A mechanism for Wnt coreceptor activation
A mechanism for Wnt coreceptor activation
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DOI：
10.1016/s1097-2765(03)00484-2
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发表时间：
2004-01-16
期刊：
影响因子：
16
通讯作者：
He, X
中科院分区：
文献类型：
--
作者：
Tamai, K;Zeng, X;He, X
LDL受体相关蛋白5和6（LRP 5/6）及其果蝇同源物Arrow是Wnt/β-连环蛋白信号传导所必需的单跨膜蛋白，可能通过作为Wnt共受体起作用。Wnt如何激活LRP 5/6/Arrow启动信号转导尚不清楚。在这里，我们表明，PPPSP基序，这是在LRP 5/6/箭头细胞内结构域重复5次，是必要的，足以触发Wnt/β-连环蛋白信号。一个单一的PPPSP基序，转移到LDL受体，完全激活Wnt通路，诱导非洲爪蟾和TCF/β-连环蛋白在人类细胞中的反应性转录轴完全复制。我们进一步表明，Wnt信号刺激，并需要，磷酸化的PPPSP基序，这创造了一个可诱导的对接网站轴蛋白，支架蛋白控制β-连环蛋白的稳定性。我们的研究确定了一个关键的信号传导模块和Wnt受体复合物的关键磷酸化依赖性激活步骤，并揭示了一个统一的逻辑跨膜信号传导的蛋白质，生长因子和细胞因子。
LDL receptor related proteins 5 and 6 (LRP5/6) and their Drosophila homolog Arrow are single-span transmembrane proteins essential for Wnt/beta-catenin signaling, likely via acting as Wnt coreceptors. How Wnt activates LRP5/6/Arrow to initiate signal transduction is not well defined. Here we show that a PPPSP motif, which is reiterated five times in the LRP5/6/Arrow intracellular domain, is necessary and sufficient to trigger Wnt/beta-catenin signaling. A single PPPSP motif, upon transfer to the LDL receptor, fully activates the Wnt pathway, inducing complete axis duplication in Xenopus and TCF/beta-catenin-responsive transcription in human cells. We further show that Wnt signaling stimulates, and requires, phosphorylation of the PPPSP motif, which creates an inducible docking site for Axin, a scaffolding protein controlling beta-catenin stability. Our study identifies a critical signaling module and a key phosphorylation-dependent activation step of the Wnt receptor complex and reveals a unifying logic for transmembrane signaling by Writs, growth factors, and cytokines.