EIF2AK2

The protein encoded by this gene is a serine/threonine protein kinase that is activated by autophosphorylation after binding to dsRNA. The activated form of the encoded protein can phosphorylate translation initiation factor EIF2S1, which in turn inhibits protein synthesis. This protein is also activated by manganese ions and heparin. Three transcript variants encoding two different isoforms have been found for this gene.

eukaryotic translation initiation factor 2 alpha kinase 2

IFN-induced dsRNA-dependent serine/threonine-protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) and plays a key role in the innate immune response to viral infection (PubMed:18835251, PubMed:19507191, PubMed:19189853, PubMed:21123651, PubMed:21072047, PubMed:22948139, PubMed:23229543, PubMed:22381929).

Inhibits viral replication via the integrated stress response (ISR): EIF2S1/eIF-2-alpha phosphorylation in response to viral infection converts EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, resulting to a shutdown of cellular and viral protein synthesis, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activator ATF4 (PubMed:19189853, PubMed:21123651, PubMed:22948139, PubMed:23229543).

Exerts its antiviral activity on a wide range of DNA and RNA viruses including hepatitis C virus (HCV), hepatitis B virus (HBV), measles virus (MV) and herpes simplex virus 1 (HHV-1) (PubMed:11836380, PubMed:19189853, PubMed:20171114, PubMed:19840259, PubMed:21710204, PubMed:23115276, PubMed:23399035).

Also involved in the regulation of signal transduction, apoptosis, cell proliferation and differentiation: phosphorylates other substrates including p53/TP53, PPP2R5A, DHX9, ILF3, IRS1 and the HHV-1 viral protein US11 (PubMed:11836380, PubMed:22214662, PubMed:19229320).

In addition to serine/threonine-protein kinase activity, also has tyrosine-protein kinase activity and phosphorylates CDK1 at 'Tyr-4' upon DNA damage, facilitating its ubiquitination and proteosomal degradation (PubMed:20395957).

Either as an adapter protein and/or via its kinase activity, can regulate various signaling pathways (p38 MAP kinase, NF-kappa-B and insulin signaling pathways) and transcription factors (JUN, STAT1, STAT3, IRF1, ATF3) involved in the expression of genes encoding proinflammatory cytokines and IFNs (PubMed:22948139, PubMed:23084476, PubMed:23372823).

Activates the NF-kappa-B pathway via interaction with IKBKB and TRAF family of proteins and activates the p38 MAP kinase pathway via interaction with MAP2K6 (PubMed:10848580, PubMed:15121867, PubMed:15229216).

Can act as both a positive and negative regulator of the insulin signaling pathway (ISP) (PubMed:20685959).

Negatively regulates ISP by inducing the inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) at 'Ser-312' and positively regulates ISP via phosphorylation of PPP2R5A which activates FOXO1, which in turn up-regulates the expression of insulin receptor substrate 2 (IRS2) (PubMed:20685959).

Can regulate NLRP3 inflammasome assembly and the activation of NLRP3, NLRP1, AIM2 and NLRC4 inflammasomes (PubMed:22801494).

Plays a role in the regulation of the cytoskeleton by binding to gelsolin (GSN), sequestering the protein in an inactive conformation away from actin (By similarity).

Activation of MAPKK activity Source: UniProtKB
Cellular response to amino acid starvation Source: UniProtKB
Defense response to virus Source: ARUK-UCL
Endoplasmic reticulum unfolded protein response Source: Ensembl
Innate immune response Source: UniProtKB-KW
Negative regulation of apoptotic process Source: Ensembl
Negative regulation of cell population proliferation Source: ProtInc
Negative regulation of osteoblast proliferation Source: UniProtKB
Negative regulation of translation Source: UniProtKB
Negative regulation of viral genome replication Source: UniProtKB
Positive regulation of chemokine production Source: UniProtKB
Positive regulation of cytokine production Source: UniProtKB
Positive regulation of NF-kappaB transcription factor activity Source: UniProtKB
Positive regulation of NIK/NF-kappaB signaling Source: UniProtKB
Positive regulation of stress-activated MAPK cascade Source: UniProtKB
Protein autophosphorylation Source: UniProtKB
Protein phosphorylation Source: UniProtKB
Regulation of hematopoietic progenitor cell differentiation Source: UniProtKB
Regulation of hematopoietic stem cell differentiation Source: UniProtKB
Regulation of hematopoietic stem cell proliferation Source: UniProtKB
Regulation of NLRP3 inflammasome complex assembly Source: UniProtKB
Response to interferon-alpha Source: UniProtKB
Response to virus Source: UniProtKB
Translation Source: Ensembl

Nucleus; Cytoplasm; Perinuclear region. Nuclear localization is elevated in acute leukemia, myelodysplastic syndrome (MDS), melanoma, breast, colon, prostate and lung cancer patient samples or cell lines as well as neurocytes from advanced Creutzfeldt-Jakob disease patients.

Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome (LEUDEN):
An autosomal dominant disorder characterized by global developmental delay apparent in early childhood, cognitive impairment, ataxia, poor or absent speech with dysarthria, hypotonia, hypertonia, extrapyramidal signs, tremor, and abnormal involuntary movements. Affected individuals also exhibit neurological regression in the setting of febrile illness or infection. Many patients have seizures. Brain imaging shows diffuse white matter abnormalities with poor myelination.

Autophosphorylated on several Ser, Thr and Tyr residues. Autophosphorylation of Thr-451 is dependent on Thr-446 and is stimulated by dsRNA binding and dimerization. Autophosphorylation apparently leads to the activation of the kinase. Tyrosine autophosphorylation is essential for efficient dsRNA-binding, dimerization, and kinase activation.