IER2

Summary

IER2 (immediate early response 2, HGNC:28871) is a protein-coding gene on chromosome 19p13.13, encoding Immediate early response gene 2 protein (Q9BTL4). DNA-binding protein that seems to act as a transcription factor.

Predicted to enable DNA binding activity. Involved in cell motility and positive regulation of transcription by RNA polymerase II. Located in cytoplasm and nucleoplasm. Implicated in colorectal cancer and hepatocellular carcinoma. Biomarker of childhood acute myeloid leukemia; colorectal adenocarcinoma; hepatocellular carcinoma; and melanoma.

Source: NCBI Gene 9592 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 37 total
• MANE Select transcript: NM_004907

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28871
Approved symbol	IER2
Name	immediate early response 2
Location	19p13.13
Locus type	gene with protein product
Status	Approved
Aliases	ETR101
Ensembl gene	ENSG00000160888
Ensembl biotype	protein_coding
OMIM	620036
Entrez	9592

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 7 protein_coding

ENST00000292433, ENST00000587885, ENST00000588173, ENST00000864420, ENST00000925358, ENST00000925359, ENST00000966250

RefSeq mRNA: 1 — MANE Select: NM_004907 NM_004907

CCDS: CCDS12295

Canonical transcript exons

ENST00000292433 — 2 exons

Exon	Start	End
ENSE00001055228	13152944	13154911
ENSE00001413226	13150411	13150552

Expression profiles

Bgee: expression breadth ubiquitous, 297 present calls, max score 99.59.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 202.5819 / max 5898.0402, expressed in 1825 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
174141	196.4477	1824
174138	4.5134	1509
174139	0.6847	407
174140	0.5229	199
174142	0.4132	214

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
nipple	UBERON:0002030	99.59	gold quality
upper leg skin	UBERON:0004262	99.58	gold quality
trachea	UBERON:0003126	99.50	gold quality
penis	UBERON:0000989	99.42	gold quality
mucosa of stomach	UBERON:0001199	99.42	gold quality
renal medulla	UBERON:0000362	99.36	gold quality
saphenous vein	UBERON:0007318	99.31	gold quality
granulocyte	CL:0000094	99.23	gold quality
cardia of stomach	UBERON:0001162	99.16	gold quality
vena cava	UBERON:0004087	99.14	gold quality
mucosa of urinary bladder	UBERON:0001259	99.00	gold quality
periodontal ligament	UBERON:0008266	98.96	gold quality
pharyngeal mucosa	UBERON:0000355	98.88	gold quality
epithelium of mammary gland	UBERON:0003244	98.87	gold quality
lower lobe of lung	UBERON:0008949	98.86	gold quality
left uterine tube	UBERON:0001303	98.83	gold quality
pylorus	UBERON:0001166	98.81	gold quality
mammary duct	UBERON:0001765	98.80	gold quality
mucosa of paranasal sinus	UBERON:0005030	98.74	gold quality
monocyte	CL:0000576	98.71	gold quality
mononuclear cell	CL:0000842	98.71	gold quality
leukocyte	CL:0000738	98.68	gold quality
urethra	UBERON:0000057	98.61	gold quality
gingival epithelium	UBERON:0001949	98.51	gold quality
palpebral conjunctiva	UBERON:0001812	98.49	gold quality
seminal vesicle	UBERON:0000998	98.45	gold quality
synovial joint	UBERON:0002217	98.41	gold quality
endometrium epithelium	UBERON:0004811	98.19	gold quality
parietal pleura	UBERON:0002400	98.10	gold quality
gingiva	UBERON:0001828	98.02	gold quality

Single-cell (SCXA)

Detected in 25 experiment(s), a significant marker in 20.

Experiment	Marker?	Max mean expression
E-HCAD-11	yes	12636.39
E-MTAB-9841	yes	5665.57
E-MTAB-8142	yes	2287.68
E-HCAD-56	yes	1411.26
E-HCAD-4	yes	92.14
E-CURD-122	yes	43.61
E-CURD-88	yes	28.19
E-GEOD-81547	yes	23.73
E-MTAB-10553	yes	19.04
E-MTAB-9221	yes	18.06
E-CURD-46	yes	13.66
E-MTAB-9388	yes	10.86
E-GEOD-130148	yes	9.90
E-HCAD-1	yes	9.67
E-MTAB-10042	yes	8.85

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

6 targets.

Target	Regulation
CNTN2
IER2
ISYNA1	Activation
MAPK1
SRC
TRIB3

Upstream regulators (CollecTRI, top): ELK1, ETS1, IER2

miRNA regulators (miRDB)

39 targeting IER2, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-488-3P	99.61	68.79	1731
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-888-5P	99.30	70.15	1855
HSA-MIR-6719-3P	99.29	67.78	1387
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-6809-5P	99.13	68.45	1223
HSA-MIR-455-3P	98.94	67.68	878
HSA-MIR-4725-5P	98.67	65.42	628

Literature-anchored findings (GeneRIF, showing 10)

• the functioning of ETR101 as a transcriptional activator for the gene ISYNA1 (PMID:19584537)
• ectopic Ier2 expression promoted the motility and invasiveness of poorly metastatic 1AS pancreatic tumor cells in vitro (PMID:22120713)
• results from western blot analysis showed that the activity of the focal adhesion kinase (FAK) can be regulated by IER2. (PMID:26260137)
• IER2 promoted hepatocellular carcinoma cell adhesion and motility by directly increasing ITGB1 expression and subsequently activating the ITGB1FAKSrcpaxillin signal pathway. (PMID:27840969)
• The results suggest that IER2, IER5, and IER5L proteins are target protein-specific regulators of PP2A (protein phosphatase 2A) activity and modulate cell proliferation through CDC25A (cell division cycle 25A protein) activity. (PMID:30599213)
• Immediate early response protein 2 promotes the migration and invasion of hepatocellular carcinoma cells via regulating the activity of Rho GTPases. (PMID:32009420)
• IER2-induced senescence drives melanoma invasion through osteopontin. (PMID:34611309)
• Long Non-Coding RNA PCAT19 Regulates the Malignant Progression of Bladder Cancer through the miR-335-5p/IER2 Axis. (PMID:36017918)
• PP2A-B55 and its adapter proteins IER2 and IER5 regulate the activity of RB family proteins and the expression of cell cycle-related genes. (PMID:36047562)
• Hypoxic Upregulation of IER2 Increases Paracrine GMFG Signaling of Endoplasmic Reticulum Stress-CAF to Promote Chordoma Progression via Targeting ITGB1. (PMID:39207055)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ier2b	ENSDARG00000086881
mus_musculus	Ier2	ENSMUSG00000053560
rattus_norvegicus	Ier2	ENSRNOG00000074928

Paralogs (2): IER5 (ENSG00000162783), IER5L (ENSG00000188483)

Protein

Protein identifiers

Immediate early response gene 2 protein — Q9BTL4 (reviewed: Q9BTL4)

Alternative names: Protein ETR101

All UniProt accessions (1): Q9BTL4

UniProt curated annotations — full annotation on UniProt →

Function. DNA-binding protein that seems to act as a transcription factor. Involved in the regulation of neuronal differentiation, acts upon JNK-signaling pathway activation and plays a role in neurite outgrowth in hippocampal cells. May mediate with FIBP FGF-signaling in the establishment of laterality in the embryo. Promotes cell motility, seems to stimulate tumor metastasis.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Expressed in activated T-cells (at protein level). Expression increases in metastatic tumor cells (at protein level).

Induction. By growth factors and 12-O-tetradecanoylphorbol-13-acetate (TPA).

Similarity. Belongs to the IER family.

RefSeq proteins (1): NP_004898* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008653	IER	Family

Pfam: PF05760

UniProt features (7 total): compositionally biased region 2, chain 1, region of interest 1, modified residue 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BTL4-F1	64.67	0.15

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 (1): 1

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 368 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, BERENJENO_ROCK_SIGNALING_NOT_VIA_RHOA_DN, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_NEUROGENESIS, NAGASHIMA_NRG1_SIGNALING_UP, CHANDRAN_METASTASIS_DN, YY1_Q6, SRF_Q5_01, BILD_HRAS_ONCOGENIC_SIGNATURE, SRF_01, GERY_CEBP_TARGETS, OSWALD_HEMATOPOIETIC_STEM_CELL_IN_COLLAGEN_GEL_UP, SRF_C, GNF2_MCL1, YY1_02

GO Biological Process (4): neuron differentiation (GO:0030182), positive regulation of transcription by RNA polymerase II (GO:0045944), cell motility (GO:0048870), response to fibroblast growth factor (GO:0071774)

GO Molecular Function (2): DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (3): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
cell differentiation	1
generation of neurons	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
cellular process	1
response to growth factor	1
nucleic acid binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

514 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IER2	FOSB	P53539	656
IER2	DUSP1	P28562	632
IER2	EGR1	P18146	599
IER2	ATF3	P18847	578
IER2	NR4A2	P43354	535
IER2	FOS	P01100	515
IER2	PHLDA1	Q8WV24	493
IER2	DUSP12	Q9UNI6	479
IER2	NR4A1	P22736	474
IER2	PLPPR2	Q96GM1	461
IER2	ETS1	P14921	460
IER2	IER3	P46695	457
IER2	BTG2	P78543	457
IER2	EGR2	P11161	456
IER2	TMEM125	Q96AQ2	442

IntAct

23 interactions, top by confidence:

A	B	Type	Score
PPP2R2D	YEATS4	psi-mi:“MI:0914”(association)	0.730
PPP2R2B	MYO9A	psi-mi:“MI:0914”(association)	0.640
PPP2R2C	TCP1	psi-mi:“MI:0914”(association)	0.640
HSF2BP	IER2	psi-mi:“MI:0915”(physical association)	0.560
ATG12	IER2	psi-mi:“MI:0915”(physical association)	0.560
IER2	KPNA3	psi-mi:“MI:0914”(association)	0.530
IER2	KPNA4	psi-mi:“MI:0914”(association)	0.530
PPP2R1A	ENSA	psi-mi:“MI:0914”(association)	0.530
PPP2R2D	BAG2	psi-mi:“MI:0914”(association)	0.350
PPP2R2B	A2ML1	psi-mi:“MI:0914”(association)	0.350
PPP2R2B	ARHGAP10	psi-mi:“MI:0914”(association)	0.350
PPP2R2C	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
IER2	HSF2BP	psi-mi:“MI:0915”(physical association)	0.000
ATG12	IER2	psi-mi:“MI:0915”(physical association)	0.000
IER2	pheS	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (76): ZBTB40 (Affinity Capture-MS), RANBP2 (Affinity Capture-MS), RGPD8 (Affinity Capture-MS), KPNA4 (Affinity Capture-MS), KPNA3 (Affinity Capture-MS), PPP2R1B (Affinity Capture-MS), PPP2R1A (Affinity Capture-MS), PPP2R2D (Affinity Capture-MS), PPP2R2A (Affinity Capture-MS), HDGFRP2 (Affinity Capture-MS), MCM3AP (Affinity Capture-MS), BRCA2 (Affinity Capture-MS), NUP153 (Affinity Capture-MS), GLE1 (Affinity Capture-MS), CDCA2 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GUA6, A0FGR0, A0JMD2, A6NMN3, A7LKB2, B7SXM5, F1QB81, F1QDF8, O70361, P0CAX8, P15375, P16075, P16076, P17950, P19335, P23409, P34060, Q04891, Q14B48, Q2T9I9, Q2TBN9, Q32NH9, Q3YFL6, Q499D0, Q5REU9, Q5SW75, Q60439, Q60664, Q66IG8, Q66IT9, Q66J77, Q6NRK3, Q6NWJ0, Q6P7D3, Q6PBC9, Q6PUV5, Q76I76, Q76I79, Q7YS80, Q8CJE2

Diamond homologs: B7SXM5, O89113, P17950, Q5PQP0, Q5T953, Q5VY09, Q66IT9, Q6NYT3, Q6P7D3, Q6PBC9, Q99J55, Q9BTL4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	36
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

456 predictions. Top by Δscore:

Variant	Effect	Δscore
19:13150489:TTC:T	donor_gain	0.9900
19:13150553:G:GG	donor_gain	0.9900
19:13150549:C:T	donor_gain	0.9800
19:13150681:TCCC:T	donor_gain	0.9800
19:13150470:TCC:T	donor_gain	0.9700
19:13150548:GCAAT:G	donor_gain	0.9700
19:13151716:G:GT	donor_gain	0.9700
19:13153153:C:A	acceptor_gain	0.9700
19:13150593:T:TG	donor_gain	0.9400
19:13153152:CCGGG:C	acceptor_gain	0.9400
19:13150585:GC:G	donor_gain	0.9300
19:13151670:G:GT	donor_gain	0.9200
19:13153154:G:A	acceptor_gain	0.9100
19:13150854:G:GA	donor_gain	0.9000
19:13150582:GCGGC:G	donor_gain	0.8900
19:13150853:T:TA	donor_gain	0.8900
19:13153156:G:C	acceptor_gain	0.8800
19:13152061:G:GT	donor_gain	0.8700
19:13153153:CGGG:C	acceptor_gain	0.8700
19:13150682:CCCG:C	donor_gain	0.8600
19:13151666:G:T	donor_gain	0.8600
19:13150586:C:G	donor_gain	0.8400
19:13150773:G:T	donor_gain	0.8200
19:13150808:G:GT	donor_gain	0.8200
19:13152941:A:AC	acceptor_gain	0.8000
19:13150508:G:GT	donor_gain	0.7900
19:13150720:G:GA	donor_gain	0.7900
19:13150773:G:GT	donor_gain	0.7900
19:13150604:G:T	donor_gain	0.7800
19:13150679:GGTCC:G	donor_gain	0.7800

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000264223 (19:13151707 G>A), RS1000314104 (19:13152715 A>T), RS1000698409 (19:13151415 G>T), RS1001019889 (19:13155325 C>T), RS1001054108 (19:13155181 C>G), RS1001727092 (19:13151822 C>T), RS1001968013 (19:13152440 A>C,G), RS1002056929 (19:13149465 T>C), RS1002336917 (19:13152685 A>T), RS1002607192 (19:13154911 C>T), RS1002639729 (19:13154597 A>G), RS1002799337 (19:13150068 G>A,C), RS1003179219 (19:13150261 C>G,T), RS1003635216 (19:13153670 C>T), RS1003773073 (19:13148841 C>T)

Disease associations

OMIM: gene MIM:620036 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST008839_97	Height	2.000000e-08
GCST009391_1595	Metabolite levels	7.000000e-06
GCST009391_800	Metabolite levels	1.000000e-06
GCST90000050_81	Age at first birth	3.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0010376	phosphatidylcholine 34:2 measurement
EFO:0010396	sphingomyelin 22:1 measurement
EFO:0009101	age at first birth measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	4
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, affects expression, increases expression	4
Benzo(a)pyrene	decreases methylation, increases expression	3
Cisplatin	decreases expression, increases expression	3
Cyclosporine	increases expression	3
cupric chloride	increases expression	2
Acetaminophen	increases expression	2
Hydrogen Peroxide	affects expression, affects cotreatment, decreases expression	2
Ozone	affects expression, affects cotreatment, increases oxidation, increases abundance	2
Smoke	increases abundance, increases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
GSK-J4	decreases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
pirinixic acid	decreases expression, increases activity, affects binding	1
bisphenol A	decreases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, increases reaction	1
sodium bichromate	decreases expression	1
afimoxifene	affects reaction, increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
nickel chloride	increases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
nickel sulfate	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1U7	Abcam HeLa IER2 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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