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. c66 Cysteine residues are oxidized, causing KEAP1 to dislocate from NRF2 Cysteine residues are oxidized, causing KEAP1 to dislocate from NRF2 parentid=Q16236; parentsymbol=NRF2; site=SREVFDFsQRRkEYE; position=ser40; sitegrpid=450082; ptm=p; direction=u parentid=Q16236; parentsymbol=NRF2; site=SREVFDFsQRRkEYE; position=ser40; sitegrpid=450082; ptm=p; direction=u ab9 parent=C9J0Y1; position=Tyr568; ptm=p; direction=d Oxidation fcc fcc ea7 fcc ab9 25514926 PubMed PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucleic Acids Res 2015 Hornbeck PV Zhang B Murray B Kornhauser JM Latham V Skrzypek E nuclear factor, erythroid derived 2, like 2 signaling pathway PW:0000369 Pathway Ontology 22819548 PubMed The Nrf2-antioxidant response element pathway: a target for regulating energy metabolism. J Nutr Biochem 2012 Vomhof-Dekrey EE Picklo MJ Sr 14570043 PubMed Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer 2003 Surh YJ 23434765 PubMed Regulation of Nrf2-an update. Free Radic Biol Med 2014 Niture SK Khatri R Jaiswal AK nuclear factor, erythroid 2 like 2 signaling pathway PW:0000369 Pathway Ontology oxidative stress response pathways PW:0000378 Pathway Ontology