TISIDB

Summary
Symbol	EIF2AK4
Name	eukaryotic translation initiation factor 2 alpha kinase 4
Aliases	GCN2; KIAA1338; PVOD2; GCN2 eIF2alpha kinase; GCN2-like protein; general control nonderepressible 2; Eukaryo ......
Chromosomal Location	15q13.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Basic function annotation. > Subcellular Location, Domain and Function > Gene Ontology > KEGG and Reactome Pathway

> Subcellular Location, Domain and Function [ TOP ]
Subcellular Location	Cytoplasm
Domain	PF12745 Anticodon binding domain of tRNAs PF00069 Protein kinase domain PF05773 RWD domain
Function	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 (By similarity). ; FUNCTION: (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).

> Gene Ontology [ TOP ]
Biological Process	GO:0002230 positive regulation of defense response to virus by host GO:0002250 adaptive immune response GO:0002263 cell activation involved in immune response GO:0002285 lymphocyte activation involved in immune response GO:0002286 T cell activation involved in immune response GO:0002366 leukocyte activation involved in immune response GO:0002697 regulation of immune effector process GO:0002819 regulation of adaptive immune response GO:0002821 positive regulation of adaptive immune response GO:0002831 regulation of response to biotic stimulus GO:0006413 translational initiation GO:0006417 regulation of translation GO:0006446 regulation of translational initiation GO:0006914 autophagy GO:0007050 cell cycle arrest GO:0007159 leukocyte cell-cell adhesion GO:0007611 learning or memory GO:0007612 learning GO:0007613 memory GO:0007616 long-term memory GO:0007631 feeding behavior GO:0009266 response to temperature stimulus GO:0009267 cellular response to starvation GO:0009314 response to radiation GO:0009409 response to cold GO:0009411 response to UV GO:0009416 response to light stimulus GO:0009615 response to virus GO:0009991 response to extracellular stimulus GO:0010506 regulation of autophagy GO:0010508 positive regulation of autophagy GO:0010608 posttranscriptional regulation of gene expression GO:0010721 negative regulation of cell development GO:0010998 regulation of translational initiation by eIF2 alpha phosphorylation GO:0016049 cell growth GO:0017148 negative regulation of translation GO:0019048 modulation by virus of host morphology or physiology GO:0019054 modulation by virus of host process GO:0019058 viral life cycle GO:0019079 viral genome replication GO:0019080 viral gene expression GO:0019081 viral translation GO:0031667 response to nutrient levels GO:0031668 cellular response to extracellular stimulus GO:0031669 cellular response to nutrient levels GO:0032055 negative regulation of translation in response to stress GO:0032056 positive regulation of translation in response to stress GO:0032057 negative regulation of translational initiation in response to stress GO:0032058 positive regulation of translational initiation in response to stress GO:0032792 negative regulation of CREB transcription factor activity GO:0034198 cellular response to amino acid starvation GO:0034248 regulation of cellular amide metabolic process GO:0034249 negative regulation of cellular amide metabolic process GO:0034250 positive regulation of cellular amide metabolic process GO:0034644 cellular response to UV GO:0034976 response to endoplasmic reticulum stress GO:0035821 modification of morphology or physiology of other organism GO:0036490 regulation of translation in response to endoplasmic reticulum stress GO:0036491 regulation of translation initiation in response to endoplasmic reticulum stress GO:0036492 eiF2alpha phosphorylation in response to endoplasmic reticulum stress GO:0039519 modulation by virus of host autophagy GO:0039520 induction by virus of host autophagy GO:0042110 T cell activation GO:0042594 response to starvation GO:0043433 negative regulation of sequence-specific DNA binding transcription factor activity GO:0043555 regulation of translation in response to stress GO:0043558 regulation of translational initiation in response to stress GO:0043900 regulation of multi-organism process GO:0043901 negative regulation of multi-organism process GO:0043903 regulation of symbiosis, encompassing mutualism through parasitism GO:0044003 modification by symbiont of host morphology or physiology GO:0044033 multi-organism metabolic process GO:0044068 modulation by symbiont of host cellular process GO:0044708 single-organism behavior GO:0044788 modulation by host of viral process GO:0044793 negative regulation by host of viral process GO:0044827 modulation by host of viral genome replication GO:0044828 negative regulation by host of viral genome replication GO:0045069 regulation of viral genome replication GO:0045071 negative regulation of viral genome replication GO:0045665 negative regulation of neuron differentiation GO:0045727 positive regulation of translation GO:0045786 negative regulation of cell cycle GO:0045947 negative regulation of translational initiation GO:0045948 positive regulation of translational initiation GO:0046777 protein autophosphorylation GO:0048167 regulation of synaptic plasticity GO:0048525 negative regulation of viral process GO:0048588 developmental cell growth GO:0050688 regulation of defense response to virus GO:0050691 regulation of defense response to virus by host GO:0050768 negative regulation of neurogenesis GO:0050792 regulation of viral process GO:0050795 regulation of behavior GO:0050804 modulation of synaptic transmission GO:0050806 positive regulation of synaptic transmission GO:0050890 cognition GO:0051090 regulation of sequence-specific DNA binding transcription factor activity GO:0051607 defense response to virus GO:0051701 interaction with host GO:0051702 interaction with symbiont GO:0051817 modification of morphology or physiology of other organism involved in symbiotic interaction GO:0051851 modification by host of symbiont morphology or physiology GO:0051961 negative regulation of nervous system development GO:0060259 regulation of feeding behavior GO:0060291 long-term synaptic potentiation GO:0060560 developmental growth involved in morphogenesis GO:0060733 regulation of eIF2 alpha phosphorylation by amino acid starvation GO:0070417 cellular response to cold GO:0070486 leukocyte aggregation GO:0070489 T cell aggregation GO:0071214 cellular response to abiotic stimulus GO:0071262 regulation of translational initiation in response to starvation GO:0071264 positive regulation of translational initiation in response to starvation GO:0071478 cellular response to radiation GO:0071482 cellular response to light stimulus GO:0071496 cellular response to external stimulus GO:0071593 lymphocyte aggregation GO:0098542 defense response to other organism GO:1900271 regulation of long-term synaptic potentiation GO:1900273 positive regulation of long-term synaptic potentiation GO:1903900 regulation of viral life cycle GO:1903901 negative regulation of viral life cycle GO:1990138 neuron projection extension GO:1990253 cellular response to leucine starvation
Molecular Function	GO:0000049 tRNA binding GO:0004674 protein serine/threonine kinase activity GO:0004694 eukaryotic translation initiation factor 2alpha kinase activity
Cellular Component	GO:0005840 ribosome GO:0005844 polysome GO:0022626 cytosolic ribosome GO:0044445 cytosolic part

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa04140 Regulation of autophagy hsa04141 Protein processing in endoplasmic reticulum
Reactome	-

Summary
Symbol	EIF2AK4
Name	eukaryotic translation initiation factor 2 alpha kinase 4
Aliases	GCN2; KIAA1338; PVOD2; GCN2 eIF2alpha kinase; GCN2-like protein; general control nonderepressible 2; Eukaryo ......
Chromosomal Location	15q13.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between EIF2AK4 and anti-tumor immunity. The specific mechanism were also collected if the literature reports that a gene specifically promotes or inhibits the infiltration or function of T/NK cells.

> Text Mining [ TOP ]
There is no record.

Summary
Symbol	EIF2AK4
Name	eukaryotic translation initiation factor 2 alpha kinase 4
Aliases	GCN2; KIAA1338; PVOD2; GCN2 eIF2alpha kinase; GCN2-like protein; general control nonderepressible 2; Eukaryo ......
Chromosomal Location	15q13.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	High-throughput screening data (e.g. CRISPR-Cas9, shRNA and RNAi) for T cell-mediated killing. Genetic screen techniques can identify mechanisms of tumor cell resistance (e.g., PTPN2) and sensitivity (e.g., APLNR) to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. After comprehensively searching, eight groups of screening data sets were collected in the current database. In this tab, users can check whether their selected genes cause resistance or increase sensitivity to T cell-mediated killing in various data sets.

> High-throughput Screening

[ TOP ]

Statistical results of EIF2AK4 in screening data sets for detecting immune reponses.

PMID	Screening System	Cancer Type	Cell Line	Data Set	Statistical Results	Relation to immunity
29301958	CRISPR-Cas9	melanoma	B16F10	Pmel-1 T cell	logFC: -2.75; FDR: 0.01020	Resistant to T cell-mediated killing
29301958	CRISPR-Cas9	melanoma	B16F10	OT-1 T cell	NA/NS	NA/NS
28783722	CRISPR-Cas9	melanoma	Mel624	2CT-CRISPR	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX+Anti-PD1	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX	NA/NS	NA/NS
25691366	RNAi	Breast cancer	MCF7	Luc-CTL assay	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Primary screen	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Secondary screen	NA/NS	NA/NS

Summary
Symbol	EIF2AK4
Name	eukaryotic translation initiation factor 2 alpha kinase 4
Aliases	GCN2; KIAA1338; PVOD2; GCN2 eIF2alpha kinase; GCN2-like protein; general control nonderepressible 2; Eukaryo ......
Chromosomal Location	15q13.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Transcriptomic and genomic profiling of pre-treated tumor biopsies from responders and non-responders to immunotherapy. These data were used to identify signatures and mechanisms of response to checkpoint blockade (e.g., anti-PDL1 and anti-PD1). One example is that mutations in the gene PBRM1 benefit clinical survival of patients with clear cell renal cell carcinoma. After comprehensively searching, we collected 5 and 6 of transcriptomic and genomic data sets, respectively. In this tab, users can check whether their selected genes have significant difference of expression or mutation between responders and non-responders in various data sets. > Expression difference between responders and non-responders > Mutation difference between responders and non-responders

> Expression difference between responders and non-responders

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Points in the above scatter plot represent the expression difference of EIF2AK4 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	Log2 (Fold Change)	P value
1	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	14	12	0.235	0.439
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	1.01	0.572
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	-0.332	0.803
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	-0.227	0.323
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	-0.352	0.882
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	-0.068	0.982
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0.078	0.845
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	-0.08	0.965
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	0.301	0.877
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	0.784	0.558
11	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	2	0	0	1
12	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	2	8	1.169	0.575
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	-0.027	0.624

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of EIF2AK4 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/Res	% Mut/NRes	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	7.1	0	7.1	0.452
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	10	0	10	1
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	0	0	0	1
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	3.7	5.5	-1.8	1
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	3.7	6.8	-3.1	1
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	9.5	0	9.5	0.492
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	0	0	0	1
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	15.4	0	15.4	0.482
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0	0	0	1
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0	0	0	1
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0	0	0	1
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	2.6	0	2.6	1
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	4.5	0	4.5	1
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	0	0	0	1
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	0	0	0	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	0	0	0	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	0	0	1

Summary
Symbol	EIF2AK4
Name	eukaryotic translation initiation factor 2 alpha kinase 4
Aliases	GCN2; KIAA1338; PVOD2; GCN2 eIF2alpha kinase; GCN2-like protein; general control nonderepressible 2; Eukaryo ......
Chromosomal Location	15q13.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of EIF2AK4. The immune-related signatures of 28 TIL types from Charoentong's study, which can be viewed in the download page. For each cancer type, the relative abundance of TILs were inferred by using gene set variation analysis (GSVA) based on gene expression profile. In this tab, users can examine which kinds of TILs might be regulated by the current gene.

> Lymphocyte [ TOP ]

Summary
Symbol	EIF2AK4
Name	eukaryotic translation initiation factor 2 alpha kinase 4
Aliases	GCN2; KIAA1338; PVOD2; GCN2 eIF2alpha kinase; GCN2-like protein; general control nonderepressible 2; Eukaryo ......
Chromosomal Location	15q13.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of EIF2AK4. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by EIF2AK4. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	EIF2AK4
Name	eukaryotic translation initiation factor 2 alpha kinase 4
Aliases	GCN2; KIAA1338; PVOD2; GCN2 eIF2alpha kinase; GCN2-like protein; general control nonderepressible 2; Eukaryo ......
Chromosomal Location	15q13.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of EIF2AK4. In this tab, users can examine which chemokines (or receptors) might be regulated by the current gene. > Chemokine > Receptor

> Chemokine [ TOP ]

> Receptor [ TOP ]

Summary
Symbol	EIF2AK4
Name	eukaryotic translation initiation factor 2 alpha kinase 4
Aliases	GCN2; KIAA1338; PVOD2; GCN2 eIF2alpha kinase; GCN2-like protein; general control nonderepressible 2; Eukaryo ......
Chromosomal Location	15q13.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of EIF2AK4 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	EIF2AK4
Name	eukaryotic translation initiation factor 2 alpha kinase 4
Aliases	GCN2; KIAA1338; PVOD2; GCN2 eIF2alpha kinase; GCN2-like protein; general control nonderepressible 2; Eukaryo ......
Chromosomal Location	15q13.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between EIF2AK4 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	EIF2AK4
Name	eukaryotic translation initiation factor 2 alpha kinase 4
Aliases	GCN2; KIAA1338; PVOD2; GCN2 eIF2alpha kinase; GCN2-like protein; general control nonderepressible 2; Eukaryo ......
Chromosomal Location	15q13.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting EIF2AK4 collected from DrugBank database.

> Drugs from DrugBank database [ TOP ]
There is no record.

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