R-spondins can potentiate WNT signaling without LGRs.
R-spondins can potentiate WNT signaling without LGRs.
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DOI：
10.7554/elife.33126
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发表时间：
2018-02-06
期刊：
影响因子：
7.7
通讯作者：
Rohatgi R
中科院分区：
文献类型：
--
作者：
Lebensohn AM;Rohatgi R
WNT信号通路调节发育过程中的模式和形态发生，并促进成体组织更新和再生。R-spondin（RSPO）家族的四种分泌蛋白RSPO 1 -4通过增加WNT受体水平来放大靶细胞对WNT配体的敏感性。富含亮氨酸重复的G蛋白偶联受体（LGR）4-6被认为是RSPO的专性高亲和力受体。我们发现RSPO 2和RSPO 3，而不是RSPO 1或RSPO 4，可以在所有三种LGR都不存在的情况下增强WNT/β-catenin信号传导。通过绘制RSPO 3上的结构域，这是必要的和足够的这种活动，我们表明，对LGR的要求是由RSPO 3和ZNRF 3/RNF 43 E3泛素连接酶之间的相互作用和LGR独立的信号依赖于硫酸乙酰肝素蛋白聚糖（HSPGs）。我们建议，RSPO可以通过不同的机制，不同的使用无论是LGRs或HSPGs增强WNT信号，理解其生物学功能的影响。
The WNT signaling pathway regulates patterning and morphogenesis during development and promotes tissue renewal and regeneration in adults. The R-spondin (RSPO) family of four secreted proteins, RSPO1-4, amplifies target cell sensitivity to WNT ligands by increasing WNT receptor levels. Leucine-rich repeat-containing G-protein coupled receptors (LGRs) 4-6 are considered obligate high-affinity receptors for RSPOs. We discovered that RSPO2 and RSPO3, but not RSPO1 or RSPO4, can potentiate WNT/β-catenin signaling in the absence of all three LGRs. By mapping the domains on RSPO3 that are necessary and sufficient for this activity, we show that the requirement for LGRs is dictated by the interaction between RSPOs and the ZNRF3/RNF43 E3 ubiquitin ligases and that LGR-independent signaling depends on heparan sulfate proteoglycans (HSPGs). We propose that RSPOs can potentiate WNT signals through distinct mechanisms that differ in their use of either LGRs or HSPGs, with implications for understanding their biological functions.