DegronMD - Q9BQI3(EIF2AK1)

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 (PubMed:32132706, PubMed:32132707). Key activator of the integrated stress response (ISR) required for adaptation to various stress, such as heme deficiency, oxidative stress, osmotic shock, mitochondrial dysfunction and heat shock (PubMed:32132706, PubMed:32132707). 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 activator ATF4, and hence allowing ATF4-mediated reprogramming (PubMed:32132706, PubMed:32132707). Acts as a key sensor of heme-deficiency: in normal conditions, binds hemin via a cysteine thiolate and histidine nitrogenous coordination, leading to inhibit the protein kinase activity (By similarity). This binding occurs with moderate affinity, allowing it to sense the heme concentration within the cell: heme depletion relieves inhibition and stimulates kinase activity, activating the ISR (By similarity). Thanks to this unique heme-sensing capacity, plays a crucial role to shut off protein synthesis during acute heme-deficient conditions (By similarity). In red blood cells (RBCs), controls hemoglobin synthesis ensuring a coordinated regulation of the synthesis of its heme and globin moieties (By similarity). It thereby plays an essential protective role for RBC survival in anemias of iron deficiency (By similarity). Similarly, in hepatocytes, involved in heme-mediated translational control of CYP2B and CYP3A and possibly other hepatic P450 cytochromes (By similarity). May also regulate endoplasmic reticulum (ER) stress during acute heme-deficient conditions (By similarity). Also activates the ISR in response to mitochondrial dysfunction: HRI/EIF2AK1 protein kinase activity is activated upon binding to the processed form of DELE1 (S-DELE1), thereby promoting the ATF4-mediated reprogramming (PubMed:32132706, PubMed:32132707). {ECO:0000250|UniProtKB:Q9Z2R9, ECO:0000269|PubMed:32132706, ECO:0000269|PubMed:32132707, ECO:0000269|PubMed:32197074}. View more >>

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GO - Cellular component (CC): View more >>

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Mutation	Sample	Cancer	Dataset	Degron hit	Class	Location	Type	Impact score
p.R291C	TCGA-50-6594	LUAD	TCGA	PTPEKE	DEG_SCF_FBW7_2	284:289	Mutation rewiring degron network	0.2778
p.R291C	TCGA-50-6594	LUAD	TCGA	FAEPTPEK	DEG_SCF_SKP2-CKS1_1	281:288	Mutation rewiring degron network	0.25
p.E294K	TCGA-AN-A046	BRCA	TCGA	PTPEKE	DEG_SCF_FBW7_2	284:289	Mutation rewiring degron network	0.1944
p.E294K	TCGA-AN-A046	BRCA	TCGA	FAEPTPEK	DEG_SCF_SKP2-CKS1_1	281:288	Mutation rewiring degron network	0.1667
p.E294K	TCGA-GD-A3OP	BLCA	TCGA	PTPEKE	DEG_SCF_FBW7_2	284:289	Mutation rewiring degron network	0.1944
p.E294K	TCGA-GD-A3OP	BLCA	TCGA	FAEPTPEK	DEG_SCF_SKP2-CKS1_1	281:288	Mutation rewiring degron network	0.1667
p.R291H	TCGA-AP-A0LM	UCEC	TCGA	PTPEKE	DEG_SCF_FBW7_2	284:289	Mutation rewiring degron network	0.2778
p.R291H	TCGA-AP-A0LM	UCEC	TCGA	FAEPTPEK	DEG_SCF_SKP2-CKS1_1	281:288	Mutation rewiring degron network	0.25
p.S277A	TCGA-B5-A1MR	UCEC	TCGA	PTPEKE	DEG_SCF_FBW7_2	284:289	Mutation rewiring degron network	0.1389
p.S277A	TCGA-B5-A1MR	UCEC	TCGA	FAEPTPEK	DEG_SCF_SKP2-CKS1_1	281:288	Mutation rewiring degron network	0.2222
p.S278F	TCGA-EE-A29N	SKCM	TCGA	PTPEKE	DEG_SCF_FBW7_2	284:289	Mutation rewiring degron network	0.1667
p.S278F	TCGA-EE-A29N	SKCM	TCGA	FAEPTPEK	DEG_SCF_SKP2-CKS1_1	281:288	Mutation rewiring degron network	0.25
p.S276C	TCGA-UF-A7J9	HNSC	TCGA	PTPEKE	DEG_SCF_FBW7_2	284:289	Mutation blocking phosphorylation signal	0.5556
p.S276C	TCGA-UF-A7J9	HNSC	TCGA	FAEPTPEK	DEG_SCF_SKP2-CKS1_1	281:288	Mutation blocking phosphorylation signal	0.6389
p.A286T	DO1608	BRCA	ICGC	PTPEKE	DEG_SCF_FBW7_2	284:289	Mutation altering degron motif	0.7139
p.A286T	DO1608	BRCA	ICGC	FAEPTPEK	DEG_SCF_SKP2-CKS1_1	281:288	Mutation altering degron motif	0.7139
p.R279W	DO233737	GACA	ICGC	PTPEKE	DEG_SCF_FBW7_2	284:289	Mutation rewiring degron network	0.1944
p.R279W	DO233737	GACA	ICGC	FAEPTPEK	DEG_SCF_SKP2-CKS1_1	281:288	Mutation rewiring degron network	0.2778
p.R277W	DO233889	GACA	ICGC	PTPEKE	DEG_SCF_FBW7_2	284:289	Mutation rewiring degron network	0.1389
p.R277W	DO233889	GACA	ICGC	FAEPTPEK	DEG_SCF_SKP2-CKS1_1	281:288	Mutation rewiring degron network	0.2222
p.T296A	DO15006	HNSC	ICGC	PTPEKE	DEG_SCF_FBW7_2	284:289	Mutation rewiring degron network	0.1389
p.T296A	DO15006	HNSC	ICGC	FAEPTPEK	DEG_SCF_SKP2-CKS1_1	281:288	Mutation rewiring degron network	0.1111
p.N275K	DO228985	LICA	ICGC	PTPEKE	DEG_SCF_FBW7_2	284:289	Mutation blocking phosphorylation signal	0.5278
p.N275K	DO228985	LICA	ICGC	FAEPTPEK	DEG_SCF_SKP2-CKS1_1	281:288	Mutation blocking phosphorylation signal	0.6111
p.R277L	DO230982	LUSC	ICGC	PTPEKE	DEG_SCF_FBW7_2	284:289	Mutation rewiring degron network	0.1389
p.R277L	DO230982	LUSC	ICGC	FAEPTPEK	DEG_SCF_SKP2-CKS1_1	281:288	Mutation rewiring degron network	0.2222
p.R277L	DO224613	LUSC	ICGC	PTPEKE	DEG_SCF_FBW7_2	284:289	Mutation rewiring degron network	0.1389
p.R277L	DO224613	LUSC	ICGC	FAEPTPEK	DEG_SCF_SKP2-CKS1_1	281:288	Mutation rewiring degron network	0.2222
p.E284K	DO219136	LUSC	ICGC	PTPEKE	DEG_SCF_FBW7_2	284:289	Mutation altering degron motif	0.7022
p.E284K	DO219136	LUSC	ICGC	FAEPTPEK	DEG_SCF_SKP2-CKS1_1	281:288	Mutation altering degron motif	0.7022
p.S285Y	DO232224	PBCA	ICGC	PTPEKE	DEG_SCF_FBW7_2	284:289	Mutation altering degron motif	0.712
p.S285Y	DO232224	PBCA	ICGC	FAEPTPEK	DEG_SCF_SKP2-CKS1_1	281:288	Mutation altering degron motif	0.712
p.P288S	DO47419	SKCM	ICGC	PTPEKE	DEG_SCF_FBW7_2	284:289	Mutation altering degron motif	0.6752
p.P288S	DO47419	SKCM	ICGC	FAEPTPEK	DEG_SCF_SKP2-CKS1_1	281:288	Mutation altering degron motif	0.6752
p.E273K	DO43154	UCEC	ICGC	FAEPTPEK	DEG_SCF_SKP2-CKS1_1	281:288	Mutation rewiring degron network	0.1111
p.E273K	DO41572	UCEC	ICGC	FAEPTPEK	DEG_SCF_SKP2-CKS1_1	281:288	Mutation rewiring degron network	0.1111
p.E273K	DO42608	UCEC	ICGC	FAEPTPEK	DEG_SCF_SKP2-CKS1_1	281:288	Mutation rewiring degron network	0.1111
p.E280D	DO42665	UCEC	ICGC	PTPEKE	DEG_SCF_FBW7_2	284:289	Mutation rewiring degron network	0.2222
p.E280D	DO42665	UCEC	ICGC	FAEPTPEK	DEG_SCF_SKP2-CKS1_1	281:288	Mutation rewiring degron network	0.3056
p.S276R	SIDM00938	Breast Carcinoma	GDSC	PTPEKE	DEG_SCF_FBW7_2	284:289	Mutation blocking phosphorylation signal	0.5556
p.S276R	SIDM00938	Breast Carcinoma	GDSC	FAEPTPEK	DEG_SCF_SKP2-CKS1_1	281:288	Mutation blocking phosphorylation signal	0.6389
p.S276R	ACH-000902	Breast Cancer	CCLE	PTPEKE	DEG_SCF_FBW7_2	284:289	Mutation blocking phosphorylation signal	0.5556
p.S276R	ACH-000902	Breast Cancer	CCLE	FAEPTPEK	DEG_SCF_SKP2-CKS1_1	281:288	Mutation blocking phosphorylation signal	0.6389
p.S276R	CAL-148	breast	COSMIC	PTPEKE	DEG_SCF_FBW7_2	284:289	Mutation blocking phosphorylation signal	0.5556
p.S276R	CAL-148	breast	COSMIC	FAEPTPEK	DEG_SCF_SKP2-CKS1_1	281:288	Mutation blocking phosphorylation signal	0.6389
p.T297A	SIDM01013	B-Cell Non-Hodgkin's Lymphoma	GDSC	PTPEKE	DEG_SCF_FBW7_2	284:289	Mutation blocking phosphorylation signal	0.5556
p.T297A	SIDM01013	B-Cell Non-Hodgkin's Lymphoma	GDSC	FAEPTPEK	DEG_SCF_SKP2-CKS1_1	281:288	Mutation blocking phosphorylation signal	0.5278
p.T297A	ACH-000106	Lymphoma	CCLE	PTPEKE	DEG_SCF_FBW7_2	284:289	Mutation blocking phosphorylation signal	0.5556
p.T297A	ACH-000106	Lymphoma	CCLE	FAEPTPEK	DEG_SCF_SKP2-CKS1_1	281:288	Mutation blocking phosphorylation signal	0.5278
p.T297A	JVM-2	haematopoietic and lymphoid tissue	COSMIC	PTPEKE	DEG_SCF_FBW7_2	284:289	Mutation blocking phosphorylation signal	0.5556
p.T297A	JVM-2	haematopoietic and lymphoid tissue	COSMIC	FAEPTPEK	DEG_SCF_SKP2-CKS1_1	281:288	Mutation blocking phosphorylation signal	0.5278

Kaplan plot for EIF2AK1 in

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*NOTE: the Kaplan plots were collected from OncoLnc

DegronMD: protein-targeted degradation, mutation and drug response to degrons

EIF2AK1

UniProt ID: Q9BQI3

Entrez ID: 27102

Protein name: Eukaryotic translation initiation factor 2-alpha kinase 1 (EC 2.7.11.1) (Heme-controlled repressor) (HCR) (Heme-regulated eukaryotic initiation factor eIF-2-alpha kinase) (Heme-regulated inhibitor) (hHRI) (Hemin-sensitive initiation factor 2-alpha kinase)

External links: UniprotKB HGNC RefSeq COSMIC

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Kaplan plot for EIF2AK1 in