PA2G4

Summary

PA2G4 (proliferation-associated 2G4, HGNC:8550) is a protein-coding gene on chromosome 12q13.2, encoding Proliferation-associated protein 2G4 (Q9UQ80). May play a role in a ERBB3-regulated signal transduction pathway. It is a selective cancer dependency (DepMap: 40.1% of cell lines).

This gene encodes an RNA-binding protein that is involved in growth regulation. This protein is present in pre-ribosomal ribonucleoprotein complexes and may be involved in ribosome assembly and the regulation of intermediate and late steps of rRNA processing. This protein can interact with the cytoplasmic domain of the ErbB3 receptor and may contribute to transducing growth regulatory signals. This protein is also a transcriptional co-repressor of androgen receptor-regulated genes and other cell cycle regulatory genes through its interactions with histone deacetylases. This protein has been implicated in growth inhibition and the induction of differentiation of human cancer cells. Six pseudogenes, located on chromosomes 3, 6, 9, 18, 20 and X, have been identified.

Source: NCBI Gene 5036 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 28 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 40.1% of screened cell lines
• MANE Select transcript: NM_006191

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8550
Approved symbol	PA2G4
Name	proliferation-associated 2G4
Location	12q13.2
Locus type	gene with protein product
Status	Approved
Aliases	EBP1, ITAF45
Ensembl gene	ENSG00000170515
Ensembl biotype	protein_coding
OMIM	602145
Entrez	5036

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 14 protein_coding, 3 retained_intron

ENST00000303305, ENST00000550166, ENST00000551061, ENST00000552266, ENST00000552528, ENST00000552766, ENST00000553057, ENST00000870200, ENST00000870201, ENST00000937954, ENST00000937955, ENST00000937956, ENST00000937957, ENST00000937958, ENST00000937959, ENST00000937960, ENST00000956764

RefSeq mRNA: 1 — MANE Select: NM_006191 NM_006191

CCDS: CCDS8902

Canonical transcript exons

ENST00000303305 — 13 exons

Exon	Start	End
ENSE00001144284	56111182	56111309
ENSE00001144293	56110964	56111058
ENSE00001144302	56110559	56110692
ENSE00001144310	56110399	56110477
ENSE00001144320	56109857	56109935
ENSE00001242625	56111476	56111529
ENSE00001322593	56112823	56113910
ENSE00001324147	56104559	56104825
ENSE00003514919	56109230	56109293
ENSE00003586228	56107187	56107256
ENSE00003589629	56107521	56107613
ENSE00003623057	56106990	56107095
ENSE00003665855	56106588	56106716

Expression profiles

Bgee: expression breadth ubiquitous, 301 present calls, max score 97.74.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 161.7953 / max 1107.9898, expressed in 1828 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
126056	161.7645	1828
126057	0.0308	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skin of abdomen	UBERON:0001416	97.74	gold quality
skin of leg	UBERON:0001511	97.74	gold quality
esophagus mucosa	UBERON:0002469	97.41	gold quality
rectum	UBERON:0001052	97.37	gold quality
ganglionic eminence	UBERON:0004023	97.35	gold quality
cortical plate	UBERON:0005343	97.28	gold quality
islet of Langerhans	UBERON:0000006	97.23	gold quality
ventricular zone	UBERON:0003053	97.19	gold quality
tendon of biceps brachii	UBERON:0008188	97.16	gold quality
lower esophagus mucosa	UBERON:0035834	97.15	gold quality
gastrocnemius	UBERON:0001388	97.14	gold quality
body of pancreas	UBERON:0001150	97.04	gold quality
muscle of leg	UBERON:0001383	96.93	gold quality
esophagus	UBERON:0001043	96.81	gold quality
lymph node	UBERON:0000029	96.69	gold quality
left uterine tube	UBERON:0001303	96.59	gold quality
popliteal artery	UBERON:0002250	96.58	gold quality
tibial artery	UBERON:0007610	96.57	gold quality
right coronary artery	UBERON:0001625	96.53	gold quality
vermiform appendix	UBERON:0001154	96.50	gold quality
pancreas	UBERON:0001264	96.45	gold quality
zone of skin	UBERON:0000014	96.44	gold quality
calcaneal tendon	UBERON:0003701	96.43	gold quality
mucosa of transverse colon	UBERON:0004991	96.43	gold quality
tendon	UBERON:0000043	96.42	gold quality
smooth muscle tissue	UBERON:0001135	96.42	gold quality
ectocervix	UBERON:0012249	96.34	gold quality
left coronary artery	UBERON:0001626	96.33	gold quality
coronary artery	UBERON:0001621	96.31	gold quality
caecum	UBERON:0001153	96.30	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	144.22
E-GEOD-125970	yes	22.98
E-MTAB-9067	yes	22.46
E-CURD-122	yes	20.35
E-HCAD-13	yes	19.88
E-MTAB-10042	yes	14.21
E-MTAB-8271	yes	11.39
E-MTAB-8060	no	921.06
E-CURD-89	no	353.40
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

5 targets.

Target	Regulation
AGR2	Activation
AR	Unknown
E2F1	Repression
ERBB2	Unknown
KLK3	Repression

Upstream regulators (CollecTRI, top): AR, E2F1, NRG1, SNAI1

miRNA regulators (miRDB)

87 targeting PA2G4, 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-3163	100.00	77.23	8605
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 40.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• EBP1 is in the cytoplasm & nucleolus. Nucleolar localization requires AA sequences at the NH2- and COOH-ends. Overexpression inhibits proliferation of human fibroblasts. It is part of RNP complexes & associates with different rRNAs. (PMID:15064750)
• ErbB3-binding protein Ebp1 binding to E2F promoter elements and E2F-mediated transcription are regulated by heregulin. (PMID:15073182)
• These studies suggest that Ebp1 is an AR corepressor whose biological activity can be regulated by the ErbB3 ligand, HRG. (PMID:15583694)
• Ebp1 suppresses androgen receptor-mediated gene transcription and tumorigenesis of prostate cancer cells. (PMID:15994225)
• Ebp1 is present in protein-ARE(bcl-2) RNA complexes. Ebp1 & nucleolin are present in the same bcl-2 mRNP complexes. Ebp1 decreases the rate of decay of beta-globin-ARE(bcl-2) transcripts. Ebp1 contributes to bcl-2 expression regulation in HL-60 cells. (PMID:16396631)
• Our results demonstrate that Ebp1 is a new dsRNA-binding protein that acts as a cellular inhibitor of eIF2alpha phosphorylation suggesting that it could be involved in protein translation control (PMID:16631606)
• over-expression of Ebp1 interfered with virus production (PMID:17295834)
• PKC-delta antagonizes apoptosis through phosphorylating Ebp1 and protects it from apoptotic degradation. (PMID:17316401)
• ErbB-3-binding protein-1 is an immunogenic protein with cancer-related immunoreactivity, capable of eliciting CD8-positive T cell-mediated responses in vivo and in vitro. (PMID:17641068)
• The structure provides insights in how Ebp1 discriminates between its different interaction partners. (PMID:17765895)
• ErbB-3-binding protein 1 (Ebp1) is a member of the family of proliferation-associated 2G4 proteins (PA2G4s) and plays a role in cellular growth and differentiation. (PMID:17768350)
• B23 distinctively binds Ebp1 isoforms and regulates cell proliferation and survival through p42 and p48, respectively. (PMID:17951246)
• These results suggest that EBP1, by down-regulating ErbB signal transduction, attentuates HRG-mediated growth of breast cancer cells. (PMID:18355957)
• These data support a role for EBP1 in the development of hormone-refractory prostate cancer. (PMID:18852121)
• hBre1 inhibits Ebp1’s tumor suppressive activity through mediating its polyubiquitination and degradation. (PMID:19037095)
• our results reveal an EBP1-Foxa-AGR2 signaling circuit with functional significance in metastatic prostate cancer (PMID:20048076)
• Ablation of EBP1 expression led to tamoxifen resistance in breast cancer. (PMID:20379846)
• Data show that E2F is likely a central coordinator of multiple responses that culminate in regulation of EBP1 gene expression, and which may vary depending on cell type and context. (PMID:21085677)
• Findings suggest that eBP1 p48 functions as an oncogene by promoting glioma tumorigenicity via interactions with HDM2 that contribute to p53 downregulation. (PMID:21098709)
• Ebp1 contributes to neuronal cell differentiation and growth factor specificity through the activation of protein kinase Cdelta acting as a crucial downstream effector of neurotrophin signaling. (PMID:21145366)
• the Ebp1 promoter localizes between -664 nt and the initiation site of the Ebp1 gene, +317-nt long sequence in the noncoding region is required for regulation of Ebp1 gene expression. (PMID:21794029)
• It was shown that high level of Ebp1 expression led to enhancee HDM2 phosphorylation by Akt and inhibited the self-ubiquitination of HDM2 by up-regulation of Akt activity. (PMID:21930127)
• These studies suggest that one pathway of EBP1 down-regulation of AR levels may be lost in castration-resistant prostate cancer. (PMID:21965718)
• Performed immunohistochemical analysis on 132 primary adenoid cystic carcinoma and adjacent non-cancerous tissues.The expression of EBP1 was significantly higher in non-cancerous adjacent tissues compared with corresponding cancer tissues. (PMID:23110497)
• The major effect of EBP1 on ErbB2 mRNA expression levels is at the transcriptional level. (PMID:23242156)
• Down-regulation of the ErbB3 binding protein 1 in human bladder cancer promotes tumor progression and cell proliferation. (PMID:23283744)
• identified among endothelial antigens to which antibodies are produced during heart transplant rejection (PMID:23707440)
• data suggest that Vpr may inhibit Ebp1 to stabilize p53, which in turn leads to G2 arrest and apoptosis in U87MG cells (PMID:23828502)
• Ebp1 p42 isoform regulates the proteasomal degradation of the p85 regulatory subunit of PI3K by recruiting a chaperone-E3 ligase complex HSP70/CHIP. (PMID:24651434)
• Ebp1 functionality is independent from heat-shock-protein-regulated progression networks in prostate cancer. (PMID:24798454)
• P48Ebp1 acts as an oncoprotein. (PMID:25154617)
• Data suggest that inhibiting ErbB3-binding protein 1 Ebp1 phosphorylation may be an effective mechanism for inhibiting T-cell activation and proliferation. (PMID:25691158)
• Our results suggest a novel function of Ebp1 as a binding protein and negative regulator of Anxa2. The functional association between Anxa2 and EBP1 may participate in regulating cancer cell proliferation and invasion, contributing to cancer progression. (PMID:25917452)
• Data highlight the tissue specificity function of EBP1 isoforms and show that only the oncogene p48 activates MHC II expression in human solid tumors, via STAT1 phosphorylation, in order to affect tumor progression by triggering specific immune response. (PMID:26081906)
• EBP1 participates in the regulation of intestinal inflammation via mediating Akt signaling pathway. (PMID:26256794)
• The combined determination of Ebp1 and p53 expression levels in cervical cancer patients could support the effective prediction of metastatic potential and patient prognosis. (PMID:26436510)
• The results demonstrate an important role of Ebp1 in promoting cell proliferation in Acute Myelogenous Leukemic Cells through the regulation of both rRNA synthesis and Proliferating Cell Nuclear Antigen expression. (PMID:26813358)
• results show that EBP1 interacts directly with PPIns and associate with PtdIns(3,4,5)P3 in the nucleolus. (PMID:27118868)
• In this study, the authors demonstrated that overexpression of ErbB3-binding protein 1 (EBP1) promoted not only a reduction of wild type of p85 subunit of phosphoinositide 3-kinase but also oncogenic mutant forms of p85 which were identified in human cancers. (PMID:27464702)
• The adapter function of EBP1 P42 stabilized the interaction of FBXW7 with its substrates and promoted FBXW7-mediated degradation of oncogenic targets, enhancing its overall tumor-suppressing function. Results establish distinct physical and functional interactions between FBXW7 and EBP1 isoforms, which yield their mechanistically unique isoform-specific functions of EBP1 in cancer. (PMID:28209614)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	pa2g4a	ENSDARG00000039578
mus_musculus	Pa2g4	ENSMUSG00000025364
rattus_norvegicus	Pa2g4	ENSRNOG00000004904
rattus_norvegicus	AABR07065265.1	ENSRNOG00000021751
drosophila_melanogaster	und	FBGN0283478
caenorhabditis_elegans	app-1	WBGENE00000155
caenorhabditis_elegans		WBGENE00003130
caenorhabditis_elegans		WBGENE00021555

Paralogs (7): XPNPEP1 (ENSG00000108039), METAP2 (ENSG00000111142), XPNPEP2 (ENSG00000122121), PEPD (ENSG00000124299), METAP1 (ENSG00000164024), METAP1D (ENSG00000172878), XPNPEP3 (ENSG00000196236)

Protein

Protein identifiers

Proliferation-associated protein 2G4 — Q9UQ80 (reviewed: Q9UQ80)

Alternative names: Cell cycle protein p38-2G4 homolog, ErbB3-binding protein 1

All UniProt accessions (4): Q9UQ80, F8VR77, F8VZ69, F8W0A3

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in a ERBB3-regulated signal transduction pathway. Seems be involved in growth regulation. Acts a corepressor of the androgen receptor (AR) and is regulated by the ERBB3 ligand neuregulin-1/heregulin (HRG). Inhibits transcription of some E2F1-regulated promoters, probably by recruiting histone acetylase (HAT) activity. Binds RNA. Associates with 28S, 18S and 5.8S mature rRNAs, several rRNA precursors and probably U3 small nucleolar RNA. May be involved in regulation of intermediate and late steps of rRNA processing. May be involved in ribosome assembly. Mediates cap-independent translation of specific viral IRESs (internal ribosomal entry site). Regulates cell proliferation, differentiation, and survival. Isoform 1 suppresses apoptosis whereas isoform 2 promotes cell differentiation.

Subunit / interactions. Isoform 2 interacts with the cytoplasmic domain of non-phosphorylated ERBB3; the interaction requires PKC activity. Interacts with AR. Treatment with HRG leads to dissociation from ERBB3 and increases association with AR. Interacts with NCL/nucleolin. Component of a ribonucleoprotein complex containing at least PA2G4, NCL, TOP1, PABPC2, RPLP0, acetylated histone H1 (HIST1H1A or H1F1), histone H1 2/4, RPL4, RPL8, RPL15, RPL18, RPL18A, RPL21, RPL11, RPL12, RPL28, RPL27, RPLP2 and RPL24. Interacts with HDAC2. Interacts with RB1; the interaction is enhanced upon PA2G4 dephosphorylation. Interacts with AKT1. Isoform 1 and isoform 2 interact with RNF20. Isoform 2 interacts with HUWE1. Interacts with DNAJC21.

Subcellular location. Cytoplasm. Nucleus. Nucleolus Cytoplasm.

Tissue specificity. Isoform 2 is undetectable whereas isoform 1 is strongly expressed in cancer cells (at protein level). Isoform 1 and isoform 2 are widely expressed, including heart, brain, lung, pancreas, skeletal muscle, kidney, placenta and liver.

Post-translational modifications. Phosphorylated on serine and threonine residues. Phosphorylation is enhanced by HRG treatment. Basal phosphorylation is PKC-dependent and HRG-induced phosphorylation is predominantly PKC-independent. Phosphorylation at Ser-361 by PKC/PRKCD regulates its nucleolar localization. In cancer cells, isoform 2 is polyubiquitinated leading to its proteasomal degradation and phosphorylation by PKC/PRKCD enhances polyubiquitination.

Similarity. Belongs to the peptidase M24 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UQ80-1	1, p48	yes
Q9UQ80-2	2, p42

RefSeq proteins (1): NP_006182* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000994	Pept_M24	Domain
IPR004545	PA2G4	Family
IPR018349	Pept_M24A_MAP2_BS	Binding_site
IPR036005	Creatinase/aminopeptidase-like	Homologous_superfamily
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR047113	PA2G4/ARX1	Family

Pfam: PF00557

UniProt features (47 total): strand 13, helix 10, modified residue 6, mutagenesis site 6, region of interest 5, initiator methionine 1, chain 1, cross-link 1, splice variant 1, sequence conflict 1, turn 1, compositionally biased region 1

Structure

Experimental structures (PDB)

39 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
2Q8K	X-RAY DIFFRACTION	1.6
8K2C	ELECTRON MICROSCOPY	2.4
8XSX	ELECTRON MICROSCOPY	2.4
9P7D	ELECTRON MICROSCOPY	2.57
9P7E	ELECTRON MICROSCOPY	2.59
6WM8	X-RAY DIFFRACTION	2.6
6ZMI	ELECTRON MICROSCOPY	2.6
9PA7	ELECTRON MICROSCOPY	2.67
6ZM7	ELECTRON MICROSCOPY	2.7
9P7C	ELECTRON MICROSCOPY	2.78
9P7A	ELECTRON MICROSCOPY	2.81
9B0P	ELECTRON MICROSCOPY	2.82
9FQZ	ELECTRON MICROSCOPY	2.85
9P9J	ELECTRON MICROSCOPY	2.87
6Z6N	ELECTRON MICROSCOPY	2.9
9P78	ELECTRON MICROSCOPY	2.9
9P9K	ELECTRON MICROSCOPY	2.96
6Z6L	ELECTRON MICROSCOPY	3
6ZME	ELECTRON MICROSCOPY	3
8XSY	ELECTRON MICROSCOPY	3
6Z6M	ELECTRON MICROSCOPY	3.1
6ZMO	ELECTRON MICROSCOPY	3.1
9P79	ELECTRON MICROSCOPY	3.1
9P8C	ELECTRON MICROSCOPY	3.11
6LSR	ELECTRON MICROSCOPY	3.13
6CHT	X-RAY DIFFRACTION	3.17
8XSZ	ELECTRON MICROSCOPY	3.2
6SXO	ELECTRON MICROSCOPY	3.3
7BHP	ELECTRON MICROSCOPY	3.3
9GJ5	ELECTRON MICROSCOPY	4.61

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UQ80-F1	92.75	0.89

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 (7): 335, 361, 366, 386, 298, 2, 2

Mutagenesis-validated functional residues (6):

Position	Phenotype
20–22	loss of nucleolar localization.
361	loss of phosphorylation and interaction with erbb3 and huwe1.
361	no effect on phosphorylation and loss of nucleolar localization.
363	no effect on in vitro phosphorylation by pkc.
364–365	only partial nucleolar localization.
366	decreases in vitro phosphorylation by pkc.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation

MSigDB gene sets: 292 (showing top): GNF2_CKS1B, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, GOBP_RIBOSOME_BIOGENESIS, REACTOME_INNATE_IMMUNE_SYSTEM, GOCC_SECRETORY_GRANULE, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GNF2_MCM5, GGGTGGRR_PAX4_03, GGAMTNNNNNTCCY_UNKNOWN, USF_C, GNF2_RRM1, TTGGGAG_MIR150, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, AACWWCAANK_UNKNOWN, PUJANA_CHEK2_PCC_NETWORK

GO Biological Process (5): rRNA processing (GO:0006364), regulation of translation (GO:0006417), negative regulation of apoptotic process (GO:0043066), positive regulation of cell differentiation (GO:0045597), negative regulation of DNA-templated transcription (GO:0045892)

GO Molecular Function (5): nucleic acid binding (GO:0003676), transcription corepressor activity (GO:0003714), RNA binding (GO:0003723), ubiquitin protein ligase binding (GO:0031625), protein binding (GO:0005515)

GO Cellular Component (8): extracellular region (GO:0005576), nucleus (GO:0005634), nucleolus (GO:0005730), cytoplasm (GO:0005737), membrane (GO:0016020), azurophil granule lumen (GO:0035578), extracellular exosome (GO:0070062), ribonucleoprotein complex (GO:1990904)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
binding	2
RNA processing	1
rRNA metabolic process	1
ribosome biogenesis	1
translation	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
cell differentiation	1
regulation of cell differentiation	1
positive regulation of cellular process	1
positive regulation of developmental process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
transcription coregulator activity	1
negative regulation of DNA-templated transcription	1
nucleic acid binding	1
ubiquitin-like protein ligase binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
vacuolar lumen	1
secretory granule lumen	1
azurophil granule	1
extracellular vesicle	1
protein-containing complex	1

Protein interactions and networks

STRING

5632 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PA2G4	ERBB3	P21860	983
PA2G4	ZNF622	Q969S3	641
PA2G4	MAK16	Q9BXY0	627
PA2G4	NIFK	Q9BYG3	624
PA2G4	RSL1D1	O76021	618
PA2G4	GTPBP4	Q9BZE4	595
PA2G4	HDAC2	Q92769	584
PA2G4	POLI	Q9UNA4	543
PA2G4	TRIM28	Q13263	541
PA2G4	SFPQ	P23246	521
PA2G4	ILF3	Q12906	516
PA2G4	POLR1B	Q9H9Y6	502
PA2G4	PRKCA	P17252	494
PA2G4	HNRNPC	P07910	477
PA2G4	TBL3	Q12788	472

IntAct

196 interactions, top by confidence:

A	B	Type	Score
PRKAA1	PRKAB2	psi-mi:“MI:0914”(association)	0.950
PRKAG1	PRKAB2	psi-mi:“MI:0914”(association)	0.940
PA2G4	TMED7	psi-mi:“MI:0915”(physical association)	0.640
PA2G4	SIN3A	psi-mi:“MI:0915”(physical association)	0.600
SIN3A	PA2G4	psi-mi:“MI:0407”(direct interaction)	0.600
PDPK1	PDPK1	psi-mi:“MI:0914”(association)	0.530
PA2G4	RB1	psi-mi:“MI:0915”(physical association)	0.520
PA2G4	RPL35	psi-mi:“MI:0915”(physical association)	0.500
NCL	PA2G4	psi-mi:“MI:0915”(physical association)	0.500
PA2G4	NPM1	psi-mi:“MI:0403”(colocalization)	0.490
SPICE1	IPO5	psi-mi:“MI:0914”(association)	0.420
Sin3a	PA2G4	psi-mi:“MI:0915”(physical association)	0.400
Erbb3	PA2G4	psi-mi:“MI:0915”(physical association)	0.400
PA2G4	PDIA6	psi-mi:“MI:0915”(physical association)	0.400
MYBPC2	PA2G4	psi-mi:“MI:0915”(physical association)	0.400
CETN3	PA2G4	psi-mi:“MI:0915”(physical association)	0.400
TARBP1	PA2G4	psi-mi:“MI:0915”(physical association)	0.400
PA2G4	HSPA5	psi-mi:“MI:0915”(physical association)	0.400
Bles03		psi-mi:“MI:0915”(physical association)	0.400
	GNAT3	psi-mi:“MI:0915”(physical association)	0.400
PA2G4	E2F1	psi-mi:“MI:0915”(physical association)	0.400
ERBB3	PA2G4	psi-mi:“MI:0915”(physical association)	0.400
AR	PA2G4	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (404): NPM1 (Affinity Capture-MS), ERBB3 (Affinity Capture-MS), DHX9 (Affinity Capture-MS), LAMB1 (Affinity Capture-MS), NCL (Affinity Capture-MS), DDX21 (Affinity Capture-MS), HSPA1B (Affinity Capture-MS), PKN1 (Affinity Capture-MS), VIM (Affinity Capture-MS), ACTB (Affinity Capture-MS), HNRNPA2B1 (Affinity Capture-MS), PA2G4 (Biochemical Activity), RNF20 (Affinity Capture-Western), RNF20 (Co-localization), PA2G4 (Affinity Capture-RNA)

ESM2 similar proteins: A1CH02, A1CXT5, A4RDI6, A6QLA4, A6ZKL2, A8QBZ2, B3LNM2, B5VDQ0, B6Q1N3, B8LUH2, B8NA06, C5DE35, C7GSF3, C7YS77, C8Z3V4, D1ZEN1, D8PR70, E3QW41, M1CZC0, O08663, O60085, O82491, P38062, P38174, P50579, P50580, P53582, Q09184, Q0CL94, Q0UTI9, Q1ZXG4, Q3ZC89, Q4QRK0, Q55C21, Q56Y85, Q5I0A0, Q5RBF3, Q5ZIM5, Q6AYD3, Q6BVB8

Diamond homologs: M1CZC0, P0A078, P0A079, P0A080, P50580, P99121, Q09184, Q1ZXG4, Q5AI37, Q5HEN6, Q6AYD3, Q6G846, Q6GFG9, Q96327, Q9UQ80, A1CYM1, A4RDI6, A5DR89, A5E5I9, B0XTJ7, B6H5L5, B6YTG0, B8NLL0, C4R2P3, C4Y1F8, C4YSA9, C5M8M4, D8PR70, O27355, O28438, O51132, O58362, O59730, O66489, O84859, P0A5J3, P22624, P56218, P75313, P95963

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
PAK1	up-regulates	PA2G4	phosphorylation
PRKCD	up-regulates	PA2G4	phosphorylation
FUS	“up-regulates activity”	PA2G4	sumoylation
PRKCA	unknown	PA2G4	phosphorylation
PRKCB	unknown	PA2G4	phosphorylation
PRKCG	unknown	PA2G4	phosphorylation
EIF2AK2	“up-regulates activity”	PA2G4	phosphorylation
PA2G4	“down-regulates quantity by repression”	KLK3	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 227 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
Activation of AMPK downstream of NMDARs	5	11.8×	3e-03
SRP-dependent cotranslational protein targeting to membrane	16	10.0×	4e-09
MTOR signalling	6	9.9×	1e-03
Peptide chain elongation	12	9.5×	8e-07
Viral mRNA Translation	12	9.5×	8e-07
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	12	9.3×	8e-07
Selenocysteine synthesis	12	9.0×	8e-07
Eukaryotic Translation Termination	12	9.0×	8e-07

GO biological processes:

GO term	Partners	Fold	FDR
U2-type prespliceosome assembly	5	15.8×	6e-03
cytoplasmic translation	14	13.1×	5e-09
cellular response to nutrient levels	5	11.8×	9e-03
positive regulation of fibroblast proliferation	6	9.0×	9e-03
positive regulation of miRNA transcription	6	8.8×	9e-03
epidermal growth factor receptor signaling pathway	7	8.8×	6e-03
translation	15	7.8×	8e-07
response to endoplasmic reticulum stress	8	6.7×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	13
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1950 predictions. Top by Δscore:

Variant	Effect	Δscore
12:56104826:G:GG	donor_gain	1.0000
12:56106582:CCTCA:C	acceptor_loss	1.0000
12:56106583:CTCAG:C	acceptor_loss	1.0000
12:56106584:TCAG:T	acceptor_loss	1.0000
12:56106585:CA:C	acceptor_loss	1.0000
12:56106586:AGG:A	acceptor_gain	1.0000
12:56106587:G:GT	acceptor_loss	1.0000
12:56106587:GGG:G	acceptor_gain	1.0000
12:56106712:GAAAG:G	donor_gain	1.0000
12:56106713:AAAG:A	donor_loss	1.0000
12:56106714:AAGG:A	donor_loss	1.0000
12:56106717:GT:G	donor_loss	1.0000
12:56106717:GTA:G	donor_loss	1.0000
12:56106718:T:A	donor_loss	1.0000
12:56107076:G:GT	donor_gain	1.0000
12:56107077:A:T	donor_gain	1.0000
12:56107096:G:GG	donor_gain	1.0000
12:56107184:CAGTG:C	acceptor_loss	1.0000
12:56107185:A:AG	acceptor_gain	1.0000
12:56107185:A:AT	acceptor_loss	1.0000
12:56107185:A:G	acceptor_loss	1.0000
12:56107185:AGT:A	acceptor_gain	1.0000
12:56107186:G:GC	acceptor_gain	1.0000
12:56107186:G:GT	acceptor_gain	1.0000
12:56107186:G:T	acceptor_loss	1.0000
12:56107186:GT:G	acceptor_gain	1.0000
12:56107186:GTG:G	acceptor_gain	1.0000
12:56107186:GTGAC:G	acceptor_gain	1.0000
12:56107257:G:GC	donor_loss	1.0000
12:56107257:GT:G	donor_loss	1.0000

AlphaMissense

2623 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:56104798:T:G	Y21D	1.000
12:56104811:G:A	G25D	1.000
12:56106645:G:A	C49Y	1.000
12:56106653:G:C	G52R	1.000
12:56106689:T:C	F64L	1.000
12:56106691:C:A	F64L	1.000
12:56106691:C:G	F64L	1.000
12:56106716:G:C	G73R	1.000
12:56106990:G:T	G73V	1.000
12:56106996:C:A	A75D	1.000
12:56106998:T:C	F76L	1.000
12:56107000:T:A	F76L	1.000
12:56107000:T:G	F76L	1.000
12:56107002:C:A	P77H	1.000
12:56107002:C:G	P77R	1.000
12:56107013:T:C	S81P	1.000
12:56107034:C:G	H88D	1.000
12:56107036:C:A	H88Q	1.000
12:56107036:C:G	H88Q	1.000
12:56107194:G:A	G111R	1.000
12:56107194:G:C	G111R	1.000
12:56107194:G:T	G111W	1.000
12:56107195:G:A	G111E	1.000
12:56107210:G:A	G116D	1.000
12:56107210:G:T	G116V	1.000
12:56107585:C:A	A153D	1.000
12:56107591:G:C	R155P	1.000
12:56107594:T:C	L156P	1.000
12:56107597:T:A	V157D	1.000
12:56109865:T:C	S187P	1.000

dbSNP variants (sampled 300 via entrez): RS1000153578 (12:56112008 G>A), RS1000436264 (12:56112632 TATAGTCCCAGCTACC>T), RS1000449914 (12:56105238 G>A,T), RS1000454579 (12:56111881 G>T), RS1000760175 (12:56106006 T>G), RS1000819664 (12:56108957 C>G,T), RS1001059341 (12:56113864 T>C), RS1001277460 (12:56108431 C>G), RS1001292542 (12:56110838 G>A), RS1001310153 (12:56107986 G>A), RS1001437665 (12:56112276 A>T), RS1002257371 (12:56110074 C>G), RS1002491076 (12:56114225 G>A), RS1002867118 (12:56102667 T>C), RS1002949582 (12:56106170 G>C)

Disease associations

OMIM: gene MIM:602145 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST001670_1	Vitiligo	8.000000e-12
GCST004367_1	Anorexia nervosa	4.000000e-09
GCST007563_23	Allergic disease (asthma, hay fever or eczema)	4.000000e-10
GCST007564_9	Asthma or allergic disease (pleiotropy)	1.000000e-13
GCST008916_124	Asthma	1.000000e-16
GCST009798_45	Asthma	1.000000e-15
GCST010002_217	Refractive error	6.000000e-174
GCST010988_495	Adult body size	1.000000e-14

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067073 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 3 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.44	Kd	364.6	nM	CHEMBL5653589
6.44	ED50	364.6	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 4 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148925: Binding affinity to human PA2G4 incubated for 45 mins by Kinobead based pull down assay	kd	0.3646	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, decreases methylation, decreases expression	4
sodium arsenite	decreases expression, increases activity, increases expression	4
bisphenol AF	increases expression	2
Quercetin	decreases expression, increases expression	2
Nanotubes, Carbon	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
TAK-243	increases sumoylation	1
deoxynivalenol	increases expression	1
geraniol	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
arsenite	affects binding, increases reaction	1
cobaltous chloride	decreases expression	1
hydroquinone	affects expression	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	affects expression	1
epigallocatechin gallate	increases expression	1
bicalutamide	affects binding, increases reaction, increases response to substance	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	increases reaction, affects binding	1
chloropicrin	decreases expression	1
tanespimycin	increases expression, affects cotreatment	1
K 7174	decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
belinostat	decreases expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
2-amino-14,16-dimethyloctadecan-3-ol	increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases expression, increases response to substance	1
bisphenol S	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651967	Binding	Binding affinity to human PA2G4 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A5C0	SEES3-1V human PA2G4, clone1	Embryonic stem cell	Male
CVCL_A5C1	SEES3-1V human PA2G4, clone2	Embryonic stem cell	Male
CVCL_A5C2	SEES3-1V human PA2G4, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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