ETS2

Summary

ETS2 (ETS proto-oncogene 2, transcription factor, HGNC:3489) is a protein-coding gene on chromosome 21q22.2, encoding Protein C-ets-2 (P15036). Transcription factor activating transcription. In precision oncology, ETS2 RS461155 confers sensitivity to Paclitaxel + Cisplatin in Lung Non-small Cell Carcinoma (CIViC Level B).

This gene encodes a transcription factor which regulates genes involved in development and apoptosis. The encoded protein is also a protooncogene and shown to be involved in regulation of telomerase. A pseudogene of this gene is located on the X chromosome. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 2114 — RefSeq curated summary.

At a glance

• GWAS associations: 19
• Clinical variants (ClinVar): 65 total — 1 pathogenic
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• Transcription factor: yes — 126 downstream targets (CollecTRI)
• MANE Select transcript: NM_005239

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3489
Approved symbol	ETS2
Name	ETS proto-oncogene 2, transcription factor
Location	21q22.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000157557
Ensembl biotype	protein_coding
OMIM	164740
Entrez	2114

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 21 protein_coding

ENST00000360214, ENST00000360938, ENST00000432278, ENST00000456966, ENST00000653642, ENST00000662305, ENST00000665212, ENST00000666778, ENST00000667466, ENST00000859949, ENST00000859950, ENST00000859951, ENST00000859952, ENST00000859953, ENST00000859954, ENST00000938968, ENST00000938969, ENST00000938970, ENST00000968689, ENST00000968690, ENST00000968691

RefSeq mRNA: 2 — MANE Select: NM_005239 NM_001256295, NM_005239

CCDS: CCDS13659

Canonical transcript exons

ENST00000360938 — 10 exons

Exon	Start	End
ENSE00001033362	38819503	38819766
ENSE00001033363	38817008	38817091
ENSE00001033370	38805929	38806120
ENSE00001033372	38813003	38813114
ENSE00001033374	38814273	38814392
ENSE00001302098	38821586	38821704
ENSE00001427195	38822674	38824955
ENSE00001771688	38810035	38810106
ENSE00003788495	38818425	38818646
ENSE00003791296	38814781	38814981

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 98.81.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 91.4127 / max 1797.1597, expressed in 1812 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
189134	86.0977	1811
189135	4.4307	1324
189131	0.2830	149
189132	0.1532	57
189138	0.1403	53
189140	0.1371	46
189133	0.1058	42
189137	0.0648	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skin of abdomen	UBERON:0001416	98.81	gold quality
mucosa of urinary bladder	UBERON:0001259	98.65	gold quality
skin of leg	UBERON:0001511	98.56	gold quality
mucosa of stomach	UBERON:0001199	98.35	gold quality
rectum	UBERON:0001052	98.34	gold quality
spleen	UBERON:0002106	98.33	gold quality
upper lobe of left lung	UBERON:0008952	98.31	gold quality
upper lobe of lung	UBERON:0008948	98.17	gold quality
ectocervix	UBERON:0012249	98.04	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.00	gold quality
right lung	UBERON:0002167	97.96	gold quality
colonic epithelium	UBERON:0000397	97.92	gold quality
gall bladder	UBERON:0002110	97.86	gold quality
endocervix	UBERON:0000458	97.80	gold quality
zone of skin	UBERON:0000014	97.73	gold quality
left uterine tube	UBERON:0001303	97.57	gold quality
vagina	UBERON:0000996	97.54	gold quality
descending thoracic aorta	UBERON:0002345	97.50	gold quality
upper leg skin	UBERON:0004262	97.43	gold quality
lung	UBERON:0002048	97.39	gold quality
lower lobe of lung	UBERON:0008949	97.28	gold quality
ascending aorta	UBERON:0001496	97.22	gold quality
small intestine Peyer’s patch	UBERON:0003454	97.19	gold quality
middle temporal gyrus	UBERON:0002771	97.18	gold quality
urinary bladder	UBERON:0001255	97.17	gold quality
thoracic aorta	UBERON:0001515	97.17	gold quality
omental fat pad	UBERON:0010414	97.16	gold quality
peritoneum	UBERON:0002358	97.15	gold quality
transverse colon	UBERON:0001157	97.06	gold quality
small intestine	UBERON:0002108	97.00	gold quality

Single-cell (SCXA)

Detected in 12 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-GEOD-86618	yes	426.63
E-CURD-114	yes	64.07
E-GEOD-135922	yes	49.54
E-CURD-112	yes	22.72
E-GEOD-125970	yes	17.83
E-MTAB-10553	yes	6.98
E-ENAD-27	yes	6.74
E-MTAB-10042	yes	6.10
E-GEOD-130148	yes	5.16
E-CURD-122	yes	4.53
E-MTAB-10596	no	212.89
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

126 targets.

Target	Regulation
ABCB1
ACKR3
ADAM2
ADIPOQ
ANGPT2	Activation
ANPEP	Activation
AP1	Unknown
APP	Unknown
BCL2L1	Unknown
BGLAP	Activation
BIRC3
BRCA1	Repression
C1QTNF5
CAT
CCND1	Activation
CD163	Unknown
CD34
CD4	Activation
CD79A
CDK1	Unknown
CDKN1A	Unknown
CDKN2A	Unknown
CGA	Activation
CGB3
CHRNE	Activation
CREBBP
CSF1	Unknown
CSF1R	Unknown
CSF2	Activation
CSF3R	Activation

JASPAR motifs

Motif	Name	Family
MA1484.1	ETS2	Ets-related
MA1484.2	ETS2	Ets-related

JASPAR matrix evidence (PMIDs): PMID:20517297

Upstream regulators (CollecTRI, top): ARX, ERF, ETS1, ETS2, ETV7, FLI1, JUN, JUNB, KDM6A, MYB, MYC, PGR, SP1, SPI1, TAF1, TBP, ZNF699

miRNA regulators (miRDB)

112 targeting ETS2, 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-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-4668-3P	100.00	68.74	2635
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-300	99.92	71.76	2856

Literature-anchored findings (GeneRIF, showing 40)

• Linkage of elevated expression to hepatocarcinogenesis (PMID:12174931)
• Two closely spaced Ets-2 binding sites in the proximal promoter of the human chorionic gonadotropin beta5 (hCGbeta5) gene constitute a major enhancer for hCGbeta gene expression in JAr and JEG-3 human choriocarcinoma cells and in mouse NIH3T3 cells. (PMID:12511603)
• Overexpression of ETS2 in human esophageal squamous cell carcinoma in both mRNA and protein levels. (PMID:12532432)
• ets-2 has a role as a repressor and indicate that components of the mammalian SNF/SWI complex are required as co-repressors (PMID:12637547)
• ETS2 is a target of protein kinase C and upregulates GM-CSF (PMID:12646185)
• Ets-2 and its targets play essential roles in endothelial cell function (PMID:14507917)
• Ras/mitogen-activated kinase signaling activates ETS2 by CBP/p300 recruitment. (PMID:15572696)
• Coexpression of Ets-2 and SRC-1 significantly associated with the rate of recurrence and HER expression in breast cancer (PMID:15788656)
• Phosphorylated ERK1/2 was further associated with the presence of VEGFR2 (cohorts II and III) and the degree of phosphorylated Ets-2, indicating in vivo, a signalling cascade from VEGFR2 via ERK1/2 to Ets-2 phosphorylation (PMID:15806151)
• analysis of Ets2 in cell-seeded three-dimensional bone constructs (PMID:15900611)
• c-Myb and c-Ets family members (Ets-1/2, PU.1, and Spi-B) control hGR 1A promoter regulation in T- and B-lymphoblast cells (PMID:16263717)
• Data show that transcription of the putative tumor suppressor gene HCCS1 requires binding of ETS-2 to its consensus near the transcription start site. (PMID:16953216)
• Results suggest that there is a strong interplay of Ets2 with bone-specific proteins in cell-seeded three-dimensional bone constructs. (PMID:17703088)
• data of study population indicate a higher ETS2 RNA concentration compared with uPA in the case of bladder cancer, resulting in an increased ETS2:uPA RNA ratio in urine (PMID:17921261)
• Data show that there are combinatorial effects of Ets2, PKA, and CBP/p300 and triggered via growth factors released from maternal endometrium. (PMID:17975022)
• Expression of Ets-2, SRC-1 and c-Myc individually are all associated with reduced disease-free survival in breast cancer (PMID:18059336)
• In erythroleukemia cells, induction of ETS2 caused an erythroid-to-megakaryocytic phenotypic switch, cytokine & transcription factor upregulation,& sensitivity to ara-C & daunorubicin. (PMID:18094719)
• hTERT gene expression is maintained by a mechanism involving Ets2 interactions with the c-Myc transcription factor and the hTERT gene promoter, a protein-DNA complex critical for hTERT gene expression and breast cancer cell proliferation. (PMID:18586674)
• Hepatitis B virus-induced hFGL2 transcription is dependent on c-Ets-2 and MAPK signal pathway (PMID:18801734)
• These results indicate that intron 1 of DUSP6 plays a crucial role in transcriptional regulation of DUSP6 in a feedback loop manner responding to MAPK1 via ETS2 in human cells. (PMID:18848526)
• Ets2 may be an important transcription factor driving inflammation in acute as well as chronic inflammatory disease (PMID:18942749)
• This study analysed differences in the expression pattern of the osteogenic transcription factor Ets2 in primary bone precursor cells grown in different three-dimensional scaffolds; scaffold type has an influence on the expression level of Ets2. (PMID:19318269)
• Fluorescent in situ hybridisation analysis on FGFR4, ETS2 and brachyury failed to show either amplification or translocation for ERG and ETS2 loci (PMID:19407855)
• Ets-2 and p53 mediate cAMP- induced trophoblast invasiveness, through regulation of MMP-2. (PMID:19939245)
• Ets2 is a central driver of a transcriptional program in tumor-associated macrophages that acts to promote lung metastasis of breast tumors. (PMID:20145133)
• the differential up-regulation of MKP3 by Ets2 and of DUSP5 by c-Jun may converge in similar functional roles for these MAP kinase phosphatases in the growth arrest versus proliferation decisions of breast cancer cells (PMID:20554528)
• transcription factors Ets-1 and Ets-2 play a key role in controlling the expression of miR-126 and suggest that miR-126 may mediate some of their vascular effects (PMID:20671229)
• Allelic discrimination of deleterious SNPs in ETS2 may play a regulatory role in the differential development of malignancy in Down syndrome subjects. (PMID:21526717)
• These data indicate the importance of phosphorylated ets-2 in the pathogenesis of pulmonary fibrosis through the expression of Type I collagen and (myo)fibroblast activation. (PMID:21562315)
• evidence for the plaque-destabilizing role of Ets2 in atherosclerosis development by induction of an intraplaque proinflammatory phenotype in endothelial cells. (PMID:21700929)
• data firmly implicate RuvBl2 in Ets2 mediated regulation of hTERT in colon cancer which has functional and clinical consequences (PMID:21763315)
• rs461155 and rs2073601, in ETS2 and SIM2 genes respectively, showed significant redundant interaction in probands with Down syndrome (PMID:22048266)
• a stage-specific Ets-1-independent regulatory role for Ets-2 in early thymocyte development and survival (PMID:22128184)
• Amplified segment in the ‘Down syndrome critical region’ on HSA21 shared between Down syndrome and euploid AML-M0 excludes RUNX1, ERG and ETS2. (PMID:22221250)
• demonstrated that miR-196b was transcriptionally regulated by ETS2 and there was an inverse expression profile between miR-196b and ETS2 in clinical samples (PMID:22298639)
• c-Jun in cooperation with Ets2 increases the expression of Syk and contributes to Syk-mediated heightened calcium responses in systemic lupus erythematosus T cells. (PMID:22354960)
• In embryonic stem cells [which express ETS2 (proto-oncogene c-ETS-2) but not CGA (alpha subunit chorionic gonadotropin)], ETS2 does not occupy binding site on CGA promoter but is found as soluble complex with POU5F1 (Oct3 transcription factor). (PMID:22446105)
• The SAM domain of human TEL2 can inhibit the transcriptional activities of ETS1/2 and TEL1. (PMID:22615925)
• Data suggest that the regulation of MDR1 expression by ETS2 may provide potential ways to overcome MDR in cancer treatment. (PMID:22819965)
• Transcription factors ETS2 and MESP1 transdifferentiate human dermal fibroblasts into cardiac progenitors. (PMID:22826236)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ets2	ENSMUSG00000022895
rattus_norvegicus	Ets2	ENSRNOG00000001647

Paralogs (28): ETV1 (ENSG00000006468), ETV7 (ENSG00000010030), SPI1 (ENSG00000066336), ELF4 (ENSG00000102034), ETV2 (ENSG00000105672), ERF (ENSG00000105722), ELF2 (ENSG00000109381), ELK3 (ENSG00000111145), ETV3 (ENSG00000117036), ELF1 (ENSG00000120690), SPDEF (ENSG00000124664), ELK1 (ENSG00000126767), ETS1 (ENSG00000134954), EHF (ENSG00000135373), ELF5 (ENSG00000135374), ETV6 (ENSG00000139083), FLI1 (ENSG00000151702), GABPA (ENSG00000154727), ERG (ENSG00000157554), ELK4 (ENSG00000158711), ELF3 (ENSG00000163435), FEV (ENSG00000163497), SPIC (ENSG00000166211), ETV4 (ENSG00000175832), ETV5 (ENSG00000244405), ETV3L (ENSG00000253831), ERFL (ENSG00000268041), SPIB (ENSG00000269404)

Protein

Protein identifiers

Protein C-ets-2 — P15036 (reviewed: P15036)

All UniProt accessions (5): P15036, A0A0C4DG47, A0A590UJP9, A0A590UJR2, C9JAG2

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor activating transcription. Binds specifically the DNA GGAA/T core motif (Ets-binding site or EBS) in gene promoters and stimulates transcription.

Subcellular location. Nucleus.

Post-translational modifications. Phosphorylation by CDK10 at Ser-220 and Ser-225 creates a phosphodegron that targets ETS2 for proteasomal degradation.

Similarity. Belongs to the ETS family.

RefSeq proteins (2): NP_001243224, NP_005230* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000418	Ets_dom	Domain
IPR003118	Pointed_dom	Domain
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR016311	Transform_prot_C-ets	Family
IPR027276	Transform_prot_C-ets-2	Family
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR045688	Ets1_N_flank	Domain
IPR046328	ETS_fam	Family

Pfam: PF00178, PF02198, PF19525

UniProt features (35 total): helix 18, strand 6, modified residue 5, turn 2, chain 1, domain 1, DNA-binding region 1, region of interest 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4MHV	X-RAY DIFFRACTION	2.45
4BQA	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P15036-F1	63.96	0.27

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 (5): 220, 225, 295, 298, 301

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2559585	Oncogene Induced Senescence

MSigDB gene sets: 455 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, GSE45365_NK_CELL_VS_CD11B_DC_DN, WALLACE_PROSTATE_CANCER_RACE_UP, GOBP_AXIS_SPECIFICATION, DORSAM_HOXA9_TARGETS_UP, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_FORMATION_OF_PRIMARY_GERM_LAYER, JAEGER_METASTASIS_DN, ENK_UV_RESPONSE_KERATINOCYTE_UP, HALMOS_CEBPA_TARGETS_UP, GOBP_PRIMITIVE_STREAK_FORMATION, KEGG_DORSO_VENTRAL_AXIS_FORMATION, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, NAGASHIMA_NRG1_SIGNALING_UP

GO Biological Process (9): negative regulation of transcription by RNA polymerase II (GO:0000122), skeletal system development (GO:0001501), ectodermal cell fate commitment (GO:0001712), regulation of transcription by RNA polymerase II (GO:0006357), mesoderm development (GO:0007498), cell differentiation (GO:0030154), positive regulation of transcription by RNA polymerase II (GO:0045944), primitive streak formation (GO:0090009), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (12): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein domain specific binding (GO:0019904), nuclear glucocorticoid receptor binding (GO:0035259), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), sequence-specific double-stranded DNA binding (GO:1990837), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), plasma membrane (GO:0005886)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Cellular Senescence	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	3
transcription by RNA polymerase II	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
regulation of DNA-templated transcription	2
transcription cis-regulatory region binding	2
negative regulation of DNA-templated transcription	1
system development	1
ectoderm formation	1
ectodermal cell differentiation	1
cell fate commitment involved in formation of primary germ layer	1
tissue development	1
cellular developmental process	1
positive regulation of DNA-templated transcription	1
gastrulation with mouth forming second	1
anterior/posterior axis specification	1
anatomical structure formation involved in morphogenesis	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription repressor activity	1
nucleic acid binding	1
transcription regulator activity	1
protein binding	1
nuclear receptor binding	1
DNA-binding transcription factor binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
binding	1
DNA binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
membrane	1

Protein interactions and networks

STRING

1986 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ETS2	TP53	P04637	921
ETS2	CDK10	Q15131	874
ETS2	FOS	P01100	800
ETS2	GATA1	P15976	759
ETS2	PCP4	P48539	697
ETS2	GATA3	P23771	690
ETS2	RUNX1	Q01196	655
ETS2	SRC	P12931	608
ETS2	SMARCA4	P51532	607
ETS2	TERT	O14746	592
ETS2	ESRRB	O95718	592
ETS2	ID1	P41134	588
ETS2	FOSL2	P15408	573
ETS2	ASXL2	Q76L83	573
ETS2	ESR1	P03372	560

IntAct

59 interactions, top by confidence:

A	B	Type	Score
ETS2	TP53	psi-mi:“MI:0915”(physical association)	0.600
ETS2	TP53	psi-mi:“MI:0407”(direct interaction)	0.600
ETS2	SERPINH1	psi-mi:“MI:0915”(physical association)	0.560
ETS2		psi-mi:“MI:0915”(physical association)	0.560
ETS2	PRKACA	psi-mi:“MI:0915”(physical association)	0.560
ETS2	TGFBR2	psi-mi:“MI:0915”(physical association)	0.560
ETS2	COP1	psi-mi:“MI:0915”(physical association)	0.560
ETS2	CDK10	psi-mi:“MI:0915”(physical association)	0.520
TWIST1	ETS2	psi-mi:“MI:0915”(physical association)	0.520
TWIST2	ETS2	psi-mi:“MI:0915”(physical association)	0.520
ETS2	TWIST1	psi-mi:“MI:0915”(physical association)	0.520
NFE2L2	ETS2	psi-mi:“MI:0915”(physical association)	0.510
COP1	ETS2	psi-mi:“MI:0914”(association)	0.460
CCNQ	ETS2	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
CDK10	ETS2	psi-mi:“MI:0915”(physical association)	0.370
ZFYVE9	ETS2	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (86): CDK10 (Two-hybrid), ETS2 (Affinity Capture-Western), ETS2 (Proximity Label-MS), VPS51 (Affinity Capture-MS), CTDP1 (Affinity Capture-MS), GTF3C5 (Affinity Capture-MS), IMPACT (Affinity Capture-MS), RFWD2 (Affinity Capture-MS), MRPL14 (Affinity Capture-MS), ANKS6 (Affinity Capture-MS), RFWD2 (Affinity Capture-Western), DET1 (Affinity Capture-Western), TP53 (Affinity Capture-Western), ZMYND11 (Two-hybrid), ETS2 (Phenotypic Enhancement)

ESM2 similar proteins: A0A1B0GTS1, A0A1B0GWH4, A1A4L6, A1YGI6, A6NDR6, B8QB46, F1MJR8, F1QDF8, O35892, O35893, P09015, P15036, P15037, P23497, P52729, P59598, Q32NH9, Q3KRF1, Q3UM89, Q4G112, Q4V7E1, Q5M7N6, Q5ND04, Q5XIV2, Q5ZHX5, Q66IG8, Q6P1R3, Q6PCX9, Q6PJQ5, Q708W2, Q76I76, Q76I79, Q76N89, Q7M6U3, Q8AXQ4, Q8BVK9, Q8IUE0, Q8IUE1, Q8IWB6, Q8IXJ9

Diamond homologs: A0A1W2PQ73, A0JN51, A1A4L6, A1YF15, A1YG61, A1YG91, A2D4Z7, A2T737, A2T762, A3FEM2, A4GTP4, A8WFJ9, O00321, O01519, O70132, O70273, O95238, P01105, P10157, P11308, P11536, P13474, P14921, P15036, P15037, P15062, P18755, P18756, P19102, P19419, P20105, P26323, P27577, P28322, P28324, P29773, P29774, P29775, P29776, P32519

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
CAMK2A	down-regulates	ETS2	phosphorylation
ETS2	down-regulates	Apoptosis
ETS2	up-regulates	Macrophage_differentiation
KDM6A	“down-regulates quantity by repression”	ETS2	“transcriptional regulation”
CDK10	“down-regulates quantity by destabilization”	ETS2	phosphorylation
ETS2	“up-regulates quantity by expression”	SPP1	“transcriptional regulation”
ETS2	“up-regulates quantity by expression”	IBSP	“transcriptional regulation”
ETS2	“up-regulates quantity by expression”	SPARC	“transcriptional regulation”
ETS2	“up-regulates quantity by expression”	BGLAP	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 36 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.

GO biological processes:

GO term	Partners	Fold	FDR
cellular response to hypoxia	5	20.9×	8e-04
negative regulation of cell population proliferation	6	8.7×	5e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	56
Likely benign	0
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
204003	GRCh37/hg19 21q22.13-22.2(chr21:37839410..41427526)	Pathogenic

SpliceAI

1215 predictions. Top by Δscore:

Variant	Effect	Δscore
21:38810030:TTAA:T	acceptor_loss	1.0000
21:38810031:TAA:T	acceptor_loss	1.0000
21:38810032:A:AG	acceptor_gain	1.0000
21:38810032:AAGAT:A	acceptor_gain	1.0000
21:38810033:A:AG	acceptor_gain	1.0000
21:38810034:G:GA	acceptor_gain	1.0000
21:38810034:GAT:G	acceptor_gain	1.0000
21:38810104:AAGG:A	donor_loss	1.0000
21:38810105:AGGT:A	donor_loss	1.0000
21:38810106:GGTG:G	donor_loss	1.0000
21:38810107:G:A	donor_loss	1.0000
21:38812989:A:AG	acceptor_gain	1.0000
21:38812989:ATCT:A	acceptor_gain	1.0000
21:38812990:T:G	acceptor_gain	1.0000
21:38812992:T:A	acceptor_gain	1.0000
21:38812999:GCA:G	acceptor_loss	1.0000
21:38813000:CA:C	acceptor_loss	1.0000
21:38813001:A:AC	acceptor_loss	1.0000
21:38813001:A:AG	acceptor_gain	1.0000
21:38813001:AGC:A	acceptor_gain	1.0000
21:38813002:G:GA	acceptor_gain	1.0000
21:38813002:GC:G	acceptor_gain	1.0000
21:38813002:GCG:G	acceptor_gain	1.0000
21:38813002:GCGC:G	acceptor_gain	1.0000
21:38813002:GCGCC:G	acceptor_gain	1.0000
21:38813081:G:GT	donor_gain	1.0000
21:38813111:CATGG:C	donor_loss	1.0000
21:38813113:TGGT:T	donor_loss	1.0000
21:38813114:GGTAA:G	donor_loss	1.0000
21:38813115:GT:G	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000151383 (21:38820903 C>T), RS1000202922 (21:38806622 C>G), RS1000270999 (21:38813509 T>C), RS1000433915 (21:38806872 G>A,C), RS1000500791 (21:38820570 A>G), RS1000600004 (21:38807132 C>T), RS1000736579 (21:38819905 G>A,C,T), RS1000904045 (21:38825213 G>A), RS1001052118 (21:38812842 C>T), RS1001125602 (21:38813046 T>A), RS1001566013 (21:38819661 C>A,T), RS1001668546 (21:38820475 C>T), RS1001717591 (21:38807061 C>A), RS1001752849 (21:38825022 A>G), RS1001839874 (21:38820639 G>A)

Disease associations

OMIM: gene MIM:164740 | disease phenotypes: MIM:614104

GenCC curated gene-disease

Mondo (1): DYRK1A-related intellectual disability syndrome (MONDO:0013578)

Orphanet (1): DYRK1A-related intellectual disability syndrome (Orphanet:464306)

HPO phenotypes

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

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST000871_3	Non-small cell lung cancer (survival)	3.000000e-07
GCST002127_17	Periodontitis (Mean PAL)	4.000000e-07
GCST002783_104	Body mass index	7.000000e-06
GCST002783_186	Body mass index	4.000000e-07
GCST002783_339	Body mass index	2.000000e-08
GCST004121_18	Fibrinogen levels	5.000000e-16
GCST004122_35	Fibrinogen levels	2.000000e-14
GCST005580_37	Intraocular pressure	4.000000e-13
GCST005580_76	Intraocular pressure	1.000000e-11
GCST006105_10	Eye morphology	2.000000e-06
GCST006423_15	Fracture	3.000000e-13
GCST007205_13	Schizophrenia	9.000000e-06
GCST007615_48	C-reactive protein levels	3.000000e-20
GCST010345_3	TPE interval (response to exercise)	1.000000e-10
GCST010988_332	Adult body size	6.000000e-10
GCST010989_162	Body size at age 10	2.000000e-17
GCST90000654_71	Central corneal thickness	7.000000e-09
GCST90010717_4	Finger osteoarthritis severity (hand Klsum)	6.000000e-07
GCST90011900_15	Serum alkaline phosphatase levels	1.000000e-08

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004695	intraocular pressure measurement
EFO:0004458	C-reactive protein measurement
EFO:0004644	TPE interval measurement
EFO:0007768	response to exercise
EFO:0009819	comparative body size at age 10, self-reported
EFO:0005213	central corneal thickness
EFO:0004533	alkaline phosphatase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
ETS2 RS461155	Paclitaxel + Cisplatin	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC B	EID1060

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs73450548	Toxicity	3	carboplatin;gemcitabine	Non-Small Cell Lung Carcinoma;Thrombocytopenia

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1209950	ETS2		0.00	0
rs73450548	ETS2	3	2.50	1	carboplatin;gemcitabine

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases methylation, increases expression, increases mutagenesis	6
Estradiol	decreases reaction, affects cotreatment, decreases expression, increases expression	4
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Cadmium Chloride	decreases expression, increases expression	3
Particulate Matter	decreases expression, increases abundance, decreases methylation, increases expression	3
bisphenol A	affects cotreatment, decreases expression	2
nickel sulfate	increases expression	2
Air Pollutants	decreases expression, increases abundance, decreases methylation, increases expression	2
Cisplatin	increases expression, affects cotreatment	2
Dexamethasone	increases expression, affects cotreatment, decreases expression	2
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression, affects expression	2
Tobacco Smoke Pollution	affects expression, decreases methylation	2
tert-Butylhydroperoxide	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
TAK-243	increases sumoylation	1
dicrotophos	increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
geraniol	increases expression	1
lead acetate	decreases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
arsenite	affects binding, decreases reaction	1
sulforaphane	decreases expression	1
tanshinone	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
benzo(e)pyrene	decreases methylation	1
4-hydroxy-2-nonenal	decreases expression	1
methacrylaldehyde	affects cotreatment, increases expression	1

Cellosaurus cell lines

7 cell lines: 4 cancer cell line, 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A1M5	SEES3-1V human ETS2, clone1	Embryonic stem cell	Male
CVCL_A1M6	SEES3-1V human ETS2, clone2	Embryonic stem cell	Male
CVCL_A1M7	SEES3-1V human ETS2, clone3	Embryonic stem cell	Male
CVCL_B7X7	Abcam Raji ETS2 KO	Cancer cell line	Male
CVCL_B9XU	Abcam THP-1 ETS2 KO	Cancer cell line	Male
CVCL_C6ZP	Abcam PC-3 ETS2 KO	Cancer cell line	Male
CVCL_GZ83	K562 eGFP-ETS2	Cancer cell line	Female

Clinical trials (associated diseases)

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