The postsynaptic density 95/disc-large/zona occludens protein syntenin directly interacts with Frizzled 7 and supports noncanonical Wnt signaling
The postsynaptic density 95/disc-large/zona occludens protein syntenin directly interacts with Frizzled 7 and supports noncanonical Wnt signaling
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DOI：
10.1091/mbc.e07-08-0832
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发表时间：
2008-04-01
影响因子：
3.3
通讯作者：
Zimmermann, Pascale
中科院分区：
文献类型：
--
作者：
Luyten, Annouck;Mortier, Eva;Zimmermann, Pascale
Wnt 信号通路对于胚胎模式至关重要，并且在包括癌症在内的多种疾病中受到干扰。一个未解决的问题是如何支持和调节不同的 Wnt 通路。我们之前确定突触后密度 95/disc-large/zona occlusionns (PDZ) 蛋白 Syntenin 与 Syndecans、Wnt 辅助受体以及已知的蛋白激酶 C (PKC)α 和 CDC42 活性刺激物结合。在这里，我们发现 Syntenin 还与几种 Frizzled Wnt 受体的 C 端 PDZ 结合基序相互作用，而不会影响关键下游 Wnt 信号传导成分 Dishevelled 的募集。 Syntenin 在非洲爪蟾的早期发育过程中与同源 Frizzled 共表达。 Syntenin 的过度表达和下调会破坏会聚延伸运动，支持 Syntenin 在非经典 Wnt 信号传导中的作用。 Syntenin 刺激 c-jun 磷酸化并调节 Frizzled 7 信号传导，特别是 PKC α/CDC42 非经典 Wnt 信号传导级联。 Syntenin-Frizzled 7 结合模式表明 Syntenin 可以容纳 Frizzled 7-syndecan 复合物。我们提出 Syntenin 是 Wnt 信号转导级联的一个新成分，并且它可能充当 Frizzled 和 Syndecans 之间的直接细胞内连接。
Wnt signaling pathways are essential for embryonic patterning, and they are disturbed in a wide spectrum of diseases, including cancer. An unresolved question is how the different Wnt pathways are supported and regulated. We previously established that the postsynaptic density 95/disc-large/zona occludens (PDZ) protein syntenin binds to syndecans, Wnt coreceptors, and known stimulators of protein kinase C (PKC)alpha and CDC42 activity. Here, we show that syntenin also interacts with the C-terminal PDZ binding motif of several Frizzled Wnt receptors, without compromising the recruitment of Dishevelled, a key downstream Wnt-signaling component. Syntenin is coexpressed with cognate Frizzled during early development in Xenopus. Overexpression and down-regulation of syntenin disrupt convergent extension movements, supporting a role for syntenin in noncanonical Wnt signaling. Syntenin stimulates c-jun phosphorylation and modulates Frizzled 7 signaling, in particular the PKC alpha/CDC42 noncanonical Wnt signaling cascade. The syntenin-Frizzled 7 binding mode indicates syntenin can accommodate Frizzled 7-syndecan complexes. We propose that syntenin is a novel component of the Wnt signal transduction cascade and that it might function as a direct intracellular link between Frizzled and syndecans.