NET1

Summary

NET1 (neuroepithelial cell transforming 1, HGNC:14592) is a protein-coding gene on chromosome 10p15.1, encoding Neuroepithelial cell-transforming gene 1 protein (Q7Z628). Acts as a guanine nucleotide exchange factor (GEF) for RhoA GTPase.

This gene is part of the family of Rho guanine nucleotide exchange factors. Members of this family activate Rho proteins by catalyzing the exchange of GDP for GTP. The protein encoded by this gene interacts with RhoA within the cell nucleus and may play a role in repairing DNA damage after ionizing radiation. Pseudogenes of this gene are located on the long arms of chromosomes 1, 7 and 18. Alternative splicing results in multiple transcript variants that encode different protein isoforms.

Source: NCBI Gene 10276 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 102 total
• Druggable target: yes
• MANE Select transcript: NM_001047160

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14592
Approved symbol	NET1
Name	neuroepithelial cell transforming 1
Location	10p15.1
Locus type	gene with protein product
Status	Approved
Aliases	ARHGEF8, NET1A
Ensembl gene	ENSG00000173848
Ensembl biotype	protein_coding
OMIM	606450
Entrez	10276

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 6 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000355029, ENST00000380359, ENST00000449083, ENST00000465087, ENST00000484741, ENST00000486354, ENST00000867093, ENST00000867094, ENST00000935158

RefSeq mRNA: 2 — MANE Select: NM_001047160 NM_001047160, NM_005863

CCDS: CCDS41483, CCDS7067

Canonical transcript exons

ENST00000355029 — 12 exons

Exon	Start	End
ENSE00001235344	5453484	5453560
ENSE00001235358	5452858	5452920
ENSE00001235404	5453250	5453346
ENSE00001402045	5412557	5412820
ENSE00001661254	5456087	5456273
ENSE00003469992	5454948	5455118
ENSE00003616274	5429170	5429229
ENSE00003638669	5426655	5426721
ENSE00003666110	5452358	5452525
ENSE00003687205	5451830	5451937
ENSE00003788104	5454265	5454522
ENSE00003850269	5456588	5459056

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 99.49.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 32.2785 / max 1026.2793, expressed in 1790 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
103639	23.2717	1615
103635	7.1149	1438
103634	6.9265	1410
103636	1.1447	364
103637	0.6925	192
103638	0.0547	19

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	99.49	gold quality
mucosa of paranasal sinus	UBERON:0005030	99.07	gold quality
blood vessel layer	UBERON:0004797	98.66	gold quality
pharyngeal mucosa	UBERON:0000355	98.65	gold quality
descending thoracic aorta	UBERON:0002345	98.49	gold quality
palpebral conjunctiva	UBERON:0001812	98.38	gold quality
pericardium	UBERON:0002407	98.31	gold quality
pylorus	UBERON:0001166	98.15	gold quality
cardia of stomach	UBERON:0001162	98.05	gold quality
urethra	UBERON:0000057	98.01	gold quality
tendon	UBERON:0000043	97.99	gold quality
superior surface of tongue	UBERON:0007371	97.98	gold quality
trigeminal ganglion	UBERON:0001675	97.89	gold quality
parotid gland	UBERON:0001831	97.84	gold quality
rectum	UBERON:0001052	97.70	gold quality
esophagus squamous epithelium	UBERON:0006920	97.68	gold quality
inferior vagus X ganglion	UBERON:0005363	97.53	gold quality
saliva-secreting gland	UBERON:0001044	97.50	gold quality
minor salivary gland	UBERON:0001830	97.50	gold quality
mouth mucosa	UBERON:0003729	97.49	gold quality
tongue	UBERON:0001723	97.48	gold quality
penis	UBERON:0000989	97.47	gold quality
mucosa of sigmoid colon	UBERON:0004993	97.47	gold quality
colonic mucosa	UBERON:0000317	97.44	gold quality
calcaneal tendon	UBERON:0003701	97.42	gold quality
tibia	UBERON:0000979	97.35	gold quality
body of tongue	UBERON:0011876	97.28	gold quality
squamous epithelium	UBERON:0006914	97.18	gold quality
nasal cavity mucosa	UBERON:0001826	97.11	gold quality
medial globus pallidus	UBERON:0002477	97.03	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-8498	yes	635.33
E-CURD-114	yes	62.41
E-MTAB-10287	yes	48.92
E-MTAB-6678	yes	9.76
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

129 targeting NET1, 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-8485	100.00	77.57	4731
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 40)

• NET1 has roles in stimulating cytoskeletal reorganization and in transforming cells (PMID:15611121)
• PAK1 negatively regulates the activity of NET1 (PMID:15684429)
• The putative role for NET1 genes may provide important targets for intervention in Gastric adenocarcinoma, evidenced by their role in promoting invasion and proliferation, key phenotypic hallmarks of cancer cells. (PMID:16552434)
• These results suggest that the interaction between Net1 and Dlg1 may contribute to the mechanism of Net1-mediated transformation. (PMID:17938206)
• study concludes expression of NET-1 may relate to proliferation, metastasis & clinic stages of hepatocellular carcinoma (HCC); expression in HCC tissues may positively correlate to TMN stages; expression in HCC tissues was positively correlated with PCNA (PMID:18214716)
• NET-1 protein is expressed in cytoplasm of HCC cells as irregular granules near Golgi apparatus, and may promote the uncontrolled proliferation and abnormal differentiation in HCC cells. (PMID:18478931)
• data highlight the importance of Net1 in controlling RhoA and p38 MAPK mediated cell survival in cells exposed to DNA damaging agents (PMID:18509476)
• the importance of NET1 as a driver of tumour cell invasion (PMID:18827818)
• NET1 and integrin alpha6beta4 coexpression is independently associated with the development of distant metastasis in breast cancer. (PMID:19124484)
• Net1 requires interaction with PDZ domain proteins, such as Dlg1, to protect it from proteasome-mediated degradation and to maximally stimulate RhoA and that this interaction is regulated by cell-cell contact. (PMID:19586902)
• RNAi targeting NET-1 gene effectively down-regulates the expression of NET-1 in A431 cells, leading to an inhibition of proliferation, migration and infiltration. (PMID:20078975)
• Smad3 regulates RhoA activation and cytoskeletal reorganization by controlling NET1 in TGF-beta1-induced ARPE-19 cells. (PMID:20547485)
• NET1 plays an role in gastric cancer cell migration and invasion. The gene expression profile further elucidates the molecular mechanisms underpinning NET1-mediated aggressive GC cell behaviour. (PMID:21284875)
• A mechanism involving the nuclear GEFs Ect2 and Net1 for activating RhoB after genotoxic stress, thereby facilitating cell death after treatment with DNA damaging agents. (PMID:21373644)
• Existence of a functional Net1/RhoA signaling pathway within the nucleus of the cell and this implicates them in the DNA damage response. (PMID:21390328)
• Net1 is a CARMA-interacting molecule and brings important information on the molecular mechanisms that control NF-kappaB transcriptional activity (PMID:22343628)
• Net -1 frameshifting on a noncanonical sequence in a herpes simplex virus drug-resistant mutant is stimulated by nonstop mRNA. (PMID:22927407)
• Rac1 activation causes relocalization of Net1 isoforms outside the nucleus and stimulates Net1A catalytic activity. (PMID:23184663)
• NET-1 and VEGF silencing play a key role in inhibiting hepatocellular cell proliferation, promoting apoptosis, and reducing angiogenesis. (PMID:23636606)
• A previously unrecognized role for the Net1A isoform in controlling FAK activation during planar cell movement. (PMID:23689132)
• Results identify Net1 as a novel regulator of mitosis and indicate that altered expression of Net1, as occurs in human cancers, may adversely affect genomic stability. (PMID:23864709)
• A combination of NET1 (rs2242447) and SNAP-25 (rs3746544) is a risk factor for ADHD. (PMID:23872233)
• NET1 expression is elevated in OAC and its pre-malignant phenotype, Barrett’s oesophagus. NET1 promotes OAC cell invasion and proliferation. (PMID:23945136)
• The overexpression of NET-1 in tumor cells may be closely related to the malignant phenotype of skin squamous cell carcinoma including proliferation, invasion and tumor growth. (PMID:24196235)
• Data suggests that NET1 may be of prognostic significance in the clinical management of gastric adenocarcinoma (PMID:24375299)
• NET1 was associated with comorbidity of oppositional defiant disorder and symptoms in Attention-deficit/hyperactivity disorder probands (PMID:24942521)
• We suggest that the oncogenic properties of CML cells are probably due to deregulated expression of NET1 as a result of altered expression of miR-22. (PMID:25041463)
• High expression of neuroepithelial transforming gene 1 was associated with hepatocellular carcinoma. (PMID:25113254)
• Net1A plays a plays a previously unrecognized, Rho GTPase-independent role in controlling ATM activity and downstream signaling after DNA damage to impact cell survival. (PMID:25486363)
• These data indicate that Net1A acetylation regulates its subcellular localization to impact on RhoA activity and actin cytoskeletal organization. (PMID:25588829)
• Simultaneous silencing of NET-1 and survivin using one-chain-double-target siRNA thus provides an advantageous alternative in the development of therapeutics for skin squamous cell carcinoma . (PMID:26080853)
• AMPK phosphorylation of the RHOA guanine nucleotide exchange factor NET1A inhibits extracellular matrix degradation, an early step in cell invasion (PMID:26456332)
• Net1 mRNA and protein levels in non-small cell lung cancer tissues were significantly elevated compared with those in their corresponding nontumor tissues. (PMID:26459749)
• Net1 promotes the angiogenesis in cervical squamous cell carcinomas and siRNA targeting of Net1 can effectively reduce angiogenesis and inhibit tumor growth via VEGF signaling. (PMID:28511963)
• Net1A relocalization stimulated by EGF or JNK activation requires nuclear export mediated by CRM1. (PMID:29361525)
• Study found NET1 as a direct target for miR-22 to promote chemoresistance of bladder cancer cells. (PMID:29620229)
• This study solved the structure of a RhoA/Net1 heterodimer with X-ray crystallography at 2-A resolution. (PMID:29695506)
• data suggest that NET-1 promotes HCC invasion, adhesion and growth by regulating BAX, caspase 3, caspase 8 and BCL2 expression. (PMID:30301500)
• Regulation of RhoA activation and cell motility by c-Jun N-terminal kinases and Net1. (PMID:30332929)
• our results provide the first evidence that NET1 enhances proliferation and chemoresistance in B-ALL cells and that miR-206 regulates these effects by targeting NET1 (PMID:31046876)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	net1	ENSDARG00000032765
mus_musculus	Net1	ENSMUSG00000021215
rattus_norvegicus	Net1	ENSRNOG00000017765
drosophila_melanogaster	cyst	FBGN0032796
caenorhabditis_elegans	prhg-1	WBGENE00022391

Paralogs (8): PLEKHG6 (ENSG00000008323), ARHGEF1 (ENSG00000076928), ARHGEF18 (ENSG00000104880), ARHGEF2 (ENSG00000116584), ARHGEF11 (ENSG00000132694), ARHGEF3 (ENSG00000163947), ARHGEF12 (ENSG00000196914), ARHGEF28 (ENSG00000214944)

Protein

Protein identifiers

Neuroepithelial cell-transforming gene 1 protein — Q7Z628 (reviewed: Q7Z628)

Alternative names: Proto-oncogene p65 Net1, Rho guanine nucleotide exchange factor 8

All UniProt accessions (4): Q7Z628, Q5SQI5, Q5SQI6, Q5SQI7

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a guanine nucleotide exchange factor (GEF) for RhoA GTPase. May be involved in activation of the SAPK/JNK pathway Stimulates genotoxic stress-induced RHOB activity in breast cancer cells leading to their cell death.

Subunit / interactions. Interacts with RHOA in its GTP- and GDP-bound states, and with CDC42 in its GTP-bound state. Interacts with the PDZ 1 domain of BAIAP1.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Widely expressed.

Induction. By TGFB1. Up-regulated by DNA damaging agents like H(2)O(2) or ionizing radiation (IR).

Isoforms (2)

UniProt ID	Names	Canonical?
Q7Z628-1	1	yes
Q7Z628-2	2

RefSeq proteins (2): NP_001040625, NP_005854 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000219	DH_dom	Domain
IPR001331	GDS_CDC24_CS	Conserved_site
IPR001849	PH_domain	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR035899	DBL_dom_sf	Homologous_superfamily
IPR037853	Net1_PH	Domain
IPR051480	Endocytic_GEF_Adapter	Family
IPR055251	SOS1_NGEF_PH	Domain

Pfam: PF00621, PF22697

UniProt features (51 total): helix 18, modified residue 7, strand 7, region of interest 4, sequence conflict 3, domain 2, compositionally biased region 2, splice variant 2, sequence variant 2, short sequence motif 2, chain 1, turn 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4XH9	X-RAY DIFFRACTION	2
3EO2	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z628-F1	70.66	0.51

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): 1, 21, 32, 100, 106, 122, 508

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-193648	NRAGE signals death through JNK
R-HSA-416482	G alpha (12/13) signalling events
R-HSA-8980692	RHOA GTPase cycle
R-HSA-9013026	RHOB GTPase cycle
R-HSA-162582	Signal Transduction
R-HSA-193704	p75 NTR receptor-mediated signalling
R-HSA-194315	Signaling by Rho GTPases
R-HSA-204998	Cell death signalling via NRAGE, NRIF and NADE
R-HSA-372790	Signaling by GPCR
R-HSA-388396	GPCR downstream signalling
R-HSA-73887	Death Receptor Signaling
R-HSA-9012999	RHO GTPase cycle
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 333 (showing top): GOBP_RESPONSE_TO_IONIZING_RADIATION, JAEGER_METASTASIS_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_POSITIVE_REGULATION_OF_RHO_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_GROWTH, GOBP_REGULATION_OF_GTPASE_ACTIVITY, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, REACTOME_NRAGE_SIGNALS_DEATH_THROUGH_JNK, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, KYNG_DNA_DAMAGE_DN, KYNG_DNA_DAMAGE_BY_4NQO, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_1, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, COUP_01, GOBP_POSITIVE_REGULATION_OF_CATALYTIC_ACTIVITY

GO Biological Process (10): regulation of cell growth (GO:0001558), signal transduction (GO:0007165), positive regulation of Rho protein signal transduction (GO:0035025), intracellular signal transduction (GO:0035556), positive regulation of apoptotic process (GO:0043065), positive regulation of GTPase activity (GO:0043547), regulation of small GTPase mediated signal transduction (GO:0051056), myoblast migration (GO:0051451), cellular response to hydrogen peroxide (GO:0070301), cellular response to ionizing radiation (GO:0071479)

GO Molecular Function (2): guanyl-nucleotide exchange factor activity (GO:0005085), protein binding (GO:0005515)

GO Cellular Component (3): nucleus (GO:0005634), cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Signal Transduction	3
RHO GTPase cycle	2
Cell death signalling via NRAGE, NRIF and NADE	1
GPCR downstream signalling	1
Death Receptor Signaling	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
p75 NTR receptor-mediated signalling	1
Signaling by GPCR	1
Signaling by Rho GTPases	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular anatomical structure	2
cellular anatomical structure	2
cell growth	1
regulation of growth	1
regulation of cellular component organization	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
Rho protein signal transduction	1
regulation of Rho protein signal transduction	1
positive regulation of small GTPase mediated signal transduction	1
signal transduction	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
GTPase activity	1
regulation of GTPase activity	1
positive regulation of hydrolase activity	1
small GTPase-mediated signal transduction	1
regulation of intracellular signal transduction	1
muscle cell migration	1
cellular response to reactive oxygen species	1
response to hydrogen peroxide	1
response to ionizing radiation	1
cellular response to radiation	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
binding	1
intracellular membrane-bounded organelle	1
cytoplasm	1

Protein interactions and networks

STRING

936 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NET1	NACAD	O15069	530
NET1	RHOA	P06749	517
NET1	SCAMP2	O15127	440
NET1	RABIF	P47224	435
NET1	RHOB	P01121	410
NET1	DDX5	P17844	353
NET1	HTRA3	P83110	353
NET1	TCP1	P17987	353
NET1	TPRKB	Q9Y3C4	353
NET1	F6RGN5	F6RGN5	353
NET1	CLIC1	O00299	353
NET1	OLFM1	Q99784	353
NET1	DNAJC10	Q8IXB1	351
NET1	RTN4	Q9NQC3	351
NET1	CKS2	P33552	351

IntAct

187 interactions, top by confidence:

A	B	Type	Score
NET1	SCRIB	psi-mi:“MI:0915”(physical association)	0.780
SCRIB	NET1	psi-mi:“MI:0407”(direct interaction)	0.780
NET1	SCRIB	psi-mi:“MI:0407”(direct interaction)	0.780
MAGI1	NET1	psi-mi:“MI:0407”(direct interaction)	0.740
NET1	MAGI1	psi-mi:“MI:0407”(direct interaction)	0.740
NET1	MAGI1	psi-mi:“MI:0915”(physical association)	0.740
MAGI1	NET1	psi-mi:“MI:0915”(physical association)	0.740
DLG1	NET1	psi-mi:“MI:0915”(physical association)	0.720
DLG1	NET1	psi-mi:“MI:0407”(direct interaction)	0.720
DLG4	NET1	psi-mi:“MI:0407”(direct interaction)	0.720
NET1	DLG4	psi-mi:“MI:0407”(direct interaction)	0.720
NET1	DLG1	psi-mi:“MI:0407”(direct interaction)	0.720
NET1	DLG4	psi-mi:“MI:0915”(physical association)	0.720
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
DLG3	NET1	psi-mi:“MI:0407”(direct interaction)	0.620
NET1	DLG3	psi-mi:“MI:0407”(direct interaction)	0.620

BioGRID (62): Dlg4 (Reconstituted Complex), Dlg1 (Reconstituted Complex), Dlg3 (Reconstituted Complex), Dlg4 (Protein-peptide), Dlg3 (Protein-peptide), Magi1 (Protein-peptide), Mpp2 (Protein-peptide), Dlg1 (Protein-peptide), Mpp6 (Protein-peptide), Cask (Protein-peptide), Lin7c (Protein-peptide), NET1 (Affinity Capture-Western), NET1 (Affinity Capture-MS), NET1 (Affinity Capture-MS), NET1 (Affinity Capture-MS)

ESM2 similar proteins: A1L2W9, B2RQE8, B5XG43, G9CGD6, O08969, O88387, P59113, Q0V987, Q0VC85, Q1KKW7, Q1KKZ1, Q32LP0, Q3UUV5, Q3ZBA3, Q4V7G1, Q503L1, Q53GA4, Q5FVW6, Q5PQT7, Q5R8M5, Q5U597, Q5XGP7, Q5ZL23, Q6P0G8, Q6PG29, Q7Z628, Q7Z6J4, Q80VL0, Q80YS6, Q86UX7, Q86WV1, Q8AW35, Q8BY35, Q8IZC4, Q8K1B8, Q8N556, Q8VH46, Q91ZM9, Q91ZT5, Q925E0

Diamond homologs: A1IGU3, A1IGU4, A1IGU5, A4RF61, A5D7F8, A7E3N7, B0BNA1, B1V8A0, E2RP94, E7F1U2, F1LXF1, F1M0Z1, G5EC32, M0R4F8, O08641, O13736, O15068, O35179, O35180, O35964, O43307, O43586, O59679, O75791, O75962, O88811, P00527, P10569, P11274, P11433, P70297, P97814, Q09822, Q0KL02, Q10199, Q28923, Q28E95, Q2GT05, Q2KJB5, Q3LAC4

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
NET1	“up-regulates activity”	RHOA	“guanine nucleotide exchange factor”
PAK1	“down-regulates activity”	NET1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 111 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
Ras activation upon Ca2+ influx through NMDA receptor	6	43.4×	5e-07
Unblocking of NMDA receptors, glutamate binding and activation	6	41.3×	5e-07
Negative regulation of NMDA receptor-mediated neuronal transmission	6	41.3×	5e-07
Long-term potentiation	6	36.1×	1e-06
Assembly and cell surface presentation of NMDA receptors	9	28.9×	4e-09
Neurexins and neuroligins	10	24.9×	3e-09
Protein-protein interactions at synapses	6	20.2×	2e-05
RHOB GTPase cycle	6	11.7×	5e-04

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	11	60.9×	7e-15
protein localization to synapse	6	43.8×	6e-07
receptor clustering	7	41.6×	8e-08
regulation of postsynaptic membrane neurotransmitter receptor levels	7	33.0×	3e-07
bicellular tight junction assembly	5	15.7×	8e-04
Rho protein signal transduction	5	11.8×	2e-03
regulation of small GTPase mediated signal transduction	8	11.0×	5e-05
protein-containing complex assembly	9	9.8×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	72
Likely benign	3
Benign	7

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

3884 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:5454361:T:C	F289L	1.000
10:5454363:C:A	F289L	1.000
10:5454363:C:G	F289L	1.000
10:5452518:G:C	R175P	0.999
10:5452904:T:C	L193P	0.999
10:5453253:T:C	Y200H	0.999
10:5453253:T:G	Y200D	0.999
10:5453299:T:C	L215P	0.999
10:5453308:T:A	I218K	0.999
10:5453310:T:C	F219L	0.999
10:5453312:T:A	F219L	0.999
10:5453312:T:G	F219L	0.999
10:5454314:C:A	A273D	0.999
10:5454326:T:C	L277P	0.999
10:5454362:T:C	F289S	0.999
10:5454365:T:C	L290P	0.999
10:5454375:T:G	C293W	0.999
10:5454391:A:C	S299R	0.999
10:5454393:T:A	S299R	0.999
10:5454393:T:G	S299R	0.999
10:5454401:T:C	L302P	0.999
10:5454407:T:A	L304H	0.999
10:5454419:T:C	L308P	0.999
10:5456121:T:A	V411D	0.999
10:5456670:G:C	K489N	0.999
10:5456670:G:T	K489N	0.999
10:5456677:T:A	W492R	0.999
10:5456677:T:C	W492R	0.999
10:5452910:T:C	L195P	0.998
10:5453266:T:A	M204K	0.998

dbSNP variants (sampled 300 via entrez): RS1000020385 (10:5418673 C>T), RS1000049855 (10:5418920 A>T), RS1000059441 (10:5445924 G>C), RS1000158092 (10:5425789 T>C), RS1000186243 (10:5439748 G>A,T), RS1000216120 (10:5458959 T>C), RS1000229985 (10:5412616 A>G), RS1000279286 (10:5425543 A>G), RS1000309619 (10:5418330 G>T), RS1000400325 (10:5452161 A>G), RS1000515422 (10:5410585 C>T), RS1000586298 (10:5457775 C>G), RS1000628955 (10:5444956 T>C), RS1000642379 (10:5416998 T>C), RS1000759825 (10:5451802 T>C)

Disease associations

OMIM: gene MIM:606450 | disease phenotypes:

GenCC curated gene-disease

Mondo (2): long QT syndrome (MONDO:0002442), ependymoma (MONDO:0016698)

Orphanet (1): Ependymoma (Orphanet:251636)

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D004806	Ependymoma	C04.557.465.625.600.380.290; C04.557.470.670.380.290; C04.557.580.625.600.380.290
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295880 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects cotreatment, decreases expression, affects expression, decreases methylation	4
Benzo(a)pyrene	decreases expression, increases methylation	3
Tretinoin	decreases expression, increases expression	3
Cyclosporine	decreases expression	3
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
Acetaminophen	decreases expression	2
Indomethacin	increases expression, affects cotreatment, decreases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Aflatoxin B1	decreases methylation, decreases expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment, increases expression	2
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
nickel sulfate	increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
seocalcitol	increases expression	1
S 1 (combination)	increases response to substance	1
chloropicrin	increases expression	1
2-palmitoylglycerol	increases expression	1
K 7174	decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
ICG 001	decreases expression	1
bisphenol S	affects cotreatment, decreases expression	1
incobotulinumtoxinA	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Leflunomide	increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4150763	Binding	Inhibition of Net1 (149 to 501 residues) (unknown origin) interaction with GDP-loaded His-tagged RhoA F25N mutant (1 to 180 residues) assessed as reduction in BODIPY-GTP-GDP exchange at 200 uM pretreated for 30 mins followed by RhoA additio	Natural Inhibitors of the RhoA-p115 Complex from the Bark of Meiogyne baillonii. — J Nat Prod

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT00517959	PHASE3	UNKNOWN	SCRT Versus Conventional RT in Children and Young Adults With Low Grade and Benign Brain Tumors
NCT01096368	PHASE3	COMPLETED	Maintenance Chemotherapy or Observation Following Induction Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Ependymoma
NCT01648205	PHASE2	COMPLETED	Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
NCT02412709	PHASE2	UNKNOWN	Long QT Syndrome Screening in Newborns
NCT04581408	PHASE2	COMPLETED	Mutation-specific Therapy for the Long QT Syndrome
NCT00003479	PHASE2	TERMINATED	Antineoplaston Therapy in Treating Patients With Ependymoma
NCT00520936	PHASE2	COMPLETED	A Study of Pemetrexed in Children With Recurrent Cancer
NCT00840047	PHASE2	ACTIVE_NOT_RECRUITING	Methionine PET/CT Studies In Patients With Cancer
NCT01088035	PHASE2	TERMINATED	Carboplatin as a Radiosensitizer in Treating Childhood Ependymoma
NCT01247922	PHASE2	TERMINATED	Single-agent Erlotinib in Patients Previously Treated With Oral Etoposide in Protocol OSI-774-205
NCT01288235	PHASE2	COMPLETED	Proton Radiotherapy for Pediatric Brain Tumors Requiring Partial Brain Irradiation
NCT01295944	PHASE2	COMPLETED	Carboplatin and Bevacizumab for Recurrent Ependymoma
NCT01356290	PHASE2	RECRUITING	Antiangiogenic Therapy for Children With Recurrent Medulloblastoma, Ependymoma, ATRT and Rare CNS Tumors
NCT01836549	PHASE2	TERMINATED	Imetelstat Sodium in Treating Younger Patients With Recurrent or Refractory Brain Tumors
NCT02125786	PHASE2	ACTIVE_NOT_RECRUITING	A Trial of Surgery and Fractionated Re-Irradiation for Recurrent Ependymoma
NCT02689336	PHASE2	WITHDRAWN	Erlotinib in Combination With Temozolomide in Treating Relapsed/Recurrent/Refractory Pediatric Solid Tumors
NCT03095248	PHASE2	TERMINATED	Trial of Selumetinib in Patients With Neurofibromatosis Type II Related Tumors
NCT03155620	PHASE2	ACTIVE_NOT_RECRUITING	Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)
NCT03173950	PHASE2	COMPLETED	Immune Checkpoint Inhibitor Nivolumab in People With Recurrent Select Rare CNS Cancers
NCT03194906	PHASE2	COMPLETED	Memantine for Prevention of Cognitive Late Effects in Pediatric Patients Receiving Cranial Radiation Therapy for Localized Brain Tumors
NCT03210714	PHASE2	ACTIVE_NOT_RECRUITING	Erdafitinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With FGFR Mutations (A Pediatric MATCH Treatment Trial)
NCT03213652	PHASE2	ACTIVE_NOT_RECRUITING	Ensartinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With ALK or ROS1 Genomic Alterations (A Pediatric MATCH Treatment Trial)
NCT03213665	PHASE2	COMPLETED	Tazemetostat in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With EZH2, SMARCB1, or SMARCA4 Gene Mutations (A Pediatric MATCH Treatment Trial)
NCT03213678	PHASE2	COMPLETED	Samotolisib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With TSC or PI3K/MTOR Mutations (A Pediatric MATCH Treatment Trial)
NCT03213704	PHASE2	ACTIVE_NOT_RECRUITING	Larotrectinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With NTRK Fusions (A Pediatric MATCH Treatment Trial)
NCT03220035	PHASE2	COMPLETED	Vemurafenib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With BRAF V600 Mutations (A Pediatric MATCH Treatment Trial)
NCT03233204	PHASE2	COMPLETED	Olaparib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Defects in DNA Damage Repair Genes (A Pediatric MATCH Treatment Trial)
NCT03526250	PHASE2	COMPLETED	Palbociclib in Treating Patients With Relapsed or Refractory Rb Positive Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Activating Alterations in Cell Cycle Genes (A Pediatric MATCH Treatment Trial)
NCT03698994	PHASE2	ACTIVE_NOT_RECRUITING	Ulixertinib in Treating Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With MAPK Pathway Mutations (A Pediatric MATCH Treatment Trial)
NCT03727841	PHASE2	TERMINATED	Marizomib for Recurrent Low-Grade and Anaplastic Supratentorial, Infratentorial, and Spinal Cord Ependymoma
NCT04049669	PHASE2	ACTIVE_NOT_RECRUITING	Pediatric Trial of Indoximod With Chemotherapy and Radiation for Relapsed Brain Tumors or Newly Diagnosed DIPG
NCT04195555	PHASE2	ACTIVE_NOT_RECRUITING	Ivosidenib in Treating Patients With Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With IDH1 Mutations (A Pediatric MATCH Treatment Trial)
NCT04284774	PHASE2	ACTIVE_NOT_RECRUITING	Tipifarnib for the Treatment of Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With HRAS Gene Alterations, a Pediatric MATCH Treatment Trial
NCT04320888	PHASE2	ACTIVE_NOT_RECRUITING	Selpercatinib for the Treatment of Advanced Solid Tumors, Lymphomas, or Histiocytic Disorders With Activating RET Gene Alterations, a Pediatric MATCH Treatment Trial
NCT04374305	PHASE2	RECRUITING	Innovative Trial for Understanding the Impact of Targeted Therapies in NF2-Related Schwannomatosis (INTUITT-NF2)
NCT04743661	PHASE2	ACTIVE_NOT_RECRUITING	131I-Omburtamab, in Recurrent Medulloblastoma and Ependymoma