Interaction of frizzled related protein (FRP) with Wnt ligands and the frizzled receptor suggests alternative mechanisms for FRP inhibition of Wnt signaling
Interaction of frizzled related protein (FRP) with Wnt ligands and the frizzled receptor suggests alternative mechanisms for FRP inhibition of Wnt signaling
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DOI：
10.1074/jbc.274.23.16180
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发表时间：
1999-06-04
影响因子：
4.8
通讯作者：
Aaronson, SA
中科院分区：
文献类型：
--
作者：
Bafico, A;Gazit, A;Aaronson, SA
卷曲相关蛋白（FRPs）包括一个分泌分子家族，其含有一个n端富含半胱氨酸结构域（CRD），与膜锚定Wnt受体卷曲家族的CRD高度相似。在爪蟾发育模型中，FRPs已被证明与Wnt蛋白相互作用并拮抗Wnt信号。研究表明，在瞬时共转染和稳定转化模型中，玻璃钢都能拮抗wnt诱导的非复杂β -连环蛋白的增加，其中wnt诱导的形态改变也被抑制。我们进一步证明，使用t细胞因子荧光素酶报告因子来测量Wnt功能，FRP在旁分泌模式下抑制Wnt信号。对FRP抑制机制的研究表明，FRP通过其CRD结构域与WNT-1或WNT-2形成复合物。含有不同标签的FRP的转染分析显示FRP本身形成复合物，这种能力是由其CRD结构域赋予的。最后，我们通过共转染证明了FRP与原型卷曲形成复合物。这些发现与FRP通过与Wnt相互作用和/或与卷曲受体形成非功能复合物抑制Wnt信号传导的模型一致。
Frizzled related proteins (FRPs) comprise a family of secreted molecules that contain an N-terminal cysteine-rich domain (CRD) highly similar to the CRDs of the frizzled family of membrane-anchored Wnt receptors. FRPs have been shown to interact with Wnt proteins and antagonize Wnt signaling in a Xenopus developmental model. Fire demonstrated that FRP antagonizes the Wnt-induced increase in uncomplexed beta-catenin in both transient cotransfection and stable transformation models, where Wnt-induced morphological alterations are inhibited as well. We showed further that FRP inhibits Wnt signaling in a paracrine mode using a T-cell factor luciferase reporter to measure Wnt function. Investigation of the mechanisms responsible for FRP inhibition revealed that FRP forms complexes with WNT-1 or WNT-2 through its CRD domain. Transfection analysis with FRPs containing different tags revealed that FRP itself forms complexes and that this ability is conferred by its CRD domain. Finally, we demonstrated by cotransfection that FRP forms complexes with a prototype frizzled. AU of these findings are consistent with a model by which FRP inhibits Wnt signaling through interactions with Wnt and/or formation of nonfunctional complexes with the frizzled receptor.