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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

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_203500 6 splicing 2606 NP_987096 - 624 - 2002 12145307 NM_012289 6 splicing 2577 NP_036421 - 624 - 2002 12145307 has an alternate 5'UTR as compared to variant 1

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       highly Digestive intestine large intestine colon   lowly   liver       highly   mouth       highly Nervous nerve cranial nerve     highly Respiratory lung       lowly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum skeletal

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
	NIBAN2 induces NFE2L2 by competing for Kelch-like ECH-associated protein 1 (KEAP1) binding (the negative regulator of NFE2L2) via an ETGE motif

cell & other

REGULATION

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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
	System Type Disorder Pubmed osteoarticular bone others 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