LGR5 Interacts and Cointernalizes with Wnt Receptors To Modulate Wnt/β-Catenin Signaling
LGR5 Interacts and Cointernalizes with Wnt Receptors To Modulate Wnt/β-Catenin Signaling
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DOI：
10.1128/mcb.00272-12
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发表时间：
2012-06-01
影响因子：
5.3
通讯作者：
Liu, Qingyun
中科院分区：
文献类型：
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作者：
Carmon, Kendra S.;Lin, Qiushi;Liu, Qingyun
LGR 5是视紫红质家族的七跨膜结构域受体，是Wnt靶基因，也是胃肠道和毛囊隆起中成体干细胞的真正标志物。最近，我们和其他人证明LGR 5及其同系物作为干细胞因子的R-spondin家族的受体发挥作用，以增强Wnt/β-连环蛋白信号传导。然而，LGR 5如何增强信号输出的机制仍不清楚。在这里，我们报告了与配体R-spondin 1和Wnt 3a共刺激后，LGR 5与Wnt共受体LRP 6和Fzd 5相互作用并形成超复合物，该超复合物迅速内化，然后降解。LGR 5的内化通过发动蛋白和网格蛋白依赖性途径介导。这种内吞过程的抑制对LGR 5信号传导没有影响。LGR 5的C-末端尾部的缺失保持其与LRP 6相互作用的能力，然而与野生型受体相比，该LGR 5突变体表现出响应于R-spondin 1的增加的信号传导活性和降低的内吞速率。这项研究提供了直接证据，表明LGR 5在膜水平上成为Wnt信号复合物的一部分，以增强Wnt/β-连环蛋白信号传导。然而，LGR 5的内化似乎并不是增强经典Wnt信号传导途径所必需的。
LGR5, a seven-transmembrane domain receptor of the rhodopsin family, is a Wnt target gene and a bona fide marker of adult stem cells in the gastrointestinal tract and hair follicle bulge. Recently, we and others demonstrated that LGR5 and its homologues function as receptors of the R-spondin family of stem cell factors to potentiate Wnt/beta-catenin signaling. However, the mechanism of how LGR5 enhances the signaling output remains unclear. Here we report that following costimulation with the ligands R-spondin 1 and Wnt3a, LGR5 interacts and forms a supercomplex with the Wnt coreceptors LRP6 and Fzd5 which is rapidly internalized and then degraded. Internalization of LGR5 is mediated through a dynamin- and clathrin-dependent pathway. Inhibition of this endocytic process has no effect on LGR5 signaling. Deletion of the C-terminal tail of LGR5 maintains its ability to interact with LRP6, yet this LGR5 mutant exhibits increased signaling activity and a decreased rate of endocytosis in response to R-spondin 1 compared to the wild-type receptor. This study provides direct evidence that LGR5 becomes part of the Wnt signaling complex at the membrane level to enhance Wnt/beta-catenin signaling. However, internalization of LGR5 does not appear to be essential for potentiating the canonical Wnt signaling pathway.