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FLASH GENE
Symbol EIF2AK3 contributors: mct/npt - updated : 13-04-2017
HGNC name eukaryotic translation initiation factor 2-alpha kinase 3
HGNC id 3255
Corresponding disease
WRS Wolcott-Rallison syndrome
Location 2p11.2      Physical location : 88.856.260 - 88.927.094
Synonym name
  • pancreatic EIF2-alpha kinase
  • PRKR-like endoplasmic reticulum kinase
  • Protein kinase R-like ER kinase
  • pancreatic endoplasmic reticulum kinase
  • PKR-like ER-localized eIF2A kinase
  • Synonym symbol(s) PEK, PERK, WXRS, DKFZp781H1925, HRI, WRS
    EC.number 2.7.11.1
    DNA
    TYPE functioning gene
    STRUCTURE 70.84 kb     17 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked   status provisional
    Physical map
    SMYD1 2p11.1 SET and MYND domain containing 1 FABP1 2p12-p11.2 fatty acid binding protein 1, liver FLJ10916 2p11.2 hypothetical protein FLJ10916 MRPL45P1 2p11.2 hypothetical protein FLJ10916 LOC344167 2p11.2 similar to FoxI1c protein FLJ25369 2p11.2 hypothetical protein FLJ25369 EIF2AK3 2p12 eukaryotic translation initiation factor 2-alpha kinase 3 RPIA 2p11.1 ribose 5-phosphate isomerase A (ribose 5-phosphate epimerase) LOC388976 2 similar to protein that is immuno-reactive with anti-PTH polyclonal antibodies IGKC 2p12 immunoglobulin kappa constant IGKJ5 2p11.2 immunoglobulin kappa joining 5 IGKJ4 2p11.2 immunoglobulin kappa joining 4 IGKJ3 2p11.2 immunoglobulin kappa joining 3 IGKJ2 2p11.2 immunoglobulin kappa joining 2 IGKJ1 2p11.2 immunoglobulin kappa joining 1 IGKV4-1 2p11.2 immunoglobulin kappa variable 4-1 IGKV5-2 2p11.2 immunoglobulin kappa variable 5-2 IGKV7-3 2p11.2 immunoglobulin kappa variable 7-3 IGKV2-4 2p11.2 immunoglobulin kappa variable 2-4 IGKV1-5 2p11.2 immunoglobulin kappa variable 1-5
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    17 - 4665 - 1116 - 1999 10026192
    17 - 4233 - 965 - 1999 10026192
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveliver   highly
    Endocrinepancreas   moderately
    Lymphoid/Immunelymph node   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialsecretoryglandularendocrine 
    Epithelialsecretoryglandularexocrine 
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Endocrineislet cell (alpha,beta...)
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period pregnancy
    Text placenta
    PROTEIN
    PHYSICAL PROPERTIES Hydrophobic
    STRUCTURE
    motifs/domains
  • N terminal signal peptide
  • a luminal ER stress-sensing N-terminal domain
  • the catalytic domain
  • a large C-terminal cytoplasmic kinase domain
  • a hydrophobic region
  • HOMOLOGY
    Homologene
    FAMILY
  • protein kinase superfamily
  • Ser/Thr protein kinase family
  • GCN2 subfamily
  • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    text colocalizing with somatostatin in pancreas islet delta-cells
    basic FUNCTION
  • eukaryotic translation initiation factor, putatively involved in regulating protein synthesis in the pancreatic islets (delta cells)
  • essential for force-induced apoptosis and it may play a role in integrating force-related signals with other extracellular stimuli
  • may play an universal role in cell and tissue homeostasis
  • involved in controlling cell growth
  • activation of the PI3K-Akt pathway by ER stress is dependent on EIF2AK3, suggesting additional ways in which EIF2AK3 activity protects cells from ER stress-induced apoptosis
  • both EIF2AK3 and EIF2AK4 mediate the cell adaptation to hypoxic stress
  • positive regulator of ERAD (ER-associated degradation) and proteasomal activity
  • acts potentially as a metabolic sensor in the insulin-secreting beta-cells to modulate the trafficking and quality control of proinsulin in the ER relative to the physiological demands for circulating insulin
  • EIF2AK3, and EIF2AK4 also have a functional role on regulating translation under non-stressed conditions, apart from their long established roles as stress kinases
  • facilitates survival of ECM-detached cells by concomitantly promoting autophagy, ATP production, and an antioxidant response
  • functions as an endoplasmic reticulum (ER) stress sensor to regulate global protein synthesis
  • is necessary for AKT1 activation in response to ER stress
  • EIF2AK3-EIF2S1 signaling, which is required to maintain ER homeostasis, is also indispensable for EMT cells to invade and metastasize
  • role in endoplasmic reticulum stress-decided cell fate
  • critical role for EIF2AK3 in regulating pancreatic beta cell function
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
  • the EIF2AK3 pathway facilitates both the synthesis of ATF6 and trafficking of ATF6 from the ER to the Golgi for intramembrane proteolysis and activation of ATF6
  • EIF2AK3-dependent signaling is used during both tumor initiation and expansion to maintain redox homeostasis, thereby facilitating tumor growth
  • a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • physical interaction with ERP29 and moreover, overexpression of ERP29 enhanced endogenous levels of EIF2AK3
  • PPP3CA and PPP3CB binding to EIF2AK3 enhances inhibition of protein translation to allow the cell time to recover
  • HSPA5, in contrast to its mode of binding ATF6 and unfolded proteins, binds to ERN1 and EIF2AK3 in a different manner
  • utilizes intrinsic lipid kinase activity to generate phosphatidic acid, mediate AKT1 activation, and promote adipocyte differentiation
  • induction of DDIT4 gene expression was shown to require the protein kinase EIF2AK3 and enhanced phosphorylation of its substrate EIF2S1
  • suspension-activated EIF2AK3 promotes the activation of STK11, AMPK and TSC2, leading to the rapid induction of detachment-induced autophagy
  • PARP16 is a tail-anchored ER transmembrane protein required for activation of the functionally related ER stress sensors EIF2AK3 and ERN1
  • PARM1 may regulate EIF2AK3, ATF6, and DDIT3 expression through BMP2 expression
  • ERN1, ATF6, and EIF2AK3 signaling pathways, collectively called the unfolded protein response (UPR), regulate the functions of endoplasmic reticulum, responsible for accurate folding of membrane proteins such as RHO
  • TBL2 interacts with PKR-like ER-resident kinase (EIF2AK3), and under ER stress, it mediates protein expression of activating transcription factor 4 (ATF4)
  • depletion of CREB1 decreased the expression of ERN1 and EIF2AK3, two critical UPR signaling molecules, and CREB1 binds to the promoter region of these genes and regulates their expression
  • role of EIF2AK3 in neurons, which is EIF2A-independent
  • ELANE induces endothelial cell apoptosis by activating the EIF2AK3/DDIT3 branch of the unfolded protein response
  • cell & other
    REGULATION
    activated by at physiologically low glucose concentrations in pancreatic beta-cells
    Phosphorylated by PTPN1 deficiency that modulates EIF2AK3 phosphorylation and protein synthesis
    ASSOCIATED DISORDERS
    corresponding disease(s) WRS
    Susceptibility to lower bone mineral density
    Variant & Polymorphism SNP
  • common nonsynonymous sequence variants in EIF2AK3 have a modest effect on ER stress response and may contribute to the risk for low BMD through this mechanism
  • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    neurologyneurodegenerativealzheimer
    EIF2AK3 pathway is a potential target for therapeutic applications in neurodegenerative diseases including AD
    ANIMAL & CELL MODELS
  • EIF2AK3 null mice (Yamaguchi, 2008)