NRF2-ARE regulation (Homo sapiens)

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13332NucleusPhase II enzymesAREProteasomedegradation of NRF2AutoregulatoryloopGSK3BERKPCEBPBMAFPI3KGCLCJNKP38NRF2PPPKCHO-1SLC7A11NQO1GSTA2GCLMCEBPBPNRF2KEAP1NRF2PP1Early response to stressorLate response to stressorFYNSRCYES1NRF2PINSRPGAM5NRF2KEAP1CUL3RBX1KEAP1OKEAP1CUL3RBX1FYNSRCYES1


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.

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Ontology Terms



  1. Niture SK, Khatri R, Jaiswal AK; ''Regulation of Nrf2-an update.''; Free Radic Biol Med, 2014 PubMed Europe PMC Scholia
  2. Surh YJ; ''Cancer chemoprevention with dietary phytochemicals.''; Nat Rev Cancer, 2003 PubMed Europe PMC Scholia
  3. Vomhof-Dekrey EE, Picklo MJ Sr; ''The Nrf2-antioxidant response element pathway: a target for regulating energy metabolism.''; J Nutr Biochem, 2012 PubMed Europe PMC Scholia


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98705view18:20, 28 September 2018KhanspersModified title
98704view18:19, 28 September 2018KhanspersModified title
98702view18:14, 28 September 2018KhanspersModified description
98701view18:06, 28 September 2018KhanspersOntology Term : 'nuclear factor, erythroid 2 like 2 signaling pathway' added !
98700view18:05, 28 September 2018Khanspersfixed connection
98699view18:03, 28 September 2018KhanspersNew pathway

External references


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NameTypeDatabase referenceComment
CEBPBGeneProduct1051 (Entrez Gene)
CUL3GeneProductENSG00000036257 (Ensembl)
ERKGeneProduct2048 (Entrez Gene)
FYNGeneProductENSG00000010810 (Ensembl)
GCLCGeneProduct2729 (Entrez Gene)
GCLMGeneProduct2730 (Entrez Gene)
GSK3BGeneProductENSG00000082701 (Ensembl)
GSTA2GeneProduct2939 (Entrez Gene)
HO-1GeneProduct3162 (Entrez Gene)
INSRGeneProductENSG00000171105 (Ensembl)
JNKGeneProduct5599 (Entrez Gene)
KEAP1GeneProduct9817 (Entrez Gene) Cysteine residues are oxidized, causing KEAP1 to dislocate from NRF2
MAFGeneProduct4094 (Entrez Gene)
NQO1GeneProduct1728 (Entrez Gene)
NRF2GeneProduct4780 (Entrez Gene)
P38GeneProduct7965 (Entrez Gene)
PGAM5GeneProductENSG00000247077 (Ensembl)
PI3KGeneProduct5290 (Entrez Gene)
PKCGeneProduct5578 (Entrez Gene)
RBX1GeneProductENSG00000100387 (Ensembl)
SLC7A11GeneProductENSG00000151012 (Ensembl)
SRCGeneProductENSG00000197122 (Ensembl)
YES1GeneProductENSG00000176105 (Ensembl)

Annotated Interactions

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