Atf4
entrez
11911
canonical
uniprot
Q06507
canonical
ensembl
ENSMUSG00000042406
resolver
ensp
ENSMUSP00000105234
resolver
enst
ENSMUST00000109605
resolver
genesymbol
Atf4
resolver
genesymbol_syn
Creb2
resolver
uniprot
Q5U4B2
resolver
uniprot
Q61906
resolver
uniprot
Q8CF69
resolver
uniprot_entry
ATF4_MOUSE
resolver
uniprot_entry
Q8CF69_MOUSE
resolver
uniprot_sec
Q5U4B2
resolver
uniprot_sec
Q61906
resolver
amino_acid_sequence
MTEMSFLNSEVLAGDLMSPFDQSGLGAEESLGLLDDYLEVAKHLKPHGFSSDKAGSSEWPAMDDGLASASDTGKEDAFSGTDWMLEKMDLKEFDFDALFRMDDLETMPDELLTTLDDTCDLFAPLVQETNKEPPQTVNPIGHLPESLIKVDQVAPFTFLQPFPCSPGVLSSTPEHSFSLELGSEVDISEGDRKPDSAAYITLIPPCVKEEDTPSDNDSGICMSPESYLGSPQHSPSTSRAPPDNLPSPGGSRGSPRPKPYDPPGVSLTAKVKTEKLDKKLKKMEQNKTAATRYRQKKRAEQEALTGECKELEKKNEALKEKADSLAKEIQYLKDLIEEVRKARGKKRVP
uniprot
proteins
function
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:11106749, PubMed:12667446, PubMed:23624402, PubMed:8506317). Binds to asymmetric CRE's as a heterodimer and to palindromic CRE's as a homodimer (PubMed:23624402, PubMed:8506317). 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:11106749, PubMed:12667446). 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:11106749, PubMed:12667446). Promotes the transcription of genes linked to amino acid sufficiency and resistance to oxidative stress to protect cells against metabolic consequences of ER oxidation (PubMed:12667446). Activates the transcription of NLRP1, possibly in concert with other factors in response to ER stress (By similarity). Activates the transcription of asparagine synthetase (ASNS) in response to amino acid deprivation or ER stress (PubMed:15775988, PubMed:21159964). However, when associated with DDIT3/CHOP, the transcriptional activation of the ASNS gene is inhibited in response to amino acid deprivation (By similarity). 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 (PubMed:23624402). Activates the expression of COX7A2L/SCAF1 downstream of the EIF2AK3/PERK-mediated unfolded protein response, thereby promoting formation of respiratory chain supercomplexes and increasing mitochondrial oxidative phosphorylation (PubMed:31023583). 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, PubMed:17369260, PubMed:21159964). May cooperate with the UPR transcriptional regulator QRICH1 to regulate ER protein homeostasis which is critical for cell viability in response to ER stress (By similarity). 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 (PubMed:10096021, PubMed:10885750, PubMed:11806972, PubMed:12925279, PubMed:15109498, PubMed:22298775). 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 (PubMed:22298775). Activates transcription of SIRT4 (PubMed:23663782). Regulates the circadian expression of the core clock component PER2 and the serotonin transporter SLC6A4 (PubMed:21768648, PubMed:22572884). 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 (PubMed:21768648, PubMed:22572884). 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 (PubMed:12925279). 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:P18848, ECO:0000269|PubMed:10096021, ECO:0000269|PubMed:10885750, ECO:0000269|PubMed:11106749, ECO:0000269|PubMed:11806972, ECO:0000269|PubMed:12667446, ECO:0000269|PubMed:12925279, ECO:0000269|PubMed:15109498, ECO:0000269|PubMed:15775988, ECO:0000269|PubMed:17369260, ECO:0000269|PubMed:21159964, ECO:0000269|PubMed:21768648, ECO:0000269|PubMed:22298775, ECO:0000269|PubMed:22572884, ECO:0000269|PubMed:23624402, ECO:0000269|PubMed:23663782, ECO:0000269|PubMed:31023583, ECO:0000269|PubMed:31444471, ECO:0000269|PubMed:8506317}.
uniprot
proteins
mass_dalton
38355
uniprot
proteins
mutagenesis
MUTAGEN 212; /note="T->A: Promotes stabilization due to impaired ubiquitination; when associated with A-223; A-230; A-234 and A-247."; /evidence="ECO:0000269|PubMed:23663782"; MUTAGEN 218; /note="S->A: Promotes stabilization due to impaired ubiquitination."; /evidence="ECO:0000269|PubMed:23663782"; MUTAGEN 223; /note="S->A: Promotes stabilization due to impaired ubiquitination; when associated with A-212; A-230; A-234 and A-247."; /evidence="ECO:0000269|PubMed:23663782"; MUTAGEN 230; /note="S->A: Promotes stabilization due to impaired ubiquitination; when associated with A-212; A-223; A-234 and A-247."; /evidence="ECO:0000269|PubMed:23663782"; MUTAGEN 234; /note="S->A: Promotes stabilization due to impaired ubiquitination; when associated with A-212; A-223; A-230 and A-247."; /evidence="ECO:0000269|PubMed:23663782"; MUTAGEN 247; /note="S->A: Promotes stabilization due to impaired ubiquitination; when associated with A-212; A-223; A-230 and A-234. Does not affect phosphorylation by RPS6KA3/RSK2."; /evidence="ECO:0000269|PubMed:15109498, ECO:0000269|PubMed:23663782"; MUTAGEN 251; /note="S->A,R,D: Abolished phosphorylation by RPS6KA3/RSK2."; /evidence="ECO:0000269|PubMed:15109498"; MUTAGEN 254; /note="S->A: Does not affect phosphorylation by RPS6KA3/RSK2."; /evidence="ECO:0000269|PubMed:15109498
uniprot
proteins
post_translational_modification
PTM: Ubiquitinated by SCF(BTRC) in response to mTORC1 signal, followed by proteasomal degradation and leading to down-regulate expression of SIRT4 (PubMed:23663782). Interaction with EP300/p300 inhibits ubiquitination by SCF(BTRC) (By similarity). {ECO:0000250|UniProtKB:P18848, ECO:0000269|PubMed:23663782}.; PTM: Phosphorylation at Ser-251 by RPS6KA3/RSK2 in osteoblasts enhances transactivation activity and promotes osteoblast differentiation (PubMed:15109498). Phosphorylated on the betaTrCP degron motif at Ser-218, followed by phosphorylation at Thr-212, Ser-223, Ser-230, Ser-234 and Ser-247, promoting interaction with BTRC and ubiquitination (PubMed:23663782). Phosphorylation is promoted by mTORC1 (PubMed:23663782). Phosphorylation at Ser-214 by CK2 decreases its stability (By similarity). Phosphorylated by NEK6 (By similarity). {ECO:0000250|UniProtKB:P18848, ECO:0000269|PubMed:15109498, ECO:0000269|PubMed:23663782}.; PTM: Hydroxylated by PHD3, leading to decreased protein stability. {ECO:0000269|PubMed:24809345}.
uniprot
proteins
protein_family
BZIP family
uniprot
proteins
pubmed
10096021
uniprot
proteins
pubmed
10885750
uniprot
proteins
pubmed
11018027
uniprot
proteins
pubmed
11106749
uniprot
proteins
pubmed
11806972
uniprot
proteins
pubmed
12667446
uniprot
proteins
pubmed
12925279
uniprot
proteins
pubmed
15109498
uniprot
proteins
pubmed
15277680
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15775988
uniprot
proteins
pubmed
15911876
uniprot
proteins
pubmed
16141072
uniprot
proteins
pubmed
1631061
uniprot
proteins
pubmed
16751105
uniprot
proteins
pubmed
17369260
uniprot
proteins
pubmed
19232401
uniprot
proteins
pubmed
21159964
uniprot
proteins
pubmed
21768648
uniprot
proteins
pubmed
22298775
uniprot
proteins
pubmed
22572884
uniprot
proteins
pubmed
22974638
uniprot
proteins
pubmed
23624402
uniprot
proteins
pubmed
23663782
uniprot
proteins
pubmed
24809345
uniprot
proteins
pubmed
31023583
uniprot
proteins
pubmed
31444471
uniprot
proteins
pubmed
8506317
uniprot
proteins
sequence_length
349
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:15109498, ECO:0000269|PubMed:19232401, ECO:0000269|PubMed:22974638}. Nucleus speckle {ECO:0000250|UniProtKB:P18848}. Cytoplasm {ECO:0000269|PubMed:19232401}. Cell membrane {ECO:0000250|UniProtKB:Q9ES19}. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome {ECO:0000250|UniProtKB:P18848}. Note=Colocalizes with GABBR1 in hippocampal neuron dendritic membranes. Colocalizes with NEK6 in the centrosome (By similarity). Recruited to nuclear speckles following interaction with EP300/p300 (By similarity). {ECO:0000250|UniProtKB:P18848, ECO:0000250|UniProtKB:Q9ES19}.
uniprot
proteins