TM4SF4

Summary

TM4SF4 (transmembrane 4 L six family member 4, HGNC:11856) is a protein-coding gene on chromosome 3q25.1, encoding Transmembrane 4 L6 family member 4 (P48230). Regulates the adhesive and proliferative status of intestinal epithelial cells.

The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is a cell surface glycoprotein that can regulate cell proliferation.

Source: NCBI Gene 7104 — RefSeq curated summary.

At a glance

• GWAS associations: 15
• Clinical variants (ClinVar): 45 total
• MANE Select transcript: NM_004617

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11856
Approved symbol	TM4SF4
Name	transmembrane 4 L six family member 4
Location	3q25.1
Locus type	gene with protein product
Status	Approved
Aliases	il-TMP
Ensembl gene	ENSG00000169903
Ensembl biotype	protein_coding
OMIM	606567
Entrez	7104

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 retained_intron

ENST00000305354, ENST00000463068, ENST00000465758, ENST00000865228

RefSeq mRNA: 1 — MANE Select: NM_004617 NM_004617

CCDS: CCDS46932

Canonical transcript exons

ENST00000305354 — 5 exons

Exon	Start	End
ENSE00001209501	149475823	149475912
ENSE00001209511	149474697	149475051
ENSE00001732308	149502676	149503394
ENSE00003505343	149487619	149487755
ENSE00003606998	149498722	149498911

Expression profiles

Bgee: expression breadth ubiquitous, 138 present calls, max score 99.79.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 3.5282 / max 1144.3894, expressed in 134 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
39151	2.9301	63
39150	0.2290	27
202969	0.1238	23
39149	0.0935	49
39154	0.0510	16
39153	0.0442	16
39152	0.0355	9
39155	0.0114	4
39156	0.0099	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gall bladder	UBERON:0002110	99.79	gold quality
jejunal mucosa	UBERON:0000399	99.72	gold quality
islet of Langerhans	UBERON:0000006	98.93	gold quality
duodenum	UBERON:0002114	98.24	gold quality
liver	UBERON:0002107	97.98	gold quality
right lobe of liver	UBERON:0001114	97.54	gold quality
pancreatic ductal cell	CL:0002079	95.42	silver quality
epithelial cell of pancreas	CL:0000083	95.38	gold quality
pancreas	UBERON:0001264	94.48	gold quality
body of pancreas	UBERON:0001150	93.06	gold quality
type B pancreatic cell	CL:0000169	90.32	gold quality
ileal mucosa	UBERON:0000331	88.88	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.55	gold quality
small intestine	UBERON:0002108	82.67	gold quality
small intestine Peyer’s patch	UBERON:0003454	80.75	gold quality
jejunum	UBERON:0002115	75.96	gold quality
body of stomach	UBERON:0001161	73.52	gold quality
stomach	UBERON:0000945	72.37	gold quality
muscle layer of sigmoid colon	UBERON:0035805	66.05	gold quality
hair follicle	UBERON:0002073	66.01	gold quality
fundus of stomach	UBERON:0001160	65.85	gold quality
olfactory bulb	UBERON:0002264	65.38	gold quality
intestine	UBERON:0000160	63.46	gold quality
mucosa of paranasal sinus	UBERON:0005030	61.60	gold quality
sigmoid colon	UBERON:0001159	61.35	gold quality
adrenal tissue	UBERON:0018303	59.72	gold quality
smooth muscle tissue	UBERON:0001135	58.92	gold quality
pylorus	UBERON:0001166	58.80	gold quality
lymph node	UBERON:0000029	58.72	gold quality
germinal epithelium of ovary	UBERON:0001304	58.39	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 14.

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	6734.74
E-HCAD-31	yes	5499.37
E-MTAB-8495	yes	5280.32
E-GEOD-81608	yes	3750.75
E-ENAD-27	yes	3302.77
E-GEOD-81547	yes	3159.75
E-HCAD-9	yes	3026.77
E-GEOD-83139	yes	3018.35
E-MTAB-7407	yes	1897.19
E-MTAB-10553	yes	1858.57
E-CURD-98	yes	1305.40
E-MTAB-8410	yes	642.35
E-GEOD-125970	yes	7.19
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

45 targeting TM4SF4, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-7154-5P	99.69	70.52	1900
HSA-MIR-4735-5P	99.43	68.49	1780
HSA-MIR-6828-5P	99.31	69.21	1433
HSA-MIR-3978	99.24	68.39	2201
HSA-MIR-664A-3P	99.22	71.08	2696
HSA-MIR-2054	99.20	68.89	1699

Literature-anchored findings (GeneRIF, showing 8)

• expression of transmembrane 4 superfamily member 4 (TM4SF4) and matrix metalloproteinase 26 (MMP26) was found to be significantly decreased during the implantation window in patients with polycystic ovary syndrome. (PMID:18765015)
• Results suggest that S100B, TM4SF3, and OLFM4 overexpression may affect metastatic behavior of tumor cells in Taiwanese colorectal cancer patients. (PMID:22011044)
• TM4SF4 is a membrane protein that may have a role in attenuating liver cancer cell growth (PMID:23296076)
• TM4SF4 interacts with hTHTR-2 and influences the physiological function of the thiamine transporter in human intestinal epithelial cells. (PMID:24282057)
• TM4SF4 expression was correlated with the increased expression of IGF1, consequently resulting in IGF1R activation in lung adenocarcinoma. (PMID:25344917)
• Replacement of the transmembrane 4 L six family protein TM4SF1 or TM4SF4 C-terminus with that of TM4SF5 increased spheroids growth, transwell migration, and invasive dissemination from spheroids in 3D collagen gels. (PMID:28129652)
• TM4SF4 and LRRK2 Are Potential Therapeutic Targets in Lung and Breast Cancers through Outlier Analysis. (PMID:32972043)
• LncRNA ST8SIA6-AS1 facilitates hepatocellular carcinoma progression by governing miR-651-5p/TM4SF4 axis. (PMID:35946523)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tm4sf4	ENSDARG00000040747
mus_musculus	Tm4sf4	ENSMUSG00000027801
rattus_norvegicus	Tm4sf4	ENSRNOG00000016437

Paralogs (5): TM4SF5 (ENSG00000142484), TM4SF19 (ENSG00000145107), TM4SF18 (ENSG00000163762), TM4SF20 (ENSG00000168955), TM4SF1 (ENSG00000169908)

Protein

Protein identifiers

Transmembrane 4 L6 family member 4 — P48230 (reviewed: P48230)

Alternative names: Intestine and liver tetraspan membrane protein

All UniProt accessions (2): P48230, C9JVD2

UniProt curated annotations — full annotation on UniProt →

Function. Regulates the adhesive and proliferative status of intestinal epithelial cells. Can mediate density-dependent cell proliferation.

Subcellular location. Membrane.

Tissue specificity. Jejunum and liver.

Post-translational modifications. N-glycosylated. Glycosylation is required for the growth inhibitory effect.

Similarity. Belongs to the L6 tetraspanin family.

RefSeq proteins (1): NP_004608* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008661	L6_membrane	Family

Pfam: PF05805

UniProt features (12 total): topological domain 5, transmembrane region 4, glycosylation site 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48230-F1	77.43	0.19

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Glycosylation sites (2): 124, 156

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 113 (showing top): MODULE_52, GOBP_GROWTH, IVANOVA_HEMATOPOIESIS_MATURE_CELL, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, GOBP_REGENERATION, HNF1_Q6, MODULE_120, HSIAO_LIVER_SPECIFIC_GENES, GOBP_TISSUE_REGENERATION, MODULE_88, BASAKI_YBX1_TARGETS_DN, MODULE_175, HNF1_01, LEE_LIVER_CANCER_DENA_UP, MODULE_55

GO Biological Process (1): tissue regeneration (GO:0042246)

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

GO Cellular Component (1): membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regeneration	1
developmental growth	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1058 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TM4SF4	DIRC1	Q969H9	526
TM4SF4	ABHD15	Q6UXT9	473
TM4SF4	TM4SF20	Q53R12	455
TM4SF4	B4E171	B4E171	447
TM4SF4	KRT7	P08729	442
TM4SF4	TRIM31	Q9BZY9	424
TM4SF4	TSPAN1	O60635	422
TM4SF4	CEACAM5	P06731	418
TM4SF4	ELF3	P78545	418
TM4SF4	GSK3B	P49841	409
TM4SF4	ANAPC2	Q9UJX6	409
TM4SF4	GSTM3	P21266	404
TM4SF4	ERC2	O15083	402
TM4SF4	TSPAN8	P19075	398
TM4SF4	GULP1	Q9UBP9	393

IntAct

66 interactions, top by confidence:

A	B	Type	Score
TM4SF4	FATE1	psi-mi:“MI:0915”(physical association)	0.560
FATE1	TM4SF4	psi-mi:“MI:0915”(physical association)	0.560
TM4SF4	APH1B	psi-mi:“MI:0915”(physical association)	0.560
TM4SF4	LHFPL5	psi-mi:“MI:0915”(physical association)	0.560
TM4SF4	CLEC17A	psi-mi:“MI:0915”(physical association)	0.560
TM4SF4	CMTM2	psi-mi:“MI:0915”(physical association)	0.560
OPRM1	TM4SF4	psi-mi:“MI:0915”(physical association)	0.560
TM4SF4	GPR101	psi-mi:“MI:0915”(physical association)	0.560
KCNK5	TM4SF4	psi-mi:“MI:0915”(physical association)	0.560
CD79A	TM4SF4	psi-mi:“MI:0915”(physical association)	0.560
GJB1	TM4SF4	psi-mi:“MI:0915”(physical association)	0.560
TM4SF4	TBXA2R	psi-mi:“MI:0915”(physical association)	0.560
TM4SF4	TMEM14B	psi-mi:“MI:0915”(physical association)	0.560
TM4SF4	GJB4	psi-mi:“MI:0915”(physical association)	0.560
TM4SF4	ERGIC3	psi-mi:“MI:0915”(physical association)	0.560
GJB5	TM4SF4	psi-mi:“MI:0915”(physical association)	0.560
TM4SF4	SLC10A6	psi-mi:“MI:0915”(physical association)	0.560
GPR37L1	TM4SF4	psi-mi:“MI:0915”(physical association)	0.560
GPR42	TM4SF4	psi-mi:“MI:0915”(physical association)	0.560
TM4SF4	GPX8	psi-mi:“MI:0915”(physical association)	0.560
FFAR2	TM4SF4	psi-mi:“MI:0915”(physical association)	0.560
CREB3	TM4SF4	psi-mi:“MI:0915”(physical association)	0.550
TM4SF4	CREB3	psi-mi:“MI:0915”(physical association)	0.550
MEP1B	TM4SF4	psi-mi:“MI:0915”(physical association)	0.370
SLC6A1	TM4SF4	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (23): FATE1 (Two-hybrid), TM4SF4 (Two-hybrid), TM4SF4 (PCA), TM4SF4 (Two-hybrid), TM4SF4 (Two-hybrid), TM4SF4 (Two-hybrid), TM4SF4 (Two-hybrid), TM4SF4 (Two-hybrid), TM4SF4 (Two-hybrid), TM4SF4 (Two-hybrid), TM4SF4 (Two-hybrid), TM4SF4 (Two-hybrid), TM4SF4 (Two-hybrid), TM4SF4 (Two-hybrid), TM4SF4 (Two-hybrid)

ESM2 similar proteins: A0A2R8RY99, A0PK11, A2RVU1, A6NGA9, A9UL59, B2RVW2, E9Q9H8, O14894, O95473, P0DP42, P30408, P48230, P49111, P56749, Q0IIL2, Q0P4G7, Q11098, Q2KIG8, Q2YDD6, Q32KQ5, Q3T0Z4, Q3T110, Q3UUA0, Q53R12, Q5R6Z4, Q5R9K1, Q5REK8, Q60771, Q64302, Q6AYR5, Q6CUG3, Q6CXZ7, Q6DDK3, Q6GV27, Q6ICI0, Q8BHH8, Q8CJ58, Q8NCR9, Q8VHW1, Q8WXS4

Diamond homologs: E9Q9H8, O14894, P30408, P48230, P49111, Q2KIG8, Q5R6Z4, Q5RE43, Q64302, Q91XD3, Q96DZ7, Q9EQL5, Q3T110, Q53R12, Q96CE8, Q9CQY8, Q3T0Z4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	34
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

906 predictions. Top by Δscore:

Variant	Effect	Δscore
3:149487613:TTTCA:T	acceptor_loss	1.0000
3:149487614:TTCAG:T	acceptor_loss	1.0000
3:149487615:TCA:T	acceptor_loss	1.0000
3:149487616:CAG:C	acceptor_loss	1.0000
3:149487617:AGATG:A	acceptor_loss	1.0000
3:149487703:GGTCC:G	donor_gain	1.0000
3:149498710:T:G	acceptor_gain	1.0000
3:149474970:T:TA	acceptor_gain	0.9900
3:149474971:G:A	acceptor_gain	0.9900
3:149475038:G:GT	donor_gain	0.9900
3:149475049:TTGGT:T	donor_loss	0.9900
3:149475051:GGTG:G	donor_loss	0.9900
3:149475052:G:GG	donor_gain	0.9900
3:149475052:GT:G	donor_loss	0.9900
3:149475053:TGA:T	donor_loss	0.9900
3:149475054:GAG:G	donor_loss	0.9900
3:149475055:AG:A	donor_loss	0.9900
3:149487617:A:AG	acceptor_gain	0.9900
3:149487617:AGAT:A	acceptor_gain	0.9900
3:149487618:G:GG	acceptor_gain	0.9900
3:149487618:GA:G	acceptor_gain	0.9900
3:149487618:GAT:G	acceptor_gain	0.9900
3:149487618:GATG:G	acceptor_gain	0.9900
3:149498709:A:AG	acceptor_gain	0.9900
3:149498712:T:G	acceptor_gain	0.9900
3:149498907:GTGGG:G	donor_gain	0.9900
3:149498909:GGG:G	donor_gain	0.9900
3:149498910:GG:G	donor_gain	0.9900
3:149498910:GGG:G	donor_gain	0.9900
3:149498910:GGGT:G	donor_loss	0.9900

AlphaMissense

1316 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:149487703:G:T	G117C	0.994
3:149487712:T:A	C120S	0.993
3:149487713:G:C	C120S	0.993
3:149487746:T:G	F131C	0.993
3:149487703:G:C	G117R	0.992
3:149487735:G:C	W127C	0.992
3:149487735:G:T	W127C	0.992
3:149498756:T:A	C146S	0.992
3:149498757:G:C	C146S	0.992
3:149487745:T:C	F131L	0.991
3:149487747:C:A	F131L	0.991
3:149487747:C:G	F131L	0.991
3:149487712:T:C	C120R	0.990
3:149487641:C:A	A96D	0.989
3:149487650:G:A	G99E	0.989
3:149487704:G:A	G117D	0.988
3:149487714:C:G	C120W	0.988
3:149498785:G:C	W155C	0.988
3:149498785:G:T	W155C	0.988
3:149475040:A:C	S55R	0.986
3:149475042:C:A	S55R	0.986
3:149475042:C:G	S55R	0.986
3:149498756:T:C	C146R	0.986
3:149498840:T:C	C174R	0.986
3:149474952:C:A	N25K	0.985
3:149474952:C:G	N25K	0.985
3:149487649:G:A	G99R	0.985
3:149487649:G:C	G99R	0.985
3:149487661:G:C	A103P	0.984
3:149498749:G:C	W143C	0.984

dbSNP variants (sampled 300 via entrez): RS1000045441 (3:149502213 T>A), RS1000154229 (3:149480987 G>A), RS1000323737 (3:149475205 T>A), RS1000519063 (3:149503570 G>A), RS1000797714 (3:149492508 C>T), RS1000955317 (3:149486218 G>A), RS1001021461 (3:149482376 A>C,G,T), RS1001053984 (3:149482685 A>G), RS1001058898 (3:149492221 A>C,G), RS1001104291 (3:149501094 C>A), RS1001387965 (3:149486498 A>G), RS1001477959 (3:149498003 T>C,G), RS1001495360 (3:149490020 T>A), RS1001796571 (3:149491340 C>T), RS1001982719 (3:149484899 A>G)

Disease associations

OMIM: gene MIM:606567 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST003725_4	Gallstone disease	3.000000e-06
GCST005998_10	Alanine transaminase levels	5.000000e-15
GCST006019_26	Gamma glutamyl transferase levels	2.000000e-20
GCST006899_19	Thyroid stimulating hormone levels	7.000000e-10
GCST007209_21	Gallstone disease	4.000000e-30
GCST007725_32	Serum uric acid levels	2.000000e-08
GCST007733_12	Serum uric acid levels	2.000000e-08
GCST008972_128	Urate levels	1.000000e-08
GCST008972_2	Urate levels	3.000000e-11
GCST010653_15	Thyroid stimulating hormone levels	1.000000e-13
GCST011349_46	Gamma glutamyl transferase levels	3.000000e-18
GCST011352_21	Alanine aminotransferase levels	3.000000e-15
GCST90011898_152	Alanine aminotransferase levels	7.000000e-23
GCST90011900_81	Serum alkaline phosphatase levels	1.000000e-10
GCST90013407_110	Liver enzyme levels (gamma-glutamyl transferase)	3.000000e-19

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004532	serum gamma-glutamyl transferase measurement
EFO:0004761	uric acid measurement
EFO:0004531	urate measurement
EFO:0004533	alkaline phosphatase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	affects cotreatment, decreases expression	3
Aflatoxin B1	affects expression, decreases expression, decreases methylation	3
Arsenic Trioxide	decreases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
aristolochic acid I	increases expression	1
ascorbate-2-phosphate	affects cotreatment, increases expression, affects binding	1
sodium arsenite	decreases expression	1
4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
Chir 99021	decreases expression, affects binding, increases expression, affects cotreatment	1
trans-10,cis-12-conjugated linoleic acid	increases expression	1
abrine	decreases expression	1
jinfukang	decreases expression	1
XAV939	affects binding, affects cotreatment, increases expression	1
LDN 193189	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
3-(4-pyridyl)-1H-indole	decreases expression, affects cotreatment	1
Resveratrol	affects cotreatment, decreases expression	1
Zoledronic Acid	decreases expression	1
Ascorbic Acid	affects binding, affects cotreatment, increases expression	1
Chenodeoxycholic Acid	affects cotreatment, decreases expression	1
Cisplatin	decreases expression	1
Copper	decreases expression, affects cotreatment	1
Deoxycholic Acid	affects cotreatment, decreases expression	1
Endosulfan	increases expression	1
Estradiol	decreases expression	1
Glycochenodeoxycholic Acid	decreases expression, affects cotreatment	1
Glycocholic Acid	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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