A divergent canonical WNT-signaling pathway regulates microtubule dynamics: dishevelled signals locally to stabilize microtubules.
A divergent canonical WNT-signaling pathway regulates microtubule dynamics: dishevelled signals locally to stabilize microtubules.
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DOI：
10.1083/jcb.200309096
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发表时间：
2004-01-19
期刊：
影响因子：
--
通讯作者：
Salinas PC
中科院分区：
文献类型：
--
作者：
Ciani L;Krylova O;Smalley MJ;Dale TC;Salinas PC
Dishevelled（DVL）与轴突微管相关，并通过抑制丝氨酸/苏氨酸激酶、糖原合成酶激酶3β（GSK-3β）来调节微管稳定性。在经典WNT通路中，负调节因子Axin与β-catenin和GSK-3β形成复合物，导致β-catenin降解。通过DVL抑制GSK-3β增加β-连环蛋白稳定性和TCF转录激活。在这里，我们发现Axin与微管相关，并通过DVL出乎意料地稳定微管。反过来，DVL通过转录和β-连环蛋白非依赖性途径抑制GSK-3β来稳定微管。更重要的是，轴突微管稳定后DVL定位到轴突。微管稳定性增加与GSK-3β介导的MAP-1B磷酸化减少相关。我们提出了一个模型，其中Axin通过DVL通过抑制GSK-3β池来稳定微管，导致细胞靶点磷酸化的局部变化。我们的数据表明，在所谓的经典WNT信号通路调节微管稳定性的分歧。
Dishevelled (DVL) is associated with axonal microtubules and regulates microtubule stability through the inhibition of the serine/threonine kinase, glycogen synthase kinase 3β (GSK-3β). In the canonical WNT pathway, the negative regulator Axin forms a complex with β-catenin and GSK-3β, resulting in β-catenin degradation. Inhibition of GSK-3β by DVL increases β-catenin stability and TCF transcriptional activation. Here, we show that Axin associates with microtubules and unexpectedly stabilizes microtubules through DVL. In turn, DVL stabilizes microtubules by inhibiting GSK-3β through a transcription- and β-catenin–independent pathway. More importantly, axonal microtubules are stabilized after DVL localizes to axons. Increased microtubule stability is correlated with a decrease in GSK-3β–mediated phosphorylation of MAP-1B. We propose a model in which Axin, through DVL, stabilizes microtubules by inhibiting a pool of GSK-3β, resulting in local changes in the phosphorylation of cellular targets. Our data indicate a bifurcation in the so-called canonical WNT-signaling pathway to regulate microtubule stability.
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