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Symbol EIF2AK3 contributors: mct/npt - updated : 13-04-2017
HGNC name eukaryotic translation initiation factor 2-alpha kinase 3
HGNC id 3255
  • 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
  • protein kinase superfamily
  • Ser/Thr protein kinase family
  • GCN2 subfamily
  • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION     plasma 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 function is essential for adult pancreatic homeostasis
  • is a key regulator of protein translation, particularly at points where the functional capacity of the secretory apparatus of cells is overwhelmed by protein influx
  • 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
  • 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
    small molecule
  • 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
    activated by at physiologically low glucose concentrations in pancreatic beta-cells
    Phosphorylated by PTPN1 deficiency that modulates EIF2AK3 phosphorylation and protein synthesis
    corresponding disease(s) WRS
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional       loss of function
    regulates beta-cell homeostasis in a cell-autonomous manner
    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
    Therapy target
    EIF2AK3 pathway is a potential target for therapeutic applications in neurodegenerative diseases including AD
  • EIF2AK3 null mice (Yamaguchi, 2008)
  • deletion of Perk in either young adult or mature adult mice resulted in hyperglycemia associated with loss of islet and &
  • 946; cell architecture