R-Spondin family members regulate the Wnt pathway by a common mechanism
R-Spondin family members regulate the Wnt pathway by a common mechanism
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DOI：
10.1091/mbc.e08-02-0187
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发表时间：
2008-06-01
影响因子：
3.3
通讯作者：
Abo, Arie
中科院分区：
文献类型：
--
作者：
Kim, Kyung-Ah;Wagle, Marie;Abo, Arie
分泌蛋白的R-Spondin（RSpo）家族涉及Wnt信号传导途径的激活。尽管四个成员之间的高度结构同源性，基因敲除小鼠中的表达模式和表型已表现出惊人的差异。在这里，我们解剖和比较所有RSpo家族成员的分子和细胞功能。虽然所有四种RSpo蛋白都激活经典Wnt途径，但RSpo 2和3比RSpo 1更有效，而RSpo 4相对无活性。所有RSpo成员都需要Wnt配体和LRP 6来激活并放大Wnt 3A、Wnt 1和Wnt 7A的信号传导，这表明RSpo蛋白是典型Wnt信号传导的一般调节剂。与RSpo 1一样，RSpo 2 -4通过干扰DKK 1介导的LRP 6和Kremen缔合来拮抗DKK 1活性。对RSpo缺失突变体的分析表明，富含半胱氨酸的弗林蛋白酶结构域对于Wnt信号的扩增和DKK 1的抑制是足够的和必需的，这表明RSpo蛋白的Wnt扩增可能是DKK 1抑制的直接结果。总之，这些发现表明RSpo蛋白通过共同的机制调节Wnt通路，并表明与特定Wnt配体和DKK 1的共表达可能决定其体内生物学特异性。
The R-Spondin (RSpo) family of secreted proteins is implicated in the activation of the Wnt signaling pathway. Despite the high structural homology between the four members, expression patterns and phenotypes in knockout mice have demonstrated striking differences. Here we dissected and compared the molecular and cellular function of all RSpo family members. Although all four RSpo proteins activate the canonical Wnt pathway, RSpo2 and 3 are more potent than RSpo1, whereas RSpo4 is relatively inactive. All RSpo members require Wnt ligands and LRP6 for activity and amplify signaling of Wnt3A, Wnt1, and Wnt7A, suggesting that RSpo proteins are general regulators of canonical Wnt signaling. Like RSpo1, RSpo2-4 antagonize DKK1 activity by interfering with DKK1 mediated LRP6 and Kremen association. Analysis of RSpo deletion mutants indicates that the cysteine-rich furin domains are sufficient and essential for the amplification of Wnt signaling and inhibition of DKK1, suggesting that Wnt amplification by RSpo proteins may be a direct consequence of DKK1 inhibition. Together, these findings indicate that RSpo proteins modulate the Wnt pathway by a common mechanism and suggest that coexpression with specific Wnt ligands and DKK1 may determine their biological specificity in vivo.