Disease relevance of KEAP1

• Sequencing of KEAP1 in 12 cell lines and 54 non-small-cell lung cancer (NSCLC) samples revealed somatic mutations in KEAP1 in a total of six cell lines and ten tumors at a frequency of 50% and 19%, respectively [1].
• Our results indicated that decreased Kelch-like ECH-associated protein, Keap1, might be an important mechanism for the increased nuclear translocation and activation of Nrf2 in response to hypoxia/reoxygenation [2].
• As oxidative stress is a hallmark of several neurodegenerative disorders, including Parkinson's disease, pharmacological agents that selectively target the Keap1-Nrf2 pathway may provide a novel neuroprotective strategy for the treatment of these diseases [3].
• Chronic hyperglycemia exacerbated IHEC apoptosis in accordance with exaggerated cytosolic and mitochondrial glutathione and protein-thiol redox imbalance, and actin/Keap-1 S-glutathionylation [4].

Psychiatry related information on KEAP1

• Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species [5].

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

• INrf2 tethering of the transcription factor Nrf2 in the cytosol prevents Nrf2 activation of antioxidant response element (ARE) mediated gene expression [14].
• Keap1 can target to the ES in the absence of myosin-VIIa, suggesting that Keap1 associates with other molecules in the adhesion plaque [15].
• Interestingly, in many epithelial cell types including cells derived from retina and inner ear, Keap1 is a component of focal adhesions and zipper junctions [15].
• Differential responses of the Nrf2-Keap1 system to laminar and oscillatory shear stresses in endothelial cells [16].
• Thus, induction of the phase 2 response and suppression of the iNOS induction was abrogated in nrf2(-/-) and keap1(-/-) mouse embryonic fibroblasts [17].

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].

References