Spatiotemporal regulation of c-Fos by ERK5 and the E3 ubiquitin ligase UBR1, and its biological role.
c-Fos is regulated by phosphorylation and multiple turnover mechanisms. We found that c-Fos was ubiquitylated in the cytoplasm during IL-6/gp130 stimulation under MEK inhibition and sought the mechanisms involved in the regulation. We show that sustained ERK5 activity and the E3 ligase UBR1 regulate the stability and subcellular localization of c-Fos. UBR1, rapidly induced by STAT3, interacts with and ubiquitylates c-Fos in the cytoplasm for its accelerated degradation. ERK5 inhibits the nuclear export of c-Fos by phosphorylating Thr232 in the c-Fos NES(221-233) and disrupts the interaction of c-Fos with UBR1 by phosphorylating Ser32. Moreover, UBR1 depletion in HeLa cells, which constitutively express UBR1 at a high level, enhances both c-Fos expression and cell growth, whereas ERK5 depletion reduces both of them. Interestingly, an NES mutant of c-Fos, but not wild-type, substitutes ERK5 activity for HeLa cell proliferation. Thus, this spatiotemporal regulation of c-Fos by ERK5 and UBR1 is critical for the regulation of c-Fos/AP-1.
Sasaki
Takanori
T
Department of Immunology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
Kojima
Hirotada
H
Kishimoto
Rikiya
R
Ikeda
Ayu
A
Kunimoto
Hiroyuki
H
Nakajima
Koich
K
D002460:Cell Line; D049109:Cell Proliferation; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D048054:Mitogen-Activated Protein Kinase 7 / Q000502:physiology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D025941:Protein Interaction Mapping; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
D005419:Flavonoids; D015850:Interleukin-6; D016760:Proto-Oncogene Proteins c-fos; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D018808:Transcription Factor AP-1; D025801:Ubiquitin; D050822:Cytokine Receptor gp130; C113474:UBR1 protein, human; D044767:Ubiquitin-Protein Ligases; D048054:Mitogen-Activated Protein Kinase 7; D020929:Mitogen-Activated Protein Kinase Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one