Wnt/Wingless signaling through beta-catenin requires the function of both LRP/Arrow and frizzled classes of receptors.
Wnt/Wingless signaling through beta-catenin requires the function of both LRP/Arrow and frizzled classes of receptors.
复制标题
DOI：
10.1186/1471-2121-4-4
复制
发表时间：
2003-05-02
期刊：
影响因子：
--
通讯作者：
Varmus H
中科院分区：
文献类型：
--
作者：
Schweizer L;Varmus H
Wnt/Wingless （Wg）信号由7个跨膜卷曲蛋白（Fzs）和单跨膜ldl -受体相关蛋白5或6 （LRP5/6）或Arrow转导。据报道，LRP和Fz的氨基端仅在Wnt存在时结合，这意味着Wnt配体与两种不同的受体形成三聚体复合物。然而，最近有报道称，lrp通过与Axin以不依赖于disheveled的方式结合来激活Wnt/β-catenin通路，而Fzs通过disheveled转导Wnt信号来稳定β-catenin。因此，Wnt蛋白可能与Fzs和lrp形成单独的复合物，分别转导Wnt信号，但在Wnt/β-catenin通路中向下游聚集。那么问题来了，这两个受体是否绝对需要转导Wnt信号。我们在果蝇S2细胞中建立了一种敏感的荧光素酶报告试验，以确定Wg刺激信号的水平。我们在这里证明了Wg可以与DFz2协同并与LRP协同激活β-catenin/Armadillo信号通路。双链RNA干扰干扰任一受体类型的合成可显著损害Wg信号传导活性。重要的是，添加Wg和DFz2的显著协同效应依赖于Arrow和disheveled。这种协同作用需要DFz2的富含半胱氨酸的胞外结构域，而不是它的羧基端。最后，哺乳动物LRP6及其活化形式缺乏该蛋白的大部分胞外结构域，可以激活Wg信号通路，并在S2细胞中与Wg和DFz2合作。我们还发现LRP/Arr的氨基端是Wg和DFz2协同作用所必需的。我们的研究表明，S2细胞中的Wg信号转导依赖于LRPs和DFz2的功能，结果与Wnt/Wg通过其双受体的氨基末端区域发出信号，通过Dishevelled激活靶基因的观点一致。
Wnt/Wingless (Wg) signals are transduced by seven-transmembrane Frizzleds (Fzs) and the single-transmembrane LDL-receptor-related proteins 5 or 6 (LRP5/6) or Arrow. The aminotermini of LRP and Fz were reported to associate only in the presence of Wnt, implying that Wnt ligands form a trimeric complex with two different receptors. However, it was recently reported that LRPs activate the Wnt/β-catenin pathway by binding to Axin in a Dishevelled – independent manner, while Fzs transduce Wnt signals through Dishevelled to stabilize β-catenin. Thus, it is possible that Wnt proteins form separate complexes with Fzs and LRPs, transducing Wnt signals separately, but converging downstream in the Wnt/β-catenin pathway. The question then arises whether both receptors are absolutely required to transduce Wnt signals. We have established a sensitive luciferase reporter assay in Drosophila S2 cells to determine the level of Wg – stimulated signaling. We demonstrate here that Wg can synergize with DFz2 and function cooperatively with LRP to activate the β-catenin/Armadillo signaling pathway. Double-strand RNA interference that disrupts the synthesis of either receptor type dramatically impairs Wg signaling activity. Importantly, the pronounced synergistic effect of adding Wg and DFz2 is dependent on Arrow and Dishevelled. The synergy requires the cysteine-rich extracellular domain of DFz2, but not its carboxyterminus. Finally, mammalian LRP6 and its activated forms, which lack most of the extracellular domain of the protein, can activate the Wg signaling pathway and cooperate with Wg and DFz2 in S2 cells. We also show that the aminoterminus of LRP/Arr is required for the synergy between Wg and DFz2. Our study indicates that Wg signal transduction in S2 cells depends on the function of both LRPs and DFz2, and the results are consistent with the proposal that Wnt/Wg signals through the aminoterminal domains of its dual receptors, activating target genes through Dishevelled.
登录
查看更多内容
影响因子：
64.8
作者：
Wehrli, M;Dougan, ST;DiNardo, S
通讯作者：
DiNardo, S
影响因子：
64.8
作者：
Bhanot, P;Brink, M;Nusse, R
通讯作者：
Nusse, R
影响因子：
5.3
作者：
Hsu, SC;Galceran, J;Grosschedl, R
通讯作者：
Grosschedl, R
影响因子：
64.8
作者：
NOORDERMEER, J;KLINGENSMITH, J;NUSSE, R
通讯作者：
NUSSE, R
影响因子：
56.9
作者：
Boutros, M;Mihaly, J;Mlodzik, M
通讯作者：
Mlodzik, M