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Gene Review

KEAP1  -  kelch-like ECH-associated protein 1

Homo sapiens

Synonyms: Cytosolic inhibitor of Nrf2, INRF2, INrf2, KIAA0132, KLHL19, ...
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Disease relevance of KEAP1


Psychiatry related information on KEAP1


High impact information on KEAP1

  • However, upon recognition of chemical signals imparted by oxidative and electrophilic molecules, Nrf2 is released from Keap1, escapes proteasomal degradation, translocates to the nucleus, and transactivates the expression of several dozen cytoprotective genes that enhance cell survival [6].
  • Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer [7].
  • A peptide containing the ETGE motif of Nrf2 binds the beta propeller of Keap1 at the entrance of the central cavity on the bottom side via electrostatic interactions with conserved arginine residues [7].
  • These properties were sensitive to DTT, suggesting that avicins affect one or more critical cysteine residues, probably on the Keap1 molecule [8].
  • Keap1 is a BTB-Kelch substrate adaptor protein that regulates steady-state levels of Nrf2, a bZIP transcription factor, in response to oxidative stress [9].

Biological context of KEAP1

  • Loss of KEAP1 function leading to constitutive activation of NRF2-mediated gene expression in cancer suggests that tumor cells manipulate the NRF2 pathway for their survival against chemotherapeutic agents [1].
  • Our results suggest that the ability of Keap1 to assemble into a functional E3 ubiquitin ligase complex is the critical determinant that controls steady-state levels of Nrf2 in response to cancer-preventive compounds and oxidative stress [10].
  • Keap1 functions as a sensor of oxidative stress, such that the inhibition of Keap1-dependent degradation of Nrf2 activates a genetic program that protects cells from reactive chemicals and maintains cellular redox homeostasis [11].
  • The siRNA lowered endogenous Keap1 mRNA to <30% of control levels between 24 and 72 h after transfection in human HaCaT keratinocyte cells and was capable of blocking ectopic expression of FLAG-tagged human Keap1 protein but not that of ectopic V5-tagged mouse Keap1 protein [12].
  • The functional significance of a putative ARE in the GI-GPx promoter was validated by transcriptional activation of reporter gene constructs upon exposure to electrophiles (tBHQ, SFN, and curcumin) or overexpression of Nrf2 and by reversal of these effects by mutation of the ARE in the promoter and by overexpressed Keap1 [13].

Anatomical context of KEAP1


Associations of KEAP1 with chemical compounds

  • Neither quinone-induced oxidative stress nor sulforaphane disrupts association between Keap1 and Nrf2 [10].
  • Redox-sensitive interaction between KIAA0132 and Nrf2 mediates indomethacin-induced expression of gamma-glutamylcysteine synthetase [18].
  • A peptide that competes with endogenous Nrf2 for INrf2 binding was able to induce ARE activity more effectively than t-butylhydroquinone, and Nrf2 that accumulated in the nucleus as a result was not phosphorylated [19].
  • The beta-turn region fits into a binding pocket on the top face of the Kelch domain and the glutamate residues form multiple hydrogen bonds with highly conserved residues in Keap1 [9].
  • Concomitant with an increase in viability, treatment with flunarizine resulted in a marked dissociation of Nrf2/Keap1 and subsequent intranuclear translocation of Nrf2, which was mediated by PI3K-Akt signaling [20].

Physical interactions of KEAP1

  • We now report that it is as a homodimer that the substrate adaptor Keap1 interacts with Cul3 [21].
  • The N terminus of the PGAM5 protein contains a conserved NXESGE motif that binds to the substrate binding pocket in the Kelch domain of Keap1, whereas the C-terminal PGAM domain binds Bcl-X(L) [22].
  • Under basal conditions, these basic region leucine zipper (bZIP) transcription factors are located in the cytoplasm of the cell bound to Keap1, and upon challenge with inducing agents, they are released from Keap1 and translocate to the nucleus [23].

Regulatory relationships of KEAP1

  • Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex [10].

Other interactions of KEAP1

  • Disruption of FAC1 interaction with a known binding partner, kelch-like ECH-associated protein 1 (Keap1), enhances activation of caspase 3 [24].
  • In this report, we demonstrate that Keap1 functions as a substrate adaptor protein for a Cul3-dependent E3 ubiquitin ligase complex [10].
  • CAND1-mediated substrate adaptor recycling is required for efficient repression of Nrf2 by Keap1 [25].
  • The in vivo and in vitro data indicated that the prothymosin alpha-Keap1 interaction is direct, highly specific, and functionally relevant [26].
  • Our results suggest that NEPPs prevent excitotoxicity by activating the Keap1/Nrf2/HO-1 pathway [27].

Analytical, diagnostic and therapeutic context of KEAP1

  • Myosin-VIIa and Keap1 copurify with ES and colocate with each other and with F-actin at the electron microscopy level [15].
  • The structure of the Kelch domain from human Keap1 has been determined by x-ray crystallography to a resolution of 1.85 A [28].
  • Here, the crystallization of the Kelch domain of human Keap1 protein by hanging-drop vapor diffusion is reported in space group P6(5)22 [11].
  • Here, we found that, by using fluorescent tags and immunoprecipitation assays, NEPPs are taken up preferentially into neurons and bind in a thiol-dependent manner to Keap1, a negative regulator of the transcription factor Nrf2 [27].
  • A key finding in the field of chemoprevention has been the discovery that the induction of these enzymes is mediated by the cytoplasmic oxidative stress system (Nrf2-Keap1) [29].


  1. Dysfunctional KEAP1-NRF2 Interaction in Non-Small-Cell Lung Cancer. Singh, A., Misra, V., Thimmulappa, R.K., Lee, H., Ames, S., Hoque, M.O., Herman, J.G., Baylin, S.B., Sidransky, D., Gabrielson, E., Brock, M.V., Biswal, S. PLoS Med. (2006) [Pubmed]
  2. Human prx1 gene is a target of Nrf2 and is up-regulated by hypoxia/reoxygenation: implication to tumor biology. Kim, Y.J., Ahn, J.Y., Liang, P., Ip, C., Zhang, Y., Park, Y.M. Cancer Res. (2007) [Pubmed]
  3. Increased nuclear factor-erythroid 2 p45-related factor 2 activity protects SH-SY5Y cells against oxidative damage. Cao, T.T., Ma, L., Kandpal, G., Warren, L., Hess, J.F., Seabrook, G.R. J. Neurochem. (2005) [Pubmed]
  4. NRF2-Dependent Glutamate-L-Cysteine Ligase Catalytic Subunit Expression Mediates Insulin Protection Against Hyperglycemia- Induced Brain Endothelial Cell Apoptosis. Okouchi, M., Okayama, N., Alexander, J.S., Aw, T.Y. Current neurovascular research (2006) [Pubmed]
  5. Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. Kobayashi, M., Yamamoto, M. Adv. Enzyme Regul. (2006) [Pubmed]
  6. Cell Survival Responses to Environmental Stresses Via the Keap1-Nrf2-ARE Pathway. Kensler, T.W., Wakabayashi, N., Biswal, S. Annu. Rev. Pharmacol. Toxicol. (2007) [Pubmed]
  7. Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer. Padmanabhan, B., Tong, K.I., Ohta, T., Nakamura, Y., Scharlock, M., Ohtsuji, M., Kang, M.I., Kobayashi, A., Yokoyama, S., Yamamoto, M. Mol. Cell (2006) [Pubmed]
  8. Triterpenoid electrophiles (avicins) activate the innate stress response by redox regulation of a gene battery. Haridas, V., Hanausek, M., Nishimura, G., Soehnge, H., Gaikwad, A., Narog, M., Spears, E., Zoltaszek, R., Walaszek, Z., Gutterman, J.U. J. Clin. Invest. (2004) [Pubmed]
  9. Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling. Lo, S.C., Li, X., Henzl, M.T., Beamer, L.J., Hannink, M. EMBO J. (2006) [Pubmed]
  10. Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Zhang, D.D., Lo, S.C., Cross, J.V., Templeton, D.J., Hannink, M. Mol. Cell. Biol. (2004) [Pubmed]
  11. Crystallization and initial crystallographic analysis of the Kelch domain from human Keap1. Li, X., Zhang, D., Hannink, M., Beamer, L.J. Acta Crystallogr. D Biol. Crystallogr. (2004) [Pubmed]
  12. Utility of siRNA against Keap1 as a strategy to stimulate a cancer chemopreventive phenotype. Devling, T.W., Lindsay, C.D., McLellan, L.I., McMahon, M., Hayes, J.D. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  13. The GI-GPx gene is a target for Nrf2. Banning, A., Deubel, S., Kluth, D., Zhou, Z., Brigelius-Flohé, R. Mol. Cell. Biol. (2005) [Pubmed]
  14. Nrf2 degradation by the ubiquitin proteasome pathway is inhibited by KIAA0132, the human homolog to INrf2. Sekhar, K.R., Yan, X.X., Freeman, M.L. Oncogene (2002) [Pubmed]
  15. A human homologue of Drosophila kelch associates with myosin-VIIa in specialized adhesion junctions. Velichkova, M., Guttman, J., Warren, C., Eng, L., Kline, K., Vogl, A.W., Hasson, T. Cell Motil. Cytoskeleton (2002) [Pubmed]
  16. Differential responses of the Nrf2-Keap1 system to laminar and oscillatory shear stresses in endothelial cells. Hosoya, T., Maruyama, A., Kang, M.I., Kawatani, Y., Shibata, T., Uchida, K., Warabi, E., Noguchi, N., Itoh, K., Yamamoto, M. J. Biol. Chem. (2005) [Pubmed]
  17. Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress. Dinkova-Kostova, A.T., Liby, K.T., Stephenson, K.K., Holtzclaw, W.D., Gao, X., Suh, N., Williams, C., Risingsong, R., Honda, T., Gribble, G.W., Sporn, M.B., Talalay, P. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  18. Redox-sensitive interaction between KIAA0132 and Nrf2 mediates indomethacin-induced expression of gamma-glutamylcysteine synthetase. Sekhar, K.R., Spitz, D.R., Harris, S., Nguyen, T.T., Meredith, M.J., Holt, J.T., Gius, D., Marnett, L.J., Summar, M.L., Freeman, M.L., Guis, D. Free Radic. Biol. Med. (2002) [Pubmed]
  19. Phosphorylation of Nrf2 at Ser40 by protein kinase C in response to antioxidants leads to the release of Nrf2 from INrf2, but is not required for Nrf2 stabilization/accumulation in the nucleus and transcriptional activation of antioxidant response element-mediated NAD(P)H:quinone oxidoreductase-1 gene expression. Bloom, D.A., Jaiswal, A.K. J. Biol. Chem. (2003) [Pubmed]
  20. Flunarizine induces Nrf2-mediated transcriptional activation of heme oxygenase-1 in protection of auditory cells from cisplatin. So, H.S., Kim, H.J., Lee, J.H., Lee, J.H., Park, S.Y., Park, C., Kim, Y.H., Kim, J.K., Lee, K.M., Kim, K.S., Chung, S.Y., Jang, W.C., Moon, S.K., Chung, H.T., Park, R.K. Cell Death Differ. (2006) [Pubmed]
  21. Dimerization of substrate adaptors can facilitate cullin-mediated ubiquitylation of proteins by a "tethering" mechanism: a two-site interaction model for the Nrf2-Keap1 complex. McMahon, M., Thomas, N., Itoh, K., Yamamoto, M., Hayes, J.D. J. Biol. Chem. (2006) [Pubmed]
  22. PGAM5, a Bcl-XL-interacting Protein, Is a Novel Substrate for the Redox-regulated Keap1-dependent Ubiquitin Ligase Complex. Lo, S.C., Hannink, M. J. Biol. Chem. (2006) [Pubmed]
  23. Molecular basis for the contribution of the antioxidant responsive element to cancer chemoprevention. Hayes, J.D., McMahon, M. Cancer Lett. (2001) [Pubmed]
  24. Expression of the fetal Alz-50 clone 1 protein induces apoptotic cell death. Strachan, G.D., Ostrow, L.A., Jordan-Sciutto, K.L. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  25. CAND1-mediated substrate adaptor recycling is required for efficient repression of Nrf2 by Keap1. Lo, S.C., Hannink, M. Mol. Cell. Biol. (2006) [Pubmed]
  26. Nuclear oncoprotein prothymosin alpha is a partner of Keap1: implications for expression of oxidative stress-protecting genes. Karapetian, R.N., Evstafieva, A.G., Abaeva, I.S., Chichkova, N.V., Filonov, G.S., Rubtsov, Y.P., Sukhacheva, E.A., Melnikov, S.V., Schneider, U., Wanker, E.E., Vartapetian, A.B. Mol. Cell. Biol. (2005) [Pubmed]
  27. Activation of the Keap1/Nrf2 pathway for neuroprotection by electrophilic [correction of electrophillic] phase II inducers. Satoh, T., Okamoto, S.I., Cui, J., Watanabe, Y., Furuta, K., Suzuki, M., Tohyama, K., Lipton, S.A. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  28. Crystal structure of the Kelch domain of human Keap1. Li, X., Zhang, D., Hannink, M., Beamer, L.J. J. Biol. Chem. (2004) [Pubmed]
  29. Activation of the Nrf2-ARE signaling pathway: a promising strategy in cancer prevention. Giudice, A., Montella, M. Bioessays (2006) [Pubmed]
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