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FLASH GENE
Symbol KEAP1 contributors: mct - updated : 24-11-2016
HGNC name kelch-like ECH-associated protein 1
HGNC id 23177
Location 19p13.2      Physical location : 10.596.795 - 10.614.054
Synonym name
  • cytosolic inhibitor of Nrf2
  • Kelch-like protein 19
  • Synonym symbol(s) KIAA0132, MGC10630, MGC1114, MGC20887, MGC4407, MGC9454, INrf2, KLHL19
    DNA
    TYPE functioning gene
    STRUCTURE 17.26 kb     6 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence cytosine-phosphate-guanine/HTF
    text structure P1 region including 12 CpG sites (highly methylated in lung cancer)
    MAPPING cloned Y linked N status provisional
    RNA
    TRANSCRIPTS type messenger
    text two alternatively spliced variants encoding the same isoform
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    6 splicing 2606 - 624 - 2002 12145307
    6 splicing 2577 - 624 - 2002 12145307
    has an alternate 5'UTR as compared to variant 1
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly
    Digestiveintestinelarge intestinecolon lowly
     liver   highly
     mouth   highly
    Nervousnervecranial nerve  highly
    Respiratorylung   lowly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularstriatumskeletal  
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period pregnancy
    Text placenta, lowly
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N-terminal region regulating the E3 ligase activity
  • a BTB/POZ domain, playing key roles in sensing environmental electrophiles and in mediating interactions with the Cul3/Rbx1 E3 ubiquitin ligase system
  • six KELCH-1 like domains, mediating interaction with NFE2L2 and BPTF
  • an IVR (intervening region), with two critical cysteine residues, Cys272 and Cys288, that are important for repression of NFE2L2 activity
  • a DGR (double glycine repeat), that interacts with the BH2 domain of BCL2 and facilitates KEAP1:CUL3-RBX1-mediated ubiquitination of BCL2
  • CTR (C-terminal region)
  • HOMOLOGY
    interspecies ortholog to murine Keap1
    ortholog to rattus keap1
    homolog to zebrafish keap1
    Homologene
    FAMILY
  • BTB and C-terminal Kelch (BACK) domain-containing protein family
  • CATEGORY adaptor , transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,cytosolic
    intracellular,cytoplasm,cytoskeleton,microtubule,centrosome
    intracellular,nucleus,nucleolus
    text
  • localized primarily in the cytoplasm with minimal amount in the nucleus and endoplasmic reticulum
  • basic FUNCTION
  • interacts with NFE2L2 (in a redox manner) and represses its functions, resulting in the expression of the catalytic subunit of gamma-glutamyl cysteine synthetase
  • playing a protective role against acetaminophen hepatotoxicity by regulating drug metabolizing and antioxidant enzyme genes through the ARE
  • having functions thiol-dependent
  • playing a role in catalyzing the ubiquitylation of the NFE2L2 transcription factor
  • mutation in the KEAP1-NFE2L2 system may represent a novel oncogenic mechanism leading to malignancy
  • BTB-Kelch substrate adaptor protein for a CUL3-dependent ubiquitin ligase complex that functions as a sensor for thiol-reactive chemopreventive compounds and oxidative stress
  • may regulates both transcriptional and post-transcriptional responses of mammalian cells to oxidative stress
  • acting as a sensor for oxidative/electrophilic stress, an adaptor for Cullin-3-based ubiquitin ligase, and a regulator of NFE2L2 activity through the interaction with NFE2L2 Neh2 domain
  • redox-regulated substrate adaptor for a cullin-based ubiquitin ligase, targets NFE2L2 for proteosome-mediated degradation and represses NFE2L2-dependent gene expression
  • responsible for IKBKB ubiquitination, and dysregulation of KEAP1-mediated IKBKB ubiquitination may contribute to tumorigenesis
  • substrate adaptor component of a Cul3-dependent E3 ubiquitin ligase complex that contributes to the rapid degradation of NFE2L2
  • adaptor protein that mediates ubiquitination/degradation of NFE2L2 (Nrf2), a master regulator of cytoprotective gene expression
  • role for the KEAP1-NFE2L2 pathway in mediating chemotherapeutic responses in the epithelial ovarian cancer
  • central to the regulation of the NFE2L2-mediated cytoprotective response, and is increasingly recognized as an important target for therapeutic intervention in a range of diseases involving excessive oxidative stress and inflammation
  • CELLULAR PROCESS nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    autophagy pathway maintains the integrity of the KEAP1-NFE2L2 system for the normal liver function by governing the KEAP1 turnover
    a component
  • KEAP1 dimerization is required for NFE2L2 sequestration and transcriptional repression
  • forms a ternary complex containing both KEAP1 and NFE2L2, in which the dimeric KEAP1 protein simultaneously binds both PGAM5 and NFE2L2 through their conserved E(S/T)GE motifs
  • KEAP1-NFE2L2 system and autophagy are both involved in the oxidative-stress response, metabolic pathways, and innate immunity, and dysregulation of these processes is associated with pathogenic processes
  • KEAP1-NFE2L2 system regulates the cell fate determination of hematopoietic stem cells
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • binding to BPTF
  • acting as a negative regulator of NFE2L2 which modulates NFE2L2 activity through a variety of proposed mechanisms (could sequester NFE2L2 in the cytosol and prevent its nuclear localization and activation of ARE-regulated genes)
  • PGAM5, is a novel substrate for KEAP1
  • degrades endogenous antiapoptotic B-cell CLL/lymphoma 2 (BCL2) protein and controls cellular apoptosis
  • KPNA6 directly interacts with the Kelch domain of KEAP1
  • AMER1 and NFE2L2 compete for binding to KEAP1, and thus loss of AMER1 leads to rapid ubiquitination and degradation of NFE2L2 and a reduced response to cytotoxic insult
  • NFE2L2 interacts with KEAP1, in the cytoplasm
  • PALB2 directly interacts with KEAP1, an oxidative stress sensor that binds and represses the master antioxidant transcription factor NFE2L2
  • KEAP1 targets and binds to NFE2L2 for proteosomal degradation
  • under unstressed conditions, serves as an adaptor for ubiquitin E3 ligase and promotes proteasomal degradation of NFE2L2, but NFE2L2 is stabilized when KEAP1 is inactivated under oxidative/electrophilic stress conditions
  • SESN1 and SESN2 interact with the NFE2L2 suppressor KEAP1, the autophagy substrate SQSTM1, and the ubiquitin ligase RBX1 and the antioxidant function of SESNs is mediated through activation of NFE2L2 in a manner reliant on SQSTM1-dependent autophagic degradation of KEAP1
  • AMER1, PALB2, and SQSTM1 bind KEAP1 to activate NFE2L2
  • USP15, specifically deubiquitinates KEAP1, which suppresses the NFE2L2 pathway
  • NTRK2 plays a key role in regulation of the tumor suppressors RUNX3 and KEAP1
  • PSMD10 interact with the Kelch domain of KEAP1 and effectively competed with NFE2L2 for KEAP1 binding
  • PGAM5 might participate in the degradation of BCL2L1 mediated by KEAP1
  • depletion of NFE2L2 or PGAM5, but not KEAP1, inhibits mitochondrial retrograde trafficking induced by proteasome inhibition
  • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral somatic mutation      
    in breast cancer, impairing its ability to repress NFE2L2 activity
    tumoral     --low  
    downregulation in lung cancer produced by hypermethylation of CpG sites
    constitutional germinal mutation      
    in dominant multinodular goiter
    constitutional     --over  
    significant KEAP1 promoter demethylation in diabetic cataractous lenses, and possibly age-related cataracts (ARCs)
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    osteoarticularboneothers
    KEAP1-NFE2L2 axis may be a therapeutic target for the treatment of bone destructive disease
    ANIMAL & CELL MODELS
    Keap-1 deficient mice died postnatally, Nrf2 constitutively accumulates in the nucleus to stimulate transcription of cytoprotective genes
  • phenotype of Keap1 -/- mouse skin is similar to that of autosomal recessive congenital ichtyosis (ARCI) (which is located at the same locus)
  • Keap1-null mutant mice are juvenile-lethal due to hyperkeratosis of the esophagus