NETO2

Summary

NETO2 (neuropilin and tolloid like 2, HGNC:14644) is a protein-coding gene on chromosome 16q12.1, encoding Neuropilin and tolloid-like protein 2 (Q8NC67). Accessory subunit of neuronal kainate-sensitive glutamate receptors, GRIK2 and GRIK3.

This gene encodes a predicted transmembrane protein containing two extracellular CUB domains followed by a low-density lipoprotein class A (LDLa) domain. A similar gene in rats encodes a protein that modulates glutamate signaling in the brain by regulating kainate receptor function. Expression of this gene may be a biomarker for proliferating infantile hemangiomas. A pseudogene of this gene is located on the long arm of chromosome 8. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 81831 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 82 total
• GTEx eGene: eQTL in 11 tissues, sQTL in 1 (q < 0.05)
• Constraint (gnomAD): pLI 0.07 (LoF-tolerant), LOEUF 0.63 (unconstrained)
• MANE Select transcript: NM_018092
• Notable: 82 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14644
Approved symbol	NETO2
Name	neuropilin and tolloid like 2
Location	16q12.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10430, NEOT2
Ensembl gene	ENSG00000171208
Ensembl biotype	protein_coding
OMIM	607974
Entrez	81831

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 15 protein_coding, 2 nonsense_mediated_decay

MANE Select: ENST00000562435

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 3: 2, TSL 4: 1, TSL 5: 1

ENST00000562435, ENST00000303155, ENST00000562559, ENST00000563078, ENST00000564667, ENST00000878302, ENST00000878303, ENST00000878304, ENST00000935728, ENST00000935729, ENST00000935730, ENST00000962554, ENST00001042621, ENST00001042622, ENST00001042623, ENST00001115175, ENST00001139130

RefSeq mRNA: 2 — MANE Select: NM_018092 NM_001201477, NM_018092

CCDS: CCDS10727, CCDS58460

Canonical transcript exons

ENST00000562435 — 9 exons

Exon	Start	End
ENSE00001131266	47122657	47122784
ENSE00001131270	47128325	47128573
ENSE00001131278	47129224	47129364
ENSE00001165245	47109483	47109711
ENSE00001245750	47122868	47122912
ENSE00001319075	47131969	47132025
ENSE00001388767	47143579	47143945
ENSE00001696301	47086226	47086339
ENSE00002628768	47077703	47083801

Expression profiles

Bgee: expression breadth ubiquitous, 228 present calls, max score 97.72.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.0825 / max 255.9362, expressed in 1693 samples.

Highest expression (Bgee): secondary oocyte, cortical plate, ganglionic eminence, oocyte, primordial germ cell in gonad.

Genetic regulation across tissues (GTEx eQTL / sQTL)

NETO2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 11 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

12 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Brain Cortex	eqtl	1.2e-05	+0.28	16:47845128:T:G
Brain Frontal Cortex BA9	eqtl	3.6e-05	+0.24	16:47812643:C:T
Spleen	eqtl	5.1e-04	-0.59	16:48045565:G:C
Testis	eqtl	1.8e-03	-0.41	16:47375321:C:T
Whole Blood	eqtl	1.9e-03	-0.17	16:48072734:A:T
Esophagus Mucosa	eqtl	1.7e-02	-0.22	16:47034600:C:G
Brain Cerebellum	eqtl	2.1e-02	+0.82	16:48092313:C:T
Testis	sqtl	3.0e-02	-0.55	16:47681273:A:C
Brain Substantia nigra	eqtl	3.8e-02	-0.72	16:47080976:A:G
Cells EBV-transformed lymphocytes	eqtl	4.3e-02	-0.29	16:48072734:A:T
Adipose Subcutaneous	eqtl	4.5e-02	+0.56	16:46412596:A:G
Esophagus Muscularis	eqtl	5.0e-02	-0.13	16:46957380:G:A

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
157233	7.3756	1460
157234	6.5569	1582
157235	1.1500	792

Top tissues by expression

showing 100 of 277 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	97.72	gold quality
cortical plate	UBERON:0005343	96.87	gold quality
ganglionic eminence	UBERON:0004023	95.61	gold quality
oocyte	CL:0000023	94.71	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.60	gold quality
pigmented layer of retina	UBERON:0001782	92.59	gold quality
retina	UBERON:0000966	92.57	gold quality
embryo	UBERON:0000922	91.34	gold quality
adrenal tissue	UBERON:0018303	90.93	gold quality
ventricular zone	UBERON:0003053	89.17	gold quality
Brodmann (1909) area 46	UBERON:0006483	88.95	gold quality
middle temporal gyrus	UBERON:0002771	87.36	gold quality
nucleus accumbens	UBERON:0001882	86.19	gold quality
orbitofrontal cortex	UBERON:0004167	85.96	gold quality
prefrontal cortex	UBERON:0000451	85.69	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.58	gold quality
Brodmann (1909) area 23	UBERON:0013554	85.28	gold quality
caudate nucleus	UBERON:0001873	85.14	gold quality
stromal cell of endometrium	CL:0002255	84.89	gold quality
superior frontal gyrus	UBERON:0002661	84.55	gold quality
mucosa of transverse colon	UBERON:0004991	84.55	gold quality
putamen	UBERON:0001874	84.32	gold quality
frontal cortex	UBERON:0001870	83.39	gold quality
frontal lobe	UBERON:0016525	83.39	gold quality
monocyte	CL:0000576	83.31	gold quality
visceral pleura	UBERON:0002401	83.08	gold quality
neocortex	UBERON:0001950	83.07	gold quality
mononuclear cell	CL:0000842	83.00	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	82.81	gold quality
spleen	UBERON:0002106	82.50	gold quality
leukocyte	CL:0000738	82.49	gold quality
cerebral cortex	UBERON:0000956	82.13	gold quality
telencephalon	UBERON:0001893	82.13	gold quality
postcentral gyrus	UBERON:0002581	81.49	gold quality
anterior cingulate cortex	UBERON:0009835	80.93	gold quality
cingulate cortex	UBERON:0003027	80.86	gold quality
cerebellar cortex	UBERON:0002129	80.84	gold quality
cerebellar hemisphere	UBERON:0002245	80.74	gold quality
Brodmann (1909) area 9	UBERON:0013540	80.73	gold quality
cerebellum	UBERON:0002037	80.48	gold quality
right hemisphere of cerebellum	UBERON:0014890	80.44	gold quality
parietal lobe	UBERON:0001872	80.03	gold quality
right lung	UBERON:0002167	79.93	gold quality
entorhinal cortex	UBERON:0002728	79.53	gold quality
forebrain	UBERON:0001890	79.30	gold quality
choroid plexus epithelium	UBERON:0003911	79.27	gold quality
brain	UBERON:0000955	78.97	gold quality
right frontal lobe	UBERON:0002810	78.89	gold quality
primary visual cortex	UBERON:0002436	78.51	gold quality
endothelial cell	CL:0000115	78.48	silver quality
temporal lobe	UBERON:0001871	77.61	gold quality
Ammon’s horn	UBERON:0001954	77.33	gold quality
cerebellar vermis	UBERON:0004720	76.81	gold quality
right adrenal gland cortex	UBERON:0035827	76.47	gold quality
right adrenal gland	UBERON:0001233	76.30	gold quality
amygdala	UBERON:0001876	76.30	gold quality
occipital lobe	UBERON:0002021	76.26	gold quality
CA1 field of hippocampus	UBERON:0003881	76.12	gold quality
adrenal gland	UBERON:0002369	76.03	gold quality
left adrenal gland	UBERON:0001234	75.40	gold quality
upper lobe of left lung	UBERON:0008952	75.28	gold quality
adult organism	UBERON:0007023	75.25	gold quality
esophagus mucosa	UBERON:0002469	75.06	gold quality
upper lobe of lung	UBERON:0008948	74.81	gold quality
left adrenal gland cortex	UBERON:0035825	74.80	gold quality
gall bladder	UBERON:0002110	74.64	gold quality
vermiform appendix	UBERON:0001154	74.57	gold quality
esophagus squamous epithelium	UBERON:0006920	74.32	gold quality
ileal mucosa	UBERON:0000331	74.31	gold quality
adrenal cortex	UBERON:0001235	74.30	gold quality
granulocyte	CL:0000094	74.07	gold quality
transverse colon	UBERON:0001157	74.06	gold quality
testis	UBERON:0000473	74.05	gold quality
right testis	UBERON:0004534	73.54	gold quality
lung	UBERON:0002048	73.47	gold quality
hypothalamus	UBERON:0001898	73.32	gold quality
left testis	UBERON:0004533	72.56	gold quality
lymph node	UBERON:0000029	72.52	gold quality
pleura	UBERON:0000977	72.46	gold quality
pons	UBERON:0000988	72.31	gold quality
caecum	UBERON:0001153	71.56	gold quality
islet of Langerhans	UBERON:0000006	71.27	gold quality
epithelium of esophagus	UBERON:0001976	71.22	gold quality
right lobe of thyroid gland	UBERON:0001119	71.21	gold quality
lower esophagus mucosa	UBERON:0035834	71.10	gold quality
thyroid gland	UBERON:0002046	70.70	gold quality
gingiva	UBERON:0001828	70.65	gold quality
left lobe of thyroid gland	UBERON:0001120	70.62	gold quality
substantia nigra	UBERON:0002038	70.51	gold quality
gastrocnemius	UBERON:0001388	70.27	gold quality
squamous epithelium	UBERON:0006914	70.04	gold quality
muscle of leg	UBERON:0001383	69.88	gold quality
endometrium	UBERON:0001295	69.87	gold quality
midbrain	UBERON:0001891	69.72	gold quality
hindlimb stylopod muscle	UBERON:0004252	69.11	gold quality
rectum	UBERON:0001052	68.99	gold quality
gingival epithelium	UBERON:0001949	68.80	gold quality
apex of heart	UBERON:0002098	68.59	gold quality
colonic mucosa	UBERON:0000317	68.48	gold quality
lateral globus pallidus	UBERON:0002476	68.29	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.79
E-CURD-112	no	2.00

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Caudate putamen	tissue	71.2
Cerebellum	tissue	62.1	medium
Cerebral cortex	tissue	54.1	medium
Occipital cortex	tissue	54.1
Nucleus accumbens	tissue	53.5
Somatosensory cortex	tissue	52.8
Putamen	tissue	51.8
Basal ganglia	tissue	44.8	medium
Hippocampal formation	tissue	44.3
Entorhinal cortex	tissue	44.3
Motor cortex	tissue	41.4
Retrosplenial and cingulate cortex	tissue	40.2
Prefrontal cortex	tissue	39.5
Postcentral gyrus	tissue	35.0
Ventral forebrain	tissue	34.3
Temporal cortex	tissue	34.3
Insular cortex	tissue	33.4
Retrosplenial cortex	tissue	33.1
Frontal cortex	tissue	31.5
Septum	tissue	30.5
Olfactory bulb	tissue	29.1
Midbrain	tissue	25.8
Amygdala	tissue	25.1
Thalamus	tissue	23.9
Spleen	tissue	21.4	medium
Hippocampus	tissue	20.1	medium
Pons	tissue	19.0
Substantia nigra	tissue	18.3
Choroid plexus	tissue	17.2
Locus coeruleus	tissue	17.0
Superior colliculi	tissue	16.9
Hypothalamus	tissue	16.0
Periaqueductal gray	tissue	15.8
Medulla oblongata	tissue	14.3
Corpus callosum	tissue	11.2
Parathyroid gland	tissue	10.1	medium
Spinal cord	tissue	9.7
Thyroid gland	tissue	8.2	medium
Colon	tissue	8.0	medium
Testis	tissue	7.5	medium
Retina	tissue	6.9
Appendix	tissue	6.0	medium
Lymph node	tissue	5.9	medium
Tonsil	tissue	5.8	medium
Adrenal gland	tissue	5.4	medium
Thymus	tissue	5.1
Urinary bladder	tissue	4.6	medium
Esophagus	tissue	4.5	medium
Gallbladder	tissue	4.5	medium
Skeletal muscle	tissue	4.2	medium
Lung	tissue	4.2	medium
Ovary	tissue	3.6	medium
Placenta	tissue	3.2	medium
Vagina	tissue	2.8	not detected
Breast	tissue	2.6	medium
Adipose tissue	tissue	2.5	low
Bone marrow	tissue	2.3	low
Rectum	tissue	2.2	medium
Small intestine	tissue	2.2	medium
Tongue	tissue	2.1

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Caudate nucleus (54.3), Nucleus basalis of Meynert (33.9), Mammillary body (32.4), Olfactory tubercle (30.7), Nucleus raphe magnus (30.5).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NME1

miRNA regulators (miRDB)

Targeting NETO2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 113 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-106A-5P	99.90	73.94	2683

Functional genomics

gnomAD constraint: pLI 0.0652, LOEUF 0.627, missense Z 1.58 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000562435 — one region, missense o/e 0.85.

Literature-anchored findings (GeneRIF, showing 13)

• Determination of the neuropilin and tolloid-like protein 2 signal peptide cleavage site by N-terminal sequencing. (PMID:15340161)
• Rat neto2 plays a role in glutamate signaling in the brain by modulating the function of kainate receptors. (PMID:19217376)
• Results suggested that the extracellular N-terminal region including the two CUB domains was largely responsible for the distinct regulatory effects of Neto1 and Neto2 on the desensitization properties of GluK1 homomeric receptors (PMID:26277340)
• NETO2 upregulation could serve as a potential biomarker for the prediction of advanced tumor progression and unfavorable prognosis in patients with colorectal carcinoma. (PMID:26699544)
• NETO2 may be involved in colorectal cancer progression, but is not directly associated with epithelial-mesenchymal transition (PMID:29297384)
• upregulation of NETO2 gene is first stipulated by the isoform 1 (NM_018092.4), and the probable mechanism of its activation is associated with the increased expression of SAP30 transcription factor. (PMID:29989576)
• NETO2 promotes invasion and metastasis of gastric cancer cells and represents a novel prognostic indicator as well as a potential therapeutic target in gastric cancer. (PMID:30770791)
• NETO2 expression is up-regulated in Nasopharyngeal carcinoma (NPC) clinical specimens and cell lines. NETO2 down-regulation reduces proliferation, migration and invasion in irradiated NPC cell lines. (PMID:30975469)
• Neuropilin and tolloid-like 2 regulates the progression of osteosarcoma. (PMID:33157203)
• NETO2 promotes esophageal cancer progression by inducing proliferation and metastasis via PI3K/AKT and ERK pathway. (PMID:33390848)
• Kainate receptor modulation by NETO2. (PMID:34552241)
• Glioma-derived LRIG3 interacts with NETO2 in tumor-associated macrophages to modulate microenvironment and suppress tumor growth. (PMID:36639372)
• NETO2 promotes melanoma progression via activation of the Ca[2+]/CaMKII signaling pathway. (PMID:36738427)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	neto2b	ENSDARG00000063293
danio_rerio	neto2a	ENSDARG00000112100
mus_musculus	Neto2	ENSMUSG00000036902
rattus_norvegicus	Neto2	ENSRNOG00000016245

Paralogs (35): NRXN3 (ENSG00000021645), TLL1 (ENSG00000038295), CP (ENSG00000047457), DCBLD2 (ENSG00000057019), HEPH (ENSG00000089472), TLL2 (ENSG00000095587), NRP1 (ENSG00000099250), PCOLCE (ENSG00000106333), CNTNAP3 (ENSG00000106714), CUBN (ENSG00000107611), CNTNAP1 (ENSG00000108797), NRXN2 (ENSG00000110076), MEP1A (ENSG00000112818), NRP2 (ENSG00000118257), CUZD1 (ENSG00000138161), MFGE8 (ENSG00000140545), MEP1B (ENSG00000141434), PDGFC (ENSG00000145431), CNTNAP4 (ENSG00000152910), CNTNAP3B (ENSG00000154529), CNTNAP5 (ENSG00000155052), CDCP2 (ENSG00000157211), PCOLCE2 (ENSG00000163710), EDIL3 (ENSG00000164176), NETO1 (ENSG00000166342), BMP1 (ENSG00000168487), PDGFD (ENSG00000170962), CNTNAP2 (ENSG00000174469), NRXN1 (ENSG00000179915), HEPHL1 (ENSG00000181333), F8 (ENSG00000185010), ASTL (ENSG00000188886), F5 (ENSG00000198734), MFRP (ENSG00000235718), CNTNAP3C (ENSG00000283378)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1921763) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 4 distinct phenotype terms.

Mouse phenotype (MP)	Records
tremors	1
decreased locomotor activity	1
increased circulating amylase level	1
increased circulating lipase level	1

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	Q5R662	99.7%	Diamond
Bos taurus	Q5E9P5	90.8%	Diamond
Sus scrofa	Q4A3R3	73.9%	Diamond
Oryctolagus cuniculus	Q95218	72.9%	Diamond
Brugia malayi	A8Q2D1	71.1%	Diamond
Caenorhabditis elegans	Q20911	54.8%	Diamond
Drosophila melanogaster	Q9W332	51.6%	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
ITFG1-AS2	ncRNA	101927080
ITFG1-AS1	ncRNA	101927102
DNAJA2-DT	ncRNA	119545626
ITFG1	protein-coding	81533
SNORD148	snoRNA	109623466
GPT2	protein-coding	84706
DNAJA2	protein-coding	10294
PHKB	protein-coding	5257

Protein

Protein identifiers

Neuropilin and tolloid-like protein 2 — Q8NC67 (reviewed: Q8NC67)

Alternative names: Brain-specific transmembrane protein containing 2 CUB and 1 LDL-receptor class A domains protein 2

All UniProt accessions (4): Q8NC67, H3BM37, H3BSR0, H3BTE1

UniProt curated annotations — full annotation on UniProt →

Function. Accessory subunit of neuronal kainate-sensitive glutamate receptors, GRIK2 and GRIK3. Increases kainate-receptor channel activity, slowing the decay kinetics of the receptors, without affecting their expression at the cell surface, and increasing the open probability of the receptor channels. Modulates the agonist sensitivity of kainate receptors. Slows the decay of kainate receptor-mediated excitatory postsynaptic currents (EPSCs), thus directly influencing synaptic transmission.

Subunit / interactions. Interacts with GRIK2 and GRIK3, but neither with AMPA-nor with NMDA-sensitive glutamate receptors.

Subcellular location. Membrane.

Post-translational modifications. N-glycosylated.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8NC67-1	1	yes
Q8NC67-2	2
Q8NC67-3	3

RefSeq proteins (2): NP_001188406, NP_060562* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000859	CUB_dom	Domain
IPR002172	LDrepeatLR_classA_rpt	Repeat
IPR023415	LDLR_class-A_CS	Conserved_site
IPR035914	Sperma_CUB_dom_sf	Homologous_superfamily
IPR036055	LDL_receptor-like_sf	Homologous_superfamily

Pfam: PF00057, PF00431

UniProt features (26 total): disulfide bond 7, sequence conflict 5, splice variant 3, domain 3, topological domain 2, signal peptide 1, chain 1, sequence variant 1, transmembrane region 1, modified residue 1, glycosylation site 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NC67-F1	72.14	0.45

Human Protein Atlas

Protein class: Transporters, Accessory Factors Involved in Transport, Predicted membrane proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): golgi apparatus

Antibody reliability (HPA): IH uncertain · IF approved

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)

Type	Positions
Phosphoserine	409

Disulfide bonds (7)

Type	Positions
Disulfide bond	45–72, 100–122, 177–207, 234–256, 297–309, 304–322, 316–331

Glycosylation sites (1)

Type	Positions
N-linked (glcnac…) asparagine	311

Function

Pathways and Gene Ontology

Reactome pathways

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

MSigDB gene sets: 211 (showing top): ELVIDGE_HYPOXIA_DN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, TGCACTT_MIR519C_MIR519B_MIR519A, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, LEE_LIVER_CANCER_CIPROFIBRATE_DN, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, WEI_MYCN_TARGETS_WITH_E_BOX, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_ERYTHROCYTE_UP, CADWELL_ATG16L1_TARGETS_DN, ONKEN_UVEAL_MELANOMA_UP, RUTELLA_RESPONSE_TO_CSF2RB_AND_IL4_UP, GOBP_REGULATION_OF_CELLULAR_LOCALIZATION, BILD_E2F3_ONCOGENIC_SIGNATURE, RUTELLA_RESPONSE_TO_HGF_VS_CSF2RB_AND_IL4_DN, LIAO_METASTASIS

GO Biological Process (2): regulation of neurotransmitter receptor localization to postsynaptic specialization membrane (GO:0098696), neurotransmitter receptor localization to postsynaptic specialization membrane (GO:0099645)

GO Molecular Function (2): ionotropic glutamate receptor binding (GO:0035255), protein binding (GO:0005515)

GO Cellular Component (5): postsynaptic density membrane (GO:0098839), glutamatergic synapse (GO:0098978), postsynaptic density (GO:0014069), membrane (GO:0016020), synapse (GO:0045202)

GO top-level categories

20 GO namespaces:

Category	Terms
regulation of biological quality	1
neurotransmitter receptor localization to postsynaptic specialization membrane	1
regulation of protein localization to synapse	1
regulation of receptor localization to synapse	1
regulation of protein localization to cell periphery	1
regulation of protein localization to membrane	1
protein-containing complex localization	1
receptor localization to synapse	1
regulation of postsynaptic membrane neurotransmitter receptor levels	1
protein localization to postsynaptic specialization membrane	1
glutamate receptor binding	1
binding	1
postsynaptic density	1
postsynaptic membrane	1
postsynaptic specialization membrane	1
synapse	1
asymmetric synapse	1
postsynaptic specialization	1
cellular anatomical structure	1
cell junction	1

Protein interactions and networks

STRING

showing 15 of 459 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NETO2	KARS1	Q15046	670
NETO2	GRIK2	Q13002	655
NETO2	GRIK1	P39086	585
NETO2	GRIK4	Q16099	517
NETO2	GRIK5	Q16478	494
NETO2	SLC12A5	Q9H2X9	487
NETO2	C11orf87	Q6NUJ2	443
NETO2	CACNG2	Q9Y698	441
NETO2	CALB1	P05937	433
NETO2	CNIH2	Q6PI25	419
NETO2	CNIH4	Q9P003	416
NETO2	CNIH1	O95406	410
NETO2	SPADH	A0A494C103	388
NETO2	GRIK3	Q13003	384
NETO2	GRIA2	P42262	376

IntAct

Human interaction partners of NETO2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

1 partners by confidence:

Partner	Interaction type	MIscore	Records
TIA1	association	0.350	1

BioGRID (107 interactions; top human partners by supporting records): BTNL8 (Affinity Capture-MS; 3 records), HLA-C (Affinity Capture-MS; 3 records), HTR3C (Affinity Capture-MS; 3 records), IL9R (Affinity Capture-MS; 3 records), PON2 (Affinity Capture-MS; 3 records), ADAM33 (Affinity Capture-MS; 2 records), ASIC4 (Affinity Capture-MS; 2 records), CLEC2D (Affinity Capture-MS; 2 records), HLA-DRA (Affinity Capture-MS; 2 records), HTR3A (Affinity Capture-MS; 2 records), PTCH1 (Affinity Capture-MS; 2 records), TMED6 (Affinity Capture-MS; 2 records), TMEM30B (Affinity Capture-MS; 2 records), TMPRSS3 (Affinity Capture-MS; 2 records), ZNRF4 (Affinity Capture-MS; 2 records)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
NME1	“down-regulates quantity by repression”	NETO2	“transcriptional regulation”

Disease & clinical

Genetic variants

Variant evidence for NETO2: 82 ClinVar records (0 pathogenic / likely pathogenic).

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	71
Likely benign	0
Benign	1

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 36 predictions of 956):

Position(s)	Effect	Δscore	Sites
16:47122661	donor_gain	1.0000
16:47129222–47129223	donor_loss	1.0000	5
16:47129226	donor_gain	1.0000
16:47129244	donor_gain	1.0000
16:47129366	acceptor_gain	1.0000
16:47083802–47083803	acceptor_loss	0.9900	6
16:47109478–47109482	donor_loss	0.9900	9
16:47128323–47128324	donor_loss	0.9900	5
16:47128574–47128575	acceptor_loss	0.9900	6
16:47129363	acceptor_gain	0.9900

AlphaMissense

1,258 missense substitutions predicted likely pathogenic (of 3,486 scored), across 325 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
D103	8	0.996	0.999
D144	8	0.987	0.998
F152	8	0.976	0.999
F223	8	0.970	0.999
F285	8	0.966	0.998
F141	8	0.965	0.999
F88	8	0.960	0.997
D109	8	0.956	0.996
D206	8	0.949	0.986
N237	8	0.948	0.998
D327	8	0.943	0.979
D243	8	0.905	0.988
F57	8	0.894	0.998
D161	8	0.888	0.961
D262	8	0.865	0.955
D277	8	0.852	0.950
C100	7	0.998	1.000
C122	7	0.998	0.999
C256	7	0.998	0.999
C72	7	0.997	0.999

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

3 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Papillary Cell Carcinoma (TCGA)	unfavorable	3.6e-06
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	0.000516
Lung Adenocarcinoma (validation)	unfavorable	0.000817

Disease associations

OMIM: gene MIM:607974 | disease phenotypes:

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases methylation	6
bisphenol A	increases expression, affects cotreatment, decreases expression	3
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression, decreases expression	3
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
belinostat	decreases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, increases expression	2
Tretinoin	decreases expression	2
cobaltous chloride	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
ochratoxin A	increases acetylation	1
potassium chromate(VI)	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
incobotulinumtoxinA	decreases expression	1
Bortezomib	decreases expression	1
Temozolomide	decreases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	decreases expression	1
Acetaminophen	increases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Atrazine	decreases expression	1
Carbamazepine	affects expression	1
Cocaine	increases expression	1
Coumestrol	increases expression	1
Cyclophosphamide	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_F1M7	HyCyte A-549 KO-hNETO2	Cancer cell line	Male

Clinical trials (associated diseases)

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

showing 60 of 300 trials:

NCT	Phase	Status	Title
NCT00029224	Phase 4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	Phase 4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	Phase 4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	Phase 4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	Phase 4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	Phase 4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	Phase 4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	Phase 4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	Phase 4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	Phase 4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	Phase 4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	Phase 4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	Phase 4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	Phase 4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	Phase 4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	Phase 4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	Phase 4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	Phase 4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	Phase 4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	Phase 4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	Phase 4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	Phase 4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	Phase 4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	Phase 4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	Phase 4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	Phase 4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	Phase 4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	Phase 4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	Phase 4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	Phase 4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	Phase 4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	Phase 4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	Phase 4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	Phase 4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	Phase 4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	Phase 4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	Phase 4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	Phase 4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	Phase 4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	Phase 4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer
NCT01673984	Phase 4	TERMINATED	GP Extended Action Triptorelin
NCT01753297	Phase 4	COMPLETED	A Study of Immediate 9 Months Adjuvant Hormone Therapy With Triptorelin 11.25 mg Versus Active Surveillance After Radical Prostatectomy in High Risk Prostate Cancer Patients.
NCT01794793	Phase 4	COMPLETED	Study to Allow Access to Pasireotide for Patients Benefiting From Pasireotide Treatment in Novartis-sponsored Studies
NCT01950871	Phase 4	TERMINATED	Prostate Guided Biopsy Study Evaluating the Diagnostic Performance of Prostate HistoScanning
NCT01995513	Phase 4	COMPLETED	Safety Study of Continued Enzalutamide Treatment In Prostate Cancer Patients
NCT02102646	Phase 4	COMPLETED	MRI Substudy; Metabolic Changes Due to Iatrogenic Hypogonadism
NCT02116582	Phase 4	COMPLETED	A Study to Evaluate Enzalutamide After Abiraterone in Metastatic Castration-Resistant Prostate Cancer
NCT02149628	Phase 4	COMPLETED	The Effect of Propofol Based Total Intravenous Anesthesia on Oxidative Stress and Nitric Oxide
NCT02405858	Phase 4	COMPLETED	A Study of Abiraterone Acetate in Metastatic Castration-Resistant Prostate Cancer Participants Who Responded Poorly to the First-line Combined Androgen Blockade Therapy
NCT02441517	Phase 4	TERMINATED	A Study of Enzalutamide Re-treatment in Metastatic Castration-resistant Prostate Cancer After Docetaxel and/or Cabazitaxel Treatment
NCT02441894	Phase 4	COMPLETED	Combination of Cabazitaxel With Prednisolone With Primary Prophylaxis With PEG-G-CSF in Treatment of Patients With Prostate Cancer
NCT02475057	Phase 4	COMPLETED	Endothelial Function in Prostate Cancer Patients on Degarelix vs. Luteinizing Hormone-Releasing Hormone Agonists
NCT02511665	Phase 4	UNKNOWN	Metformin And Longevity
NCT02651948	Phase 4	COMPLETED	Transperineal, MRI-guided, Prostate Biopsy
NCT02721433	Phase 4	COMPLETED	4-weekly Versus 12-weekly Administration of Bone-targeted Agents in Patients With Bone Metastases
NCT02726009	Phase 4	COMPLETED	A Trial to Evaluate Safety of Firmagon® (Degarelix) in Indian Patients Diagnosed With Advanced Hormone-dependent Prostate Cancer
NCT02749825	Phase 4	TERMINATED	Comparison of Trelstar Versus Lupron or Zoladex in Advanced Prostate Cancer
NCT02757365	Phase 4	UNKNOWN	Efficiency Study of Aspirin to Prevent the Occurrence of Prostate Cancer
NCT02773251	Phase 4	COMPLETED	The Effect of Guardix-solution for the Prevention of Postoperative Intestinal Adhesion and Intestinal Obstruction After Laparoscopic Pelvic Cavity Surgery
NCT02812186	Phase 4	COMPLETED	Deep Versus Moderate Neuromuscular Blockade During Laparoscopic Surgery