Mouse anti-Human sapiens (Human) EIF2AK3 Monoclonal Antibody

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)

Subcellular Location

Endoplasmic reticulum membrane (Single-pass type I membrane protein)

Disease Association

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. [The disease is caused by variants affecting the gene represented in this entry]

Tissue Specificity

Ubiquitous. A high level expression is seen in secretory tissues

Subunit

Forms dimers with HSPA5/BIP in resting cells (PubMed:11907036). Homotetramerizes in response to endoplasmic reticulum (ER) stress, leading to its activation (PubMed:25925385). Interacts with HSP90B1/GRP94 (PubMed:11907036). Interacts with DNAJC3; inhibiting EIF2AK3/PERK activity (By similarity). Interacts with ATAD3A; ATAD3A and EIF2S1/eIF-2-alpha occupy a common binding site within the cytoplasmic loop of EIF2AK3/PERK, leading to prevent EIF2AK3/PERK association with its substrate EIF2S1/eIF-2-alpha (PubMed:39116259). Interacts with MFN2 (By similarity). Interacts with TMEM33 (PubMed:26268696). Interacts with PDIA6 (PubMed:24508390). Interacts with LACC1 (PubMed:31875558)

• Shi Y. et al. Characterization of a mutant pancreatic eIF-2alpha kinase, PEK, and co-localization with somatostatin in islet delta cells. — J. Biol. Chem. (1999)
• Sood R. et al. Pancreatic eukaryotic initiation factor-2alpha kinase (PEK) homologues in humans, Drosophila melanogaster and Caenorhabditis elegans that mediate translational control in response to endoplasmic reticulum stress. — Biochem. J. (2000)
• Delepine M. et al. EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. — Nat. Genet. (2000)
• Ota T. et al. Complete sequencing and characterization of 21,243 full-length human cDNAs. — Nat. Genet. (2004)
• Hillier L.W. et al. Generation and annotation of the DNA sequences of human chromosomes 2 and 4. — Nature (2005)
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). — Genome Res. (2004)
• Ma K. et al. Dimerization and release of molecular chaperone inhibition facilitate activation of eukaryotic initiation factor-2 kinase in response to endoplasmic reticulum stress. — J. Biol. Chem. (2002)
• Brickwood S. et al. Wolcott-Rallison syndrome: pathogenic insights into neonatal diabetes from new mutation and expression studies of EIF2AK3. — J. Med. Genet. (2003)