Wise, a context-dependent activator and inhibitor of Wnt signalling
Wise, a context-dependent activator and inhibitor of Wnt signalling
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DOI：
10.1242/dev.00674
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发表时间：
2003-09-01
期刊：
影响因子：
4.6
通讯作者：
Krumlauf, R
中科院分区：
文献类型：
--
作者：
Itasaki, N;Jones, CM;Krumlauf, R
我们通过对改变神经化非洲爪蟾动物帽前后特征的活性进行功能性筛选，分离出一种新的分泌分子——Wise。Wise编码一种能够在一定距离诱导后部神经标记物的分泌蛋白。Wise的异位表达或缺失所产生的表型与Wnt信号改变时所获得的表型相似。在动物帽实验中，Wnt家族成员可诱导后部神经标记物，并且Wise对这些标记物的诱导需要经典Wnt通路的组分。这表明在此情况下，Wise通过模拟Wnt配体的某些作用来激活Wnt信号级联。Wise驱动的β -连环蛋白的核积累进一步证实了该通路的激活。相比之下，在二次轴诱导实验中，细胞外的Wise拮抗Wnt8的轴诱导能力。因此，Wise能够以一种依赖环境的方式激活或抑制Wnt信号。Wise蛋白与Wnt共受体——脂蛋白受体相关蛋白6（LRP6）发生物理相互作用，并且能够与Wnt8竞争结合LRP6。Wise的这些活性为通过Wnt共受体复合物整合输入以调节Wnt信号的平衡提供了一种新机制。
We have isolated a novel secreted molecule, Wise, by a functional screen for activities that alter the anteroposterior character of neuralised Xenopus animal caps. Wise encodes a secreted protein capable of inducing posterior neural markers at a distance. Phenotypes arising from ectopic expression or depletion of Wise resemble those obtained when Wnt signalling is altered. In animal cap assays, posterior neural markers can be induced by Wnt family members, and induction of these markers by Wise requires components of the canonical Wnt pathway. This indicates that in this context Wise activates the Writ signalling cascade by mimicking some of the effects of Wnt ligands. Activation of the pathway was further confirmed by nuclear accumulation of P-catenin driven by Wise. By contrast, in an assay for secondary axis induction, extracellularly Wise antagonises the axis-inducing ability of Wnt8. Thus, Wise can activate or inhibit Wnt signalling in a context-dependent manner. The Wise protein physically interacts with the Wnt co-receptor, lipoprotein receptor-related protein 6 (LRP6), and is able to compete with Wnt8 for binding to LRP6. These activities of Wise provide a new mechanism for integrating inputs through the Wnt coreceptor complex to modulate the balance of Wnt signalling.