Secreted Frizzled-related Protein 2 (sFRP2) Redirects Non-canonical Wnt Signaling from Fz7 to Ror2 during Vertebrate Gastrulation
Secreted Frizzled-related Protein 2 (sFRP2) Redirects Non-canonical Wnt Signaling from Fz7 to Ror2 during Vertebrate Gastrulation
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DOI：
10.1074/jbc.m116.733766
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发表时间：
2016-06-24
影响因子：
4.8
通讯作者：
Oezbek, Suat
中科院分区：
文献类型：
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作者：
Brinkmann, Eva-Maria;Mattes, Benjamin;Oezbek, Suat
脊椎动物原肠胚形成过程中的会聚延伸运动需要非经典Wnt信号通路的平衡活性，但是在分子水平上调节这种相互作用的因素的特征很差。在这里，我们表明，分泌型卷曲相关蛋白（sFRP）家族的成员之一，sFRP 2是非洲爪蟾原肠胚形成过程中形态发生和papc表达所必需的。我们进一步提供了sFRP 2将非经典Wnt信号从Frizzled 7（Fz 7）重定向到受体酪氨酸激酶样孤儿受体2（Ror 2）的证据。在此过程中，sFRP 2通过稳定膜上的Wnt 5a-Ror 2复合物来促进Ror 2信号转导，而它可能通过阻断Fz 7受体内吞作用来抑制Fz 7信号转导。sFRP 2的富含半胱氨酸的结构域足以激活Ror 2，相关的sFRPs可以替代这一功能。值得注意的是，两种受体通过其富含半胱氨酸的结构域的直接相互作用也促进Ror 2介导的papc表达，但抑制Fz 7信号传导。我们认为sFRPs可以作为一个分子开关，引导脊椎动物原肠胚形成过程中不同非经典Wnt通路的信号输入。
Convergent extension movements during vertebrate gastrulation require a balanced activity of non-canonical Wnt signaling pathways, but the factors regulating this interplay on the molecular level are poorly characterized. Here we show that sFRP2, a member of the secreted frizzled-related protein (sFRP) family, is required for morphogenesis and papc expression during Xenopus gastrulation. We further provide evidence that sFRP2 redirects non-canonical Wnt signaling from Frizzled 7 (Fz7) to the receptor tyrosine kinase-like orphan receptor 2 (Ror2). During this process, sFRP2 promotes Ror2 signal transduction by stabilizing Wnt5a-Ror2 complexes at the membrane, whereas it inhibits Fz7 signaling, probably by blocking Fz7 receptor endocytosis. The cysteine-rich domain of sFRP2 is sufficient for Ror2 activation, and related sFRPs can substitute for this function. Notably, direct interaction of the two receptors via their cysteine-rich domains also promotes Ror2-mediated papc expression but inhibits Fz7 signaling. We propose that sFRPs can act as a molecular switch, channeling the signal input for different non-canonical Wnt pathways during vertebrate gastrulation.