EIF2AK3
GeneName
EIF2AK3
Summary
EIF2AK3, also known as PERK or PEK, is a 125 kDa serine/threonine kinase that plays a pivotal role in the endoplasmic reticulum (ER) stress response. It is primarily localised to the endoplasmic reticulum membrane and is involved in the regulation of protein translation during stress conditions, particularly in response to misfolded proteins. EIF2AK3 phosphorylates the eukaryotic translation initiation factor 2 alpha (eIF2α), leading to a reduction in general protein synthesis while selectively enhancing the translation of specific mRNAs that aid in restoring ER homeostasis. This protein is expressed in various tissues, including the pancreas and brain, and is integral to processes such as angiogenesis, cellular responses to nutrient deprivation, and the regulation of gene expression.
Importance
EIF2AK3 is relevant to: - The unfolded protein response, which is crucial for maintaining cellular homeostasis under stress conditions - Diabetes and metabolic disorders due to its role in insulin signalling and pancreatic function - Neurodegenerative diseases, as it mediates stress responses that can affect neuronal survival - Cancer biology, where it influences cell survival and proliferation under stress, impacting tumour growth and response to therapy
Top Products
For researchers investigating EIF2AK3, we recommend two excellent primary antibodies that cater to different needs. The first is the well-cited polyclonal antibody, Anti-PERK antibody (ab65142), which has garnered 77 citations and is highly regarded for its performance in Western blotting (WB) and immunocytochemistry (ICC). This product is a trusted choice for those looking to study EIF2AK3 in various contexts. Additionally, we offer the recombinant monoclonal antibody, Anti-PERK antibody [EPR19876-294] (ab229912), which has been validated in knockout models and is suitable for Western blotting (WB). With 80 citations, this antibody demonstrates its reliability and effectiveness in research. The recombinant nature of this product ensures batch-to-batch consistency, making it an ideal option for researchers seeking dependable results in their studies of EIF2AK3.
Abcam Product Citation Summary
The data indicates that EIF2AK3 is being studied in various human cell types, particularly in the context of viral infections, endoplasmic reticulum stress, and cancer. The use of Abcam antibodies in Western blotting and immunohistochemistry highlights the importance of this target in understanding cellular responses to stress and tumor growth.
Abcam Product Citation Table
Domain
The lumenal domain senses perturbations in protein folding in the ER, probably through reversible interaction with HSPA5/BIP.
The insert loop specifically recongnizes and binds EIF2S1/eIF-2-alpha.
Function
Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to various stress, such as unfolded protein response (UPR) (PubMed:10026192, PubMed:10677345, PubMed:11907036, PubMed:12086964, PubMed:25925385, PubMed:31023583). Key effector of the integrated stress response (ISR) to unfolded proteins: EIF2AK3/PERK specifically recognizes and binds misfolded proteins, leading to its activation and EIF2S1/eIF-2-alpha phosphorylation (PubMed:10677345, PubMed:27917829, PubMed:31023583). EIF2S1/eIF-2-alpha phosphorylation in response to stress converts EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, leading to a global attenuation of cap-dependent translation, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activators ATF4 and QRICH1, and hence allowing ATF4- and QRICH1-mediated reprogramming (PubMed:10026192, PubMed:10677345, PubMed:31023583, PubMed:33384352). The EIF2AK3/PERK-mediated unfolded protein response increases mitochondrial oxidative phosphorylation by promoting ATF4-mediated expression of COX7A2L/SCAF1, thereby increasing formation of respiratory chain supercomplexes (PubMed:31023583). In contrast to most subcellular compartments, mitochondria are protected from the EIF2AK3/PERK-mediated unfolded protein response due to EIF2AK3/PERK inhibition by ATAD3A at mitochondria-endoplasmic reticulum contact sites (PubMed:39116259). In addition to EIF2S1/eIF-2-alpha, also phosphorylates NFE2L2/NRF2 in response to stress, promoting release of NFE2L2/NRF2 from the BCR(KEAP1) complex, leading to nuclear accumulation and activation of NFE2L2/NRF2 (By similarity). Serves as a critical effector of unfolded protein response (UPR)-induced G1 growth arrest due to the loss of cyclin-D1 (CCND1) (By similarity). Involved in control of mitochondrial morphology and function (By similarity).
Involvement in disease
Wolcott-Rallison syndrome
WRS
A rare autosomal recessive disorder, characterized by permanent neonatal or early infancy insulin-dependent diabetes and, at a later age, epiphyseal dysplasia, osteoporosis, growth retardation and other multisystem manifestations, such as hepatic and renal dysfunctions, intellectual disability and cardiovascular abnormalities.
None
The disease is caused by variants affecting the gene represented in this entry.
Post-translational modifications
Oligomerization of the N-terminal ER luminal domain by ER stress promotes EIF2AK3/PERK trans-autophosphorylation of the C-terminal cytoplasmic kinase domain at multiple residues including Thr-982 on the kinase activation loop (By similarity). Autophosphorylated at Tyr-619 following endoplasmic reticulum stress, leading to activate its activity (PubMed:22169477). Dephosphorylated at Tyr-619 by PTPN1/PTP1B, leading to inactivate its enzyme activity (PubMed:22169477). Phosphorylation at Thr-802 by AKT (AKT1, AKT2 and/or AKT3) inactivates EIF2AK3/PERK (By similarity).
ADP-ribosylated by PARP16 upon ER stress, which increases kinase activity.
Sequence Similarities
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. GCN2 subfamily.
Tissue Specificity
Ubiquitous. A high level expression is seen in secretory tissues.
Cellular localization
- Endoplasmic reticulum membrane
- Single-pass type I membrane protein
- Localizes to the Localizes to endoplasmic reticulum membrane (By similarity). Also present at mitochondria-endoplasmic reticulum contact sites; where it interacts with ATAD3A (PubMed:39116259).
Alternative names
PEK, PERK, EIF2AK3, Eukaryotic translation initiation factor 2-alpha kinase 3, PRKR-like endoplasmic reticulum kinase, Pancreatic eIF2-alpha kinase, Protein tyrosine kinase EIF2AK3, HsPEK
Database links
swissprot:Q9NZJ5 omim:604032 entrezGene:9451
Other research areas
- Immuno-oncology