A functional connectome: regulation of Wnt/TCF-dependent transcription by pairs of pathway activators.
A functional connectome: regulation of Wnt/TCF-dependent transcription by pairs of pathway activators.
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DOI：
10.1186/s12943-015-0475-1
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发表时间：
2015-12-08
期刊：
影响因子：
37.3
通讯作者：
Dale TC
中科院分区：
文献类型：
--
作者：
Freeman J;Smith D;Latinkic B;Ewan K;Samuel L;Zollo M;Marino N;Tyas L;Jones N;Dale TC
Wnt/β-连环蛋白信号传导通常被描述为由细胞表面的Wnt配体启动的简单途径，通过“核心途径”成员之间的线性系列相互作用，诱导来自侧翼为β-连环蛋白/TCF转录因子结合位点的基因的核转录。Wnt/β-catenin信号传导也受到一组更大的“非核心调节因子”的调节。然而，“非核心监管机构”之间的关系目前还没有得到很好的理解。该通路的异常激活已被证明可在许多不同组织中驱动肿瘤发生。通过转染上调或下调由活化的LRP 6 Wnt共受体（CSNNLRP）的瞬时表达诱导的中等水平的TCF依赖性转录的蛋白质，筛选经工程改造以具有部分活性水平的Wnt/β-连环蛋白信号传导的哺乳动物细胞。鉴定了141个TCF依赖性转录的新调节子。令人惊讶的是，当在没有BNLRP激活的情况下进行测试时，大多数上调因子未能改变TCF依赖性转录。然而，当成对表达时，27%（466/1170）的基因在功能上相互作用，改变了TCF依赖性转录的水平。当蛋白质被显示为通过它们在TCF依赖性转录的调节中合作的能力而连接的节点时，揭示了功能相互作用的网络。在这个网络中，“核心途径”组件（例如，β-catenin、GSK-3、Dsh）是连接最紧密的节点。该网络中不同节点的激活影响对Wnt途径小分子拮抗剂的敏感性。这里确定的“功能性连接体”强烈支持Wnt通路作为一个复杂的上下文依赖网络的替代模型。该网络进一步表明，高度连接的Wnt信号传导节点的突变激活使细胞倾向于TCF依赖性转录水平的进一步上下文依赖性改变，这在肿瘤进展和治疗期间可能是重要的。本文的在线版本（doi：10.1186/s12943-015-0475-1）包含补充材料，可供授权用户使用。
Wnt/β-catenin signaling is often portrayed as a simple pathway that is initiated by Wnt ligand at the cell surface leading, via linear series of interactions between ‘core pathway’ members, to the induction of nuclear transcription from genes flanked by β-catenin/TCF transcription factor binding sites. Wnt/β-catenin signaling is also regulated by a much larger set of ‘non-core regulators’. However the relationship between ‘non-core regulators’ is currently not well understood. Aberrant activation of the pathway has been shown to drive tumorgenesis in a number of different tissues. Mammalian cells engineered to have a partially-active level of Wnt/β-catenin signaling were screened by transfection for proteins that up or down-regulated a mid-level of TCF-dependent transcription induced by transient expression of an activated LRP6 Wnt co-receptor (∆NLRP). 141 novel regulators of TCF-dependent transcription were identified. Surprisingly, when tested without ∆NLRP activation, most up-regulators failed to alter TCF-dependent transcription. However, when expressed in pairs, 27 % (466/1170) functionally interacted to alter levels of TCF-dependent transcription. When proteins were displayed as nodes connected by their ability to co-operate in the regulation of TCF-dependent transcription, a network of functional interactions was revealed. In this network, ‘core pathway’ components (Eg. β-catenin, GSK-3, Dsh) were found to be the most highly connected nodes. Activation of different nodes in this network impacted on the sensitivity to Wnt pathway small molecule antagonists. The ‘functional connectome’ identified here strongly supports an alternative model of the Wnt pathway as a complex context-dependent network. The network further suggests that mutational activation of highly connected Wnt signaling nodes predisposed cells to further context-dependent alterations in levels of TCF-dependent transcription that may be important during tumor progression and treatment. The online version of this article (doi:10.1186/s12943-015-0475-1) contains supplementary material, which is available to authorized users.