Under basal conditions, Nrf2 is sequestered to the cytoplasm through binding with Keap1/Cul3/RBX1 and continually degraded via the proteasome. On early response to external stressors, Keap1 is oxidized or Nrf2 is phosphorylated by PKC. Nrf2 then translocates into the nucleus and binds to ARE (antioxidant-responsive) genes in order to increase or decrease transcription. A delayed response to external stressors causes phosphorylation of GSK-3β (by unknown tyrosine kinases), GSK-3β then activates Src kinases, which then translocate to the nucleus. Src kinases phosphorylate Nrf2 (Tyr568) which allows for nuclear export, ubiquitination and degradation of Nrf2. If insulin receptor signaling is initiated, GSK-3β activity is inhibited. Keap1 is also able to regulate Nrf2 activity through sequestration with PGAM5 to the mitochondria. In addition, PI3K also phosphorylates the CEBPB, inducing its translocation to the nucleus where it binds to the CEBPB response element within the xenobiotic response element, in conjunction with NRF2 binding to ARE.
Description was adapted from Fig 1 in Vomhof-Dekrey et al, and Fig 4 in Surh et al.
Protein phosphorylation sites were added based on information from PhosphoSitePlus (R), www.phosphosite.org.c66Cysteine residues are oxidized, causing KEAP1 to dislocate from NRF2Cysteine residues are oxidized, causing KEAP1 to dislocate from NRF2parentid=Q16236; parentsymbol=NRF2; site=SREVFDFsQRRkEYE; position=ser40; sitegrpid=450082; ptm=p; direction=uparentid=Q16236; parentsymbol=NRF2; site=SREVFDFsQRRkEYE; position=ser40; sitegrpid=450082; ptm=p; direction=uab9parent=C9J0Y1; position=Tyr568; ptm=p; direction=dOxidationfccfccea7fccab925514926PubMedPhosphoSitePlus, 2014: mutations, PTMs and recalibrations.Nucleic Acids Res2015Hornbeck PVZhang BMurray BKornhauser JMLatham VSkrzypek Enuclear factor, erythroid derived 2, like 2 signaling pathwayPW:0000369Pathway Ontology22819548PubMedThe Nrf2-antioxidant response element pathway: a target for regulating energy metabolism.J Nutr Biochem2012Vomhof-Dekrey EEPicklo MJ Sr14570043PubMedCancer chemoprevention with dietary phytochemicals.Nat Rev Cancer2003Surh YJ23434765PubMedRegulation of Nrf2-an update.Free Radic Biol Med2014Niture SKKhatri RJaiswal AKnuclear factor, erythroid 2 like 2 signaling pathwayPW:0000369Pathway Ontologyoxidative stress response pathwaysPW:0000378Pathway Ontology