Regulation of FOXO1 by TAK1-Nemo-like kinase pathway.
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.
Kim
Sunhong
S
Center for Molecular Cancer Research, Korea Research Institute of Bioscience and Biotechnology, Chungbuk 363-883, Korea.
Kim
Yongsung
Y
Lee
Jiwoon
J
Chung
Jongkyeong
J
D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus / Q000502:physiology; D002522:Chlorocebus aethiops; D004330:Drosophila; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000166:cytology; D008156:Luciferases / Q000235:genetics; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D015533:Transcriptional Activation / Q000502:physiology*; D000099151:MAP Kinase Kinase Kinase 7
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D047908:Intracellular Signaling Peptides and Proteins; D008156:Luciferases; D020930:MAP Kinase Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D000099151:MAP Kinase Kinase Kinase 7; C085126:FOXO1 protein, human; C470551:NLK protein, human