Rspo2 inhibits TCF3 phosphorylation to antagonize Wnt signaling during vertebrate anteroposterior axis specification.
Rspo2 inhibits TCF3 phosphorylation to antagonize Wnt signaling during vertebrate anteroposterior axis specification.
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DOI：
10.1038/s41598-021-92824-6
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发表时间：
2021-06-28
影响因子：
4.6
通讯作者：
Sokol SY
中科院分区：
文献类型：
--
作者：
Reis AH;Sokol SY
Wnt通路通过在胚胎发育和癌症期间控制β-连环蛋白-T细胞因子（TCF）转录复合物来激活靶基因。该途径可以通过R-spondins增强，R-spondins是结合RNF 43/ZNRF 3 E3泛素连接酶和LGR 4/5受体以防止Frizzled降解的蛋白质家族。在这里，我们表明，在非洲爪蟾前后轴规范，Rspo 2作为Wnt拮抗剂的功能，无论是在形态学和基因靶点和通路介质的水平。出乎意料的是，Wnt抑制活性不需要与RNF 43/ZNRF 3和LGR 4/5的结合。此外，Rspo 2不影响响应Wnt配体的Dishevelled磷酸化，表明Frizzled活性不受影响。进一步分析表明，Wnt拮抗作用是由于Rspo 2对TCF 3/TCF 7 L1磷酸化的抑制作用，而TCF 3/TCF 7 L1磷酸化通常导致靶基因激活。与此机制相一致，Rspo 2的前化活性在TCF 3耗尽的胚胎中被拯救。这些观察结果表明，Rspo 2是TCF 3磷酸化和Wnt信号传导的环境特异性调节剂。
The Wnt pathway activates target genes by controlling the β-catenin-T-cell factor (TCF) transcriptional complex during embryonic development and cancer. This pathway can be potentiated by R-spondins, a family of proteins that bind RNF43/ZNRF3 E3 ubiquitin ligases and LGR4/5 receptors to prevent Frizzled degradation. Here we demonstrate that, during Xenopus anteroposterior axis specification, Rspo2 functions as a Wnt antagonist, both morphologically and at the level of gene targets and pathway mediators. Unexpectedly, the binding to RNF43/ZNRF3 and LGR4/5 was not required for the Wnt inhibitory activity. Moreover, Rspo2 did not influence Dishevelled phosphorylation in response to Wnt ligands, suggesting that Frizzled activity is not affected. Further analysis indicated that the Wnt antagonism is due to the inhibitory effect of Rspo2 on TCF3/TCF7L1 phosphorylation that normally leads to target gene activation. Consistent with this mechanism, Rspo2 anteriorizing activity has been rescued in TCF3-depleted embryos. These observations suggest that Rspo2 is a context-specific regulator of TCF3 phosphorylation and Wnt signaling.
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影响因子：
64.8
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通讯作者：
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