Inhibition of GSK3 by Wnt signalling - two contrasting models
Inhibition of GSK3 by Wnt signalling - two contrasting models
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DOI：
10.1242/jcs.091991
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发表时间：
2011-11-01
影响因子：
4
通讯作者：
Bienz, Mariann
中科院分区：
文献类型：
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作者：
Metcalfe, Ciara;Bienz, Mariann
Wnt 信号传导的关键读数是细胞转录谱的变化，这是由 β-连环蛋白驱动的。 β-连环蛋白水平通常通过糖原合酶激酶 3（GSK3、α-和 β-亚型）介导的磷酸化事件保持在较低水平，该激酶以 β-连环蛋白为目标进行泛素化和蛋白酶体降解。 Wnt 阻断这种磷酸化事件，从而允许 β-连环蛋白积累并共同激活细胞核中的转录。 Wnt 到底如何抑制 GSK3 对 β-catenin 的活性尚不清楚，这一直是深入研究的焦点。最近关于低密度脂蛋白受体相关蛋白（LRP，亚型 5 和 6）细胞质尾部保守 PPPSPxS 基序的作用的研究最终形成了一个生化模型：Wnt 诱导 LRP6 PPPSPxS 基序磷酸化，从而作为假底物进入 GSK3 的催化口袋，从而直接阻断其针对 β-连环蛋白的活性。最近提出了一种独特的细胞生物学模型：Wnt 蛋白诱导 GSK3 被摄取到多泡体 (MVB) 中，这一事件将酶与细胞质中新合成的 β-连环蛋白底物隔离开，从而阻止其磷酸化。这个新模型基于有趣的观察结果，但也挑战了现有的证据，因此需要进一步的实验巩固。我们将考虑这两种模型是否适用于不同的 Wnt 信号传导模式：急性与慢性。
The key read-out of Wnt signalling is a change in the transcriptional profile of the cell, which is driven by beta-catenin. beta-catenin levels are normally kept low by a phosphorylation event that is mediated by glycogen synthase kinase 3 (GSK3, alpha- and beta-isoforms), which targets beta-catenin for ubiquitylation and proteasomal degradation. Wnt blocks this phosphorylation event, thereby allowing beta-catenin to accumulate and to co-activate transcription in the nucleus. Exactly how Wnt inhibits GSK3 activity towards beta-catenin is unclear and has been the focus of intensive research. Recent studies on the role of conserved PPPSPxS motifs in the cytoplasmic tail of low-density lipoprotein receptor-related protein (LRP, isoforms 5 and 6) culminated in a biochemical model: Wnt induces the phosphorylation of LRP6 PPPSPxS motifs, which consequently access the catalytic pocket of GSK3 as pseudo-substrates, thus directly blocking its activity against beta-catenin. A distinct cell-biological model was proposed more recently: Wnt proteins induce the uptake of GSK3 into multivesicular bodies (MVBs), an event that sequesters the enzyme away from newly synthesised beta-catenin substrate in the cytoplasm, thus blocking its phosphorylation. This new model is based on intriguing observations but also challenges a body of existing evidence, so will require further experimental consolidation. We shall consider whether the two models apply to different modes of Wnt signaling: acute versus chronic.