NRF2-ARE regulation (WP4357)

Homo sapiens

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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.

Authors

Kristina Hanspers and Eric Weitz

Activity

last edited

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Organisms

Homo sapiens

Communities

CPTAC

Annotations

Pathway Ontology

nuclear factor, erythroid 2 like 2 signaling pathway oxidative stress response pathway nuclear factor, erythroid 2 like 2 signaling pathway

Participants
Query Drugst.One

Label Type Compact URI Comment
GSK3B GeneProduct ensembl:ENSG00000082701
ERK GeneProduct ncbigene:2048
CEBPB GeneProduct ncbigene:1051
MAF GeneProduct ncbigene:4094
PI3K GeneProduct ncbigene:5290
GCLC GeneProduct ncbigene:2729
JNK GeneProduct ncbigene:5599
P38 GeneProduct ncbigene:7965
NRF2 GeneProduct ncbigene:4780
PKC GeneProduct ncbigene:5578
HO-1 GeneProduct ncbigene:3162
SLC7A11 GeneProduct ensembl:ENSG00000151012
NQO1 GeneProduct ncbigene:1728
GSTA2 GeneProduct ncbigene:2939
GCLM GeneProduct ncbigene:2730
KEAP1 GeneProduct ncbigene:9817
FYN GeneProduct ensembl:ENSG00000010810
SRC GeneProduct ensembl:ENSG00000197122
YES1 GeneProduct ensembl:ENSG00000176105
INSR GeneProduct ensembl:ENSG00000171105
PGAM5 GeneProduct ensembl:ENSG00000247077
CUL3 GeneProduct ensembl:ENSG00000036257
RBX1 GeneProduct ensembl:ENSG00000100387
KEAP1 GeneProduct ncbigene:9817 Cysteine residues are oxidized, causing KEAP1 to dislocate from NRF2

References

  1. Cancer chemoprevention with dietary phytochemicals. Surh YJ. Nat Rev Cancer. 2003 Oct;3(10):768–80. PubMed Europe PMC Scholia
  2. The Nrf2-antioxidant response element pathway: a target for regulating energy metabolism. Vomhof-Dekrey EE, Picklo MJ Sr. J Nutr Biochem. 2012 Oct;23(10):1201–6. PubMed Europe PMC Scholia
  3. Regulation of Nrf2-an update. Niture SK, Khatri R, Jaiswal AK. Free Radic Biol Med. 2014 Jan;66:36–44. PubMed Europe PMC Scholia
  4. PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Hornbeck PV, Zhang B, Murray B, Kornhauser JM, Latham V, Skrzypek E. Nucleic Acids Res. 2015 Jan;43(Database issue):D512-20. PubMed Europe PMC Scholia