Transcriptional activation by NRF2 in response to phytochemicals (WP3)

Homo sapiens

Based on [ Surh, 2003, figure 4]. NRF2 is a transcription factor that regulates expression of many detoxification or antioxidant enzymes. The Kelch-like-ECH-associated protein 1 (KEAP1) is a cytoplasmic repressor of NRF2 that inhibits its ability to translocate to the nucleus. These two proteins interact with each other through the double glycine-rich domains of KEAP1 and a hydrophilic region in the NEH2 domain of NRF2. KEAP1 contains many cysteine residues. Phase II enzyme inducers and/or prooxidants can cause oxidation or covalent modification (R) of these cysteine residues. As a result, NRF2 is released from KEAP1. In addition, phosphorylation of NRF2 at serine (S) and threonine (T) residues by kinases such as phosphatidylinositol 3-kinase (PI3K), protein kinase C (PKC), c-Jun NH2-terminal kinase (JNK) and extracellular-signal-regulated kinase (ERK) is assumed to facilitate the dissociation of NRF2 from KEAP1 and subsequent translocation to the nucleus. p38 can both stimulate and inhibit the NRF2 nuclear translocation. In the nucleus, NRF2 associates with small MAF (the term is derived from musculoaponeurotic-fibrosarcoma virus), forming a heterodimer that binds to the antioxidant-responsive element (ARE) to stimulate gene expression. NRF2/MAF target genes encode phase II detoxification or antioxidant enzymes such as glutathione S-transferase alpha2 (GSTA2), NAD(P)H:quinone oxidoreductase (NQO1), gamma-glutamate cysteine ligase (gamma -GCLC and gamma -GCLM) and heme oxygenase-1 (HO-1). PI3K also phosphorylates the CCAAT/enhancer binding protein-beta (C/EBPbeta), inducing its translocation to the nucleus and binding to the CCAAT sequence of C/EBP-beta response element within the xenobiotic response element (XRE), in conjunction with NRF2 binding to ARE. Transfection of human neuroblastoma cells with PI3K activates ARE, which is attenuated by a pharmacological inhibitor of PI3K or dominant-negative NRF2. Curcumin and caffeic acid phenethyl ester (CAPE) disrupt the NRF2–KEAP1 complex, leading to increased NRF2 binding to ARE. Sulphoraphane directly interacts with KEAP1 by covalent binding to its thiol groups. 6-(Methylsulfinyl)hexyl isothiocyanate (6-HITC) — a sulphoraphane analogue from Japanese horseradish wasabi — stimulates nuclear translocation of NRF2, which subsequently activates ARE. Protein phosphorylation sites were added based on information from PhosphoSitePlus (R),


Hubert Hug , Thomas Kelder , Kristina Hanspers , Jildau Bouwman , Alex Pico , Martijn Van Iersel , Allan Kuchinsky , Daniela Digles , Egon Willighagen , Nathan Salomonis , Zahra Roudbari , and Eric Weitz


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Homo sapiens




Pathway Ontology

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


Label Type Compact URI Comment
Curcumin Metabolite hmdb:HMDB0002269
Caffeic acid phenethyl ester Metabolite chebi:8062
Sulforaphane Metabolite hmdb:HMDB0005792
6-HITC Metabolite chemspider:7991398 Full name: 6-(Methylsulfinyl)hexylisothiocyanate, or Japanese horseradish wasabi
ERK GeneProduct ncbigene:2048
C/EBP-beta 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
NRF2 GeneProduct ncbigene:4780
KEAP1 GeneProduct ncbigene:9817
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
C/EBP-beta GeneProduct ncbigene:1051
NRF2 GeneProduct ncbigene:4780
KEAP1 GeneProduct ncbigene:9817
NRF2 GeneProduct ncbigene:4780


  1. Cancer chemoprevention with dietary phytochemicals. Surh YJ. Nat Rev Cancer. 2003 Oct;3(10):768–80. PubMed Europe PMC Scholia
  2. Regulation of Nrf2-an update. Niture SK, Khatri R, Jaiswal AK. Free Radic Biol Med. 2014 Jan;66:36–44. PubMed Europe PMC Scholia
  3. 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