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): 84 total — 4 pathogenic, 1 likely-pathogenic
• Regional missense constraint (gnomAD): 2 of 5 regions constrained (≈29% of expected missense variation)
• GTEx eGene: eQTL in 4 tissues, sQTL in 1 (q < 0.05)
• Constraint (gnomAD): pLI 0.86 (intermediate), LOEUF 0.54 (moderately constrained)
• MANE Select transcript: NM_001880
• Notable: 84 clinical variants but no curated precision-oncology (CIViC) evidence yet

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: 58 — 38 protein_coding, 17 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined, 1 retained_intron

MANE Select: ENST00000264110

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 11, TSL 3: 1, TSL 4: 1, TSL 5: 5

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, ENST00000977932, ENST00000977933, ENST00000977934, ENST00001044586, ENST00001044587, ENST00001044588, ENST00001044589, ENST00001070811, ENST00001070812, ENST00001070813, ENST00001070814, ENST00001098457, ENST00001111247, ENST00001111248, ENST00001111249, ENST00001111250, ENST00001144928

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.

Highest expression (Bgee): endothelial cell, germinal epithelium of ovary, Brodmann (1909) area 23, cortical plate, corpus epididymis.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ATF2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 4 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

5 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Brain Cerebellar Hemisphere	eqtl	1.2e-04	+0.55	2:176023377:A:G
Skin Sun Exposed Lower leg	sqtl	1.6e-02	-1.19	2:174771244:A:G
Skin Sun Exposed Lower leg	eqtl	1.9e-02	-0.22	2:174625009:A:C
Brain Caudate basal ganglia	eqtl	2.5e-02	-0.19	2:175287994:G:A
Uterus	eqtl	3.9e-02	+0.90	2:174637982:T:C

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

showing 100 of 300 tissues 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
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.12	gold quality
primary visual cortex	UBERON:0002436	93.07	gold quality
jejunal mucosa	UBERON:0000399	93.00	gold quality
biceps brachii	UBERON:0001507	92.88	gold quality
superior frontal gyrus	UBERON:0002661	92.76	gold quality
islet of Langerhans	UBERON:0000006	92.62	gold quality
postcentral gyrus	UBERON:0002581	92.62	gold quality
superior vestibular nucleus	UBERON:0007227	92.58	gold quality
tibia	UBERON:0000979	92.51	gold quality
epithelium of mammary gland	UBERON:0003244	92.43	gold quality
parietal lobe	UBERON:0001872	92.41	gold quality
CA1 field of hippocampus	UBERON:0003881	92.40	gold quality
thoracic mammary gland	UBERON:0005200	92.33	gold quality
mammary gland	UBERON:0001911	92.32	gold quality
lateral nuclear group of thalamus	UBERON:0002736	92.27	gold quality
cartilage tissue	UBERON:0002418	92.21	gold quality
orbitofrontal cortex	UBERON:0004167	92.07	gold quality
oocyte	CL:0000023	92.06	gold quality
jejunum	UBERON:0002115	92.06	gold quality
occipital lobe	UBERON:0002021	92.01	gold quality
mucosa of sigmoid colon	UBERON:0004993	91.89	gold quality
middle temporal gyrus	UBERON:0002771	91.85	gold quality
bronchial epithelial cell	CL:0002328	91.76	gold quality
tendon	UBERON:0000043	91.72	gold quality
medulla oblongata	UBERON:0001896	91.71	gold quality
lower lobe of lung	UBERON:0008949	91.70	gold quality
trigeminal ganglion	UBERON:0001675	91.68	gold quality
corpus callosum	UBERON:0002336	91.54	gold quality
cerebellar vermis	UBERON:0004720	91.50	gold quality
colonic mucosa	UBERON:0000317	91.45	gold quality
prefrontal cortex	UBERON:0000451	91.36	gold quality
lateral globus pallidus	UBERON:0002476	91.18	gold quality
sperm	CL:0000019	91.17	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	91.10	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	91.02	silver quality
embryo	UBERON:0000922	90.95	gold quality
epithelium of nasopharynx	UBERON:0001951	90.87	gold quality
nasopharynx	UBERON:0001728	90.85	gold quality
oral cavity	UBERON:0000167	90.76	gold quality
Brodmann (1909) area 9	UBERON:0013540	90.73	gold quality
cerebral cortex	UBERON:0000956	90.68	gold quality
bone marrow	UBERON:0002371	90.61	gold quality
bone marrow cell	CL:0002092	90.55	gold quality
skin of hip	UBERON:0001554	90.53	gold quality
subthalamic nucleus	UBERON:0001906	90.52	gold quality
uterus	UBERON:0000995	90.39	gold quality
inferior olivary complex	UBERON:0002127	90.35	silver quality
urethra	UBERON:0000057	90.34	gold quality
connective tissue	UBERON:0002384	90.33	gold quality
frontal cortex	UBERON:0001870	90.31	gold quality
neocortex	UBERON:0001950	90.30	gold quality
ovary	UBERON:0000992	90.26	gold quality
adipose tissue	UBERON:0001013	90.23	gold quality
dorsal root ganglion	UBERON:0000044	90.21	gold quality
eye	UBERON:0000970	90.18	gold quality
renal medulla	UBERON:0000362	90.16	gold quality
temporal lobe	UBERON:0001871	90.13	gold quality
synovial joint	UBERON:0002217	90.08	gold quality
popliteal artery	UBERON:0002250	90.07	gold quality
tibial artery	UBERON:0007610	90.07	gold quality
adult organism	UBERON:0007023	90.06	gold quality
saphenous vein	UBERON:0007318	90.04	gold quality
cerebellum	UBERON:0002037	89.95	gold quality
pericardium	UBERON:0002407	89.95	gold quality
Ammon’s horn	UBERON:0001954	89.89	gold quality
gall bladder	UBERON:0002110	89.89	gold quality
artery	UBERON:0001637	89.78	gold quality
cerebellar cortex	UBERON:0002129	89.78	gold quality
tonsil	UBERON:0002372	89.78	gold quality
telencephalon	UBERON:0001893	89.73	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

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 231 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Caudate putamen	tissue	74.4
Cerebellum	tissue	72.9	high
Frontal cortex	tissue	71.7
Hippocampal formation	tissue	67.6
Cerebral cortex	tissue	67.4	high
Occipital cortex	tissue	67.4
Somatosensory cortex	tissue	65.4
Entorhinal cortex	tissue	65.2
Prefrontal cortex	tissue	64.9
Motor cortex	tissue	64.6
Retrosplenial and cingulate cortex	tissue	63.6
Olfactory bulb	tissue	62.4
Retrosplenial cortex	tissue	62.3
Temporal cortex	tissue	61.7
Putamen	tissue	61.0
Septum	tissue	61.0
Insular cortex	tissue	60.7
Pons	tissue	60.4
Hypothalamus	tissue	60.2
Midbrain	tissue	60.1
Ventral forebrain	tissue	59.6
Thalamus	tissue	58.8
Basal ganglia	tissue	58.1	medium
Postcentral gyrus	tissue	57.9
Amygdala	tissue	57.6
Corpus callosum	tissue	57.6
Locus coeruleus	tissue	56.1
Superior colliculi	tissue	55.4
Periaqueductal gray	tissue	55.4
Substantia nigra	tissue	55.3
Medulla oblongata	tissue	53.3
Spinal cord	tissue	50.4
Hippocampus	tissue	47.5	high
Nucleus accumbens	tissue	45.5
Choroid plexus	tissue	30.6
Skeletal muscle	tissue	30.4	low
Thyroid gland	tissue	29.6	high
Thymus	tissue	27.1
Thymus	tissue	26.3
Liver	tissue	24.7	medium
Cervix	tissue	24.1	medium
Ovary	tissue	23.3	medium
Ovary	tissue	23.0	medium
Tongue	tissue	22.1
Parathyroid gland	tissue	21.2	medium
Thyroid gland	tissue	21.2	high
Choroid plexus	tissue	20.7
Endometrium 1	tissue	20.4	high
Epididymis	tissue	20.4	medium
Kidney	tissue	20.3	medium
Spinal cord	tissue	20.3
Tongue	tissue	20.1
Lymph node	tissue	20.1	medium
Tonsil	tissue	20.1	medium
Adrenal gland	tissue	20.0	high
Retina	tissue	19.6
Liver	tissue	19.4	medium
Placenta	tissue	19.1	high
Adrenal gland	tissue	19.1	high
Corpus callosum	tissue	19.0

Brain sub-regions (HPA Brain Atlas): detected in 573; highest nTPM — Cerebellar cortex (70.4), Subiculum (67.6), Orbitofrontal gyrus, anterior (66.8), Dorsal hippocampus (64.9), Flocculonodular lobe (63.2).

Regulation

Is transcription factor: yes

JASPAR motifs

Motif	Name	Family
MA1632.1	ATF2	Jun-related
MA1632.2	ATF2	Jun-related
UN1073.1	ATF2::TBX4	Jun-related,TBX2-related factors

JASPAR matrix evidence (PMIDs): PMID:20581861

miRNA regulators (miRDB)

Targeting ATF2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 136 miRNAs:

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

Functional genomics

gnomAD constraint: pLI 0.859, LOEUF 0.539, missense Z 2.66 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000264110 splits into 5 regions with different missense tolerance; 2 are missense-constrained (≈29% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
2:175,074,612–175,080,687	114 / 104.0	1.10	no
2:175,080,688–175,093,196	24 / 75.4	0.32	yes (p 3.2e-09)
2:175,093,197–175,118,281	246 / 309.3	0.80	no
2:175,118,282–175,130,190	29 / 102.1	0.28	yes (p 4.7e-13)
2:175,130,191–175,136,443	20 / 16.9	1.19	no

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)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:109349) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 56 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased body weight	3
cyanosis	2
neonatal lethality, complete penetrance	2
abnormal chondrocyte morphology	1
abnormal heart morphology	1
enlarged heart	1
abnormal urinary bladder morphology	1
abnormal spleen morphology	1
tremors	1
decreased brain size	1
decreased Purkinje cell number	1
ectopic Purkinje cell	1
abnormal testis morphology	1
small testis	1
abnormal lung morphology	1
thick epidermis	1
epidermal hyperplasia	1
ataxia	1
hyperactivity	1
impaired limb coordination	1
abnormal placenta labyrinth morphology	1
eye inflammation	1
respiratory failure	1
increased skin papilloma incidence	1
abnormal skin morphology	1

+31 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pongo abelii	Q5R9C9	99.8%	Diamond
Aspergillus flavus NRRL3357	B8NLU5	99.7%	Diamond
Aspergillus oryzae RIB40	Q2U616	99.7%	Diamond
Aspergillus parasiticus SU-1	A0A0F0IP79	93.7%	Diamond
Gallus gallus	O93602	92.8%	Diamond
Bos taurus	A7YY54	86.8%	Diamond
Schizosaccharomyces pombe 972h-	P52890	73.0%	Diamond
Penicillium expansum	A0A0A2J9B3	70.5%	Diamond
Parastagonospora nodorum SN15	Q0URD7	68.2%	Diamond
Arabidopsis thaliana	Q8W191	57.5%	Diamond
Candida albicans SC5314	Q59VR1	51.7%	Diamond
Aspergillus fumigatus Af293	Q4WVQ7	50.8%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
ATP5MC3	protein-coding	518
MIR933	ncRNA	100126350
CHN1	protein-coding	1123

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): B8ZZU6, C9JCI8, E9PBF9, E9PEK8, F2Z2K2, P15336, 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	Zf-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 by resolution:

PDB	Title	Method	Resolution (Å)
6ZQS	Crystal structure of double-phosphorylated p38alpha with ATF2(83-102)	X-RAY DIFFRACTION	1.95
8YPE	The crystal structure of inactive p38 complexed with a ATF2 from 46 to 80	X-RAY DIFFRACTION	1.95
8YPF	The crystal structure of inactive p38 complexed with a ATF2 from 46 to 90	X-RAY DIFFRACTION	2
9Y0R	Importin alpha 2 in complex with ATF2 basic region	X-RAY DIFFRACTION	2.2
6ZR5	Crystal structure of JNK1 in complex with ATF2(19-58)	X-RAY DIFFRACTION	2.7
1T2K	Structure Of The DNA Binding Domains Of IRF3, ATF-2 and Jun Bound To DNA	X-RAY DIFFRACTION	3
4H36	Crystal Structure of JNK3 in Complex with ATF2 Peptide	X-RAY DIFFRACTION	3
1BHI	STRUCTURE OF TRANSACTIVATION DOMAIN OF CRE-BP1/ATF-2, NMR, 20 STRUCTURES	SOLUTION NMR

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Predicted intracellular proteins, Transcription factors, Basic domains

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm

Antibody reliability (HPA): IH supported · IF supported

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)

Type	Positions
Phosphothreonine	52, 69, 71, 73, 116
Phosphoserine	62, 90, 112, 121, 136, 328, 340, 367, 442, 446, 490, 498
N6-acetyllysine	357, 374

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

4 curated (TAS) of 55; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

55 pathways:

ID	Pathway	Evidence
R-HSA-450341	Activation of the AP-1 family of transcription factors	curated
R-HSA-9018519	Estrogen-dependent gene expression	curated
R-HSA-3214847	HATs acetylate histones	curated
R-HSA-6796648	TP53 Regulates Transcription of DNA Repair Genes	curated
R-HSA-9711097	Cellular response to starvation	—
R-HSA-8953897	Cellular responses to stimuli	—
R-HSA-2262752	Cellular responses to stress	—
R-HSA-3247509	Chromatin modifying enzymes	—
R-HSA-4839726	Chromatin organization	—
R-HSA-9909396	Circadian clock	—
R-HSA-1280215	Cytokine Signaling in Immune system	—
R-HSA-8939211	ESR-mediated signaling	—
R-HSA-9931509	Expression of BMAL (ARNTL), CLOCK, and NPAS2	electronic
R-HSA-74160	Gene expression (Transcription)	—
R-HSA-212436	Generic Transcription Pathway	—
R-HSA-9707616	Heme signaling	electronic
R-HSA-168256	Immune System	—
R-HSA-168249	Innate Immune System	—
R-HSA-448424	Interleukin-17 signaling	—
R-HSA-9006925	Intracellular signaling by second messengers	—
R-HSA-450294	MAP kinase activation	—
R-HSA-450282	MAPK targets/ Nuclear events mediated by MAP kinases	—
R-HSA-1592230	Mitochondrial biogenesis	—
R-HSA-975871	MyD88 cascade initiated on plasma membrane	—
R-HSA-975155	MyD88 dependent cascade initiated on endosome	—
R-HSA-166166	MyD88-independent TLR4 cascade	—
R-HSA-166058	MyD88:MAL(TIRAP) cascade initiated on plasma membrane	—
R-HSA-9031628	NGF-stimulated transcription	electronic
R-HSA-198725	Nuclear Events (kinase and transcription factor activation)	—
R-HSA-1852241	Organelle biogenesis and maintenance	—
R-HSA-1257604	PIP3 activates AKT signaling	—
R-HSA-6807070	PTEN Regulation	—
R-HSA-73857	RNA Polymerase II Transcription	—
R-HSA-8943724	Regulation of PTEN gene transcription	electronic
R-HSA-9633012	Response of EIF2AK4 (GCN2) to amino acid deficiency	electronic
R-HSA-162582	Signal Transduction	—
R-HSA-449147	Signaling by Interleukins	—
R-HSA-187037	Signaling by NTRK1 (TRKA)	—
R-HSA-166520	Signaling by NTRKs	—
R-HSA-9006931	Signaling by Nuclear Receptors	—
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases	—
R-HSA-975138	TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	—
R-HSA-937061	TRIF (TICAM1)-mediated TLR4 signaling	—
R-HSA-168142	Toll Like Receptor 10 (TLR10) Cascade	—
R-HSA-181438	Toll Like Receptor 2 (TLR2) Cascade	—
R-HSA-168164	Toll Like Receptor 3 (TLR3) Cascade	—
R-HSA-166016	Toll Like Receptor 4 (TLR4) Cascade	—
R-HSA-168176	Toll Like Receptor 5 (TLR5) Cascade	—
R-HSA-168181	Toll Like Receptor 7/8 (TLR7/8) Cascade	—
R-HSA-168138	Toll Like Receptor 9 (TLR9) Cascade	—
R-HSA-168179	Toll Like Receptor TLR1:TLR2 Cascade	—
R-HSA-168188	Toll Like Receptor TLR6:TLR2 Cascade	—
R-HSA-168898	Toll-like Receptor Cascades	—
R-HSA-3700989	Transcriptional Regulation by TP53	—
R-HSA-2151201	Transcriptional activation of mitochondrial biogenesis	electronic

MSigDB gene sets: 0 (showing top):

GO Biological Process (44): negative regulation of transcription by RNA polymerase II (GO:0000122), in utero embryonic development (GO:0001701), NK T cell differentiation (GO:0001865), liver development (GO:0001889), hematopoietic progenitor cell differentiation (GO:0002244), 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), heart development (GO:0007507), 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), 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), neurofilament cytoskeleton organization (GO:0060052), detection of cell density (GO:0060245), cellular response to anisomycin (GO:0072740), motor neuron apoptotic process (GO:0097049), hepatocyte apoptotic process (GO:0097284), cellular response to virus (GO:0098586), positive regulation of cardiac muscle myoblast proliferation (GO:0110024), positive regulation of mitochondrial membrane permeability involved in apoptotic process (GO:1902110), intrinsic apoptotic signaling pathway in response to hypoxia (GO:1990144), cellular response to leucine starvation (GO:1990253), MAPK cascade (GO:0000165), apoptotic process (GO:0006915), gene expression (GO:0010467)

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 (8): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrial outer membrane (GO:0005741), site of double-strand break (GO:0035861), H4 histone acetyltransferase complex (GO:1902562), membrane (GO:0016020)

Reactome top-level categories

18 top-level categories:

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
Toll Like Receptor TLR1:TLR2 Cascade	1
Toll Like Receptor TLR6:TLR2 Cascade	1
Signaling by Receptor Tyrosine Kinases	1

GO top-level categories

showing 60 of 67 GO namespaces:

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
negative regulation of DNA-templated transcription	1
chordate embryonic development	1
alpha-beta T cell differentiation	1
gland development	1
hepaticobiliary system development	1
hemopoiesis	1
cell differentiation	1
animal gross anatomical part developmental process	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
animal organ development	1
circulatory system development	1
gene expression	1
positive regulation of macromolecule biosynthetic process	1
angiogenesis	1
regulation of angiogenesis	1
negative regulation of blood vessel morphogenesis	1
protein phosphorylation	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
transcription regulator activity	1
protein-lysine-acetyltransferase activity	1
histone modifying activity	1
transition metal ion binding	1
kinase binding	1
RNA polymerase II cis-regulatory region sequence-specific DNA binding	1
protein binding	1
identical protein binding	1
LRR domain binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
chromatin binding	1
chromosome	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 35 of 77 annotations. The rest are phylogenetic / computational / electronic (IEA).

35 experimentally-supported GO terms:

GO term	NS	Evidence
DNA damage response	BP	direct assay
cellular response to leucine starvation	BP	direct assay
mitotic intra-S DNA damage checkpoint signaling	BP	mutant phenotype
negative regulation of angiogenesis	BP	mutant phenotype
negative regulation of transcription by RNA polymerase II	BP	experiment
peptidyl-threonine phosphorylation	BP	direct assay
positive regulation of cardiac muscle myoblast proliferation	BP	direct assay
positive regulation of gene expression	BP	mutant phenotype
positive regulation of mitochondrial membrane permeability involved in apoptotic process	BP	mutant phenotype
positive regulation of transcription by RNA polymerase II	BP	direct assay
regulation of DNA-templated transcription	BP	mutant phenotype
regulation of transcription by RNA polymerase II	BP	direct assay
response to osmotic stress	BP	direct assay
transcription initiation-coupled chromatin remodeling	BP	direct assay
H4 histone acetyltransferase complex	CC	direct assay
chromatin	CC	direct assay
cytoplasm	CC	direct assay
mitochondrial outer membrane	CC	direct assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
site of double-strand break	CC	direct assay
DNA-binding transcription activator activity, RNA polymerase II-specific	MF	direct assay
DNA-binding transcription factor activity	MF	direct assay
RNA polymerase II cis-regulatory region sequence-specific DNA binding	MF	direct assay
RNA polymerase II transcription regulatory region sequence-specific DNA binding	MF	mutant phenotype
RNA polymerase II-specific DNA-binding transcription factor binding	MF	physical interaction
cAMP response element binding	MF	direct assay
cAMP response element binding protein binding	MF	direct assay
cis-regulatory region sequence-specific DNA binding	MF	direct assay
histone H2B acetyltransferase activity	MF	direct assay
histone H4 acetyltransferase activity	MF	direct assay
identical protein binding	MF	physical interaction
promoter-specific chromatin binding	MF	direct assay
protein kinase binding	MF	physical interaction
sequence-specific double-stranded DNA binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,624 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATF2	MAPK8	P45983	699
ATF2	MAPK9	P45984	697
ATF2	JUN	P05412	681
ATF2	MAPK11	Q15759	661
ATF2	CREB1	P16220	615
ATF2	PPARGC1A	Q9UBK2	605
ATF2	DUSP1	P28562	578
ATF2	ATF5	Q9Y2D1	563
ATF2	PTP4A1	Q93096	553
ATF2	MAPK14	Q16539	523
ATF2	MAP2K3	P46734	493
ATF2	UBE2B	P23567	490
ATF2	MAPK13	O15264	434
ATF2	STAT3	P40763	429
ATF2	UCP1	P25874	427

IntAct

Human interaction partners of ATF2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 54 partners by confidence:

Partner	Interaction type	MIscore	Records
JUN	direct interaction	0.950	18
FOS	direct interaction	0.940	14
JUNB	direct interaction	0.820	2
FOSL2	direct interaction	0.810	5
MAPK9	physical association	0.780	10
BACH1	association	0.780	3
BATF3	direct interaction	0.780	2
JUND	direct interaction	0.760	3
SUMO1	physical association	0.720	6
ATF3	direct interaction	0.710	5
CEBPG	direct interaction	0.710	2
ATF7	direct interaction	0.690	1
FOSL1	direct interaction	0.690	1
CENPQ	physical association	0.670	3
FOSB	physical association	0.670	3
DDIT3	direct interaction	0.620	2
HK1	physical association	0.580	3
VRK1	physical association	0.570	5
KIFC3	physical association	0.560	6
BANP	physical association	0.560	3
EXOSC8	physical association	0.560	3
HBZ	direct interaction	0.560	3
LHX8	physical association	0.560	3
PIAS2	physical association	0.560	3
RNF4	physical association	0.560	3
SPOPL	physical association	0.560	3
JDP2	physical association	0.550	1
SYT-SSX2	association	0.530	10
ZDHHC17	physical association	0.510	3
SS18	physical association	0.500	2

BioGRID (401 interactions; top human partners by supporting records): MAPK14 (Biochemical Activity; 28 records), MAPK8 (Biochemical Activity; 15 records), JUN (Affinity Capture-MS; 14 records), FOS (Two-hybrid; 10 records), CREBBP (Reconstituted Complex; 9 records), MAPK9 (Biochemical Activity; 8 records), FOSL2 (Affinity Capture-MS; 4 records), MAPK1 (Biochemical Activity; 4 records), SS18 (Affinity Capture-MS; 4 records), SSX2 (Affinity Capture-MS; 4 records), USP14 (Affinity Capture-MS; 4 records), ATF3 (Two-hybrid; 3 records), BATF3 (Affinity Capture-MS; 3 records), CREB5 (Affinity Capture-MS; 3 records), HK1 (Affinity Capture-Western; 3 records)

SIGNOR signaling

showing 34 of 57 signaling 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”
Gbeta	up-regulates	ATF2	phosphorylation
p38	up-regulates	ATF2	phosphorylation
PAK1	“down-regulates activity”	ATF2	phosphorylation
AKT2	“up-regulates activity”	ATF2	phosphorylation
MAPK8	up-regulates	ATF2	phosphorylation
SMAD3/SMAD4	“up-regulates activity”	ATF2	binding
MAPK11	up-regulates	ATF2	phosphorylation
MAPK12	up-regulates	ATF2	phosphorylation
BTRC	“down-regulates quantity by destabilization”	ATF2	ubiquitination
ATF2	“down-regulates quantity by repression”	SIRT4	“transcriptional regulation”
CREB5	“up-regulates activity”	ATF2	binding
N	“up-regulates quantity by expression”	ATF2	“transcriptional regulation”
ATF2	up-regulates	Proliferation
FH	“up-regulates activity”	ATF2	binding

Protein complexes (CORUM) (2)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

2 complexes by size:

Complex	Subunits	Members
ATF2-HK1-VDAC1 complex	3	VDAC1, ATF2, HK1
★ AR-ATF2-JUN complex	3	AR, ATF2, JUN

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 54 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	7	95.2×	8e-11
MAP kinase activation	7	54.0×	5e-09
Nuclear Events (kinase and transcription factor activation)	6	51.9×	4e-08
ATF4 activates genes in response to endoplasmic reticulum stress	5	51.0×	5e-07
Interleukin-17 signaling	7	44.4×	1e-08
FCERI mediated MAPK activation	5	43.3×	1e-06
NGF-stimulated transcription	6	42.8×	8e-08
Toll Like Receptor 10 (TLR10) Cascade	7	37.7×	3e-08

GO biological processes:

GO term	Partners	Fold	FDR
integrated stress response signaling	9	129.0×	5e-15
cellular response to calcium ion	5	20.5×	4e-04
intracellular signal transduction	7	5.5×	7e-03

Disease & clinical

Genetic variants

Variant evidence for ATF2: 84 ClinVar records (5 pathogenic / likely pathogenic). Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	1
Uncertain significance	50
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (5)

Showing all 5 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
58768	GRCh38/hg38 2q31.1(chr2:173699279-175586070)x1	Pathogenic	criteria provided, single submitter	1
446338	GRCh37/hg19 2q31.1(chr2:175887486-176989647)x1	Pathogenic	criteria provided, single submitter	1
253337	GRCh37/hg19 2q31.1(chr2:174586724-176423918)x1	Likely pathogenic	criteria provided, single submitter	1
154811	GRCh38/hg38 2q31.1(chr2:173713838-175467462)x1	Pathogenic	no assertion criteria provided	1
562670	GRCh37/hg19 2q31.1(chr2:171667051-176832848)x3	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore ATF2’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

AlphaMissense

1,111 missense substitutions predicted likely pathogenic (of 3,274 scored), across 266 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M51	9	0.945	0.999
H49	8	1.000	1.000
N362	8	1.000	1.000
H45	8	0.999	1.000
H415	8	0.999	1.000
D40	8	0.998	1.000
F75	8	0.998	1.000
F36	8	0.996	1.000
H41	8	0.996	1.000
D67	8	0.994	0.998
F85	8	0.994	1.000
F358	8	0.993	1.000
N78	8	0.989	0.998
F55	8	0.975	0.998
F25	8	0.971	1.000
H47	8	0.962	0.998
N38	8	0.942	0.998
F92	8	0.929	0.988
D417	8	0.904	0.979
N391	8	0.887	0.992

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

7 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	6.98e-06
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	8.34e-06
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	1.37e-05
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	0.000184
Kidney Chromophobe (TCGA)	unfavorable	0.00038
Ovary Serous Cystadenocarcinoma (validation)	unfavorable	0.000442
Glioblastoma Multiforme (validation)	favorable	0.000565

Disease associations

OMIM: gene MIM:123811 | disease phenotypes:

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5291557 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, increases reaction, decreases expression, increases activity, increases phosphorylation (+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	affects expression, affects methylation, affects cotreatment, increases abundance, increases expression	3
Benzo(a)pyrene	increases phosphorylation, decreases methylation, increases expression	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	decreases reaction, increases phosphorylation, affects reaction, decreases expression, increases expression (+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	decreases reaction, increases expression, increases phosphorylation	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	increases expression, decreases activity, increases reaction, affects cotreatment, affects binding	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)

Via MONDO — disease-level, not drug-specific.