A Daple-Akt feed-forward loop enhances noncanonical Wnt signals by compartmentalizing β-catenin.
A Daple-Akt feed-forward loop enhances noncanonical Wnt signals by compartmentalizing β-catenin.
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DOI：
10.1091/mbc.e17-06-0405
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发表时间：
2017-12-01
影响因子：
3.3
通讯作者：
Ghosh P
中科院分区：
文献类型：
--
作者：
Aznar N;Sun N;Dunkel Y;Ear J;Buschman MD;Ghosh P
经典和非经典 Wnt 通路之间的平衡控制着 β-catenin 转录程序；非规范途径如何拮抗规范途径仍不清楚。我们证明 Daple 是一种非经典 Wnt 信号的增强剂，它通过决定细胞中 β-catenin 的亚细胞分布来实现这一目标。细胞增殖受到经典和非经典 Wnt 信号的拮抗调节；它们的不平衡会引发癌症。我们之前表明，多模块信号转导器 Daple 可以增强非经典 Wnt 信号通路内的 PI3-K→Akt 信号，并拮抗地抑制经典 Wnt 反应。在这里，我们证明 PI3-K→Akt 通路作为正反馈回路，通过划分 β-catenin 进一步增强非经典 Wnt 信号。通过磷酸化 Daple 的磷酸肌醇 (PI) 结合域，Akt 消除了 Daple 结合富含 PI3-P 的内体的能力，该内体与动力蛋白运动复合物结合，将 β-连环蛋白/E-钙粘蛋白复合物长距离运输至中心粒周围回收内体 (PCRE)。磷酸化将 Daple/β-连环蛋白/E-钙粘蛋白复合物分隔至细胞-细胞接触位点，增强非经典 Wnt 信号，从而抑制集落生长。去磷酸化可将 PCRE 上的 β-连环蛋白区分开来，这是一种专门用于长时间不受对抗的经典 Wnt 信号转导的区室，并增强集落生长。对 Akt 不敏感的癌症相关 Daple 突变体模拟组成型去磷酸化状态。这项工作不仅将 Daple 确定为 Akt 和非经典 Wnt 通路之间串扰的平台，而且还揭示了这种串扰对肿瘤细胞表型的影响，而肿瘤细胞表型对于癌症的发生和进展至关重要。
Balance between canonical and noncanonical Wnt pathways controls the β-catenin transcriptional program; how the noncanonical pathway antagonizes the canonical pathway remains unclear. We show that Daple, an enhancer of noncanonical Wnt signals, accomplishes that goal by dictating the subcellular distribution of β-catenin in cells. Cellular proliferation is antagonistically regulated by canonical and noncanonical Wnt signals; their dysbalance triggers cancers. We previously showed that a multimodular signal transducer, Daple, enhances PI3-K→Akt signals within the noncanonical Wnt signaling pathway and antagonistically inhibits canonical Wnt responses. Here we demonstrate that the PI3-K→Akt pathway serves as a positive feedback loop that further enhances noncanonical Wnt signals by compartmentalizing β-catenin. By phosphorylating the phosphoinositide- (PI) binding domain of Daple, Akt abolishes Daple’s ability to bind PI3-P-enriched endosomes that engage dynein motor complex for long-distance trafficking of β-catenin/E-cadherin complexes to pericentriolar recycling endosomes (PCREs). Phosphorylation compartmentalizes Daple/β-catenin/E-cadherin complexes to cell–cell contact sites, enhances noncanonical Wnt signals, and thereby suppresses colony growth. Dephosphorylation compartmentalizes β-catenin on PCREs, a specialized compartment for prolonged unopposed canonical Wnt signaling, and enhances colony growth. Cancer-associated Daple mutants that are insensitive to Akt mimic a constitutively dephosphorylated state. This work not only identifies Daple as a platform for cross-talk between Akt and the noncanonical Wnt pathway but also reveals the impact of such cross-talk on tumor cell phenotypes that are critical for cancer initiation and progression.