NLK positively regulates Wnt/β-catenin signalling by phosphorylating LEF1 in neural progenitor cells
NLK positively regulates Wnt/β-catenin signalling by phosphorylating LEF1 in neural progenitor cells
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DOI：
10.1038/emboj.2012.46
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发表时间：
2012-04-18
期刊：
影响因子：
11.4
通讯作者：
Ishitani, Tohru
中科院分区：
文献类型：
--
作者：
Ota, Satoshi;Ishitani, Shizuka;Ishitani, Tohru
Nemo 样激酶 (NLK/Nlk) 是一种参与 Wnt/β-catenin 信号传导的进化保守蛋白激酶。然而，NLK 在脊椎动物 Wnt/β-catenin 信号传导中的作用仍不清楚。在这里，我们发现抑制斑马鱼中的 Nlk2 功能会导致假定中脑中淋巴增强因子 1 (Lef1) 介导的基因表达和细胞增殖减少，从而导致中脑顶盖尺寸减小。这些缺陷与 Nlk2 对 Lef1 的磷酸化有关。因此，Nlk2 对于神经祖细胞 (NPC) 中 Lef1 转录活性的磷酸化和激活至关重要。在 NPC 样哺乳动物细胞中，LEF1 转录活性的磷酸化和激活也需要 NLK。 LEF1 的磷酸化诱导其与组蛋白脱乙酰酶解离，从而允许转录激活。此外，我们证明 NLK 在 Wnt/β-连环蛋白信号通路中的 Disheveled (Dvl) 下游发挥作用。我们的研究结果揭示了 NLK 在 Wnt/β-catenin 信号通路激活中的新作用。 EMBO 杂志 (2012) 31, 1904-1915。 doi：10.1038/emboj.2012.46； 2012 年 2 月 28 日在线发布
Nemo-like kinase (NLK/Nlk) is an evolutionarily conserved protein kinase involved in Wnt/beta-catenin signalling. However, the roles of NLK in Wnt/beta-catenin signalling in vertebrates remain unclear. Here, we show that inhibition of Nlk2 function in zebrafish results in decreased Lymphoid enhancer factor-1 (Lef1)-mediated gene expression and cell proliferation in the presumptive midbrain, resulting in a reduction of midbrain tectum size. These defects are related to phosphorylation of Lef1 by Nlk2. Thus, Nlk2 is essential for the phosphorylation and activation of Lef1 transcriptional activity in neural progenitor cells (NPCs). In NPC-like mammalian cells, NLK is also required for the phosphorylation and activation of LEF1 transcriptional activity. Phosphorylation of LEF1 induces its dissociation from histone deacetylase, thereby allowing transcription activation. Furthermore, we demonstrate that NLK functions downstream of Dishevelled (Dvl) in the Wnt/beta-catenin signalling pathway. Our findings reveal a novel role of NLK in the activation of the Wnt/beta-catenin signalling pathway. The EMBO Journal (2012) 31, 1904-1915. doi:10.1038/emboj.2012.46; Published online 28 February 2012