ATF2

Summary

ATF2 (activating transcription factor 2, HGNC:784) is a protein-coding gene on chromosome 2q31.1, encoding Cyclic AMP-dependent transcription factor ATF-2 (P15336). Transcriptional activator which regulates the transcription of various genes, including those involved in anti-apoptosis, cell growth, and DNA damage response.

This gene encodes a transcription factor that is a member of the leucine zipper family of DNA binding proteins. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions This protein binds to the cAMP-responsive element (CRE), an octameric palindrome. It forms a homodimer or a heterodimer with c-Jun and stimulates CRE-dependent transcription. This protein is also a histone acetyltransferase (HAT) that specifically acetylates histones H2B and H4 in vitro; thus it may represent a class of sequence-specific factors that activate transcription by direct effects on chromatin components. The encoded protein may also be involved in cell’s DNA damage response independent of its role in transcriptional regulation. Several alternatively spliced transcript variants have been found for this gene

Source: NCBI Gene 1386 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 83 total — 4 pathogenic, 1 likely-pathogenic
• Druggable target: yes
• Transcription factor: yes — 131 downstream targets (CollecTRI)
• MANE Select transcript: NM_001880

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:784
Approved symbol	ATF2
Name	activating transcription factor 2
Location	2q31.1
Locus type	gene with protein product
Status	Approved
Aliases	TREB7, CRE-BP1, HB16
Ensembl gene	ENSG00000115966
Ensembl biotype	protein_coding
OMIM	123811
Entrez	1386

Gene structure

Transcript identifiers

Ensembl transcripts: 41 — 29 protein_coding, 9 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000264110, ENST00000345739, ENST00000392544, ENST00000409437, ENST00000409499, ENST00000409635, ENST00000409833, ENST00000413123, ENST00000415955, ENST00000417080, ENST00000421438, ENST00000426833, ENST00000428760, ENST00000429579, ENST00000435004, ENST00000435231, ENST00000437522, ENST00000445349, ENST00000456655, ENST00000478905, ENST00000865358, ENST00000865359, ENST00000865360, ENST00000865361, ENST00000865362, ENST00000865363, ENST00000865364, ENST00000865365, ENST00000865366, ENST00000865367, ENST00000865368, ENST00000865369, ENST00000865370, ENST00000865371, ENST00000918099, ENST00000968241, ENST00000968242, ENST00000968243, ENST00000968244, ENST00000968245, ENST00000968246

RefSeq mRNA: 6 — MANE Select: NM_001880 NM_001256090, NM_001256091, NM_001256092, NM_001256093, NM_001256094, NM_001880

CCDS: CCDS2262, CCDS58737, CCDS58738, CCDS58739

Canonical transcript exons

ENST00000264110 — 14 exons

Exon	Start	End
ENSE00000782508	175121444	175121540
ENSE00001353075	175151060	175151158
ENSE00001579182	175168050	175168203
ENSE00003592113	175136412	175136486
ENSE00003636830	175130138	175130207
ENSE00003844591	175072259	175074835
ENSE00004283292	175111568	175111654
ENSE00004283293	175113994	175114108
ENSE00004283294	175097444	175097593
ENSE00004283295	175118251	175118369
ENSE00004283296	175080660	175080765
ENSE00004283298	175114690	175114868
ENSE00004283300	175093061	175093267
ENSE00004283301	175117990	175118118

Expression profiles

Bgee: expression breadth ubiquitous, 298 present calls, max score 98.37.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 37.5046 / max 608.3564, expressed in 1814 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
31929	35.9533	1813
31932	0.6359	273
31930	0.5699	252
31931	0.3456	171

Top tissues by expression

300 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	98.37	gold quality
germinal epithelium of ovary	UBERON:0001304	96.24	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.14	gold quality
cortical plate	UBERON:0005343	95.84	gold quality
corpus epididymis	UBERON:0004359	95.51	gold quality
caput epididymis	UBERON:0004358	95.43	gold quality
blood vessel layer	UBERON:0004797	95.23	gold quality
mucosa of paranasal sinus	UBERON:0005030	95.16	gold quality
substantia nigra pars compacta	UBERON:0001965	95.06	gold quality
cauda epididymis	UBERON:0004360	94.95	gold quality
ganglionic eminence	UBERON:0004023	94.74	gold quality
choroid plexus epithelium	UBERON:0003911	94.71	gold quality
seminal vesicle	UBERON:0000998	94.54	gold quality
parietal pleura	UBERON:0002400	94.45	gold quality
ventricular zone	UBERON:0003053	94.34	gold quality
colonic epithelium	UBERON:0000397	94.28	gold quality
superficial temporal artery	UBERON:0001614	94.25	gold quality
substantia nigra pars reticulata	UBERON:0001966	94.18	gold quality
pigmented layer of retina	UBERON:0001782	94.08	gold quality
retina	UBERON:0000966	94.06	gold quality
calcaneal tendon	UBERON:0003701	94.05	gold quality
trabecular bone tissue	UBERON:0002483	93.72	gold quality
pons	UBERON:0000988	93.59	gold quality
visceral pleura	UBERON:0002401	93.52	gold quality
entorhinal cortex	UBERON:0002728	93.51	gold quality
endometrium	UBERON:0001295	93.46	gold quality
adrenal tissue	UBERON:0018303	93.46	gold quality
mammary duct	UBERON:0001765	93.43	gold quality
pleura	UBERON:0000977	93.29	gold quality
secondary oocyte	CL:0000655	93.23	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.54

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

131 targets.

Target	Regulation
ACE
ACHE
ADAM2
APEX1	Activation
APOC3	Activation
ATF2
ATF3	Activation
ATF4
BCL2	Unknown
CASP3
CCL2	Activation
CCL5	Activation
CCNA1
CCNA2	Unknown
CCND1	Activation
CCND3	Activation
CD1A
CD74
CDK4	Unknown
CDKN1A	Unknown
CDKN2A	Activation
CEBPB	Activation
CGA	Activation
CPS1
CYP11B1	Unknown
CYP11B2	Unknown
CYP19A1
CYP2C19
DDIT3	Activation
DUSP1	Unknown

JASPAR motifs

Motif	Name	Family
MA1632.1	ATF2	Jun-related
MA1632.2	ATF2	Jun-related

JASPAR matrix evidence (PMIDs): PMID:20581861

Upstream regulators (CollecTRI, top): ATF2, ATF4, DDIT3, JDP2, JUN, NR3C1, RB1, SP1

miRNA regulators (miRDB)

136 targeting ATF2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-8485	100.00	77.57	4731
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-613	99.91	71.50	1710

Literature-anchored findings (GeneRIF, showing 40)

• Infrequent mutations of the activating transcription factor-2 gene in human lung cancer, neuroblastoma and breast cancer (PMID:11836564)
• activation by growth factors via phosphorylation of Thr71 through the Ras-MEK-ERK pathway and of Thr69 through RalGDS-Src-p38 (PMID:12110590)
• Phosphorylation of one of the downstream transcriptional factors of MAPK cascade, ATF2, was 3.2- and 2.0-fold induced by TPA and Saikosaponin a, respectively. (PMID:12592382)
• JNK-dependent phosphorylation of ATF2 plays an important role in the drug resistance phenotype likely by mediating enhanced DNA repair by a p53-independent mechanism. (PMID:12663670)
• ATF-2 and ATF3 seem to play an important role in the protective response of human cells to ionizing radiation (PMID:12833146)
• ATF4 and ATF2 have roles in regulating CHOP expression (PMID:14630918)
• In melanoma strong cytoplasmic ATF2 expression was associated with primary specimens rather than metastases and with better survival. Strong nuclear ATF2 expression was associated with metastatic specimens and with poor survival. (PMID:14678960)
• differentiation-dependent expression and phosphorylation of ATF2 protein physically and functionally interacts with C/EBPalpha and coativator ASC-2 and synergizes to induce target gene transcription during granulocytic differentiation (PMID:14734562)
• ATF2 and HO-1 are regulated and induced by biliverdin reductase (PMID:14988408)
• genes affected by ATF2 and ATF2-sm appear to belong to discrete groups (PMID:15691875)
• ATF2 expression in the neuron of normal human brain. But downregulation in the Neurodegenerative Disease( Alzheimer disease, Huntington disease and Parkinson disease). (PMID:15878807)
• Data demonstrate that the protein kinase ATM phosphorylates ATF2 on serines 490 and 498 following ionizing radiation (IR). (PMID:15916964)
• activity of the AP-1 components c-Jun, ATF2, and c-Fos is altered in renal cystic tissue of patients with autosomal dominant polycystic kidney disease (PMID:16049073)
• Resistin induces PTEN expression by activating stress signaling p38 pathway, which may activate target transcription factor ATF-2, which in turn induces PTEN expression (PMID:16418168)
• These studies establish p38 MAP kinase-mediated activation of ATF-2 as a significant mechanism in amylin-evoked beta-cell death, which may serve as a target for pharmaceutical intervention and effective suppression of beta-cell failure in type-2 diabetes. (PMID:16869889)
• gamma-gene induction by butyrate and trichostatin A involves ATF-2 and CREB1 activation via p38 MAPK signaling. (PMID:16896160)
• Sin1 may contribute to ATF-2 signaling specificity by acting as a nuclear scaffold. (PMID:17054722)
• Binding of ATF2 to the CD1A promoter in human monocytes suggests a role for ATF/cAMP response element binding protein family members in regulation of CD1A expression. (PMID:17082618)
• Shear stress and KLF2 inhibit nuclear activity of ATF2, providing a potential mechanism by which endothelial cells exposed to laminar flow are protected from basal proinflammatory, atherogenic gene expression. (PMID:17244683)
• This study demonstrates that ATF2 mediates the TGF-beta-induced MMP-2 transcriptional activation, elucidating a molecular mechanism for the malignant progression of human breast epithelial cells exerted by TGF-beta. (PMID:17258390)
• ATF-2 may be a key regulator of the human insulin promoter possibly stimulating activity in response to extracellular signals. (PMID:17337306)
• ATF2, but not CREB, was a target for the TAK1-JNK pathway, and p38 negatively regulated TAK1 activity through TAB1 phosphorylation. (PMID:17626013)
• The transcription factor ATF2, which is phosphorylated and activated by JNK, is a critical mediator for inducible expression of DUSP1 and DUSP10 in this signaling pathway. (PMID:17681939)
• ATF2/STAT3 signaling pathways are activated and may play a role in development of eccrine porocarcinoma and eccrine poroma. (PMID:17869487)
• review of signaling pathways that activate ATF-2, as well as its downstream targets [review] (PMID:18348191)
• analysis of regulation of ATM activation by ATF2-dependent control of TIP60 stability and activity (PMID:18397884)
• Overexpression of phosphorylated-ATF2 and STAT3 in cutaneous squamous cell carcinoma, Bowen’s disease and basal cell carcinoma. (PMID:18547788)
• IRF2-BP1 is a JDP2-binding protein enhancing the polyubiquitination of JDP2 and represses ATF2-mediated transcriptional activation from a CRE-containing promoter. (PMID:18671972)
• This review summarizes the current understanding of ATF2 regulation and function. (PMID:18677098)
• overexpression of p-ATF2, p-STAT3 and possibly p53, but not p63 or p73, may contribute to the tumorigenesis of cutaneous vascular tumors. (PMID:18700251)
• p53 and ATF-2 partly mediate the overexpression of COX-2 in H(2)O (2)-induced premature senescence of human fibroblasts. (PMID:19082758)
• the phosphorylation of ATF-2 at Ser-121 plays a key role in the c-Jun-mediated activation of transcription that occurs in response to TPA. (PMID:19176525)
• Data show that individuals who are homozygous for the short AP-2 beta allele display higher depression scores when psychosocial adversity is taken into account. (PMID:19184334)
• P-ATF2 and p-STAT3 are concordantly overexpressed in extramammary Paget’s disease and their expressions may possibly be associated with the tumor stage. (PMID:19278424)
• Breast cancer patients with high ATF2 expression as detected by WB had a significantly shorter overall survival. (PMID:19331149)
• Phospholipase D1 acts as an important regulator in house dust mite allergen Der f 2-induced expression and production of IL-13 through activation of activating transcription factor-2 activation in human bronchial epithelial cells. (PMID:19487697)
• show that Activating transcription factor 2 induction enhances hypoxia-inducible factor 1alpha protein stability via direct protein interaction. (PMID:19712049)
• Data reveal a new signaling pathway activated by amino acid starvation leading to ATF2 phosphorylation and subsequently positively affecting the transcription of amino acid-regulated genes. (PMID:19822663)
• JNK/ATF2 pathway is involved in iodinated contrast media-induced apoptosis (PMID:19923798)
• Stability and DNA-binding ability of the bZIP dimers formed by the ATF-2 and c-Jun. (PMID:19944700)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	atf2	ENSDARG00000023903
mus_musculus	Atf2	ENSMUSG00000027104
rattus_norvegicus	Atf2	ENSRNOG00000001597
caenorhabditis_elegans		WBGENE00000223

Paralogs (2): CREB5 (ENSG00000146592), ATF7 (ENSG00000170653)

Protein

Protein identifiers

Cyclic AMP-dependent transcription factor ATF-2 — P15336 (reviewed: P15336)

Alternative names: Activating transcription factor 2, Cyclic AMP-responsive element-binding protein 2, HB16, cAMP response element-binding protein CRE-BP1

All UniProt accessions (7): P15336, B8ZZU6, C9JCI8, E9PBF9, E9PEK8, F2Z2K2, H7C2N6

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional activator which regulates the transcription of various genes, including those involved in anti-apoptosis, cell growth, and DNA damage response. Dependent on its binding partner, binds to CRE (cAMP response element) consensus sequences (5’-TGACGTCA-3’) or to AP-1 (activator protein 1) consensus sequences (5’-TGACTCA-3’). In the nucleus, contributes to global transcription and the DNA damage response, in addition to specific transcriptional activities that are related to cell development, proliferation and death. In the cytoplasm, interacts with and perturbs HK1- and VDAC1-containing complexes at the mitochondrial outer membrane, thereby impairing mitochondrial membrane potential, inducing mitochondrial leakage and promoting cell death. The phosphorylated form (mediated by ATM) plays a role in the DNA damage response and is involved in the ionizing radiation (IR)-induced S phase checkpoint control and in the recruitment of the MRN complex into the IR-induced foci (IRIF). Exhibits histone acetyltransferase (HAT) activity which specifically acetylates histones H2B and H4 in vitro. In concert with CUL3 and RBX1, promotes the degradation of KAT5 thereby attenuating its ability to acetylate and activate ATM. Can elicit oncogenic or tumor suppressor activities depending on the tissue or cell type.

Subunit / interactions. Binds DNA as a dimer and can form a homodimer in the absence of DNA. Can form a heterodimer with JUN. Heterodimerization is essential for its transcriptional activity. Interacts with SMAD3 and SMAD4. Binds through its N-terminal region to UTF1 which acts as a coactivator of ATF2 transcriptional activity. Interacts with the HK1/VDAC1 complex. Interacts with NBN, MRE11, XPO1, KAT5 and CUL3.

Subcellular location. Nucleus. Cytoplasm. Mitochondrion outer membrane.

Tissue specificity. Ubiquitously expressed, with more abundant expression in the brain.

Post-translational modifications. Phosphorylation of Thr-69 by MAPK14 and MAPK11, and at Thr-71 by MAPK1/ERK2, MAPK3/ERK1, MAPK11, MAPK12 and MAPK14 in response to external stimulus like insulin causes increased transcriptional activity. Phosphorylated by PLK3 following hyperosmotic stress. Also phosphorylated and activated by JNK and CaMK4. ATM-mediated phosphorylation at Ser-490 and Ser-498 stimulates its function in DNA damage response. Phosphorylation at Ser-62, Thr-73 and Ser-121 activates its transcriptional activity. Phosphorylation at Thr-69 or Thr-71 enhances acetylation of histones H2B and H4.

Domain organisation. The nuclear export signal 1 (N-NES) negatively regulates its nuclear localization and transcriptional activity.

Similarity. Belongs to the bZIP family. ATF subfamily.

Isoforms (8)

UniProt ID	Names	Canonical?
P15336-1	1	yes
P15336-2	2
P15336-3	3
P15336-4	4
P15336-5	5
P15336-6	6
P15336-7	7
P15336-8	8, ATF2-small

RefSeq proteins (6): NP_001243019, NP_001243020, NP_001243021, NP_001243022, NP_001243023, NP_001871* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004827	bZIP	Domain
IPR013087	Znf_C2H2_type	Domain
IPR016378	TF_CRE-BP1-typ	Family
IPR036236	Znf_C2H2_sf	Homologous_superfamily
IPR046347	bZIP_sf	Homologous_superfamily
IPR051027

Pfam: PF00170

UniProt features (56 total): modified residue 19, splice variant 8, region of interest 6, compositionally biased region 5, mutagenesis site 3, sequence conflict 3, helix 3, short sequence motif 2, turn 2, chain 1, domain 1, zinc finger region 1, sequence variant 1, strand 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
6ZQS	X-RAY DIFFRACTION	1.95
8YPE	X-RAY DIFFRACTION	1.95
8YPF	X-RAY DIFFRACTION	2
9Y0R	X-RAY DIFFRACTION	2.2
6ZR5	X-RAY DIFFRACTION	2.7
1T2K	X-RAY DIFFRACTION	3
4H36	X-RAY DIFFRACTION	3
1BHI	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P15336-F1	58.58	0.14

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (19): 52, 62, 69, 71, 73, 90, 112, 116, 121, 136, 328, 340, 357, 367, 374, 442, 446, 490, 498

Mutagenesis-validated functional residues (3):

Position	Phenotype
69	weak histone acetyltransferase activity.
71	impairs phosphorylation by plk3. weak histone acetyltransferase activity.
121	reduced phosphorylation and repression of c-jun-mediated activation of transcription.

Function

Pathways and Gene Ontology

Reactome pathways

55 pathways

ID	Pathway
R-HSA-2151201	Transcriptional activation of mitochondrial biogenesis
R-HSA-3214847	HATs acetylate histones
R-HSA-450341	Activation of the AP-1 family of transcription factors
R-HSA-6796648	TP53 Regulates Transcription of DNA Repair Genes
R-HSA-8943724	Regulation of PTEN gene transcription
R-HSA-9018519	Estrogen-dependent gene expression
R-HSA-9031628	NGF-stimulated transcription
R-HSA-9633012	Response of EIF2AK4 (GCN2) to amino acid deficiency
R-HSA-9707616	Heme signaling
R-HSA-9931509	Expression of BMAL (ARNTL), CLOCK, and NPAS2
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1592230	Mitochondrial biogenesis
R-HSA-162582	Signal Transduction
R-HSA-166016	Toll Like Receptor 4 (TLR4) Cascade
R-HSA-166058	MyD88:MAL(TIRAP) cascade initiated on plasma membrane
R-HSA-166166	MyD88-independent TLR4 cascade
R-HSA-166520	Signaling by NTRKs
R-HSA-168138	Toll Like Receptor 9 (TLR9) Cascade
R-HSA-168142	Toll Like Receptor 10 (TLR10) Cascade
R-HSA-168164	Toll Like Receptor 3 (TLR3) Cascade
R-HSA-168176	Toll Like Receptor 5 (TLR5) Cascade
R-HSA-168179	Toll Like Receptor TLR1:TLR2 Cascade
R-HSA-168181	Toll Like Receptor 7/8 (TLR7/8) Cascade
R-HSA-168188	Toll Like Receptor TLR6:TLR2 Cascade
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-168898	Toll-like Receptor Cascades
R-HSA-181438	Toll Like Receptor 2 (TLR2) Cascade
R-HSA-1852241	Organelle biogenesis and maintenance

MSigDB gene sets: 0 (showing top):

GO Biological Process (52): negative regulation of transcription by RNA polymerase II (GO:0000122), temperature homeostasis (GO:0001659), in utero embryonic development (GO:0001701), NK T cell differentiation (GO:0001865), liver development (GO:0001889), hematopoietic progenitor cell differentiation (GO:0002244), outflow tract morphogenesis (GO:0003151), brainstem development (GO:0003360), growth plate cartilage chondrocyte differentiation (GO:0003418), growth plate cartilage chondrocyte proliferation (GO:0003419), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), protein import into nucleus (GO:0006606), lipid metabolic process (GO:0006629), response to osmotic stress (GO:0006970), DNA damage response (GO:0006974), vacuole organization (GO:0007033), JNK cascade (GO:0007254), positive regulation of gene expression (GO:0010628), negative regulation of angiogenesis (GO:0016525), peptidyl-threonine phosphorylation (GO:0018107), abducens nucleus development (GO:0021742), hypoglossal nucleus development (GO:0021743), facial nucleus development (GO:0021754), BMP signaling pathway (GO:0030509), mitotic intra-S DNA damage checkpoint signaling (GO:0031573), positive regulation of transforming growth factor beta2 production (GO:0032915), cellular response to oxidative stress (GO:0034599), p38MAPK cascade (GO:0038066), mRNA transcription by RNA polymerase II (GO:0042789), transcription initiation-coupled chromatin remodeling (GO:0045815), positive regulation of transcription by RNA polymerase II (GO:0045944), white fat cell differentiation (GO:0050872), obsolete positive regulation of DNA-binding transcription factor activity (GO:0051091), neurofilament cytoskeleton organization (GO:0060052), detection of cell density (GO:0060245), adipose tissue development (GO:0060612), brown fat cell proliferation (GO:0070342), cellular response to anisomycin (GO:0072740), energy homeostasis (GO:0097009)

GO Molecular Function (25): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), cis-regulatory region sequence-specific DNA binding (GO:0000987), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA-binding transcription factor activity (GO:0003700), histone acetyltransferase activity (GO:0004402), cAMP response element binding protein binding (GO:0008140), zinc ion binding (GO:0008270), histone H4 acetyltransferase activity (GO:0010485), protein kinase binding (GO:0019901), cAMP response element binding (GO:0035497), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), leucine zipper domain binding (GO:0043522), histone H2B acetyltransferase activity (GO:0044013), protein heterodimerization activity (GO:0046982), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), sequence-specific double-stranded DNA binding (GO:1990837), promoter-specific chromatin binding (GO:1990841), DNA binding (GO:0003677), chromatin binding (GO:0003682), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565), metal ion binding (GO:0046872)

GO Cellular Component (10): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrial outer membrane (GO:0005741), site of double-strand break (GO:0035861), RNA polymerase II transcription regulator complex (GO:0090575), H4 histone acetyltransferase complex (GO:1902562), mitochondrion (GO:0005739), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-18 pathways:

Category	Pathways
Toll-like Receptor Cascades	3
Toll Like Receptor 4 (TLR4) Cascade	2
Mitochondrial biogenesis	1
Chromatin modifying enzymes	1
MAPK targets/ Nuclear events mediated by MAP kinases	1
Transcriptional Regulation by TP53	1
PTEN Regulation	1
ESR-mediated signaling	1
Nuclear Events (kinase and transcription factor activation)	1
Cellular response to starvation	1
Cellular responses to stress	1
Circadian clock	1
Intracellular signaling by second messengers	1
Immune System	1
Organelle biogenesis and maintenance	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
transcription cis-regulatory region binding	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
growth plate cartilage development	2
regulation of gene expression	2
regulation of DNA-templated transcription	2
DNA-binding transcription factor binding	2
histone acetyltransferase activity	2
protein dimerization activity	2
intracellular membrane-bounded organelle	2
negative regulation of DNA-templated transcription	1
multicellular organismal-level homeostasis	1
chordate embryonic development	1
alpha-beta T cell differentiation	1
gland development	1
hepaticobiliary system development	1
hemopoiesis	1
cell differentiation	1
heart morphogenesis	1
anatomical structure morphogenesis	1
anatomical structure development	1
chondrocyte differentiation involved in endochondral bone morphogenesis	1
cell population proliferation	1
DNA-templated transcription	1
regulation of RNA biosynthetic process	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
primary metabolic process	1
response to stress	1
response to abiotic stimulus	1
cellular response to stress	1
organelle organization	1
MAPK cascade	1
gene expression	1
positive regulation of macromolecule biosynthetic process	1
angiogenesis	1

Protein interactions and networks

STRING

2750 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATF2	JUN	P05412	989
ATF2	FOS	P01100	853
ATF2	CREBBP	Q92793	795
ATF2	CREB1	P16220	795
ATF2	IRF3	Q14653	788
ATF2	EP300	Q09472	757
ATF2	MAPK8	P45983	723
ATF2	MAPK9	P45984	723
ATF2	MAPK11	Q15759	682
ATF2	SMAD4	Q13485	638
ATF2	TP53	P04637	623
ATF2	DUSP1	P28562	620
ATF2	MAPK1	P28482	596
ATF2	IRF7	Q92985	587
ATF2	PTP4A1	Q93096	575

IntAct

260 interactions, top by confidence:

A	B	Type	Score
FOS	JUN	psi-mi:“MI:0914”(association)	0.980
ATF2	JUN	psi-mi:“MI:0407”(direct interaction)	0.950
JUN	ATF2	psi-mi:“MI:0407”(direct interaction)	0.950
JUN	ATF2	psi-mi:“MI:0914”(association)	0.950
ATF2	JUN	psi-mi:“MI:0914”(association)	0.950
JUN	ATF2	psi-mi:“MI:0915”(physical association)	0.950
ATF2	JUN	psi-mi:“MI:0915”(physical association)	0.950
ATF2	FOS	psi-mi:“MI:0407”(direct interaction)	0.940
FOS	ATF2	psi-mi:“MI:0915”(physical association)	0.940
FOS	ATF2	psi-mi:“MI:0407”(direct interaction)	0.940
ATF2	FOS	psi-mi:“MI:0915”(physical association)	0.940
FOSL2	JUN	psi-mi:“MI:0914”(association)	0.930
BACH1	MAFG	psi-mi:“MI:0914”(association)	0.870
JUNB	ATF2	psi-mi:“MI:0407”(direct interaction)	0.820
ATF2	FOSL2	psi-mi:“MI:0407”(direct interaction)	0.810
FOSL2	ATF2	psi-mi:“MI:0407”(direct interaction)	0.810
ATF2	FOSL2	psi-mi:“MI:0915”(physical association)	0.810
ATF2	MAPK9	psi-mi:“MI:0915”(physical association)	0.780
MAPK9	ATF2	psi-mi:“MI:0915”(physical association)	0.780

BioGRID (400): ATF2 (Biochemical Activity), ATF2 (Biochemical Activity), ATF2 (Biochemical Activity), ATF2 (Biochemical Activity), ATF2 (Biochemical Activity), FOS (Two-hybrid), KIFC3 (Two-hybrid), MAPK9 (Two-hybrid), SUMO1 (Two-hybrid), EXOSC8 (Two-hybrid), ATF2 (Two-hybrid), ATF2 (Affinity Capture-Western), ATF2 (Affinity Capture-MS), ATF2 (Affinity Capture-MS), ATF2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2JTY4, A0JNC2, A2AQ25, E1BEQ5, O09000, O57539, O70305, O93602, P15336, P16951, P17544, P70365, P97305, Q00969, Q02930, Q12968, Q14157, Q15032, Q15596, Q15788, Q1LY51, Q4PJW2, Q4VCS5, Q5R9C9, Q5SFM8, Q5T5P2, Q5T6F2, Q61026, Q62415, Q6GP15, Q80TM6, Q80X50, Q86YP4, Q8CHY6, Q8IY63, Q8VCB2, Q8VHG2, Q8VHR5, Q8WXI9, Q91VX2

Diamond homologs: A0A0A2J9B3, A7YY54, B8NLU5, O77627, O93602, P05411, P05412, P05627, P09450, P11939, P12981, P15066, P15336, P16951, P17275, P17325, P17535, P17544, P18870, P23050, P24898, P27921, P52890, P52909, P54864, P56432, P78962, P79703, Q00969, Q02100, Q02930, Q09771, Q09926, Q0VBZ5, Q2U616, Q4WVQ7, Q59VR1, Q5R9C9, Q8K1L0, Q8R0S1

SIGNOR signaling

57 interactions.

A	Effect	B	Mechanism
VRK1	up-regulates	ATF2	phosphorylation
ATM	up-regulates	ATF2	phosphorylation
JNK	up-regulates	ATF2	phosphorylation
ROBO	up-regulates	ATF2	phosphorylation
MAPK1	up-regulates	ATF2	phosphorylation
MAPK14	up-regulates	ATF2	phosphorylation
MAPK3	up-regulates	ATF2	phosphorylation
MAPK9	up-regulates	ATF2	phosphorylation
PLK3	up-regulates	ATF2	phosphorylation
PRKCE	up-regulates	ATF2	phosphorylation
JDP2	“down-regulates activity”	ATF2	binding
MAPK14	“up-regulates activity”	ATF2	phosphorylation
ATF2	“up-regulates quantity by expression”	GCH1	“transcriptional regulation”
ATF2	“up-regulates quantity by expression”	PLAT	“transcriptional regulation”
ATF2	“up-regulates quantity by expression”	FGF21	“transcriptional regulation”
ATF2	“up-regulates quantity by expression”	POLB	“transcriptional regulation”
ATF2	“up-regulates quantity by expression”	ST3GAL5	“transcriptional regulation”
ATF2	up-regulates	IL6	“transcriptional regulation”
ERK1/2	up-regulates	ATF2	phosphorylation
ATF2	“up-regulates quantity by expression”	YTHDC2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 94 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
MAPK targets/ Nuclear events mediated by MAP kinases	5	46.1×	8e-06
ATF4 activates genes in response to endoplasmic reticulum stress	5	34.6×	3e-05
NGF-stimulated transcription	7	33.9×	2e-07
MAP kinase activation	5	26.2×	8e-05
Interleukin-17 signaling	5	21.5×	2e-04
Toll Like Receptor 10 (TLR10) Cascade	5	18.3×	3e-04
Toll Like Receptor 5 (TLR5) Cascade	5	18.3×	3e-04
MyD88 cascade initiated on plasma membrane	5	17.3×	4e-04

GO biological processes:

GO term	Partners	Fold	FDR
integrated stress response signaling	9	80.0×	6e-13
cellular response to calcium ion	5	12.7×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

83 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	1
Uncertain significance	49
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
154811	GRCh38/hg38 2q31.1(chr2:173713838-175467462)x1	Pathogenic
446338	GRCh37/hg19 2q31.1(chr2:175887486-176989647)x1	Pathogenic
562670	GRCh37/hg19 2q31.1(chr2:171667051-176832848)x3	Pathogenic
58768	GRCh38/hg38 2q31.1(chr2:173699279-175586070)x1	Pathogenic
253337	GRCh37/hg19 2q31.1(chr2:174586724-176423918)x1	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

3274 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:175080697:G:C	C418W	1.000
2:175080698:C:T	C418Y	1.000
2:175080699:A:G	C418R	1.000
2:175080706:A:C	H415Q	1.000
2:175080706:A:T	H415Q	1.000
2:175080708:G:C	H415D	1.000
2:175080708:G:T	H415N	1.000
2:175080711:C:G	A414P	1.000
2:175080713:A:G	L413P	1.000
2:175080716:A:G	L412P	1.000
2:175080716:A:T	L412H	1.000
2:175080719:A:G	L411P	1.000
2:175080728:A:G	L408P	1.000
2:175080728:A:T	L408Q	1.000
2:175080749:A:G	L401P	1.000
2:175093065:A:G	L394P	1.000
2:175093096:C:G	A384P	1.000
2:175093107:A:G	L380S	1.000
2:175093116:A:T	V377D	1.000
2:175093118:C:A	W376C	1.000
2:175093118:C:G	W376C	1.000
2:175093120:A:G	W376R	1.000
2:175093120:A:T	W376R	1.000
2:175093124:T:A	K374N	1.000
2:175093124:T:G	K374N	1.000
2:175093127:C:A	R373S	1.000
2:175093127:C:G	R373S	1.000
2:175093128:C:A	R373M	1.000
2:175093128:C:G	R373T	1.000
2:175093130:T:A	K372N	1.000

dbSNP variants (sampled 300 via entrez): RS1000003643 (2:175095235 T>C), RS1000049179 (2:175158767 T>G), RS1000096833 (2:175095024 T>C), RS1000107401 (2:175109460 C>A,G,T), RS1000168246 (2:175160883 T>C), RS1000228104 (2:175165582 T>C), RS1000228898 (2:175109676 A>G), RS1000267596 (2:175122552 A>G), RS1000271250 (2:175135779 C>T), RS1000386875 (2:175139663 C>A), RS1000437643 (2:175080579 T>C), RS1000442277 (2:175129046 A>G), RS1000487974 (2:175080186 C>T), RS1000528479 (2:175146993 T>C), RS1000534147 (2:175092900 C>G,T)

Disease associations

OMIM: gene MIM:123811 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5291557 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs7583431	Efficacy	3	fentanyl	Pain;Postoperative

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2302663	ATF2		0.00	0
rs3845744	ATF2		0.00	0
rs268214	ATF2, MIR933		0.00	0

CTD chemical–gene interactions

109 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases activity, increases phosphorylation, decreases reaction, increases expression, increases reaction (+1 more)	10
pyrazolanthrone	decreases reaction, increases phosphorylation, increases expression, decreases response to substance, increases activity	7
4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole	decreases reaction, increases phosphorylation, decreases response to substance, increases activity, affects phosphorylation	5
SB 203580	decreases reaction, increases phosphorylation, increases expression	5
Arsenic	increases expression, affects expression, affects methylation, affects cotreatment, increases abundance	3
Benzo(a)pyrene	increases expression, increases phosphorylation, decreases methylation	3
trichostatin A	affects cotreatment, decreases expression	2
2-aminodiphenyl	increases expression, increases phosphorylation, decreases reaction	2
cobaltous chloride	decreases reaction, increases expression, increases reaction	2
manganese chloride	increases phosphorylation, increases activity	2
hydroquinone	increases phosphorylation, affects reaction, decreases expression, increases expression, affects binding (+2 more)	2
U 0126	decreases reaction, increases expression, increases phosphorylation	2
O(2)-(2,4-dinitrophenyl) 1-((4-ethoxycarbonyl)piperazin-1-yl)diazen-1-ium-1,2-diolate	increases phosphorylation, decreases reaction	2
Bortezomib	increases expression, increases phosphorylation, decreases reaction	2
Resveratrol	increases activity, increases phosphorylation	2
Arsenic Trioxide	increases expression, increases phosphorylation, increases reaction	2
Cisplatin	decreases reaction, decreases response to substance, increases activity, increases phosphorylation, affects cotreatment (+1 more)	2
Copper	affects binding, increases expression, decreases activity, increases reaction, affects cotreatment	2
Valproic Acid	decreases methylation, decreases expression	2
Cyclosporine	increases expression	2
Copper Sulfate	decreases expression, increases phosphorylation	2
Particulate Matter	decreases reaction, increases phosphorylation, decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
dicrotophos	decreases expression	1
oxybenzone	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
bisphenol A	affects cotreatment, increases methylation	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5260503	Binding	Inhibition of ATF2 phosphorylation in human KOPT-K1 cells at 5 to 10 uM incubated for 24 hrs by immunoblot analysis	Rational Design of Highly Potent and Selective Covalent MAP2K7 Inhibitors. — ACS Med Chem Lett

Cellosaurus cell lines

15 cell lines: 10 cancer cell line, 3 embryonic stem cell, 2 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A0E2	SEES3-1V human ATF2, clone1	Embryonic stem cell	Male
CVCL_A0E3	SEES3-1V human ATF2, clone2	Embryonic stem cell	Male
CVCL_A0E4	SEES3-1V human ATF2, clone3	Embryonic stem cell	Male
CVCL_B8BK	Abcam HCT 116 ATF2 KO	Cancer cell line	Male
CVCL_B8SM	Abcam MCF-7 ATF2 KO	Cancer cell line	Female
CVCL_B9DQ	Abcam A-549 ATF2 KO	Cancer cell line	Male
CVCL_C8SL	SW1-P2	Cancer cell line	Sex unspecified
CVCL_C8SN	SW1-P2-CD83	Cancer cell line	Sex unspecified
CVCL_D7KM	Ubigene A-549 ATF2 KO	Cancer cell line	Male
CVCL_D8HK	Ubigene HCT 116 ATF2 KO	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.