Iron-independent phosphorylation of iron regulatory protein 2 regulates ferritin during the cell cycle.
Iron regulatory protein 2 (IRP2) is a key iron sensor that post-transcriptionally regulates mammalian iron homeostasis by binding to iron-responsive elements (IREs) in mRNAs that encode proteins involved in iron metabolism (e.g. ferritin and transferrin receptor 1). During iron deficiency, IRP2 binds IREs to regulate mRNA translation or stability, whereas during iron sufficiency IRP2 is degraded by the proteasome. Here, we identify an iron-independent IRP2 phosphorylation site that is regulated by the cell cycle. IRP2 Ser-157 is phosphorylated by Cdk1/cyclin B1 during G(2)/M and is dephosphorylated during mitotic exit by the phosphatase Cdc14A. Ser-157 phosphorylation during G(2)/M reduces IRP2 RNA-binding activity and increases ferritin synthesis, whereas Ser-157 dephosphorylation during mitotic exit restores IRP2 RNA-binding activity and represses ferritin synthesis. These data show that reversible phosphorylation of IRP2 during G(2)/M has a role in modulating the iron-independent expression of ferritin and other IRE-containing mRNAs during the cell cycle.
Wallander
Michelle L
ML
Department of Oncological Sciences, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA.
Zumbrennen
Kimberly B
KB
Rodansky
Eva S
ES
Romney
S Joshua
SJ
Leibold
Elizabeth A
EA
D000818:Animals; D002455:Cell Division / Q000502:physiology*; D005293:Ferritins / Q000096:biosynthesis* / Q000235:genetics; D016195:G2 Phase / Q000502:physiology*; D006367:HeLa Cells; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007501:Iron / Q000378:metabolism; D000090463:Iron Deficiencies; D035942:Iron Regulatory Protein 2 / Q000235:genetics / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000502:physiology*; D017027:Protein Tyrosine Phosphatases; D020871:RNA Stability / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats
D012333:RNA, Messenger; D005293:Ferritins; D007501:Iron; D010744:Phosphoric Monoester Hydrolases; C120902:CDC14A protein, human; D017027:Protein Tyrosine Phosphatases; D035942:Iron Regulatory Protein 2