Luyten Annouck, Mortier Eva, Van Campenhout Claude, Taelman Vincent, Degeest Gisèle, Wuytens Gunther, Lambaerts Kathleen, David Guido, Bellefroid Eric J, Zimmermann Pascale
Department of Human Genetics, K.U. Leuven, B-3000 Leuven, Belgium.
Mol Biol Cell. 2008 Apr;19(4):1594-604. doi: 10.1091/mbc.e07-08-0832. Epub 2008 Feb 6.
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 PKCalpha/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.
Wnt信号通路对于胚胎模式形成至关重要，并且在包括癌症在内的多种疾病中受到干扰。一个尚未解决的问题是不同的Wnt通路如何得到支持和调控。我们之前证实，突触后致密物95/盘状大蛋白/紧密连接蛋白（PDZ）家族蛋白syntenin可与多配体蛋白聚糖、Wnt共受体以及已知的蛋白激酶C（PKC）α和细胞分裂周期蛋白42（CDC42）活性刺激因子结合。在此，我们表明syntenin还能与几种卷曲蛋白（Frizzled）Wnt受体的C末端PDZ结合基序相互作用，而不影响关键下游Wnt信号成分散乱蛋白（Dishevelled）的募集。在非洲爪蟾的早期发育过程中，syntenin与同源卷曲蛋白共同表达。syntenin的过表达和下调会破坏汇聚延伸运动，这支持了syntenin在非经典Wnt信号传导中的作用。Syntenin刺激c-jun磷酸化并调节卷曲蛋白7信号传导，特别是PKCα/CDC42非经典Wnt信号级联反应。Syntenin与卷曲蛋白7的结合模式表明syntenin可以容纳卷曲蛋白7-多配体蛋白聚糖复合物。我们提出syntenin是Wnt信号转导级联反应的一个新组分，并且它可能作为卷曲蛋白和多配体蛋白聚糖之间直接的细胞内连接发挥作用。
