Secreted Frizzled-related protein potentiation versus inhibition of Wnt3a/β-catenin signaling.
Secreted Frizzled-related protein potentiation versus inhibition of Wnt3a/β-catenin signaling.
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DOI：
10.1016/j.cellsig.2013.09.016
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发表时间：
2014-01
影响因子：
4.8
通讯作者：
Rubin JS
中科院分区：
文献类型：
--
作者：
Xavier CP;Melikova M;Chuman Y;Üren A;Baljinnyam B;Rubin JS
Wnt信号在胚胎发育和成体中调节多种细胞过程。这些活性中的许多由卷曲家族的七次跨膜受体介导，卷曲家族通过保守的富含半胱氨酸的结构域（CRD）结合Wnt。分泌型卷曲相关蛋白（sFRPs）含有一个氨基末端卷曲样CRD和一个羧基末端肝素结合netrin样结构域。先前的研究将sFRPs鉴定为可溶性Wnt拮抗剂，其直接与Wnt结合并阻止它们与Frizzleds相互作用。然而，随后的观察表明sFRPs和Frizzleds通过它们各自的CRD形成同源二聚体和异源二聚体，并且sFRPs可以刺激信号转导。在这里，我们提出的证据表明，sFRP 1抑制或增强Wnt 3a/β-catenin途径中的信号转导，这取决于其浓度和细胞环境。纳摩尔浓度的sFRP 1增加了Wnt 3a信号传导，而更高浓度的sFRP 1在表达SuperTopFlash报告基因的HEK 293细胞中阻断了Wnt 3a信号传导。在C57 MG细胞中，sFRP 1主要增强Wnt 3a/β-catenin信号传导，但在L929成纤维细胞中，sFRP 1表现为拮抗剂。sFRP 1增强了L细胞中的报道活性，所述L细胞被工程化以稳定表达Frizzled 5，但不表达Frizzled 2。这意味着Frizzled表达模式可以决定对sFRP 1的反应。在HEK 293、C57 MG和L细胞报告基因测定中，sFRP 2获得了类似的结果。CRDsFRP 1在多个环境中模拟sFRP 1的增强作用，与最初的预期相矛盾，该结构域将抑制Wnt信号传导。此外，与sFRP 1相比，CRDsFRP 1对Wnt 3a的亲合力很小，这意味着CRDsFRP 1的增强机制可能不需要与Wnt蛋白相互作用。总之，这些发现表明sFRPs可以促进或抑制Wnt/β-连环蛋白信号传导，这取决于细胞环境、浓度和最可能的Fzd受体的表达模式。
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 bind Wnts 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 soluble Wnt antagonists that bind directly to Wnts and prevent their interaction with Frizzleds. However, subsequent observations suggested that sFRPs and Frizzleds form homodimers 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 results were obtained with 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.
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影响因子：
5.7
作者：
Cooper SJ;von Roemeling CA;Kang KH;Marlow LA;Grebe SK;Menefee ME;Tun HW;Colon-Otero G;Perez EA;Copland JA
通讯作者：
Copland JA
影响因子：
64.8
作者：
Ishitani, T;Ninomiya-Tsuji, J;Matsumoto, K
通讯作者：
Matsumoto, K
影响因子：
64.8
作者：
Bhanot, P;Brink, M;Nusse, R
通讯作者：
Nusse, R
影响因子：
4.8
作者：
Bafico, A;Gazit, A;Aaronson, SA
通讯作者：
Aaronson, SA
影响因子：
3.7
作者：
Baljinnyam, Bolormaa;Klauzinska, Malgorzata;Rubin, Jeffrey S.
通讯作者：
Rubin, Jeffrey S.