TMEM8B

Summary

TMEM8B (transmembrane protein 8B, HGNC:21427) is a protein-coding gene on chromosome 9p13.3, encoding Transmembrane protein 8B (A6NDV4). May function as a regulator of the EGFR pathway.

Involved in cell-matrix adhesion. Located in cell surface and plasma membrane.

Source: NCBI Gene 51754 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 94 total
• MANE Select transcript: NM_001042590

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21427
Approved symbol	TMEM8B
Name	transmembrane protein 8B
Location	9p13.3
Locus type	gene with protein product
Status	Approved
Aliases	NAG-5, NGX6, NGX6a, FP588
Ensembl gene	ENSG00000137103
Ensembl biotype	protein_coding
OMIM	616888
Entrez	51754

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000377988, ENST00000377991, ENST00000377996, ENST00000439587, ENST00000464519, ENST00000473947, ENST00000490199, ENST00000643932, ENST00000650015, ENST00000952339

RefSeq mRNA: 7 — MANE Select: NM_001042590 NM_001042589, NM_001042590, NM_001363620, NM_001363621, NM_001363622, NM_001363625, NM_016446

CCDS: CCDS43800, CCDS6595, CCDS94406

Canonical transcript exons

ENST00000643932 — 13 exons

Exon	Start	End
ENSE00000699536	35846258	35846381
ENSE00000699537	35846469	35846611
ENSE00001475789	35853141	35853257
ENSE00001475791	35852827	35852973
ENSE00001475793	35846817	35846995
ENSE00001906989	35841134	35841267
ENSE00001932139	35829228	35829955
ENSE00003612671	35845975	35846068
ENSE00003817466	35835011	35835218
ENSE00003823414	35842392	35842717
ENSE00003825773	35853505	35865515
ENSE00003826830	35834461	35834650
ENSE00003827573	35841526	35841794

Expression profiles

Bgee: expression breadth ubiquitous, 219 present calls, max score 91.72.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.6010 / max 406.3673, expressed in 1677 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
96640	21.2384	1675
96641	0.3627	155

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ovary	UBERON:0002119	91.72	gold quality
right ovary	UBERON:0002118	91.00	gold quality
adenohypophysis	UBERON:0002196	90.77	gold quality
tendon of biceps brachii	UBERON:0008188	90.76	silver quality
right uterine tube	UBERON:0001302	90.39	gold quality
pituitary gland	UBERON:0000007	89.97	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	89.70	gold quality
popliteal artery	UBERON:0002250	89.68	gold quality
tibial artery	UBERON:0007610	89.67	gold quality
lower esophagus muscularis layer	UBERON:0035833	89.67	gold quality
right frontal lobe	UBERON:0002810	89.64	gold quality
lower esophagus	UBERON:0013473	89.59	gold quality
right adrenal gland cortex	UBERON:0035827	89.44	gold quality
aorta	UBERON:0000947	89.20	gold quality
body of uterus	UBERON:0009853	89.16	gold quality
ovary	UBERON:0000992	89.15	gold quality
mucosa of stomach	UBERON:0001199	89.10	gold quality
right adrenal gland	UBERON:0001233	89.05	gold quality
endocervix	UBERON:0000458	88.85	gold quality
ascending aorta	UBERON:0001496	88.76	gold quality
right lobe of thyroid gland	UBERON:0001119	88.74	gold quality
prefrontal cortex	UBERON:0000451	88.71	gold quality
left adrenal gland cortex	UBERON:0035825	88.71	gold quality
thoracic aorta	UBERON:0001515	88.70	gold quality
right coronary artery	UBERON:0001625	88.39	gold quality
left adrenal gland	UBERON:0001234	88.29	gold quality
left lobe of thyroid gland	UBERON:0001120	88.28	gold quality
adrenal cortex	UBERON:0001235	88.26	gold quality
descending thoracic aorta	UBERON:0002345	88.20	gold quality
muscle layer of sigmoid colon	UBERON:0035805	88.00	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.82
E-MTAB-6386	no	8.29

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 21)

• down-regulation may be closely associated with tumorigenesis and metastasis of colorectal carcinoma; may not contribute to development and progression of gastric carcinoma. (PMID:12918109)
• NGX6 plays a role in cell adhesion modulation in NPC cells. (PMID:15498789)
• We demonstrated the subcellular localization and the effect of NGX6 and its mutants on the growth, proliferation, migration, or adhesion of nasopharyngeal carcinoma 5-8F cells. (PMID:17641538)
• propose that NGX6 expression is lost in the process of human colorectal carcinogenesis. Its overexpression can inhibit expression of transcription factors AP-1 and Ets-1, and down-regulate transcriptional activity of the cyclin D1 promoter in human CRC (PMID:19499154)
• NGX6a was significantly downregulated in nasopharyngeal caaarcinoma and is associated with tumor metastasis. (PMID:19755717)
• Down-regulation of NGX6 gene is related to the promoter methylation. DNA methylation of NGX6 promoter might be a potential molecular marker for diagnosis or prognosis, or serve as a therapeutic target in colorectal cancer. (PMID:20423473)
• The short transcript of NGX6 play an important role in colorectal cancer, and reduced expression may contribute to metastasis. (PMID:20543461)
• Data show that NGX6 could suppress the translocation of beta-catenin from nucleus and cytoplasm to plasma membrane, inhibit the activity of TCF4 transcript factor, and down-regulate the expression of Wnt-direct-targeted genes. (PMID:20705583)
• NGX6 plays an important role in regulation of apoptosis, mobility/migration, and hydrolase as well as activity of JNK and Notch pathways through NGX6-mediated miRNA expression (PMID:20859756)
• NGX6 could inhibit the expression of Wnt signaling downstream target genes in colon cancer. (PMID:21464545)
• Data suggest that nasopharyngeal carcinoma-associated gene 6 (NGX6) may inhibit colon cancer through the regulation of proteins involved in cell proliferation, metastasis, apoptosis, cytoskeletal structure, metabolism, and signal transduction. (PMID:22647848)
• The present study was aimed to investigate the possible association between 19-base pair (bp) deletion polymorphism of the DHFR gene (rs70991108), null genotype of UGT2B17 as well as the expression level of NGX6 with the risk of breast cancer. (PMID:23053953)
• the levels of the NGX6 protein and mRNA were lower in patients with tamoxifen-resistant tumors compared to patients with tamoxifen-sensitive tumors (PMID:23588848)
• downregulation of NGX6 expression contributes to the development and progression of gastric cancer (PMID:24338274)
• These results demonstrate that Egr-1 regulates NGX6 gene transcription through an overlapping Sp1/Egr-1 binding site as a positive regulator of NGX6 gene. (PMID:25029911)
• The seven-transmembrane domain of NGX6a was found to be the critical region for the degradation of NGX6a, and the amino terminus of ezrin is required for the induction of NGX6a degradation. (PMID:25378401)
• From our analysis, variants in the genes ABCB4, TP53AIP1, ARHGAP32 and TMEM88B were identified linked to the alexithymia phenotype. (PMID:25882097)
• Ultrasonographic features are associated with NGX6 expression in invasive ductal breast carcinoma. NGX6 is involved in the invasion and metastasis activity of IDBC. (PMID:26261522)
• NGX6 possesses various biological functions, such as regulating protein expression of related genes, involving cell signal transduction pathways, negatively controlling cell cycle progression, inhibiting angiogenesis, and increasing the sensitivity of patients to anti-cancer drugs. Review. (PMID:26880583)
• NGX6 is lowly expressed in nasopharyngeal carcinoma, and it can inhibit the proliferation and invasion of nasopharyngeal carcinoma cells. (PMID:29243779)
• Nasopharyngeal carcinomaassociated gene 6 inhibits cell viability, migration, invasion and induces apoptosis in osteosarcoma cells by inactivating the Wnt/betacatenin signaling pathway. (PMID:33300077)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	TMEM8B	ENSDARG00000075126
danio_rerio	si:dkey-84j12.1	ENSDARG00000094625
mus_musculus	Tmem8b	ENSMUSG00000078716
rattus_norvegicus	Tmem8b	ENSRNOG00000015664

Paralogs (2): PGAP6 (ENSG00000129925), MYMK (ENSG00000187616)

Protein

Protein identifiers

Transmembrane protein 8B — A6NDV4 (reviewed: A6NDV4)

Alternative names: Nasopharyngeal carcinoma-associated gene 6 protein, Protein NAG-5, Protein NGX6

All UniProt accessions (2): A0A2R8Y2M5, A6NDV4

UniProt curated annotations — full annotation on UniProt →

Function. May function as a regulator of the EGFR pathway. Probable tumor suppressor which may function in cell growth, proliferation and adhesion.

Subunit / interactions. Isoform 2 (via its cytoplasmic part) interacts with EZR.

Subcellular location. Cell membrane. Cytoplasm. Nucleus. Mitochondrion. Endoplasmic reticulum.

Post-translational modifications. Isoform 2 is N-glycosylated.

Induction. Isoform 2 is down-regulated in nasopharyngeal carcinoma cells.

Similarity. Belongs to the TMEM8 family.

Isoforms (3)

UniProt ID	Names	Canonical?
A6NDV4-1	1	yes
A6NDV4-2	2
A6NDV4-3	3

RefSeq proteins (7): NP_001036054, NP_001036055, NP_001350549, NP_001350550, NP_001350551, NP_001350554, NP_057530 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000742	EGF	Domain
IPR021910	NGX6/PGAP6/MYMK	Family

Pfam: PF12036

UniProt features (28 total): topological domain 8, transmembrane region 7, splice variant 4, disulfide bond 3, glycosylation site 2, chain 1, domain 1, region of interest 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A6NDV4-F1	81.71	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.

Disulfide bonds (3): 186–196, 190–209, 211–220

Glycosylation sites (2): 92, 100

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 119 (showing top): PAX4_01, SP3_Q3, GOCC_CELL_SURFACE, GGGTGGRR_PAX4_03, CAGCTG_AP4_Q5, GOBP_REGULATION_OF_CELL_CYCLE, chr9p13, GOBP_MITOTIC_CELL_CYCLE, MORF_EPHA7, KIM_GASTRIC_CANCER_CHEMOSENSITIVITY, HAN_SATB1_TARGETS_DN, GOBP_CELL_SUBSTRATE_ADHESION, GOBP_CELL_MATRIX_ADHESION, MORF_DCC, MODULE_204

GO Biological Process (3): cell-matrix adhesion (GO:0007160), regulation of mitotic cell cycle (GO:0007346), cell adhesion (GO:0007155)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (7): nucleus (GO:0005634), mitochondrion (GO:0005739), endoplasmic reticulum (GO:0005783), plasma membrane (GO:0005886), cell surface (GO:0009986), cytoplasm (GO:0005737), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	3
cellular anatomical structure	3
cytoplasm	2
cell-substrate adhesion	1
mitotic cell cycle	1
regulation of cell cycle	1
cellular process	1
binding	1
endomembrane system	1
membrane	1
cell periphery	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

368 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMEM8B	CCDC136	Q96JN2	671
TMEM8B	BRD7	Q9NPI1	626
TMEM8B	TSPAN4	O14817	571
TMEM8B	SPAG8	Q99932	530
TMEM8B	EZR	P15311	522
TMEM8B	SPAAR	A0A1B0GVQ0	474
TMEM8B	CHIT1	Q13231	459
TMEM8B	FAM221B	A6H8Z2	415
TMEM8B	PRR14	Q9BWN1	391
TMEM8B	ZNF782	Q6ZMW2	365
TMEM8B	UAP1	Q16222	351
TMEM8B	NPR2	P20594	348
TMEM8B	PLPP6	Q8IY26	345
TMEM8B	EFCAB14	O75071	341
TMEM8B	TMEM41A	Q96HV5	339

IntAct

3 interactions, top by confidence:

A	B	Type	Score
TMEM8B	ARHGDIB	psi-mi:“MI:0915”(physical association)	0.400
CHRM2	TMEM8B	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (5): TMEM8B (Affinity Capture-RNA), TMEM8B (Two-hybrid), ARHGDIB (Affinity Capture-MS), TMEM8B (Affinity Capture-RNA), TMEM8B (Two-hybrid)

ESM2 similar proteins: A0A3Q2HW92, A6NDV4, A6NFX1, A6QLK4, B1AWJ5, F1NCD6, F1NJ67, F1PZV2, O35308, O35595, O70461, O95907, Q08DX7, Q0IHM1, Q0P5C0, Q0P5M9, Q13286, Q14728, Q29611, Q2YDU8, Q3T9M1, Q3U481, Q501I9, Q5R8G5, Q5R9A1, Q5U419, Q60HH0, Q61124, Q66H95, Q6NUT3, Q6UXD7, Q6ZMD2, Q7RTT9, Q8BFQ6, Q8CE47, Q8NA29, Q8R0G7, Q8R139, Q8TB61, Q8VCW4

Diamond homologs: A6NDV4, A6NI61, A6QLK4, B1AWJ5, Q6IQ69, Q9D1N4, Q9ESN3, Q9HCN3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	70
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3179 predictions. Top by Δscore:

Variant	Effect	Δscore
9:35818900:T:TA	donor_gain	1.0000
9:35841268:G:GG	donor_gain	1.0000
9:35842731:A:T	donor_gain	1.0000
9:35846463:GCGCA:G	acceptor_loss	1.0000
9:35846464:CGCA:C	acceptor_loss	1.0000
9:35846465:GCAGG:G	acceptor_loss	1.0000
9:35846466:CAG:C	acceptor_loss	1.0000
9:35846467:A:T	acceptor_loss	1.0000
9:35846468:G:GT	acceptor_loss	1.0000
9:35846957:G:GT	donor_gain	1.0000
9:35846994:CGG:C	donor_loss	1.0000
9:35846996:G:GG	donor_gain	1.0000
9:35846996:GT:G	donor_loss	1.0000
9:35846997:T:A	donor_loss	1.0000
9:35847004:T:TA	donor_gain	1.0000
9:35847005:G:GA	donor_gain	1.0000
9:35852078:G:GT	donor_gain	1.0000
9:35852825:A:AG	acceptor_gain	1.0000
9:35852826:G:GA	acceptor_gain	1.0000
9:35852826:GTT:G	acceptor_gain	1.0000
9:35852826:GTTCT:G	acceptor_gain	1.0000
9:35852970:GCAG:G	donor_gain	1.0000
9:35852971:CAG:C	donor_loss	1.0000
9:35852972:AG:A	donor_loss	1.0000
9:35852973:GGTC:G	donor_loss	1.0000
9:35852975:T:G	donor_loss	1.0000
9:35814983:C:A	donor_gain	0.9900
9:35818903:T:TA	donor_gain	0.9900
9:35819006:CAGC:C	acceptor_gain	0.9900
9:35828461:AC:A	donor_gain	0.9900

AlphaMissense

5865 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:35846527:T:A	C186S	1.000
9:35846527:T:C	C186R	1.000
9:35846528:G:A	C186Y	1.000
9:35846528:G:C	C186S	1.000
9:35846529:C:G	C186W	1.000
9:35846540:G:A	C190Y	1.000
9:35846541:C:G	C190W	1.000
9:35846552:G:A	G194D	1.000
9:35846557:T:A	C196S	1.000
9:35846558:G:C	C196S	1.000
9:35846597:G:A	C209Y	1.000
9:35846602:T:A	C211S	1.000
9:35846602:T:C	C211R	1.000
9:35846603:G:C	C211S	1.000
9:35846834:T:A	C220S	1.000
9:35846834:T:C	C220R	1.000
9:35846835:G:A	C220Y	1.000
9:35846835:G:C	C220S	1.000
9:35846836:C:G	C220W	1.000
9:35846900:A:C	S242R	1.000
9:35846901:G:T	S242I	1.000
9:35846902:C:A	S242R	1.000
9:35846902:C:G	S242R	1.000
9:35846905:C:A	N243K	1.000
9:35846905:C:G	N243K	1.000
9:35852833:C:A	H276N	1.000
9:35852833:C:G	H276D	1.000
9:35852840:G:A	C278Y	1.000
9:35852840:G:T	C278F	1.000
9:35852841:T:G	C278W	1.000

dbSNP variants (sampled 300 via entrez): RS1000307321 (9:35850815 T>C), RS1000332561 (9:35844687 A>G), RS1000462952 (9:35857492 C>T), RS1000469125 (9:35861324 C>T), RS1000480699 (9:35833069 A>T), RS1000664807 (9:35846348 T>C), RS1000717546 (9:35838396 C>T), RS1000877855 (9:35846431 T>C,G), RS1000899613 (9:35862142 G>A), RS1000914833 (9:35839968 G>A), RS1001066256 (9:35855986 T>C), RS1001150110 (9:35831802 A>G), RS1001209618 (9:35836760 G>A,T), RS1001236414 (9:35855937 A>G), RS1001287180 (9:35855640 C>T)

Disease associations

OMIM: gene MIM:616888 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
entinostat	decreases expression, affects cotreatment	2
Acetaminophen	decreases expression, increases expression	2
Benzo(a)pyrene	decreases expression, decreases methylation	2
Valproic Acid	affects cotreatment, decreases expression	2
Cadmium Chloride	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
trichostatin A	affects expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
butyraldehyde	decreases expression	1
monomethylarsonous acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
jinfukang	affects cotreatment, increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Temozolomide	decreases expression	1
Atrazine	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Niclosamide	increases expression	1
Phthalic Acids	decreases methylation	1
Silicon Dioxide	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	increases expression	1
Okadaic Acid	decreases expression	1
Acrylamide	decreases expression	1
Particulate Matter	increases expression	1

Clinical trials (associated diseases)

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