Affinage

TM4SF5

Transmembrane 4 L6 family member 5 · UniProt O14894

Length
197 aa
Mass
20.8 kDa
Annotated
2026-04-28
63 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TM4SF5 is a four-transmembrane L6-family glycoprotein that organizes plasma membrane and intracellular signaling microdomains to coordinate integrin/growth factor receptor signaling, metabolic reprogramming, and immune evasion. Its second extracellular loop engages integrins α2 and α5, CD44, and EGFR in N-glycosylation- and cholesterol-dependent complexes, while its cytoplasmic C-terminus directly binds and activates FAK (by relieving autoinhibition) and c-Src (via the SH1 kinase domain), driving epithelial–mesenchymal transition, invadopodia formation, and metastasis (PMID:18357344, PMID:23077174, PMID:34335982, PMID:28073834). On intracellular membranes, TM4SF5 functions as a lysosomal arginine sensor activating mTORC1, partners with nutrient transporters (GLUT1, GLUT8, xCT/CD98hc) to regulate glucose/fructose uptake and de novo lipogenesis, and localizes to mitochondria–lysosome contact sites where it binds FKBP8 and NPC1 to mediate cholesterol export and regulate mitochondrial fission (PMID:34187836, PMID:36063136, PMID:35123128, PMID:38133457). TM4SF5 also promotes immune evasion by trafficking SLAMF7 to lysosomes for degradation, suppressing NK cell cytotoxicity, and by modulating macrophage polarization and chemokine secretion to facilitate NAFLD/NASH and hepatocellular carcinoma progression (PMID:39828766, PMID:34788612, PMID:32918742).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2006 High

    Establishing TM4SF5 as a membrane organizer of integrin–FAK signaling: it was unknown how TM4SF5 influenced adhesion signaling; Co-IP showed TM4SF5 associates with integrin α2 and controls FAK Y925/paxillin Y118 phosphorylation in a serum-dependent manner, demonstrating TM4SF5 as a regulator of focal contact dynamics.

    Evidence Co-immunoprecipitation, integrin-blocking antibody, FAK Y925F mutagenesis, migration assays in Cos7 cells

    PMID:16828471

    Open questions at the time
    • Stoichiometry and directness of TM4SF5–integrin α2 binding not resolved
    • Whether TM4SF5 binds FAK directly was unknown at this stage
  2. 2008 High

    Defining the EMT/pro-tumorigenic axis: TM4SF5 was shown to stabilize cytosolic p27Kip1, inactivate RhoA, and suppress E-cadherin, driving EMT and multilayer growth in hepatocarcinoma; concurrently, TM4SF5 retained integrin α5 at the surface to activate c-Src/STAT3/VEGF for angiogenesis, establishing two parallel downstream pathways.

    Evidence shRNA knockdown, ectopic expression, nude mouse xenograft, HUVEC tube formation, E-cadherin reconstitution, anti-integrin α5 blockade

    PMID:18357344 PMID:19036703

    Open questions at the time
    • Direct physical contacts between TM4SF5 and p27Kip1 or RhoA not demonstrated
    • Structural basis for integrin α5 retention was unresolved
  3. 2009 High

    Mapping the interaction interface: the second extracellular loop (EL2) of TM4SF5 was identified as the integrin α2-binding domain, and N-glycosylation of TM4SF5 was shown to be required for protein–protein interactions and drug responsiveness, establishing the glycosylation-dependent nature of TM4SF5 function.

    Evidence EL2 peptide competition, site-directed mutagenesis of N-glycosylation sites, collagen I spreading/migration assays

    PMID:19177595 PMID:19789264

    Open questions at the time
    • Three-dimensional structure of EL2 was unknown
    • Which specific glycan species mediate interaction was not determined
  4. 2012 High

    Defining direct kinase activation mechanisms: TM4SF5 was shown to directly bind FAK, relieving its autoinhibitory intramolecular fold, and the TM4SF5 C-terminus was mapped as the c-Src/EGFR Y845 signaling platform, resolving the molecular basis of two key downstream kinase activations.

    Evidence Co-IP with domain mapping, FAK mutagenesis, EGFR Y845F mutagenesis, C-terminal deletion mutant, in vivo metastasis model

    PMID:23077174 PMID:23220047

    Open questions at the time
    • Crystal/cryo-EM structure of TM4SF5–FAK or TM4SF5–c-Src complex not available
    • Whether FAK and c-Src bind TM4SF5 simultaneously was not tested
  5. 2012 High

    Placing TM4SF5 induction within TGFβ signaling: TGFβ1/Smad activation was shown to induce TM4SF5 expression via EGFR, establishing that TM4SF5 is a downstream effector of TGFβ-mediated EMT and explaining how hepatocytes acquire TM4SF5 expression.

    Evidence Smad overexpression, EGFR kinase inhibitor, Smad7 epistasis, normal and cancer hepatocyte comparison

    PMID:22292774

    Open questions at the time
    • Direct Smad-binding site in TM4SF5 promoter not mapped
    • Contribution of other EMT-inducing signals to TM4SF5 induction not tested
  6. 2014 Medium

    Expanding the tetraspanin-web and developmental roles: TM4SF5 was shown to control CD151/CD63 sorting (internalizing CD63 to lysosomes), and zebrafish morpholino studies demonstrated a requirement for TM4SF5 in integrin α5-dependent muscle development, broadening TM4SF5 function beyond cancer.

    Evidence Co-IP for TM4SF5–CD151, CD63 subcellular fractionation, zebrafish morpholino knockdown with mRNA rescue, C2C12 differentiation

    PMID:24897542 PMID:25033048

    Open questions at the time
    • Whether CD63 internalization is direct or requires adaptor proteins was unknown
    • Zebrafish morpholino studies lack genetic knockout confirmation
  7. 2015 High

    Establishing TM4SF5 as a self-renewal/stemness driver: TM4SF5 was found to bind CD44 through N-glycosylation-dependent extracellular domain interactions, activating c-Src/STAT3/Twist1/Bmi1 for spheroid formation, and co-expressed with IGF1R/EGFR to form a complex conferring EGFR-inhibitor resistance.

    Evidence Co-IP with domain mapping, N-glycosylation mutagenesis, pathway epistasis, orthotopic liver model with CTC detection, EGFR inhibitor sensitivity assays

    PMID:25627085 PMID:26190015

    Open questions at the time
    • Relative contribution of CD44 vs. IGF1R complexes to stemness not dissected
    • Whether TM4SF5/CD44/IGF1R/EGFR exist in a single supercomplex or separate pools was unclear
  8. 2017 High

    Visualizing TM4SF5 microdomain dynamics at the leading edge: live single-molecule cross-correlation spectroscopy confirmed TM4SF5 co-diffuses with EGFR and integrin α5 at the plasma membrane in a cholesterol- and palmitoylation-dependent manner, providing biophysical evidence for tetraspanin-enriched microdomain organization.

    Evidence Live fluorescence cross-correlation spectroscopy, super-resolution microscopy, cholesterol depletion, palmitoylation mutagenesis, 2D/3D migration

    PMID:28073834

    Open questions at the time
    • Lipid composition requirements beyond cholesterol not characterized
    • Whether palmitoylation directly mediates partner binding or affects membrane partitioning was not distinguished
  9. 2019 High

    Revealing metabolic/transporter functions: TM4SF5 was found to complex with the xCT/CD98hc cystine–glutamate antiporter via CD44v8-10 splice-variant induction, regulating glutathione homeostasis and ROS defense; Tm4sf5-KO mice showed attenuated pulmonary fibrosis, linking TM4SF5 to metabolic redox control in vivo.

    Evidence Co-IP of TM4SF5–CD98hc/xCT, glutathione assay, alternative splicing analysis, Tm4sf5-KO mouse bleomycin model

    PMID:31501417

    Open questions at the time
    • Whether TM4SF5 directly transports any metabolite or acts purely as a scaffolding organizer was unresolved
    • Tissue-specificity of the xCT complex function beyond lung not tested
  10. 2021 High

    Defining TM4SF5 as a lysosomal nutrient sensor and intracellular trafficking hub: TM4SF5 was identified as a lysosomal arginine sensor activating mTORC1 in adipocytes (KO reduced adiposity and improved glucose tolerance); simultaneously, the C-terminus/SH1-domain interaction with c-Src was structurally modeled and validated, and TM4SF5 vesicle trafficking was shown to depend on a TM4SF5/HDAC6/SLAC2B complex riding acetylated microtubules.

    Evidence mTORC1 activity and autophagy assays in KO mice, metabolic phenotyping, Co-IP domain mapping of c-Src SH1, cell-penetrating peptide competition, live vesicle tracking, HDAC6/SLAC2B Co-IP

    PMID:33554392 PMID:34187836 PMID:34335982

    Open questions at the time
    • The arginine-sensing mechanism (direct binding vs. indirect) not biochemically resolved
    • Whether HDAC6/SLAC2B complex exists on lysosomal vs. plasma-membrane-directed vesicles was unclear
  11. 2021 Medium

    Establishing immune evasion functions: TM4SF5 in hepatocytes suppressed NK cell ligands (SLAMF6/7, MICA/B) and promoted macrophage M1-to-M2 reprogramming via IL-6/CCL20 secretion, linking TM4SF5 to both innate immune evasion and NAFLD progression.

    Evidence Tm4sf5 transgenic and DEN-induced liver cancer models, NK cell cytotoxicity assays, macrophage polarization co-culture, IL-6 neutralization, TSAHC inhibitor

    PMID:34788612 PMID:34921636

    Open questions at the time
    • Direct mechanism by which TM4SF5 downregulates NK ligands (transcriptional vs. post-translational) was not fully resolved
    • In vivo contribution of macrophage vs. NK evasion to tumor progression not separated
  12. 2022 Medium

    Expanding sugar transporter partnerships: TM4SF5 was shown to bind GLUT1 for glucose uptake and GLUT8 for fructose uptake/de novo lipogenesis; hepatocyte-derived TM4SF5-containing extracellular vesicles targeted brown adipose tissue to improve systemic glucose clearance, revealing an inter-organ signaling role.

    Evidence Co-IP of TM4SF5–GLUT1 and TM4SF5–GLUT8, glucose/fructose uptake assays, sEV isolation and in vivo delivery via liver-closed vein circuit, Tm4sf5-KO mice on high-sucrose diets

    PMID:35123128 PMID:36063136

    Open questions at the time
    • Whether TM4SF5 in sEVs retains functional transporter-scaffolding activity in recipient cells was not shown
    • The GLUT8 release mechanism upon fructose stimulation was not molecularly defined
  13. 2023 High

    Defining mitochondria–lysosome contact site (MLCS) functions: TM4SF5 was shown to enrich at MLCSs via binding lysosomal TM4SF5 to mitochondrial FKBP8; proximity labeling revealed DRP1 and mitophagy receptor clustering, and TM4SF5 mediated NPC1-dependent cholesterol transfer from lysosomes to mitochondria, impairing oxidative phosphorylation.

    Evidence Co-IP of TM4SF5–FKBP8 and TM4SF5–NPC1, BioID proximity proteomics, cholesterol transport reconstitution, mitophagy assay, DRP1 phosphorylation, in vivo mouse models

    PMID:38133457

    Open questions at the time
    • Whether MLCS enrichment requires mTORC1 activity (linking to the arginine-sensing role) was not tested
    • Structural basis of the TM4SF5–FKBP8 interaction unknown
  14. 2025 High

    Resolving the NK-evasion mechanism and structural features: TM4SF5 was shown to directly bind SLAMF7 in an N-glycosylation-dependent manner and traffic it to lysosomes for degradation, suppressing NK cytotoxicity; the LEL was structurally characterized as a β-sheet fold (distinct from genuine tetraspanins) that forms N-glycosylation-dependent dimers and binds cholesterol; TM4SF5 also modulates KEAP1 stability independently of NRF2.

    Evidence Co-IP with N-glycosylation mutagenesis, SLAMF7 trafficking imaging, TSI inhibitor treatment, xenograft models, structural/domain analysis, KEAP1 proteasomal degradation assay, Tm4sf5-KO and Nrf2-mutant mice

    PMID:39828766 PMID:41349605 PMID:41608638

    Open questions at the time
    • High-resolution structure of the TM4SF5 LEL dimer still lacking
    • Mechanism by which pathological lipid conditions switch TM4SF5 from KEAP1 degradation to stabilization is not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of TM4SF5 (alone and in complex with key partners such as FAK, c-Src, integrins, or SLAMF7) is needed to understand the allosteric mechanisms by which it activates kinases and organizes multi-protein complexes; the direct arginine-binding mechanism on lysosomes remains biochemically unresolved.
  • No crystal or cryo-EM structure available
  • Arginine-sensing mechanism (direct binding site, affinity) not biochemically defined
  • Relative physiological importance of individual TM4SF5 complexes in specific tissues unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 6 GO:0098772 molecular function regulator activity 4 GO:0008289 lipid binding 2 GO:0140299 molecular sensor activity 1
Localization
GO:0005886 plasma membrane 5 GO:0005764 lysosome 4 GO:0005576 extracellular region 1 GO:0005739 mitochondrion 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 10 R-HSA-1430728 Metabolism 5 R-HSA-1500931 Cell-Cell communication 4 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-9612973 Autophagy 2 R-HSA-1640170 Cell Cycle 1
Partners
CD44EGFRFKBP8ITGA2ITGA5PTK2SLAMF7SRC
Complex memberships
TM4SF5/CD44v8-10/CD98hc/xCT transporter complexTM4SF5/HDAC6/SLAC2B vesicle trafficking complexTM4SF5/IGF1R/EGFR signaling complexTM4SF5/integrin α5/EGFR leading-edge complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 TM4SF5 overexpression in hepatocarcinoma causes cytosolic stabilization of p27Kip1 and RhoA inactivation, leading to epithelial-mesenchymal transition (EMT) with loss of E-cadherin and aberrant multilayer cell growth; suppression of TM4SF5, cytosolic p27Kip1, or reconstitution of E-cadherin abolished these effects. Ectopic expression, shRNA knockdown, anchorage-independent growth assay, S-phase transition assay, nude mouse tumor formation, E-cadherin reconstitution The Journal of clinical investigation High 18357344
2006 TM4SF5 associates with integrin α2 subunit, and this association is abolished by serum treatment; TM4SF5 regulates actin organization and focal contact dynamics via serum-dependent differential regulation of FAK Tyr925 and paxillin Tyr118 phosphorylations; Y925F FAK mutation abolished TM4SF5 effects; functional blocking of integrin α2 abolished TM4SF5-enhanced signaling and caused abnormal actin organization. Co-immunoprecipitation, ectopic expression in Cos7 cells, anti-integrin blocking antibody, FAK point mutagenesis, phosphorylation assays, migration assays Experimental cell research High 16828471
2008 TM4SF5 retains integrin α5 on the cell surface to induce VEGF expression and secretion; TM4SF5-mediated VEGF induction and angiogenesis required integrin α5, c-Src, and STAT3; anti-integrin α5 antibody abolished TM4SF5-mediated VEGF expression and tube formation by endothelial cells. Anti-integrin α5 antibody blockade, conditioned media assay, HUVEC tube formation, aorta ring outgrowth, anti-VEGF antibody neutralization, nude mouse xenograft Blood High 19036703
2009 The second extracellular loop (EL2) of TM4SF5 directly interacts with integrin α2 in a collagen type I environment, inhibiting integrin α2 functions such as cell spreading and migration toward collagen I; EL2 peptide or mutagenesis of EL2 recovered integrin α2 function. Co-immunoprecipitation, EL2 peptide blocking, site-directed mutagenesis, cell spreading and migration assays on collagen I Carcinogenesis High 19789264
2009 N-glycosylation of TM4SF5 is required for TM4SF5-specific responsiveness to the antagonist TSAHC; point mutations of putative N-glycosylation sites abolished this responsiveness, indicating that glycosylation of the extracellular region is important for TM4SF5 protein-protein interactions. Site-directed mutagenesis of N-glycosylation sites, TSAHC drug treatment, multilayer growth assay, migration/invasion assay Hepatology (Baltimore, Md.) Medium 19177595
2010 TM4SF5 accelerates G1/S phase progression by facilitating CDK4/cyclin D1 nuclear entry and complex formation, Rb phosphorylation, and cyclin D1/E upregulation; these effects were blocked by p27Kip1 siRNA silencing or constitutively active RhoA; ROCK inhibition mimicked TM4SF5 effects in control cells. siRNA knockdown, active RhoA infection, ROCK pharmacological inhibition, cell cycle analysis, co-IP for CDK4/cyclin D1 complex, subcellular fractionation Biochimica et biophysica acta Medium 20399237
2010 TM4SF5 expression facilitates invadopodia formation, MMP activation, and invasion in hepatocarcinoma cells, leading to lung metastasis in nude mice; shRNA suppression of TM4SF5 blocked these effects. shRNA knockdown, in vitro invasion assay, MMP activity assay, invadopodia assay, nude mouse lung metastasis model Journal of cellular biochemistry Medium 20506553
2011 TM4SF5-mediated Ser10 phosphorylation of p27Kip1 (required for cytosolic localization) is dependent on JNK activity; JNK inhibition or suppression in TM4SF5-expressing cells decreased p27Kip1 Ser10 phosphorylation and rescued E-cadherin expression and localization at cell-cell contacts. JNK pharmacological inhibition, JNK siRNA knockdown, p27Kip1 phosphorylation assays, immunofluorescence of adherens junction molecules Cancer letters Medium 22014979
2011 TM4SF5 expression inhibits proteasome activity and proteasome subunit expression in hepatocarcinoma cells, causing loss of cell-cell contacts and E-cadherin; shRNA against TM4SF5 recovered proteasome expression and cell-cell adhesion. shRNA knockdown, proteasome activity assay, proteasome subunit expression analysis, immunofluorescence of E-cadherin Journal of cellular biochemistry Medium 21328452
2012 TM4SF5 directly binds FAK in an adhesion-dependent manner; this binding causes a structural alteration releasing the inhibitory intramolecular interaction in FAK, activating FAK at the cell's leading edge for migration/invasion and in vivo metastasis; impaired TM4SF5-FAK interaction attenuated FAK phosphorylation and metastatic potential. Co-IP (direct binding), mutagenesis to impair TM4SF5-FAK interaction, phosphorylation assays, cell migration/invasion assay, in vivo metastasis model, immunofluorescence of leading-edge localization Journal of cell science High 23077174
2012 The C-terminus of TM4SF5 binds c-Src (both inactive and active forms); TM4SF5 modulates c-Src activity to promote invasive protrusion formation; c-Src activity correlates with EGFR Tyr845 phosphorylation; Y845F EGFR mutation abolished TM4SF5-mediated invasive protrusions but not c-Src phosphorylation, establishing a TM4SF5/c-Src/EGFR(Y845) signaling axis for invasion. Co-IP (C-terminus domain mapping), TM4SF5 C-terminal deletion mutant (ΔC), site-directed EGFR Y845F mutagenesis, migration and invasion assays, phosphorylation assays Biochimica et biophysica acta High 23220047
2012 TGFβ1-mediated Smad activation induces TM4SF5 expression and EMT through EGFR pathway activation; Smad overexpression activated EGFR and induced TM4SF5 in the absence of serum; EGFR kinase inhibition, EGF depletion, or Smad7 expression abolished TM4SF5 induction and EMT, placing TGFβ1→Smad→EGFR→TM4SF5 as a signaling axis. Smad overexpression, Smad7 inhibition, EGFR kinase inhibitor treatment, EGF depletion, small compound TM4SF5 inhibition, TM4SF5 expression monitoring in normal hepatocytes The Biochemical journal High 22292774
2014 TM4SF5 interacts with CD151 (tumorigenic tetraspanin) and causes internalization of CD63 (tumor-suppressive tetraspanin) from the cell surface into late lysosomal membranes; TM4SF5 controls expression levels of CD151 and CD63, but not vice versa; TM4SF5 could overcome CD151 tumorigenic effects on migration and ECM degradation. Co-IP (TM4SF5-CD151 interaction), subcellular fractionation/immunofluorescence showing CD63 internalization, shRNA epistasis experiments, TGFβ1-treated Chang cell model PloS one Medium 25033048
2014 IL-6 treatment activates FAK and STAT3 in TM4SF5-null cells but decreases TM4SF5-dependent FAK activity in TM4SF5-expressing cancer cells; TM4SF5 expression in hepatocellular carcinoma cells causes invasive ECM degradation negatively dependent on IL-6/IL-6R signaling, establishing that cancer cells adopt TM4SF5-dependent FAK activation by lowering IL-6 to avoid immune surveillance. IL-6 treatment, STAT3 suppression (siRNA), FAK activity modulation, Co-IP-established TM4SF5/FAK pathway, ECM degradation assay, comparison of normal vs. cancerous hepatocytes Molecular and cellular biology Medium 24912675
2015 TM4SF5 physically interacts with CD44 through their extracellular domains in an N-glycosylation-dependent manner; TM4SF5/CD44 interaction activates c-Src/STAT3/Twist1/Bmi1 signaling for spheroid (self-renewal) formation; disrupting any component of this pathway inhibited spheroid formation; TM4SF5-positive cells circulate in blood after orthotopic liver injection, and anti-TM4SF5 reagent blocked metastasis to distal organs. Co-IP (extracellular domain mapping), N-glycosylation mutagenesis, pathway component siRNA/inhibitor epistasis, 3D spheroid assay, in vivo orthotopic model with laser scanning endomicroscopy for CTC detection Hepatology (Baltimore, Md.) High 25627085
2015 TM4SF5 and IGF1R transcriptionally modulate each other's expression; TM4SF5 and IGF1R form a protein complex (also including EGFR) in a TM4SF5-dependent manner; co-expression promotes ERK, Akt, and S6K signaling and residual EGFR activity after EGFR kinase inhibitor treatment, causing resistance to erlotinib and gefitinib. Co-IP (TM4SF5/IGF1R/EGFR complex), ectopic TM4SF5 expression, IGF1R siRNA knockdown, EGFR kinase inhibitor treatment, 2D/3D culture drug sensitivity assays Lung cancer (Amsterdam, Netherlands) Medium 26190015
2017 TM4SF5 physically associates with EGFR and integrin α5 at the leading edge of migratory cells (visualized by live fluorescence cross-correlation spectroscopy); cholesterol depletion and disruption of TM4SF5 N-glycosylation or palmitoylation alter these interactions and reduce cell migration speed and directionality in 2D and 3D conditions. Live fluorescence cross-correlation spectroscopy (FCS), super-resolution microscopy, cholesterol depletion (methyl-β-cyclodextrin), N-glycosylation and palmitoylation mutagenesis, 2D/3D migration assays FASEB journal High 28073834
2018 CD133 phosphorylation induces TM4SF5 expression; TM4SF5 binds CD133 and promotes c-Src activity for CD133 phosphorylation (positive feedback); TM4SF5 also binds PTPRF and promotes paxillin phosphorylation; sphere growth decreased by CD133 suppression was recovered by TM4SF5 expression and partially by PTPRF suppression. Co-IP (TM4SF5-CD133, TM4SF5-PTPRF), siRNA knockdown epistasis, paxillin phosphorylation assay, 3D sphere growth assay Cancer letters Medium 30217560
2019 TM4SF5 induces the alternatively spliced CD44v8-10 variant through an inverse ZEB2/ESRP linkage; TM4SF5 forms complexes with the cystine/glutamate antiporter system (xCT) via TM4SF5- and CD44v8-10-dependent CD98hc plasma membrane enrichment; dynamic TM4SF5 binding to CD98hc required CD44v8-10 under ROS-generating conditions; this complex upregulates cystine/glutamate antiporter activity and intracellular glutathione for ROS modulation and cell survival. Tm4sf5-null mice showed attenuated bleomycin-induced pulmonary fibrosis. Co-IP (TM4SF5-CD98hc, TM4SF5-CD44v8-10), alternative splicing analysis (RT-PCR), ZEB2/ESRP expression analysis, glutathione assay, xCT activity assay, Tm4sf5 KO mouse bleomycin model Cell death & disease High 31501417
2020 TM4SF5 forms protein-protein complexes with amino acid transporters including xCT (cystine/glutamate antiporter) and regulates cystine uptake from extracellular space and arginine export from lysosomal lumen to cytosol; diverse amino acid transporters co-precipitate with TM4SF5 by proteomic analysis. Co-IP, proximity-based proteomics, amino acid transport assays Experimental & molecular medicine Medium 31956272
2020 TM4SF5-overexpressing mice develop age-dependent nonalcoholic steatosis and NASH; in young mice TM4SF5 decreases SIRT1, increases SREBPs, and inactivates STAT3 via SOCS1/3 upregulation; in older mice TM4SF5 promotes SIRT1 expression and STAT3 activity for ECM production; CCL20 suppression reduced immune cell infiltration and ECM production; active STAT3 increases collagen I and laminin γ2, which in turn support SIRT1/STAT3 activity. TM4SF5 transgenic and KO mouse models, diet/chemical-treated mice, primary hepatocyte culture, CCL20 suppression, collagen I/laminin γ2 knockdown, human tissue analysis The Journal of pathology High 32918742
2021 TM4SF5 induction in differentiated macrophages promotes glucose uptake, glycolysis, and M1-type macrophage activation; activated M1 macrophages secrete IL-6, which induces CCL20 and CXCL10 secretion from TM4SF5-positive hepatocytes; chronic exposure to these chemokines reprograms macrophages toward M2-type, supporting NAFLD progression. TM4SF5 overexpression in macrophages, glycolysis assay, cytokine ELISA, co-culture systems, macrophage polarization assays, IL-6 neutralization Cell reports Medium 34788612
2021 TM4SF5 expression in cancer cells downregulates stimulatory NK cell ligands and receptors (SLAMF6, SLAMF7, MICA/B), causing NK cell exhaustion-like phenotypes; TM4SF5 suppression or inhibition with TSAHC reduced STAT3 signaling, recovered NK cell receptor levels and NK cell surveillance, and reduced liver cancer progression. TM4SF5 transgenic and DEN-induced liver cancer mouse models, TSAHC inhibitor treatment, NK cell activity assays, flow cytometry for NK ligand/receptor expression, STAT3 modulation Cellular and molecular life sciences Medium 34921636
2021 The TM4SF5 C-terminus binds the c-Src SH1 kinase domain (preferentially in its inactive closed form) along with PTP1B which dephosphorylates Tyr530; the SH1 domain alone bound TM4SF5 to cause c-Src Tyr419 and FAK Y861 phosphorylation; cell-penetrating TM4SF5 C-terminal peptides blocked TM4SF5-c-Src interaction and prevented tumor initiation/progression in vivo. Co-IP (domain mapping: C-terminus vs. SH1), homology modeling, molecular dynamics simulation, mutagenesis validation, cell-penetrating peptide competition, in vivo xenograft model Theranostics High 34335982
2021 TM4SF5 intracellular vesicle traffic toward the leading edge is controlled by cell adhesion to fibronectin and microtubule acetylation; TM4SF5 palmitoylation is required for directed traffic; TM4SF5 forms a trimeric complex with HDAC6 and SLAC2B at perinuclear cytosol; SLAC2B suppression allows acetylated microtubules to extend to leading edges, facilitating TM4SF5 translocation and persistent migration; HDAC6 inhibition (via paxillin at new adhesion sites) promotes TM4SF5 traffic. Live-cell imaging of TM4SF5 vesicle tracking, palmitoylation-deficient mutant, SLAC2B siRNA, HDAC6 inhibition, Co-IP (TM4SF5-HDAC6-SLAC2B trimeric complex), immunofluorescence of acetylated tubulin FASEB journal Medium 33554392
2021 TM4SF5 functions as a lysosomal arginine sensor and activates mTORC1; TM4SF5 KO in adipocytes reduces mTORC1 activation, enhances autophagy and lipolysis, increases PPARα and mitochondrial oxidative metabolism gene expression, reduces adiposity, and prevents HFD-induced glucose intolerance. TM4SF5 KO mouse model, mTORC1 activity assays, autophagy assays (LC3 flux), lipolysis assay, RNA sequencing of adipose tissue, metabolic phenotyping Diabetes Medium 34187836
2022 Hepatic TM4SF5 binds GLUT1 at the plasma membrane to promote glucose uptake and glycolysis; excessive glucose causes hepatocytes to secrete TM4SF5-loaded small extracellular vesicles (sEVs); liver-derived sEVs containing TM4SF5 target brown adipose tissue (BAT) to improve glucose clearance independent of UCP1. Co-IP (TM4SF5-GLUT1), glucose uptake assay, sEV isolation and characterization, liver-closed vein circuit (LCVC) in vivo delivery of sEVs from TM4SF5-overexpressing mice, glucose tolerance tests in KO mice, BAT targeting assay Journal of extracellular vesicles Medium 36063136
2022 TM4SF5 binds GLUT8 at the plasma membrane; following fructose treatment, TM4SF5-GLUT8 binding transiently decreases, allowing GLUT8 translocation to the plasma membrane for fructose uptake and de novo lipogenesis; Tm4sf5 suppression or KO reduced fructose uptake, DNL, and steatosis in vivo. Co-IP (TM4SF5-GLUT8), GLUT8 localization by immunofluorescence (translocation assay), fructose uptake assay, DNL measurement, Tm4sf5 KO mouse with high-sucrose/fructose diet Molecular metabolism Medium 35123128
2023 Upon glucose repletion following depletion, TM4SF5 becomes enriched at mitochondria-lysosome contact sites (MLCSs) via interaction between mitochondrial FKBP8 and lysosomal TM4SF5; proximity labeling revealed clustering of phospho-DRP1 and mitophagy receptors at TM4SF5-enriched MLCSs, promoting mitochondrial fission and autophagy; TM4SF5 binds NPC1 and free cholesterol, mediating cholesterol export from lysosomes to mitochondria and impairing oxidative phosphorylation. Co-IP (TM4SF5-FKBP8, TM4SF5-NPC1), proximity-labeling proteomics (BioID), organelle reconstitution, cholesterol transport assay, mitophagy assay, DRP1 phosphorylation analysis, in vivo mouse hepatocyte models Cancer communications (London, England) High 38133457
2014 TM4SF5 suppression in zebrafish impairs trunk muscle development, aberrant muscle fibre morphology, and alters integrin α5 expression; integrin α5-related signaling molecules (fibronectin, FAK, vinculin, actin) are aberrantly localized in tm4sf5 morphants; aberrant muscle development was rescued by injection of tm4sf5 or integrin α5 mRNA, establishing TM4SF5 function in muscle differentiation via integrin α5-dependent signaling. Morpholino knockdown (zebrafish), mRNA rescue injection, immunofluorescence of muscle and signaling molecules, C2C12 mouse myoblast differentiation assay The Biochemical journal Medium 24897542
2025 TM4SF5 expressed by hepatocytes reduces NK cell cytotoxicity by binding SLAMF7 in an N-glycosylation-dependent manner, causing intracellular trafficking of SLAMF7 from the plasma membrane to lysosomes for degradation; TM4SF5-specific isoxazole (TSI) compounds block this binding and trafficking, restoring NK cell surveillance and reducing HCC development in xenograft models. Co-IP (TM4SF5-SLAMF7, N-glycosylation mutagenesis), immunofluorescence tracking of SLAMF7 trafficking to lysosomes, TSI small molecule treatment, NK cell cytotoxicity assay, mouse xenograft and Tm4sf5-KO models Signal transduction and targeted therapy High 39828766
2025 TM4SF5-mediated macropinocytosis of albumin requires cytosolic stabilization of NCOA3 and PTEN inactivation through TM4SF5 binding; albumin uptake via macropinocytosis supports ATP-linked respiration and cellular migration in TM4SF5-expressing hepatocytes. Co-IP (TM4SF5-NCOA3, TM4SF5-PTEN), NCOA3 and PTEN expression/activity assays, macropinocytosis assay, albumin uptake assay, ATP-linked respiration (Seahorse), TM4SF5 KO and reintroduction, in vivo orthotopic mouse model Experimental & molecular medicine Medium 40186033
2025 TM4SF5 modulates KEAP1 independently of NRF2: the cytosolic TM4SF5 C-terminus binds KEAP1 to promote its proteasomal degradation under physiological conditions; in hyperlipidemic/pathological states TM4SF5 stabilizes KEAP1, leading to oxidative stress and hepatic inflammation; Keap1 suppression nullified TM4SF5-mediated MASLD phenotypes. Co-IP (TM4SF5 C-terminus binding to KEAP1), proteasome inhibitor treatment, Tm4sf5 KO and Nrf2 mutant mouse models, Keap1 siRNA suppression, in vitro and in vivo MASLD models International journal of biological sciences Medium 41608638
2025 TM4SF5 forms an N-glycosylation-dependent dimer in its large extracellular loop (LEL); the LEL has a β-sheet configuration (unlike the α-helices of genuine tetraspanins or CD20-like family); TM4SF5 has two conserved cysteines (without the CCG motif) affecting N-glycosylation and dimer formation, and the LEL contributes to cholesterol binding. Structural analysis, sequence/domain comparison, N-glycosylation mutagenesis, cholesterol binding assay Journal of advanced research Medium 41349605

Source papers

Stage 0 corpus · 63 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Tetraspanin TM4SF5 mediates loss of contact inhibition through epithelial-mesenchymal transition in human hepatocarcinoma. The Journal of clinical investigation 102 18357344
2009 Blockade of four-transmembrane L6 family member 5 (TM4SF5)-mediated tumorigenicity in hepatocytes by a synthetic chalcone derivative. Hepatology (Baltimore, Md.) 64 19177595
1998 Identification of a new tumour-associated antigen TM4SF5 and its expression in human cancer. Gene 60 9479038
2008 Cooperation between integrin alpha5 and tetraspan TM4SF5 regulates VEGF-mediated angiogenic activity. Blood 56 19036703
2015 Interaction of tetraspan(in) TM4SF5 with CD44 promotes self-renewal and circulating capacities of hepatocarcinoma cells. Hepatology (Baltimore, Md.) 55 25627085
2012 Tetraspan TM4SF5-dependent direct activation of FAK and metastatic potential of hepatocarcinoma cells. Journal of cell science 43 23077174
2012 Cross-talk between TGFβ1 and EGFR signalling pathways induces TM4SF5 expression and epithelial-mesenchymal transition. The Biochemical journal 41 22292774
2015 Transmembrane 4 L Six Family Member 5 (TM4SF5)-Mediated Epithelial-Mesenchymal Transition in Liver Diseases. International review of cell and molecular biology 35 26404468
2006 Focal adhesion and actin organization by a cross-talk of TM4SF5 with integrin alpha2 are regulated by serum treatment. Experimental cell research 33 16828471
2017 Dynamic and coordinated single-molecular interactions at TM4SF5-enriched microdomains guide invasive behaviors in 2- and 3-dimensional environments. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 31 28073834
2010 Transmembrane 4 L six family member 5 (TM4SF5) enhances migration and invasion of hepatocytes for effective metastasis. Journal of cellular biochemistry 31 20506553
2012 The COOH-terminus of TM4SF5 in hepatoma cell lines regulates c-Src to form invasive protrusions via EGFR Tyr845 phosphorylation. Biochimica et biophysica acta 29 23220047
2020 Differential TM4SF5-mediated SIRT1 modulation and metabolic signaling in nonalcoholic steatohepatitis progression. The Journal of pathology 28 32918742
2011 Gefitinib resistance of cancer cells correlated with TM4SF5-mediated epithelial-mesenchymal transition. Biochimica et biophysica acta 27 22178131
2010 TM4SF5 accelerates G1/S phase progression via cytosolic p27Kip1 expression and RhoA activity. Biochimica et biophysica acta 26 20399237
2021 TM4SF5-dependent crosstalk between hepatocytes and macrophages to reprogram the inflammatory environment. Cell reports 25 34788612
2014 Membrane Proteins Involved in Epithelial-Mesenchymal Transition and Tumor Invasion: Studies on TMPRSS4 and TM4SF5. Genomics & informatics 25 24748857
2021 TM4SF5-mediated liver malignancy involves NK cell exhaustion-like phenotypes. Cellular and molecular life sciences : CMLS 24 34921636
2014 Correlations between transmembrane 4 L6 family member 5 (TM4SF5), CD151, and CD63 in liver fibrotic phenotypes and hepatic migration and invasive capacities. PloS one 24 25033048
2009 The extracellular loop 2 of TM4SF5 inhibits integrin alpha2 on hepatocytes under collagen type I environment. Carcinogenesis 24 19789264
2022 Liver-originated small extracellular vesicles with TM4SF5 target brown adipose tissue for homeostatic glucose clearance. Journal of extracellular vesicles 22 36063136
2017 Anti-cancer Activity of Novel TM4SF5-Targeting Antibodies through TM4SF5 Neutralization and Immune Cell-Mediated Cytotoxicity. Theranostics 22 28255353
2014 Cross talk between the TM4SF5/focal adhesion kinase and the interleukin-6/STAT3 pathways promotes immune escape of human liver cancer cells. Molecular and cellular biology 22 24912675
2012 Prevention and therapy of hepatocellular carcinoma by vaccination with TM4SF5 epitope-CpG-DNA-liposome complex without carriers. PloS one 22 22427965
2014 TM4SF5-mediated protein-protein networks and tumorigenic roles. BMB reports 21 25027595
2022 Crosstalk between TM4SF5 and GLUT8 regulates fructose metabolism in hepatic steatosis. Molecular metabolism 19 35123128
2014 Monoclonal antibody targeting of the cell surface molecule TM4SF5 inhibits the growth of hepatocellular carcinoma. Cancer research 18 24802189
2016 Anti-metastatic effect of the TM4SF5-specific peptide vaccine and humanized monoclonal antibody on colon cancer in a mouse lung metastasis model. Oncotarget 17 27816969
2018 A peptide-CpG-DNA-liposome complex vaccine targeting TM4SF5 suppresses growth of pancreatic cancer in a mouse allograft model. OncoTargets and therapy 16 30584324
2014 Therapeutic effect of a TM4SF5-specific peptide vaccine against colon cancer in a mouse model. BMB reports 16 24286311
2018 CD133-induced TM4SF5 expression promotes sphere growth via recruitment and blocking of protein tyrosine phosphatase receptor type F (PTPRF). Cancer letters 15 30217560
2015 Bidirectional signaling between TM4SF5 and IGF1R promotes resistance to EGFR kinase inhibitors. Lung cancer (Amsterdam, Netherlands) 15 26190015
2013 A high level of TM4SF5 is associated with human esophageal cancer progression and poor patient survival. Digestive diseases and sciences 15 23633159
2011 JNK signaling activity regulates cell-cell adhesions via TM4SF5-mediated p27(Kip1) phosphorylation. Cancer letters 15 22014979
2023 Glucose-mediated mitochondrial reprogramming by cholesterol export at TM4SF5-enriched mitochondria-lysosome contact sites. Cancer communications (London, England) 14 38133457
2020 Amino acid transporters as tetraspanin TM4SF5 binding partners. Experimental & molecular medicine 14 31956272
2019 TM4SF5-mediated CD44v8-10 splicing variant promotes survival of type II alveolar epithelial cells during idiopathic pulmonary fibrosis. Cell death & disease 14 31501417
2021 TM4SF5 Knockout Protects Mice From Diet-Induced Obesity Partly by Regulating Autophagy in Adipose Tissue. Diabetes 13 34187836
2015 Self-renewal and circulating capacities of metastatic hepatocarcinoma cells required for collaboration between TM4SF5 and CD44. BMB reports 13 25772760
2012 Induction of immunological memory response by vaccination with TM4SF5 epitope-CpG-DNA-liposome complex in a mouse hepatocellular carcinoma model. Oncology reports 13 23138455
2021 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. Theranostics 12 34335982
2011 Proteasome inhibition causes epithelial-mesenchymal transition upon TM4SF5 expression. Journal of cellular biochemistry 11 21328452
2023 Three Members of Transmembrane-4-Superfamily, TM4SF1, TM4SF4, and TM4SF5, as Emerging Anticancer Molecular Targets against Cancer Phenotypes and Chemoresistance. Pharmaceuticals (Basel, Switzerland) 10 36678607
2014 Therapeutic effect of a TM4SF5-specific monoclonal antibody against colon cancer in a mouse model. Oncotarget 10 25268742
2022 TM4SF5-Mediated Regulation of Hepatocyte Transporters during Metabolic Liver Diseases. International journal of molecular sciences 9 35955521
2013 Prophylactic effect of a peptide vaccine targeting TM4SF5 against colon cancer in a mouse model. Biochemical and biophysical research communications 9 23624388
2008 Regulation of TM4SF5-mediated tumorigenesis through induction of cell detachment and death by tiarellic acid. Biochimica et biophysica acta 9 18501196
2025 Isoxazole-based molecules restore NK cell immune surveillance in hepatocarcinogenesis by targeting TM4SF5 and SLAMF7 linkage. Signal transduction and targeted therapy 8 39828766
2022 Therapeutic effects of TM4SF5-targeting chimeric and humanized monoclonal antibodies in hepatocellular and colon cancer models. Molecular therapy oncolytics 8 35211652
2015 TM4SF5-CTD-2354A18.1-miR-4697-3P may play a key role in the pathogenesis of gastric cancer. Bratislavske lekarske listy 8 26531872
2014 TM4SF5 suppression disturbs integrin α5-related signalling and muscle development in zebrafish. The Biochemical journal 7 24897542
2017 TM4SF5-Mediated Roles in the Development of Fibrotic Phenotypes. Mediators of inflammation 6 28458469
2019 Targeting TM4SF5 with anti-TM4SF5 monoclonal antibody suppresses the growth and motility of human pancreatic cancer cells. Oncology letters 5 31897180
2022 Systemic TM4SF5 overexpression in ApcMin/+ mice promotes hepatic portal hypertension associated with fibrosis. BMB reports 4 36104259
2017 TM4SF5 promotes metastatic behavior of cells in 3D extracellular matrix gels by reducing dependency on environmental cues. Oncotarget 4 29137358
2023 TM4SF5-mediated abnormal food-intake behavior and apelin expression facilitate non-alcoholic fatty liver disease features. iScience 3 37670786
2020 Metastatic behavior analyses of tetraspanin TM4SF5-expressing spheres in three-dimensional (3D) cell culture environment. Archives of pharmacal research 3 33222072
2019 Clinicopathological significance of TM4SF5 expression in human hepatocellular carcinoma tissues. Oncology letters 3 31186734
2025 Hepatocyte TM4SF5-mediated cytosolic NCOA3 stabilization and macropinocytosis support albumin uptake and bioenergetics for hepatocellular carcinoma progression. Experimental & molecular medicine 2 40186033
2021 SLAC2B-dependent microtubule acetylation regulates extracellular matrix-mediated intracellular TM4SF5 traffic to the plasma membranes. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2 33554392
2024 Association between hepatocyte TM4SF5 expression and gut microbiome dysbiosis during non-alcoholic fatty liver disease development. Life sciences 1 39454995
2026 TM4SF5-mediated KEAP1 Regulation in Hepatocytes Irrelevant to NRF2 Expression and Activity Promotes Oxidative Stress and Inflammation to Develop Metabolic Dysfunction-Associated Steatotic Liver Disease. International journal of biological sciences 0 41608638
2025 Unique molecular architecture of N-glycosylated TM4SF5 dimer highlights evolutionary and structural divergence among small four-transmembrane protein families. Journal of advanced research 0 41349605