TM4SF5

Summary

TM4SF5 (transmembrane 4 L six family member 5, HGNC:11857) is a protein-coding gene on chromosome 17p13.2, encoding Transmembrane 4 L6 family member 5 (O14894). Acts as a lysosomal membrane arginine sensor.

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 and is highly similar in sequence and structure to transmembrane 4 superfamily member 1. It may play a role in cell proliferation, and overexpression of this protein may be associated with the uncontrolled growth of tumour cells.

Source: NCBI Gene 9032 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 29 total
• Druggable target: yes
• MANE Select transcript: NM_003963

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11857
Approved symbol	TM4SF5
Name	transmembrane 4 L six family member 5
Location	17p13.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000142484
Ensembl biotype	protein_coding
OMIM	604657
Entrez	9032

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 retained_intron

ENST00000270560, ENST00000576530, ENST00000861274, ENST00000861275

RefSeq mRNA: 1 — MANE Select: NM_003963 NM_003963

CCDS: CCDS11054

Canonical transcript exons

ENST00000270560 — 5 exons

Exon	Start	End
ENSE00001125855	4782503	4782639
ENSE00001125881	4782854	4783037
ENSE00001215768	4771886	4772099
ENSE00003490946	4780789	4780869
ENSE00003505443	4783114	4783211

Expression profiles

Bgee: expression breadth broad, 77 present calls, max score 98.32.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.0502 / max 262.5942, expressed in 46 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
158938	1.0502	46

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	98.32	gold quality
right lobe of liver	UBERON:0001114	97.38	gold quality
duodenum	UBERON:0002114	94.77	gold quality
ileal mucosa	UBERON:0000331	92.33	gold quality
liver	UBERON:0002107	92.16	gold quality
mucosa of transverse colon	UBERON:0004991	88.57	gold quality
pancreatic ductal cell	CL:0002079	87.84	silver quality
small intestine Peyer’s patch	UBERON:0003454	85.53	gold quality
small intestine	UBERON:0002108	85.04	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.10	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.85	gold quality
nephron tubule	UBERON:0001231	80.30	silver quality
rectum	UBERON:0001052	78.09	gold quality
adult mammalian kidney	UBERON:0000082	77.86	gold quality
colonic mucosa	UBERON:0000317	76.33	gold quality
kidney epithelium	UBERON:0004819	76.16	silver quality
jejunum	UBERON:0002115	75.32	gold quality
mucosa of sigmoid colon	UBERON:0004993	75.18	gold quality
renal glomerulus	UBERON:0000074	73.81	silver quality
transverse colon	UBERON:0001157	73.03	gold quality
metanephric glomerulus	UBERON:0004736	72.83	silver quality
epithelial cell of pancreas	CL:0000083	71.55	gold quality
body of stomach	UBERON:0001161	70.52	gold quality
kidney	UBERON:0002113	70.44	gold quality
gall bladder	UBERON:0002110	70.35	gold quality
stomach	UBERON:0000945	67.59	gold quality
intestine	UBERON:0000160	67.39	gold quality
cortex of kidney	UBERON:0001225	66.47	gold quality
islet of Langerhans	UBERON:0000006	64.96	gold quality
metanephros	UBERON:0000081	63.56	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-8410	yes	569.55
E-GEOD-125970	yes	63.18
E-MTAB-5061	no	3.74
E-HCAD-31	no	3.04
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 30)

• The ectopic expression of TM4SF5 in Cos7 cells reduced integrin signaling under serum-containing conditions, but increased integrin signaling upon serum-free replating on substrates. (PMID:16828471)
• observations have revealed a role for TM4SF5 in causing uncontrolled growth of human hepatocarcinoma cells through epithelial-mesenchymal transition (PMID:18357344)
• TM4SF5 facilitates angiogenesis of neighboring endothelial cells through VEGF induction, mediated by cooperation between TM4SF5 and integrin alpha(5) of epithelial cells (PMID:19036703)
• TM4SF5 in hepatocytes negatively regulates integrin alpha2 function via an interaction between the extracellular loop 2 of TM4SF5 and integrin alpha2 during cell spreading on and migration through collagen I environment (PMID:19789264)
• Data suggest that TM4SF5 accelerates G1/S phase progression with facilitated CDK4/cyclin D1 entry into the nucleus, which might be supported by TM4SF5-mediated actin reorganization through cytosolic p27Kip1 expression and Rho GTPase activity. (PMID:20399237)
• Data show that TM4SF5 expression facilitated migration, invadopodia formation, MMP activation, invasion, and eventually lung metastasis in vitro and in nude mice, but suppression of TM4SF5 with its shRNA blocked the effects. (PMID:20506553)
• TM4SF5 plays a central regulatory role in a wide variety of physiological processes through cross-talk with integrins.[review] (PMID:21196261)
• TM4SF5 expression appeared to cause loss of cell-cell adhesions via proteasome suppression and thereby proteasome inhibition (PMID:21328452)
• involvement of JNKs in TM4SF5-mediated p27(Kip1) Ser10 phosphorylation and localization during epithelial-mesenchymal transition. (PMID:22014979)
• Results indicate that TM4SF5-mediated epithelial-mesenchymal transition may have an important function in the gefitinib resistance of cancer cells. (PMID:22178131)
• results indicate that TGFbeta1- and growth factor-mediated signalling activities mediate TM4SF5 expression leading to acquisition of mesenchymal cell features, suggesting that TM4SF5 induction may be involved in the development of liver pathologies (PMID:22292774)
• Findings demonstrate that TM4SF5 directly binds to and activates FAK in an adhesion-dependent manner, to regulate cell migration and invasion in hepatocellular carcinoma. (PMID:23077174)
• TM4SF5 is positively associated with esophageal cancer invasiveness (PMID:23633159)
• TM4SF5 expression in SNU761 cells caused invasive extracellular matrix degradation negatively depending on IL-6/IL-6 receptor signaling. (PMID:24912675)
• TM4SF5 interacted with CD151, and caused the internalization of CD63 from the cell surface. (PMID:25033048)
• TM4SF5-specific monoclonal antibody has a therapeutic effect against colon cancer. (PMID:25268742)
• promotes self-renewal and circulating tumor cell properties (PMID:25627085)
• TM4SF5-positive tumors exhibited locally-increased CD44 expression, suggesting tumor cell differentiation (PMID:25772760)
• TM4SF5-miR-4697-3P- CTD-2354A18.1 may play a key role in the pathogenesis of gastric cancer (PMID:26531872)
• 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)
• The review discusses the antifibrotic strategies that target TM4SF5 and its associated protein networks that regulate the intracellular signaling necessary for fibrotic functions of hepatocytes. (PMID:28458469)
• These results suggest that our novel antibody can be used to detect endogenous and recombinant TM4SF5, and that TM4SF5 may be a possible marker for the poor prognosis of patients with colorectal cancer (PMID:29749436)
• Data show that protein tyrosine phosphatase receptor type F (PTPRF) activity suppressed CD133/transmembrane 4L six family member 5 (TM4SF5)-mediated sphere growth. (PMID:30217560)
• Transmembrane 4 L Six Family Member 5 Senses Arginine for mTORC1 Signaling. (PMID:30956113)
• TM4SF5-mediated CD44v8-10 splicing variant promotes survival of type II alveolar epithelial cells during idiopathic pulmonary fibrosis. (PMID:31501417)
• SLAC2B-dependent microtubule acetylation regulates extracellular matrix-mediated intracellular TM4SF5 traffic to the plasma membranes. (PMID:33554392)
• TM4SF5 Knockout Protects Mice From Diet-Induced Obesity Partly by Regulating Autophagy in Adipose Tissue. (PMID:34187836)
• N-terminus-independent activation of c-Src via binding to a tetraspan(in) TM4SF5 in hepatocellular carcinoma is abolished by the TM4SF5 C-terminal peptide application. (PMID:34335982)
• Tetraspanin TM4SF5 in hepatocytes negatively modulates SLC27A transporters during acute fatty acid supply. (PMID:34364885)
• TM4SF5-mediated liver malignancy involves NK cell exhaustion-like phenotypes. (PMID:34921636)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tm4sf5	ENSDARG00000055185
mus_musculus	Tm4sf5	ENSMUSG00000018919
rattus_norvegicus	Tm4sf5	ENSRNOG00000019510

Paralogs (5): TM4SF19 (ENSG00000145107), TM4SF18 (ENSG00000163762), TM4SF20 (ENSG00000168955), TM4SF4 (ENSG00000169903), TM4SF1 (ENSG00000169908)

Protein

Protein identifiers

Transmembrane 4 L6 family member 5 — O14894 (reviewed: O14894)

Alternative names: Tetraspan transmembrane protein L6H

All UniProt accessions (1): O14894

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a lysosomal membrane arginine sensor. Forms a complex with MTOR and SLC38A9 on lysosomal membranes in an arginine-regulated manner, leading to arginine efflux which enables the activation of mTORC1 which subsequently leads to RPS6KB1 and EIF4EBP1 phosphorylations. Facilitates cell cycle G1/S phase progression and the translocation of the CDK4-CCND1 complex into the nucleus. CDKN1B and RHOA/ROCK signaling activity are involved in TM4SF5-mediated acceleration of G1/S phase progression.

Subunit / interactions. Interacts with MTOR; the interaction is positively regulated by arginine and is negatively regulated by leucine. Interacts with SLC38A9. Interacts with SLC7A1; the interaction is negatively regulated by arginine. Interacts with CASTOR1; the interaction is positively regulated by leucine and is negatively regulated by arginine.

Subcellular location. Lysosome membrane. Cell membrane.

Tissue specificity. Intestine. Overexpressed in pancreatic cancers.

Similarity. Belongs to the L6 tetraspanin family.

RefSeq proteins (1): NP_003954* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008661	L6_membrane	Family

Pfam: PF05805

UniProt features (21 total): mutagenesis site 6, topological domain 5, transmembrane region 4, glycosylation site 2, chain 1, region of interest 1, binding site 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14894-F1	85.87	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.

Ligand- & substrate-binding residues (1): 124–129

Glycosylation sites (2): 138, 155

Mutagenesis-validated functional residues (6):

Position	Phenotype
124	disrupts arginine-binding.
125	disrupts arginine-binding.
126	disrupts arginine-binding.
127	disrupts arginine-binding.
128	disrupts arginine-binding.
129	disrupts arginine-binding.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 116 (showing top): MORF_RAGE, MORF_FLT1, GOCC_VACUOLAR_MEMBRANE, MODULE_64, GNF2_HPN, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_REGULATION_OF_CELL_CYCLE, GNF2_LCAT, GOBP_REGULATION_OF_CELL_CYCLE_G1_S_PHASE_TRANSITION, GOBP_CELL_CYCLE_G1_S_PHASE_TRANSITION, GOBP_MITOTIC_CELL_CYCLE, GNF2_HPX, SANSOM_APC_TARGETS_DN, MODULE_88, GATA1_02

GO Biological Process (1): regulation of G1/S transition of mitotic cell cycle (GO:2000045)

GO Molecular Function (2): arginine binding (GO:0034618), protein binding (GO:0005515)

GO Cellular Component (4): lysosomal membrane (GO:0005765), plasma membrane (GO:0005886), membrane (GO:0016020), lysosome (GO:0005764)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G1/S transition of mitotic cell cycle	1
regulation of mitotic cell cycle phase transition	1
regulation of cell cycle G1/S phase transition	1
amino acid binding	1
carboxylic acid binding	1
cation binding	1
binding	1
lysosome	1
lytic vacuole membrane	1
membrane	1
cell periphery	1
cellular anatomical structure	1
lytic vacuole	1

Protein interactions and networks

STRING

805 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TM4SF5	TSPAN1	O60635	801
TM4SF5	B4E171	B4E171	800
TM4SF5	CDHR1	Q96JP9	781
TM4SF5	EGFR	P00533	740
TM4SF5	CD151	P48509	657
TM4SF5	ITGA5	P08648	633
TM4SF5	ITGA2	P17301	538
TM4SF5	CD44	P16070	533
TM4SF5	PROM1	O43490	497
TM4SF5	IGF1R	P08069	489
TM4SF5	CASTOR1	Q8WTX7	460
TM4SF5	SLC38A9	Q8NBW4	449
TM4SF5	TCF15	Q12870	447
TM4SF5	POMC	P01189	437
TM4SF5	FOS	P01100	436

IntAct

27 interactions, top by confidence:

A	B	Type	Score
MTOR	TM4SF5	psi-mi:“MI:0915”(physical association)	0.600
TM4SF5	MTOR	psi-mi:“MI:0914”(association)	0.600
MTOR	TM4SF5	psi-mi:“MI:0403”(colocalization)	0.600
TM4SF5	AMIGO1	psi-mi:“MI:0915”(physical association)	0.560
TM4SF5		psi-mi:“MI:0915”(physical association)	0.560
SLC38A9	TM4SF5	psi-mi:“MI:0915”(physical association)	0.460
SLC38A9	TM4SF5	psi-mi:“MI:0403”(colocalization)	0.460
	TM4SF5	psi-mi:“MI:0407”(direct interaction)	0.440
TM4SF5	Mtor	psi-mi:“MI:0915”(physical association)	0.400
TM4SF5	CASTOR1	psi-mi:“MI:0915”(physical association)	0.400
CASTOR1	TM4SF5	psi-mi:“MI:0915”(physical association)	0.400
SLC7A1	TM4SF5	psi-mi:“MI:0915”(physical association)	0.400
MEP1B	TM4SF5	psi-mi:“MI:0915”(physical association)	0.370
TM4SF5	PLSCR1	psi-mi:“MI:0914”(association)	0.350
TM4SF5	AMIGO1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (31): AMIGO1 (Two-hybrid), LCLAT1 (Affinity Capture-MS), PXMP2 (Affinity Capture-MS), ARL6IP1 (Affinity Capture-MS), RTN4 (Affinity Capture-MS), ATL2 (Affinity Capture-MS), NUS1 (Affinity Capture-MS), PRAF2 (Affinity Capture-MS), LGALS3 (Affinity Capture-MS), RAC3 (Affinity Capture-MS), PLSCR1 (Affinity Capture-MS), LETMD1 (Affinity Capture-MS), PTRH2 (Affinity Capture-MS), SLC31A1 (Affinity Capture-MS), ATL3 (Affinity Capture-MS)

ESM2 similar proteins: A2VE58, A3KQ86, A6H7B0, A6NC51, A6NDP7, A6NFC5, B1AQL3, B2RZ87, E9Q9H8, O14894, O43761, P0C5X8, P30408, P47987, Q08AU7, Q08DL4, Q13021, Q1HG44, Q2KIG8, Q2KJ98, Q3UUA0, Q49LS7, Q4VV71, Q58CW5, Q5RE43, Q5RFC1, Q5XGR0, Q63175, Q63ZU3, Q64302, Q6DFR5, Q7TQJ1, Q7Z7N9, Q8BHJ6, Q8K177, Q8R191, Q91X49, Q923Z0, Q96DZ7, Q9BSK0

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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	23
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

564 predictions. Top by Δscore:

Variant	Effect	Δscore
17:4780868:GG:G	donor_gain	1.0000
17:4780869:GG:G	donor_gain	1.0000
17:4772058:C:T	donor_gain	0.9900
17:4772095:TAATG:T	donor_loss	0.9900
17:4772096:AATGG:A	donor_loss	0.9900
17:4772098:TGGTG:T	donor_loss	0.9900
17:4772101:T:G	donor_loss	0.9900
17:4782496:C:G	acceptor_gain	0.9900
17:4782638:GC:G	donor_gain	0.9900
17:4782640:G:GG	donor_gain	0.9900
17:4782853:GGGGA:G	acceptor_gain	0.9900
17:4772100:G:GG	donor_gain	0.9800
17:4772102:GA:G	donor_loss	0.9800
17:4780783:CCACA:C	acceptor_loss	0.9800
17:4780784:CACA:C	acceptor_loss	0.9800
17:4780785:ACAG:A	acceptor_loss	0.9800
17:4780786:CA:C	acceptor_loss	0.9800
17:4780787:AGGT:A	acceptor_loss	0.9800
17:4780865:GCAGG:G	donor_gain	0.9800
17:4780866:CAGGG:C	donor_loss	0.9800
17:4780867:AGGGT:A	donor_loss	0.9800
17:4780868:GGGT:G	donor_loss	0.9800
17:4780870:G:A	donor_loss	0.9800
17:4780870:G:GG	donor_gain	0.9800
17:4780871:T:TC	donor_loss	0.9800
17:4782492:A:AG	acceptor_gain	0.9800
17:4782493:C:G	acceptor_gain	0.9800
17:4782525:C:A	acceptor_gain	0.9800
17:4782852:AGG:A	acceptor_gain	0.9800
17:4782853:GGG:G	acceptor_gain	0.9800

AlphaMissense

1256 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:4782627:T:G	F128C	0.992
17:4782616:G:C	W124C	0.991
17:4782616:G:T	W124C	0.991
17:4782884:G:C	W142C	0.989
17:4782884:G:T	W142C	0.989
17:4782556:C:G	C104W	0.983
17:4782588:G:A	G115E	0.983
17:4771974:T:C	C18R	0.982
17:4782596:T:A	C118S	0.982
17:4782597:G:C	C118S	0.982
17:4782891:T:A	C145S	0.982
17:4782892:G:C	C145S	0.982
17:4772052:A:C	S44R	0.980
17:4772054:C:A	S44R	0.980
17:4772054:C:G	S44R	0.980
17:4782591:C:A	P116H	0.979
17:4782920:G:C	W154C	0.979
17:4782920:G:T	W154C	0.979
17:4782626:T:C	F128L	0.978
17:4782628:C:A	F128L	0.978
17:4782628:C:G	F128L	0.978
17:4782955:C:T	S166F	0.978
17:4771997:C:A	N25K	0.976
17:4771997:C:G	N25K	0.976
17:4782543:G:A	G100D	0.975
17:4782627:T:C	F128S	0.975
17:4782596:T:C	C118R	0.974
17:4782955:C:A	S166Y	0.974
17:4782505:G:A	M87I	0.972
17:4782505:G:C	M87I	0.972

dbSNP variants (sampled 300 via entrez): RS1000053008 (17:4774664 T>A,C), RS1000193585 (17:4782120 G>A), RS1000270960 (17:4780410 G>C), RS1000476522 (17:4770401 G>A), RS1000593828 (17:4777055 G>A,T), RS1000955246 (17:4770751 A>G), RS1001086836 (17:4776148 C>A,T), RS1001270335 (17:4774372 A>G), RS1001296490 (17:4781918 C>T), RS1001665794 (17:4781669 A>G), RS1002058166 (17:4777146 G>A), RS1002087701 (17:4777483 A>G), RS1002361167 (17:4772299 G>A,C), RS1002700062 (17:4783443 A>G), RS1002988627 (17:4773417 T>C)

Disease associations

OMIM: gene MIM:604657 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001639_10	Metabolite levels	1.000000e-11
GCST002897_15	Triglycerides	8.000000e-09
GCST006633_33	Initial alcohol sensitivity	4.000000e-06
GCST010244_312	Triglyceride levels	9.000000e-12

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004723	coronary artery calcification
EFO:0004530	triglyceride measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523127 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, increases expression	3
Resveratrol	increases expression, affects cotreatment, decreases expression	2
Cyclosporine	decreases expression, increases expression	2
dicrotophos	decreases expression	1
propionaldehyde	decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	affects expression	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
CGP 52608	affects binding, increases reaction	1
entinostat	decreases expression	1
Hydrogen Peroxide	affects expression	1
Lead	decreases expression	1
Methapyrilene	increases methylation	1
Plant Extracts	decreases expression, affects cotreatment	1
Silicon Dioxide	decreases expression	1
Valproic Acid	increases methylation	1
Palmitic Acid	decreases expression	1
Okadaic Acid	decreases expression	1

ChEMBL screening assays

23 unique, capped per target: 23 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4420791	Binding	Inhibition of TM4SF5 in human SNU449Tp cells assessed as reduction in cell number at 5 to 40 uM incubated up to 2 days	Method for screening anti-cancer compounds inhibiting function of TM4SF5 and anti-cancer composition containing chalcone compounds

Clinical trials (associated diseases)

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