Regulation of FOXO1 by TAK1-Nemo-like Kinase Pathway
Regulation of FOXO1 by TAK1-Nemo-like Kinase Pathway
复制标题
DOI：
10.1074/jbc.m110.101824
复制
发表时间：
2010-03-12
影响因子：
4.8
通讯作者：
Chung, Jongkyeong
中科院分区：
文献类型：
--
作者：
Kim, Sunhong;Kim, Yongsung;Chung, Jongkyeong
FOXO家族在应激反应、代谢、细胞周期、凋亡、寿命等方面具有重要的功能。FOXO的转录活性和亚细胞定位受到翻译后修饰的严格调控，包括被各种激酶磷酸化。在这里，我们报告说，转化生长因子β激活激酶（TAK 1）-Nemo样激酶（NLK）途径负调控FOXO 1。我们表明，NLK结合和磷酸化FOXO 1在Pro-指导的Ser/Thr残基的反式激活结构域。通过TAK 1-NLK途径磷酸化抑制FOXO 1的转录活性并将FOXO 1从细胞核中排除，这不依赖于磷脂酰肌醇3-激酶/Akt途径。因此，TAK 1-NLK途径的敲低使FOXO 1去磷酸化并降低磷酸-Ser-329 FOXO 1水平。它还诱导FOXO 1移位到细胞核中，并导致FOXO靶基因的mRNA水平增加和聚（ADPribose）聚合酶切割。此外，我们发现NLK和FOXO 1之间的相互作用是进化保守的果蝇。总的来说，这些发现提供了TAK 1-NLK通路是FOXO 1的新调节因子的第一个证据。
The FOXO family of forkhead transcription factors has a variety of important functions in stress response, metabolism, cell cycle, apoptosis, longevity, etc. The transcriptional activity and subcellular localization of FOXO are tightly regulated by post-translational modifications, including phosphorylation by various kinases. Here, we report that the transforming growth factor-beta-activated kinase (TAK1)-Nemo-like kinase (NLK) pathway negatively regulates FOXO1. We show that NLK binds and phosphorylates FOXO1 at Pro-directed Ser/Thr residues in the transactivation domain. The phosphorylation by TAK1-NLK pathway inhibits the transcriptional activity of FOXO1 and excludes FOXO1 from the nucleus, which is independent of phosphatidylinositol 3-kinase/Akt pathway. Consistently, knockdown of TAK1-NLK pathway dephosphorylates FOXO1 and decreases phospho-Ser-329 FOXO1 level. It also induces translocation of FOXO1 into the nucleus and leads to an increase in mRNA levels of FOXO target genes and poly(ADPribose) polymerase cleavage. In addition, we show the interaction between NLK and FOXO1 is evolutionarily conserved in Drosophila. Collectively, these findings provide the first evidence that TAK1-NLK pathway is a novel regulator of FOXO1.