Atf4

This gene encodes a transcription factor that was originally identified as a widely expressed mammalian DNA binding protein that could bind a tax-responsive enhancer element in the LTR of HTLV-1. The encoded protein was also isolated and characterized as the cAMP-response element binding protein 2 (CREB-2). The protein encoded by this gene belongs to a family of DNA-binding proteins that includes the AP-1 family of transcription factors, cAMP-response element binding proteins (CREBs) and CREB-like proteins. These transcription factors share a leucine zipper region that is involved in protein-protein interactions, located C-terminal to a stretch of basic amino acids that functions as a DNA binding domain. Two alternative transcripts encoding the same protein have been described. Two pseudogenes are located on the X chromosome at q28 in a region containing a large inverted duplication. [provided by RefSeq, Sep 2011]

Activating Transcription Factor 4

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).
(Microbial infection) Binds to a Tax-responsive enhancer element in the long terminal repeat of HTLV-I.

Bone mineralization Source: UniProtKB
Cellular calcium ion homeostasis Source: Ensembl
Cellular response to amino acid starvation Source: UniProtKB
Cellular response to dopamine Source: CAFA
Cellular response to glucose starvation Source: ParkinsonsUK-UCL
Cellular response to oxidative stress Source: UniProtKB
Cellular response to oxygen-glucose deprivation Source: Ensembl
Cellular response to UV Source: UniProtKB
Circadian regulation of gene expression Source: UniProtKB
Embryonic hemopoiesis Source: UniProtKB
Endoplasmic reticulum unfolded protein response Source: UniProtKB
Gamma-aminobutyric acid signaling pathway Source: Ensembl
Gluconeogenesis Source: UniProtKB
HRI-mediated signaling Source: UniProtKB
Integrated stress response signaling Source: UniProtKB
Intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress Source: UniProtKB
L-asparagine metabolic process Source: UniProtKB
Lens fiber cell morphogenesis Source: UniProtKB
mRNA transcription by RNA polymerase II Source: UniProtKB
Negative regulation of cold-induced thermogenesis Source: YuBioLab
Negative regulation of oxidative stress-induced neuron death Source: ParkinsonsUK-UCL
Negative regulation of potassium ion transport Source: Ensembl
Negative regulation of transcription by RNA polymerase II Source: UniProtKB
Negative regulation of translational initiation in response to stress Source: UniProtKB
Neuron differentiation Source: Ensembl
PERK-mediated unfolded protein response Source: UniProtKB
Positive regulation of apoptotic process Source: ParkinsonsUK-UCL
Positive regulation of biomineral tissue development Source: Ensembl
Positive regulation of gene expression Source: ARUK-UCL
Positive regulation of neuron apoptotic process Source: UniProtKB
Positive regulation of sodium-dependent phosphate transport Source: Ensembl
Positive regulation of transcription, DNA-templated Source: UniProtKB
Positive regulation of transcription by RNA polymerase I Source: ParkinsonsUK-UCL
Positive regulation of transcription by RNA polymerase II Source: UniProtKB
Positive regulation of transcription from RNA polymerase II promoter in response to arsenic-containing substance Source: ParkinsonsUK-UCL
Positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress Source: ParkinsonsUK-UCL
Positive regulation of transcription from RNA polymerase II promoter in response to oxidative stress Source: ParkinsonsUK-UCL
Positive regulation of transcription from RNA polymerase II promoter in response to stress Source: ParkinsonsUK-UCL
Positive regulation of vascular associated smooth muscle cell apoptotic process Source: Ensembl
Positive regulation of vascular endothelial growth factor production Source: ParkinsonsUK-UCL
Regulation of eIF2 alpha phosphorylation by heme Source: Reactome
Regulation of osteoblast differentiation Source: UniProtKB
Regulation of synaptic plasticity Source: UniProtKB
Regulation of transcription, DNA-templated Source: UniProtKB
Regulation of transcription by RNA polymerase II Source: GO_Central
Response to endoplasmic reticulum stress Source: UniProtKB
Response to manganese-induced endoplasmic reticulum stress Source: Ensembl
Response to nutrient levels Source: UniProtKB
Response to toxic substance Source: Ensembl
Transcription by RNA polymerase II Source: UniProtKB

Nucleus; Nucleus speckle; Cytoplasm; Cell membrane; Centrosome.Colocalizes with GABBR1 in hippocampal neuron dendritic membranes (By similarity). Colocalizes with NEK6 at the centrosome (PubMed:20873783). Recruited to nuclear speckles following interaction with EP300/p300 (PubMed:16219772).

Ubiquitinated by SCF(BTRC) in response to mTORC1 signal, followed by proteasomal degradation and leading to down-regulate expression of SIRT4 (PubMed:11238952). Interaction with EP300/p300 inhibits ubiquitination by SCF(BTRC) (PubMed:16219772).
Phosphorylation at Ser-245 by RPS6KA3/RSK2 in osteoblasts enhances transactivation activity and promotes osteoblast differentiation (PubMed:15109498). Phosphorylated on the betaTrCP degron motif at Ser-219, followed by phosphorylation at Thr-213, Ser-224, Ser-231, Ser-235 and Ser-248, promoting interaction with BTRC and ubiquitination (By similarity). Phosphorylation is promoted by mTORC1 (By similarity). Phosphorylation at Ser-215 by CK2 decreases its stability (PubMed:23123191). Phosphorylated by NEK6 (PubMed:20873783).
Hydroxylated by PHD3, leading to decreased protein stability.