DegronMD - P18848(ATF4)

FUNCTION: Transcription factor that binds the cAMP response element (CRE) (consensus: 5'-GTGACGT[AC][AG]-3') and displays two biological functions, as regulator of metabolic and redox processes under normal cellular conditions, and as master transcription factor during integrated stress response (ISR) (PubMed:17684156, PubMed:16682973, PubMed:31444471, PubMed:32132707). Binds to asymmetric CRE's as a heterodimer and to palindromic CRE's as a homodimer (By similarity). Core effector of the ISR, which is required for adaptation to various stress such as endoplasmic reticulum (ER) stress, amino acid starvation, mitochondrial stress or oxidative stress (PubMed:32132707). During ISR, ATF4 translation is induced via an alternative ribosome translation re-initiation mechanism in response to EIF2S1/eIF-2-alpha phosphorylation, and stress-induced ATF4 acts as a master transcription factor of stress-responsive genes in order to promote cell recovery (PubMed:32132706, PubMed:32132707). Promotes the transcription of genes linked to amino acid sufficiency and resistance to oxidative stress to protect cells against metabolic consequences of ER oxidation (By similarity). Activates the transcription of NLRP1, possibly in concert with other factors in response to ER stress (PubMed:26086088). Activates the transcription of asparagine synthetase (ASNS) in response to amino acid deprivation or ER stress (PubMed:11960987). However, when associated with DDIT3/CHOP, the transcriptional activation of the ASNS gene is inhibited in response to amino acid deprivation (PubMed:18940792). Together with DDIT3/CHOP, mediates programmed cell death by promoting the expression of genes involved in cellular amino acid metabolic processes, mRNA translation and the terminal unfolded protein response (terminal UPR), a cellular response that elicits programmed cell death when ER stress is prolonged and unresolved (By similarity). Together with DDIT3/CHOP, activates the transcription of the IRS-regulator TRIB3 and promotes ER stress-induced neuronal cell death by regulating the expression of BBC3/PUMA in response to ER stress (PubMed:15775988). May cooperate with the UPR transcriptional regulator QRICH1 to regulate ER protein homeostasis which is critical for cell viability in response to ER stress (PubMed:33384352). In the absence of stress, ATF4 translation is at low levels and it is required for normal metabolic processes such as embryonic lens formation, fetal liver hematopoiesis, bone development and synaptic plasticity (By similarity). Acts as a regulator of osteoblast differentiation in response to phosphorylation by RPS6KA3/RSK2: phosphorylation in osteoblasts enhances transactivation activity and promotes expression of osteoblast-specific genes and post-transcriptionally regulates the synthesis of Type I collagen, the main constituent of the bone matrix (PubMed:15109498). Cooperates with FOXO1 in osteoblasts to regulate glucose homeostasis through suppression of beta-cell production and decrease in insulin production (By similarity). Activates transcription of SIRT4 (By similarity). Regulates the circadian expression of the core clock component PER2 and the serotonin transporter SLC6A4 (By similarity). Binds in a circadian time-dependent manner to the cAMP response elements (CRE) in the SLC6A4 and PER2 promoters and periodically activates the transcription of these genes (By similarity). Mainly acts as a transcriptional activator in cellular stress adaptation, but it can also act as a transcriptional repressor: acts as a regulator of synaptic plasticity by repressing transcription, thereby inhibiting induction and maintenance of long-term memory (By similarity). Regulates synaptic functions via interaction with DISC1 in neurons, which inhibits ATF4 transcription factor activity by disrupting ATF4 dimerization and DNA-binding (PubMed:31444471). {ECO:0000250|UniProtKB:Q06507, ECO:0000269|PubMed:11960987, ECO:0000269|PubMed:15109498, ECO:0000269|PubMed:15775988, ECO:0000269|PubMed:16682973, ECO:0000269|PubMed:17684156, ECO:0000269|PubMed:18940792, ECO:0000269|PubMed:26086088, ECO:0000269|PubMed:31444471, ECO:0000269|PubMed:32132706, ECO:0000269|PubMed:32132707, ECO:0000269|PubMed:33384352}.; FUNCTION: (Microbial infection) Binds to a Tax-responsive enhancer element in the long terminal repeat of HTLV-I. {ECO:0000269|PubMed:1847461}. View more >>

GO - Biological processes (BP): bone mineralization [GO:0030282]; cellular calcium ion homeostasis [GO:0006874]; cellular response to amino acid starvation [GO:0034198]; cellular response to dopamine [GO:1903351]; cellular response to glucose starvation [GO:0042149]; cellular response to leucine starvation [GO:1990253]; cellular response to oxidative stress [GO:0034599]; cellular response to oxygen-glucose deprivation [GO:0090650]; cellular response to UV [GO:0034644]; circadian regulation of gene expression [GO:0032922]; embryonic hemopoiesis [GO:0035162]; endoplasmic reticulum unfolded protein response [GO:0030968]; gamma-aminobutyric acid signaling pathway [GO:0007214]; gluconeogenesis [GO:0006094]; HRI-mediated signaling [GO:0140468]; integrated stress response signaling [GO:0140467]; intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress [GO:0070059]; L-asparagine metabolic process [GO:0070982]; lens fiber cell morphogenesis [GO:0070309]; mRNA transcription by RNA polymerase II [GO:0042789]; negative regulation of cold-induced thermogenesis [GO:0120163]; negative regulation of oxidative stress-induced neuron death [GO:1903204]; negative regulation of potassium ion transport [GO:0043267]; negative regulation of transcription by RNA polymerase II [GO:0000122]; negative regulation of translational initiation in response to stress [GO:0032057]; neuron differentiation [GO:0030182]; PERK-mediated unfolded protein response [GO:0036499]; positive regulation of apoptotic process [GO:0043065]; positive regulation of biomineral tissue development [GO:0070169]; positive regulation of gene expression [GO:0010628]; positive regulation of neuron apoptotic process [GO:0043525]; positive regulation of sodium-dependent phosphate transport [GO:2000120]; positive regulation of transcription, DNA-templated [GO:0045893]; positive regulation of transcription by RNA polymerase I [GO:0045943]; positive regulation of transcription by RNA polymerase II [GO:0045944]; positive regulation of transcription from RNA polymerase II promoter in response to arsenic-containing substance [GO:0061395]; positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress [GO:1990440]; positive regulation of transcription from RNA polymerase II promoter in response to oxidative stress [GO:0036091]; positive regulation of transcription from RNA polymerase II promoter in response to stress [GO:0036003]; positive regulation of vascular associated smooth muscle cell apoptotic process [GO:1905461]; positive regulation of vascular endothelial growth factor production [GO:0010575]; regulation of osteoblast differentiation [GO:0045667]; regulation of synaptic plasticity [GO:0048167]; regulation of transcription, DNA-templated [GO:0006355]; regulation of transcription by RNA polymerase II [GO:0006357]; response to endoplasmic reticulum stress [GO:0034976]; response to manganese-induced endoplasmic reticulum stress [GO:1990737]; response to nutrient levels [GO:0031667]; response to toxic substance [GO:0009636]; transcription by RNA polymerase II [GO:0006366] View more >>

GO - Molecular function (MF): View more >>

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

Choose a PDB ID:
Open in full screen with detailed sequence annotations

Mutation	Sample	Cancer	Dataset	Degron hit	Class	Location	Type	Impact score
p.G220C	TCGA-77-8153	LUSC	TCGA	DSGICMS	DEG_SCF_TRCP1_1	218:224	Mutation altering degron motif	0.76
p.G220C	DO45426	LUSC	ICGC	DSGICMS	DEG_SCF_TRCP1_1	218:224	Mutation altering degron motif	0.76
p.S171T	TCGA-AX-A2H2	UCEC	TCGA	LSSTPDHS	DEG_SCF_FBW7_1	170:177	Mutation altering degron motif	0.6005
p.S171T	TCGA-AX-A2H2	UCEC	TCGA	VLSST	DEG_SPOP_SBC_1	169:173	Mutation altering degron motif	0.6005
p.S171T	DO41959	UCEC	ICGC	LSSTPDHS	DEG_SCF_FBW7_1	170:177	Mutation altering degron motif	0.6005
p.S171T	DO41959	UCEC	ICGC	VLSST	DEG_SPOP_SBC_1	169:173	Mutation altering degron motif	0.6005
p.D175Y	TCGA-B5-A1MR	UCEC	TCGA	LSSTPDHS	DEG_SCF_FBW7_1	170:177	Mutation altering degron motif	0.6214
p.D175Y	DO41758	UCEC	ICGC	LSSTPDHS	DEG_SCF_FBW7_1	170:177	Mutation altering degron motif	0.6214
p.L229V	TCGA-C5-A1MK	CESC	TCGA	DSGICMS	DEG_SCF_TRCP1_1	218:224	Mutation rewiring degron network	0.1944
p.L229V	DO6290	CESC	ICGC	DSGICMS	DEG_SCF_TRCP1_1	218:224	Mutation rewiring degron network	0.1944
p.L229M	TCGA-CN-A63T	HNSC	TCGA	DSGICMS	DEG_SCF_TRCP1_1	218:224	Mutation rewiring degron network	0.1944
p.L229M	DO49040	HNSC	ICGC	DSGICMS	DEG_SCF_TRCP1_1	218:224	Mutation rewiring degron network	0.1944
p.D187N	TCGA-CV-A6JD	HNSC	TCGA	LSSTPDHS	DEG_SCF_FBW7_1	170:177	Mutation rewiring degron network	0.0556
p.D187N	DO49035	HNSC	ICGC	LSSTPDHS	DEG_SCF_FBW7_1	170:177	Mutation rewiring degron network	0.0556
p.L170M	TCGA-D1-A177	UCEC	TCGA	LSSTPDHS	DEG_SCF_FBW7_1	170:177	Mutation altering degron motif	0.5999
p.L170M	TCGA-D1-A177	UCEC	TCGA	VLSST	DEG_SPOP_SBC_1	169:173	Mutation altering degron motif	0.5999
p.L170M	DO42528	UCEC	ICGC	LSSTPDHS	DEG_SCF_FBW7_1	170:177	Mutation altering degron motif	0.5999
p.L170M	DO42528	UCEC	ICGC	VLSST	DEG_SPOP_SBC_1	169:173	Mutation altering degron motif	0.5999
p.P225Q	TCGA-D3-A2JO	SKCM	TCGA	DSGICMS	DEG_SCF_TRCP1_1	218:224	Mutation rewiring degron network	0.3056
p.P225Q	DO47619	SKCM	ICGC	DSGICMS	DEG_SCF_TRCP1_1	218:224	Mutation rewiring degron network	0.3056
p.S215L	TCGA-D3-A51R	SKCM	TCGA	DSGICMS	DEG_SCF_TRCP1_1	218:224	Mutation blocking phosphorylation signal	0.6944
p.S215L	DO47480	SKCM	ICGC	DSGICMS	DEG_SCF_TRCP1_1	218:224	Mutation blocking phosphorylation signal	0.6944
p.P214L	TCGA-D3-A8GI	SKCM	TCGA	DSGICMS	DEG_SCF_TRCP1_1	218:224	Mutation rewiring degron network	0.2222
p.P214L	DO50901	LICA	ICGC	DSGICMS	DEG_SCF_TRCP1_1	218:224	Mutation rewiring degron network	0.2222
p.P214L	DO50284	SKCM	ICGC	DSGICMS	DEG_SCF_TRCP1_1	218:224	Mutation rewiring degron network	0.2222
p.S227F	TCGA-EE-A3J7	SKCM	TCGA	DSGICMS	DEG_SCF_TRCP1_1	218:224	Mutation rewiring degron network	0.25
p.S227F	DO48770	SKCM	ICGC	DSGICMS	DEG_SCF_TRCP1_1	218:224	Mutation rewiring degron network	0.25
p.E211K	TCGA-FR-A728	SKCM	TCGA	DSGICMS	DEG_SCF_TRCP1_1	218:224	Mutation rewiring degron network	0.1389
p.E211K	DO48550	SKCM	ICGC	DSGICMS	DEG_SCF_TRCP1_1	218:224	Mutation rewiring degron network	0.1389
p.T213I	TCGA-OR-A5JD	ACC	TCGA	DSGICMS	DEG_SCF_TRCP1_1	218:224	Mutation rewiring degron network	0.1944
p.Q161L	DO222586	ESCA	ICGC	LSSTPDHS	DEG_SCF_FBW7_1	170:177	Mutation rewiring degron network	0.0833
p.Q161L	DO222586	ESCA	ICGC	VLSST	DEG_SPOP_SBC_1	169:173	Mutation rewiring degron network	0.1111
p.I208M	SIDM00622	Glioblastoma	GDSC	DSGICMS	DEG_SCF_TRCP1_1	218:224	Mutation rewiring degron network	0.0556
p.I208M	SIDM01323	Oral Cavity Carcinoma	GDSC	DSGICMS	DEG_SCF_TRCP1_1	218:224	Mutation rewiring degron network	0.0556
p.S219T	SIDM01613	Colorectal Carcinoma	GDSC	DSGICMS	DEG_SCF_TRCP1_1	218:224	Mutation altering degron motif	0.8227
p.S219T	ACH-000199	Non-Cancerous	CCLE	DSGICMS	DEG_SCF_TRCP1_1	218:224	Mutation altering degron motif	0.8227
p.I208V	ACH-001421	Eye Cancer	CCLE	DSGICMS	DEG_SCF_TRCP1_1	218:224	Mutation rewiring degron network	0.0556

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

ATF4

UniProt ID: P18848

Entrez ID: 468

External links: UniprotKB HGNC RefSeq COSMIC

Data table is loading....

Kaplan plot for ATF4 in