The human frizzled 6 (HFz6) acts as a negative regulator of the canonical Wnt•β-Catenin signaling cascade
The human frizzled 6 (HFz6) acts as a negative regulator of the canonical Wnt•β-Catenin signaling cascade
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DOI：
10.1074/jbc.m306421200
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发表时间：
2004-04-09
影响因子：
4.8
通讯作者：
Gazit, A
中科院分区：
文献类型：
--
作者：
Golan, T;Yaniv, A;Gazit, A
此前，我们已经克隆了人Frizzled1(HFz1)，并表明它传递Wnt-3a诱导的典型途径。我们还克隆了人Frizzled6(HFz6)，并在本研究中表明，与HFz1相反，HFz6在暴露于各种WNT后不激活典型的WNT途径，无论是属于WNT-1还是属于WNT-5a组。此外，当HFz6与HFz1共表达时，我们发现HFz6抑制了Wnt-3a诱导的规范信号。HFz6抑制了典型的Wnt级联反应，Wnt信号也被细胞内介质激活，如稳定的β-连环蛋白(S33Y)突变体Dishevelleed-1，以及LiCl介导的对糖原合成酶-3β活性的抑制。去除HFz6的N‘或C’端序列可消除HFz6的抑制活性。由于HFz6的抑制作用与β-连环素水平的降低无关，因此，我们认为HFz6不影响β-连环素的稳定，这意味着HFz6传递了一个抑制信号，该信号与β-连环素破坏复合体下游的典型Wnt通路相互作用并被抑制。HFz6不影响核T细胞因子4(TCF4)水平，也不影响β-连环蛋白-TCF4复合体的形成。然而，电泳迁移率改变分析表明，HFz6抑制了TCF/淋巴增强因子转录因子与靶DNA的结合。此外，我们提供的数据表明，HFz6激活了转化生长因子-β-激活激酶-Nemo样激酶途径，该途径阻断了TCF/淋巴增强因子与靶启动子的结合，从而抑制了β-catenin激活Wnt靶基因转录的能力。
Previously we have cloned the human Frizzled 1 (HFz1) and shown that it transmits the Wnt-3a-induced canonical pathway. We also cloned the human Frizzled 6 (HFz6) and show in the present study that, as opposed to HFz1, HFz6 did not activate the canonical Wnt pathway following exposure to various Wnts, whether belonging to the Wnt-1 or to the Wnt-5a group. Moreover we show that HFz6 repressed Wnt-3a-induced canonical signaling when co-expressed with HFz1. HFz6 repressed the canonical Wnt cascade activated also by various Wnt signaling intracellular mediators such as Dishevelled-1, a stabilized beta-catenin(S33Y) mutant, and LiCl-mediated repression of glycogen synthase kinase-3beta activity. Removal of HFz6 N'- or C'-terminal sequences abolished HFz6 repressive activity. As the HFz6 repressive effect was not associated with a decrease in the level of beta-catenin, it is suggested that HFz6 does not affect beta-catenin stabilization, implying that HFz6 transmits a repressive signaling that cross-talks with and inhibits the canonical Wnt pathway downstream of beta-catenin destruction complex. HFz6 did not affect the level of nuclear T-cell factor 4 (TCF4) nor did it affect beta-catenin.TCF4 complex formation. However, electrophoretic mobility shift assays indicated that HFz6 repressed the binding of TCF/lymphoid enhancer factor transcription factors to target DNA. Moreover we present data suggesting that HFz6 activates the transforming growth factor-beta-activated kinase-NEMO-like kinase pathway that blocks TCF/lymphoid enhancer factor binding to target promoters, thereby inhibiting the ability of beta-catenin to activate transcription of Wnt target genes.