Phospho-EIF2AK3 (Thr980)

The protein encoded by this gene phosphorylates the alpha subunit of eukaryotic translation-initiation factor 2, leading to its inactivation, and thus to a rapid reduction of translational initiation and repression of global protein synthesis. This protein is thought to modulate mitochondrial function. It is a type I membrane protein located in the endoplasmic reticulum (ER), where it is induced by ER stress caused by malfolded proteins. Mutations in this gene are associated with Wolcott-Rallison syndrome. [provided by RefSeq, Sep 2015]

Full Name

Eukaryotic Translation Initiation Factor 2 Alpha Kinase 3

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 conditions. Key activator of the integrated stress response (ISR) required for adaptation to various stress, such as unfolded protein response (UPR) and low amino acid availability (By similarity).

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:33384352).

Serves as a critical effector of unfolded protein response (UPR)-induced G1 growth arrest due to the loss of cyclin-D1 (CCND1). Involved in control of mitochondrial morphology and function (By similarity).

Biological Process

Activation of cysteine-type endopeptidase activity involved in apoptotic process Source: UniProtKB
Angiogenesis Source: ParkinsonsUK-UCL
Bone mineralization Source: UniProtKB
Calcium-mediated signaling Source: UniProtKB
Cellular response to amino acid starvation Source: UniProtKB
Cellular response to cold Source: UniProtKB
Cellular response to glucose starvation Source: ParkinsonsUK-UCL
Chondrocyte development Source: UniProtKB
EiF2alpha phosphorylation in response to endoplasmic reticulum stress Source: UniProtKB
Endocrine pancreas development Source: UniProtKB
Endoplasmic reticulum organization Source: UniProtKB
Endoplasmic reticulum unfolded protein response Source: UniProtKB
ER overload response Source: UniProtKB
Insulin-like growth factor receptor signaling pathway Source: UniProtKB
Negative regulation of myelination Source: UniProtKB
Negative regulation of translation Source: UniProtKB
Negative regulation of translational initiation in response to stress Source: UniProtKB
Ossification Source: UniProtKB
Peptidyl-serine phosphorylation Source: ParkinsonsUK-UCL
PERK-mediated unfolded protein response Source: ParkinsonsUK-UCL
Positive regulation of gene expression Source: ParkinsonsUK-UCL
Positive regulation of protein localization to nucleus Source: ParkinsonsUK-UCL
Positive regulation of transcription by RNA polymerase I Source: ParkinsonsUK-UCL
Positive regulation of vascular endothelial growth factor production Source: ParkinsonsUK-UCL
Protein autophosphorylation Source: UniProtKB
Protein phosphorylation Source: UniProtKB
Regulation of endoplasmic reticulum stress-induced eIF2 alpha phosphorylation Source: UniProtKB
Regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway Source: ParkinsonsUK-UCL
Regulation of translational initiation by eIF2 alpha phosphorylation Source: ParkinsonsUK-UCL
Response to endoplasmic reticulum stress Source: BHF-UCL
Response to manganese-induced endoplasmic reticulum stress Source: Ensembl
Skeletal system development Source: UniProtKB

Cellular Location

Endoplasmic reticulum membrane

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, mental retardation and cardiovascular abnormalities.

Topology

Lumenal: 30-514
Helical: 515-535
Cytoplasmic: 536-1116

PTM

Oligomerization of the N-terminal ER luminal domain by ER stress promotes PERK trans-autophosphorylation of the C-terminal cytoplasmic kinase domain at multiple residues including Thr-982 on the kinase activation loop (By similarity). Autophosphorylated. Phosphorylated at Tyr-619 following endoplasmic reticulum stress, leading to activate its tyrosine-protein kinase activity. Dephosphorylated by PTPN1/TP1B, leading to inactivate its enzyme activity.
N-glycosylated.
ADP-ribosylated by PARP16 upon ER stress, which increases kinase activity.