作用，从而负调控 Wnt 信号。
