Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
Chemistry
Ligand Efficiency Plot
Pathways
Family Cladogram
Interaction Network
Gene Expression
Gene Copy Number Variation
RNAi
Mutations
Germline Genetics

EIF2AK4 (Q9P2K8) - Overview - Molecular Target Synopsis

Protein


EIF2AK4, eIF-2-alpha kinase GCN2
Enzyme Classification 2.7.11.1
UniProt Q9P2K8

Also Known as E2AK4_HUMAN, EIF2AK4, GCN2, KIAA1338

Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (eIF-2-alpha/EIF2S1) on 'Ser-52' in response to low amino acid availability (PubMed:25329545). Plays a role as an activator of the integrated stress response (ISR) required for adapatation to amino acid starvation. Converts phosphorylated eIF-2-alpha/EIF2S1 either to a competitive inhibitor of the translation initiation factor eIF-2B, leading to a global protein synthesis repression, and thus to a reduced overall utilization of amino acids, or to a translational initiation activation of specific mRNAs, such as the transcriptional activator ATF4, and hence allowing ATF4-mediated reprogramming of amino acid biosynthetic gene expression to alleviate nutrient depletion. Binds uncharged tRNAs (By similarity). Involved in cell cycle arrest by promoting cyclin D1 mRNA translation repression after the unfolded protein response pathway (UPR) activation or cell cycle inhibitor CDKN1A/p21 mRNA translation activation in response to amino acid deprivation (PubMed:26102367). Plays a role in the consolidation of synaptic plasticity, learning as well as formation of long-term memory. Plays a role in neurite outgrowth inhibition. Plays a proapoptotic role in response to glucose deprivation. Promotes global cellular protein synthesis repression in response to UV irradiation independently of the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 MAPK signaling pathways (By similarity). Plays a role in the antiviral response against alphavirus infection; impairs early viral mRNA translation of the incoming genomic virus RNA, thus preventing alphavirus replication., (Microbial infection) Plays a role in modulating the adaptive immune response to yellow fever virus infection; promotes dendritic cells to initiate autophagy and antigene presentation to both CD4(+) and CD8(+) T-cells under amino acid starvation (PubMed:24310610). Homodimer; homodimerization is important for kinase activation by uncharged tRNAs. Interacts with GCN1; this interaction stimulates EIF2AK4/GCN2 kinase activity and is impaired by IMPACT upon a variety of stress conditions, such as amino acid depletion, UV-C irradiation, proteasome inhibitor treatment and glucose deprivation. Interacts with DNAJC3; this interaction inhibits EIF2AK4/GCN2 kinase activity during endoplasmic reticulum (ER), hypothermic and amino acid-starving stress conditions.

Isoforms / Transcripts (Protein Coding)


Sub-cellular localization


UniProt: EIF2AK4 is active in the following subcellular-locations: cytoplasm.
GO terms: EIF2AK4 is active in the following subcellular-locations: cytosolic ribosome, polysome.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project EIF2AK4 has gain in 0 cell-lines, loss in 1 cell-lines and no signal in 1003 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: MDA_MB_231, UACC_62, SK_MEL_2

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: COV434, COLO-818, LN-229

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: NHLF, HSMM, HMEC

(see details)

RNA Interference


EIF2AK4 was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: CROE33, BT20. (see details)

3D Structures


At greater than 90% identity similarity to EIF2AK4 there are:
1 structures (2 chains) solved
0 are solved in complex with at least one small molecule ligand



(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


EIF2AK4 has been screened with 144 compounds (181 bioactivities), 32 compounds have bioactivities that show binding affinity of <= 500nM (42 bioactivities). (see details)