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首页> 外文期刊>Cellular Signalling >Secreted Frizzled-related protein potentiation versus inhibition of Wnt3a/β-catenin signaling
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Secreted Frizzled-related protein potentiation versus inhibition of Wnt3a/β-catenin signaling

机译：分泌的卷曲蛋白相关蛋白增强与Wnt3a /β-catenin信号转导的抑制

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摘要

Wnt signaling regulates a variety of cellular processes during embryonic development and in the adult. Many of these activities are mediated by the Frizzled family of seven-pass transmembrane receptors, which bindWnts via a conserved cysteine-rich domain (CRD). Secreted Frizzled-related proteins (sFRPs) contain an amino-terminal, Frizzled-like CRD and a carboxyl-terminal, heparin-binding netrin-like domain. Previous studies identified sFRPs as solubleWnt antagonists that bind directly toWnts and prevent their interactionwith Frizzleds.However, subsequent observations suggested that sFRPs and Frizzleds formhomodimers and heterodimers via their respective CRDs, and that sFRPs can stimulate signal transduction. Here, we present evidence that sFRP1 either inhibits or enhances signaling in the Wnt3a/β-catenin pathway, depending on its concentration and the cellular context. Nanomolar concentrations of sFRP1 increased Wnt3a signaling, while higher concentrations blocked it in HEK293 cells expressing a SuperTopFlash reporter. sFRP1 primarily augmented Wnt3a/β-catenin signaling in C57MG cells, but it behaved as an antagonist in L929 fibroblasts. sFRP1 enhanced reporter activity in L cells that were engineered to stably express Frizzled 5, though not Frizzled 2. This implied that the Frizzled expression pattern could determine the response to sFRP1. Similar resultswere obtainedwith sFRP2 in HEK293, C57MG and L cell reporter assays. CRDsFRP1 mimicked the potentiating effect of sFRP1 inmultiple settings, contradicting initial expectations that this domain would inhibit Wnt signaling. Moreover, CRDsFRP1 showed little avidity for Wnt3a compared to sFRP1, implying that the mechanism for potentiation by CRDsFRP1 probably does not require an interaction with Wnt protein. Together, these findings demonstrate that sFRPs can either promote or suppress Wnt/β-catenin signaling, depending on cellular context, concentration and most likely the expression pattern of Fzd receptors.
机译：Wnt信号调节胚胎发育过程中和成年期的各种细胞过程。这些活性中的许多是由七遍跨膜受体的卷曲家族介导的，其通过保守的富含半胱氨酸的结构域（CRD）结合Wnt。分泌的卷曲蛋白相关蛋白（sFRP）包含一个氨基末端的卷曲蛋白样CRD和一个羧基末端的肝素结合网蛋白样结构域。以前的研究将sFRPs识别为可直接与Wnts结合并阻止其与Frizzleds相互作用的可溶性Wnt拮抗剂，但随后的观察结果表明sFRPs和Frizzleds通过各自的CRD形成同二聚体和异二聚体，并且sFRPs可以刺激信号转导。在这里，我们提供证据表明sFRP1抑制或增强Wnt3a /β-catenin途径中的信号传导，具体取决于其浓度和细胞环境。纳摩尔浓度的sFRP1增加Wnt3a信号传导，而更高的浓度在表达SuperTopFlash报告基因的HEK293细胞中将其阻断。 sFRP1主要增强C57MG细胞中的Wnt3a /β-catenin信号传导，但在L929成纤维细胞中起着拮抗剂的作用。 sFRP1增强了L细胞的报道基因活性，该L细胞经过稳定工程设计可稳定表达卷曲蛋白5，而不是卷曲蛋白2。这表明卷曲蛋白表达模式可以确定对sFRP1的反应。 sFRP2在HEK293，C57MG和L细胞报告基因检测中获得了相似的结果。 CRDsFRP1模仿了sFRP1在多种环境中的增强作用，这与最初的预期相反，即该域会抑制Wnt信号传导。此外，与sFRP1相比，CRDsFRP1对Wnt3a的亲和力很小，这表明CRDsFRP1增强作用的机制可能不需要与Wnt蛋白相互作用。总之，这些发现表明，sFRP可以促进或抑制Wnt /β-catenin信号传导，具体取决于细胞环境，浓度以及Fzd受体的表达模式。

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