Regulation of FOXO1 by TAK1-Nemo-like Kinase Pathway

• DOI: 10.1074/jbc.m110.101824
• Publication Date: 2010-01-09T02:06:43Z
• Authors: Sunhong Kim; Yongsung Kim; Jiwoon Lee; Jongkyeong Chung
• Keywords: Cell Nucleus; Transcriptional Activation; 570; 0303 health sciences; Forkhead Box Protein O1; Intracellular Signaling Peptides and Proteins; Forkhead Transcription Factors; Protein Serine-Threonine Kinases; Kidney; MAP Kinase Kinase Kinases; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; COS Cells; Chlorocebus aethiops; Animals; Humans; Drosophila; RNA, Messenger; Phosphorylation; Luciferases; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt; Signal Transduction

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(ADP-ribose) 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.