{"gene":"TM4SF1","run_date":"2026-04-28T21:42:59","timeline":{"discoveries":[{"year":1992,"finding":"TM4SF1 (L6 antigen) was cloned and found to encode a ~24 kDa cell surface protein with three N-terminal hydrophobic transmembrane regions followed by a hydrophilic region with two potential N-linked glycosylation sites and a C-terminal hydrophobic transmembrane region, placing it in a family of proteins with similar predicted membrane topology implicated in cell growth.","method":"Expression cloning in COS cells; antibody reactivity; hydropathy/sequence analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — original expression cloning with functional antibody validation; foundational structural characterization paper","pmids":["1565644"],"is_preprint":false},{"year":2009,"finding":"TM4SF1 is highly expressed in endothelial cell filopodia in a banded pattern; TM4SF1 knockdown prevented filopodia formation, inhibited cell mobility, blocked cytokinesis, and caused EC senescence. Integrin-α5 and integrin-β1 interacted constitutively with TM4SF1, while integrin subunits αV, β3, and β5 interacted with TM4SF1 only after VEGF-A or thrombin stimulation. TM4SF1 knockdown substantially inhibited VEGF-A-induced angiogenesis in vivo.","method":"siRNA knockdown; immunostaining; co-immunoprecipitation; in vivo angiogenesis assay; live imaging","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, clean KD with defined cellular phenotypes (filopodia loss, cytokinesis block, senescence), and in vivo validation","pmids":["19351819"],"is_preprint":false},{"year":2011,"finding":"TM4SF1 is necessary for the formation of unusually long, thin EC projections termed 'nanopodia'; TM4SF1 localizes in a regularly spaced banded pattern in nanopodia; overexpression drives nanopodia formation even in fibroblasts. Mass spectrometry demonstrated TM4SF1 interacts with myosin-10 and β-actin. TM4SF1 acts as a molecular organizer that interacts with membrane and cytoskeleton-associated proteins to initiate nanopodia and facilitate cell polarization and migration.","method":"Adenoviral transduction; live-cell GFP imaging; immunostaining (light and electron microscopy); mass spectrometry interaction proteomics; siRNA knockdown","journal":"Angiogenesis","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (live imaging, EM, MS interactome, KD/OE), single lab with strong mechanistic depth","pmids":["21626280"],"is_preprint":false},{"year":2008,"finding":"TM4SF1 (L6-Ag) is abundant on the plasma membrane and on intracellular vesicles co-localizing with late endosomal/lysosomal markers (Lamp1/Lamp2, LBPA); it is targeted to late endocytic organelles predominantly via a biosynthetic pathway. On the plasma membrane it is associated with tetraspanin-enriched microdomains (TERM); all three predicted cytoplasmic regions are required for effective recruitment to TERM. Recruitment to TERM correlates with pro-migratory activity. TM4SF1 is ubiquitylated, and ubiquitylation is essential for its function in cell migration. TM4SF1 depletion selectively reduces surface expression of tetraspanins CD63 and CD82.","method":"siRNA knockdown; antibody internalization; live-imaging; subcellular fractionation; domain mapping; ubiquitylation assay; surface expression analysis","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal approaches (live imaging, fractionation, domain mapping, ubiquitylation assay, functional migration readout), moderate evidence strength","pmids":["18270265"],"is_preprint":false},{"year":2003,"finding":"TM4SF1 (TAL6) expression correlates with in vitro invasiveness of lung carcinoma cell lines; forced TM4SF1 expression on CL1-0 cells significantly increased in vitro invasiveness and decreased survival in an experimental metastasis model. Antibody-mediated clustering of TM4SF1 on the cell surface was required for the anti-invasive effect of anti-L6 antibody.","method":"Forced overexpression; Transwell invasion assay; SCID mouse experimental metastasis model; antibody clustering experiment","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — KO/OE with defined invasion/metastasis phenotype plus antibody clustering mechanistic requirement; single lab","pmids":["12855661"],"is_preprint":false},{"year":2017,"finding":"TM4SF1 co-localizes with DDR1 and physically interacts with DDR1 in pancreatic cancer cells; TM4SF1 silencing reduces DDR1 expression, impairs invadopodia formation and function, and decreases MMP2 and MMP9 expression; restoring DDR1 expression rescues these defects, establishing a TM4SF1→DDR1→MMP2/MMP9 axis promoting invadopodia-mediated invasion.","method":"Co-immunoprecipitation; double fluorescence immunostaining; siRNA knockdown; DDR1 rescue experiments; gelatin degradation invadopodia assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus epistatic rescue experiments; single lab, moderate evidence","pmids":["28368050"],"is_preprint":false},{"year":2020,"finding":"TM4SF1 promotes EMT and cancer stemness in colorectal cancer via the Wnt/β-catenin/c-Myc/SOX2 axis; TM4SF1 knockdown suppresses Wnt/β-catenin activation and reduces c-Myc binding to the SOX2 promoter; TM4SF1 modulates SOX2 expression in a Wnt/β-catenin-dependent manner.","method":"siRNA/shRNA knockdown; GSEA pathway analysis; Western blotting; chromatin immunoprecipitation (c-Myc binding to SOX2 promoter); xenograft mouse model; sphere formation assay","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus Western blot pathway validation plus in vivo model; single lab","pmids":["33153498"],"is_preprint":false},{"year":2019,"finding":"TM4SF1 promotes NSCLC proliferation, invasion, and chemo-resistance by regulating DDR1 expression and its downstream Akt/ERK/mTOR pathway; TM4SF1 silencing induced G2/M arrest and apoptosis, and sensitized cells to cisplatin and paclitaxel.","method":"siRNA knockdown; Western blotting; flow cytometry; MTS/clonogenic assay; Transwell assay","journal":"Respiratory research","confidence":"Medium","confidence_rationale":"Tier 3 — KD with defined phenotype and pathway readout; single lab, no direct protein interaction validation","pmids":["31142317"],"is_preprint":false},{"year":2019,"finding":"TM4SF1 physically interacts with DVL2 in hepatocellular carcinoma cells, strengthening the DVL2-Axin interaction and thereby activating Wnt/β-catenin signaling; TM4SF1 knockdown promotes β-catenin ubiquitination and reduces Axin2 and cyclin D1 expression.","method":"Co-immunoprecipitation; Western blotting; siRNA knockdown; ubiquitination assay; reporter gene assay","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP identifying binding partner plus ubiquitination and downstream signaling readouts; single lab","pmids":["31876386"],"is_preprint":false},{"year":2022,"finding":"TM4SF1 promotes esophageal squamous cell carcinoma cell adhesion, spreading, migration, and invasion in a laminin-dependent manner by directly interacting with integrin α6; the TM4SF1/integrin α6/FAK signaling axis mediates cell migration; inhibiting FAK or knocking down TM4SF1 attenuates migration and lung metastasis.","method":"Co-immunoprecipitation; siRNA knockdown; FAK inhibitor treatment; laminin-coated Transwell assay; in vivo lung metastasis model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP identifying integrin α6 as binding partner plus FAK pathway epistasis with in vivo validation; single lab","pmids":["35835740"],"is_preprint":false},{"year":2015,"finding":"TM4SF1 is internalized upon antibody binding; anti-TM4SF1 antibody-drug conjugates selectively kill TM4SF1-expressing tumor and endothelial cells in vitro and induce tumor regression in vivo, demonstrating that antibody-induced internalization of TM4SF1 is sufficient to deliver cytotoxic payload intracellularly.","method":"ADC internalization assay; cell viability assay; xenograft mouse tumor models","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 — direct internalization functional assay with in vivo efficacy data; single lab","pmids":["26089370"],"is_preprint":false},{"year":2017,"finding":"TM4SF1 regulates apoptosis, cell cycle progression, and ROS metabolism in bladder cancer cells via the PPARγ-SIRT1 feedback loop; knockdown of TM4SF1 upregulates ROS, induces cell cycle arrest and apoptosis, and these effects are reversed by the PPARγ antagonist GW9662 or the SIRT1 activator resveratrol.","method":"siRNA knockdown; flow cytometry (cell cycle and apoptosis); ROS measurement; pharmacological rescue with GW9662 and resveratrol; xenograft model","journal":"Cancer letters","confidence":"Low","confidence_rationale":"Tier 3 — pharmacological rescue supports pathway placement but no direct binding/interaction demonstrated; single lab","pmids":["29175458"],"is_preprint":false},{"year":2023,"finding":"TM4SF1 upregulates MYH9, which in turn activates the NOTCH pathway, promoting cancer stemness and lenvatinib resistance in hepatocellular carcinoma; protein mass spectrometry identified MYH9 as a downstream interactor of TM4SF1.","method":"Protein mass spectrometry; bioinformatics; Western blotting; in vitro and in vivo functional assays; lenvatinib-resistant cell line generation","journal":"Biology direct","confidence":"Low","confidence_rationale":"Tier 3 — MS identifies interaction but no direct Co-IP validation of TM4SF1-MYH9; single lab","pmids":["37069693"],"is_preprint":false},{"year":2021,"finding":"B7-H3 prevents DOX-induced cellular senescence through the AKT/TM4SF1/SIRT1 pathway in colorectal cancer; blocking TM4SF1 (downstream of AKT) reverses B7-H3-mediated resistance to senescence, positioning TM4SF1 as an effector in this anti-senescence signaling cascade.","method":"RNA-seq; Western blotting; pathway inhibition experiments; siRNA knockdown; senescence assay; in vivo xenograft","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 — TM4SF1 placed in pathway by RNA-seq + Western blot + knockdown; no direct TM4SF1 biochemical mechanism elucidated","pmids":["33958586"],"is_preprint":false}],"current_model":"TM4SF1 is a tetraspanin-like four-transmembrane plasma membrane glycoprotein that functions as a molecular organizer in endothelial cell filopodia/nanopodia (forming banded domains), constitutively interacts with integrins α5/β1 (and conditionally with αV/β3/β5 upon VEGF-A or thrombin stimulation), interacts with myosin-10 and β-actin to regulate actin-based cell protrusions, associates with tetraspanin-enriched microdomains via its cytoplasmic regions, undergoes ubiquitylation required for its pro-migratory function, is internalized via a biosynthetic route to late endosomes, and in cancer contexts signals through DDR1/MMP2/MMP9, Wnt/β-catenin/c-Myc/SOX2, and integrin α6/FAK axes to promote invasion, metastasis, and stemness."},"narrative":{"teleology":[{"year":1992,"claim":"Molecular cloning established TM4SF1 as a four-transmembrane surface glycoprotein with topology resembling the tetraspanin superfamily, providing the structural framework for all subsequent functional studies.","evidence":"Expression cloning in COS cells with antibody validation and hydropathy analysis","pmids":["1565644"],"confidence":"High","gaps":["No function assigned beyond predicted membrane topology","Post-translational modifications not characterized","Binding partners unknown"]},{"year":2003,"claim":"Forced expression and antibody-clustering experiments demonstrated that TM4SF1 directly enhances tumor cell invasiveness and experimental metastasis, establishing it as a functionally pro-invasive membrane protein.","evidence":"TM4SF1 overexpression in lung carcinoma cells; Transwell invasion assays; SCID mouse metastasis model; antibody clustering","pmids":["12855661"],"confidence":"Medium","gaps":["Downstream signaling pathways uncharacterized","Mechanism by which antibody clustering blocks invasion unknown","Endogenous loss-of-function data not yet available for cancer context"]},{"year":2008,"claim":"Subcellular trafficking and post-translational modification studies revealed that TM4SF1 is recruited to tetraspanin-enriched microdomains via its cytoplasmic domains, is ubiquitylated, and that both TERM association and ubiquitylation are required for its pro-migratory activity.","evidence":"Antibody internalization tracking, subcellular fractionation, domain-deletion mapping, ubiquitylation assays, and migration readouts in multiple cell lines","pmids":["18270265"],"confidence":"High","gaps":["E3 ligase mediating TM4SF1 ubiquitylation not identified","Structural basis for TERM recruitment unknown","Relationship between late-endosomal targeting and signaling unclear"]},{"year":2009,"claim":"Identification of integrin partners and in vivo angiogenesis requirement showed that TM4SF1 constitutively binds integrins α5/β1, conditionally binds αV/β3/β5 upon VEGF-A or thrombin stimulation, and is essential for endothelial filopodia formation, cytokinesis, and VEGF-A–driven angiogenesis.","evidence":"Reciprocal co-immunoprecipitation; siRNA knockdown; live imaging; in vivo Matrigel angiogenesis assay","pmids":["19351819"],"confidence":"High","gaps":["Direct versus indirect integrin interaction not resolved","How VEGF-A/thrombin remodel the TM4SF1 interactome mechanistically unknown","Cytokinesis failure mechanism not detailed"]},{"year":2011,"claim":"Discovery of nanopodia as TM4SF1-organized structures, together with identification of myosin-10 and β-actin as interaction partners, established TM4SF1 as a membrane–cytoskeleton organizer that initiates actin-based cell protrusions and polarized migration.","evidence":"Adenoviral overexpression; live-cell GFP imaging; electron microscopy; interaction proteomics (mass spectrometry); siRNA knockdown in endothelial cells and fibroblasts","pmids":["21626280"],"confidence":"High","gaps":["Structural basis of periodic banding along nanopodia unresolved","Whether myosin-10 interaction is direct or via actin scaffolding unknown","In vivo nanopodia relevance beyond EC not demonstrated"]},{"year":2017,"claim":"In pancreatic cancer, TM4SF1 was shown to physically interact with DDR1 and to drive invadopodia formation via a TM4SF1→DDR1→MMP2/MMP9 axis, extending its role from endothelial protrusions to cancer cell invasion machinery.","evidence":"Co-immunoprecipitation; DDR1 rescue after TM4SF1 knockdown; gelatin degradation invadopodia assay","pmids":["28368050"],"confidence":"Medium","gaps":["Whether DDR1 interaction is direct or bridged by integrins unclear","Not tested in non-pancreatic cancer contexts at the time","Collagen dependence of the TM4SF1–DDR1 axis not examined"]},{"year":2019,"claim":"Two studies expanded TM4SF1's signaling repertoire: interaction with DVL2 activates Wnt/β-catenin signaling in hepatocellular carcinoma, and TM4SF1-dependent DDR1 regulation was linked to Akt/ERK/mTOR signaling and chemoresistance in NSCLC.","evidence":"Co-immunoprecipitation of TM4SF1–DVL2; ubiquitination of β-catenin upon TM4SF1 knockdown; pathway inhibition in NSCLC cells","pmids":["31876386","31142317"],"confidence":"Medium","gaps":["Direct binding interface between TM4SF1 and DVL2 not mapped","DDR1-Akt/ERK connection in NSCLC based on Western blot without interaction data","Whether Wnt activation and DDR1 regulation are independent or convergent pathways unknown"]},{"year":2020,"claim":"TM4SF1 was shown to drive EMT and cancer stemness in colorectal cancer through Wnt/β-catenin–dependent c-Myc activation, with c-Myc binding the SOX2 promoter, establishing a transcriptional mechanism linking TM4SF1 to stemness reprogramming.","evidence":"ChIP for c-Myc at SOX2 promoter; shRNA knockdown; sphere formation; xenograft model","pmids":["33153498"],"confidence":"Medium","gaps":["How TM4SF1 activates Wnt/β-catenin upstream not mechanistically resolved","Direct versus indirect regulation of c-Myc/SOX2 not distinguished","Single cancer type examined"]},{"year":2022,"claim":"Identification of integrin α6 as a direct TM4SF1 partner and the TM4SF1/integrin α6/FAK axis as a driver of laminin-dependent migration and lung metastasis extended the integrin-partnership model beyond endothelial cells into epithelial cancer invasion.","evidence":"Co-immunoprecipitation; FAK inhibitor epistasis; laminin-coated Transwell assay; in vivo lung metastasis model in esophageal squamous cell carcinoma","pmids":["35835740"],"confidence":"Medium","gaps":["Whether integrin α6 partnership is distinct from α5/β1 in a common complex unknown","Laminin isoform specificity not examined","Structural basis of TM4SF1–integrin interaction unresolved"]},{"year":null,"claim":"The structural basis of TM4SF1's interactions with integrins and cytoskeletal partners, the identity of its E3 ubiquitin ligase, and the mechanism by which it selectively activates multiple signaling pathways in different cellular contexts remain unknown.","evidence":"","pmids":[],"confidence":"High","gaps":["No atomic-resolution structure of TM4SF1 or any TM4SF1–partner complex","E3 ligase responsible for ubiquitylation not identified","Whether TM4SF1 functions as a passive scaffold or has intrinsic signaling activity unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,3,5,8,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,2,3]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[3]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,5,6,7,8,9]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[1,9]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[5,9]}],"complexes":["tetraspanin-enriched microdomains (TERM)"],"partners":["ITGA5","ITGB1","MYO10","DDR1","DVL2","ITGA6","ACTB","ITGB3"],"other_free_text":[]},"mechanistic_narrative":"TM4SF1 is a tetraspanin-like four-transmembrane glycoprotein that functions as a molecular organizer of membrane–cytoskeleton interactions to drive cell protrusion, polarization, migration, and invasion. On endothelial cells it localizes in a periodic banded pattern along filopodia and nanopodia, constitutively interacts with integrins α5/β1 (and conditionally with αV/β3/β5 upon VEGF-A or thrombin stimulation), and associates with myosin-10 and β-actin; knockdown abolishes nanopodia formation, blocks cytokinesis, induces senescence, and inhibits VEGF-A–driven angiogenesis in vivo [PMID:19351819, PMID:21626280]. TM4SF1 resides in tetraspanin-enriched microdomains via its cytoplasmic domains, undergoes ubiquitylation required for pro-migratory function, and is internalized through a biosynthetic route to late endosomes [PMID:18270265]. In cancer cells, TM4SF1 promotes invasion and metastasis by physically engaging DDR1 to sustain MMP2/MMP9 expression and invadopodia function, by interacting with DVL2 to activate Wnt/β-catenin signaling, and by coupling with integrin α6 to activate FAK-dependent migration [PMID:28368050, PMID:31876386, PMID:35835740]."},"prefetch_data":{"uniprot":{"accession":"P30408","full_name":"Transmembrane 4 L6 family member 1","aliases":["Membrane component chromosome 3 surface marker 1","Tumor-associated antigen L6"],"length_aa":202,"mass_kda":21.6,"function":"","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/P30408/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TM4SF1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TM4SF1","total_profiled":1310},"omim":[{"mim_id":"606567","title":"TRANSMEMBRANE 4 SUPERFAMILY, MEMBER 4; TM4SF4","url":"https://www.omim.org/entry/606567"},{"mim_id":"604657","title":"TRANSMEMBRANE 4 SUPERFAMILY, MEMBER 5; TM4SF5","url":"https://www.omim.org/entry/604657"},{"mim_id":"191155","title":"TRANSMEMBRANE 4 L6 FAMILY, MEMBER 1; TM4SF1","url":"https://www.omim.org/entry/191155"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TM4SF1"},"hgnc":{"alias_symbol":["L6"],"prev_symbol":["M3S1"]},"alphafold":{"accession":"P30408","domains":[{"cath_id":"-","chopping":"3-72_82-202","consensus_level":"high","plddt":83.5688,"start":3,"end":202}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P30408","model_url":"https://alphafold.ebi.ac.uk/files/AF-P30408-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P30408-F1-predicted_aligned_error_v6.png","plddt_mean":80.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TM4SF1","jax_strain_url":"https://www.jax.org/strain/search?query=TM4SF1"},"sequence":{"accession":"P30408","fasta_url":"https://rest.uniprot.org/uniprotkb/P30408.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P30408/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P30408"}},"corpus_meta":[{"pmid":"10330141","id":"PMC_10330141","title":"Protein kinase B/Akt participates in 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Integrin-α5 and integrin-β1 interacted constitutively with TM4SF1, while integrin subunits αV, β3, and β5 interacted with TM4SF1 only after VEGF-A or thrombin stimulation. TM4SF1 knockdown substantially inhibited VEGF-A-induced angiogenesis in vivo.\",\n      \"method\": \"siRNA knockdown; immunostaining; co-immunoprecipitation; in vivo angiogenesis assay; live imaging\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, clean KD with defined cellular phenotypes (filopodia loss, cytokinesis block, senescence), and in vivo validation\",\n      \"pmids\": [\"19351819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TM4SF1 is necessary for the formation of unusually long, thin EC projections termed 'nanopodia'; TM4SF1 localizes in a regularly spaced banded pattern in nanopodia; overexpression drives nanopodia formation even in fibroblasts. Mass spectrometry demonstrated TM4SF1 interacts with myosin-10 and β-actin. TM4SF1 acts as a molecular organizer that interacts with membrane and cytoskeleton-associated proteins to initiate nanopodia and facilitate cell polarization and migration.\",\n      \"method\": \"Adenoviral transduction; live-cell GFP imaging; immunostaining (light and electron microscopy); mass spectrometry interaction proteomics; siRNA knockdown\",\n      \"journal\": \"Angiogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (live imaging, EM, MS interactome, KD/OE), single lab with strong mechanistic depth\",\n      \"pmids\": [\"21626280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TM4SF1 (L6-Ag) is abundant on the plasma membrane and on intracellular vesicles co-localizing with late endosomal/lysosomal markers (Lamp1/Lamp2, LBPA); it is targeted to late endocytic organelles predominantly via a biosynthetic pathway. On the plasma membrane it is associated with tetraspanin-enriched microdomains (TERM); all three predicted cytoplasmic regions are required for effective recruitment to TERM. Recruitment to TERM correlates with pro-migratory activity. TM4SF1 is ubiquitylated, and ubiquitylation is essential for its function in cell migration. TM4SF1 depletion selectively reduces surface expression of tetraspanins CD63 and CD82.\",\n      \"method\": \"siRNA knockdown; antibody internalization; live-imaging; subcellular fractionation; domain mapping; ubiquitylation assay; surface expression analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches (live imaging, fractionation, domain mapping, ubiquitylation assay, functional migration readout), moderate evidence strength\",\n      \"pmids\": [\"18270265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TM4SF1 (TAL6) expression correlates with in vitro invasiveness of lung carcinoma cell lines; forced TM4SF1 expression on CL1-0 cells significantly increased in vitro invasiveness and decreased survival in an experimental metastasis model. Antibody-mediated clustering of TM4SF1 on the cell surface was required for the anti-invasive effect of anti-L6 antibody.\",\n      \"method\": \"Forced overexpression; Transwell invasion assay; SCID mouse experimental metastasis model; antibody clustering experiment\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO/OE with defined invasion/metastasis phenotype plus antibody clustering mechanistic requirement; single lab\",\n      \"pmids\": [\"12855661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TM4SF1 co-localizes with DDR1 and physically interacts with DDR1 in pancreatic cancer cells; TM4SF1 silencing reduces DDR1 expression, impairs invadopodia formation and function, and decreases MMP2 and MMP9 expression; restoring DDR1 expression rescues these defects, establishing a TM4SF1→DDR1→MMP2/MMP9 axis promoting invadopodia-mediated invasion.\",\n      \"method\": \"Co-immunoprecipitation; double fluorescence immunostaining; siRNA knockdown; DDR1 rescue experiments; gelatin degradation invadopodia assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus epistatic rescue experiments; single lab, moderate evidence\",\n      \"pmids\": [\"28368050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TM4SF1 promotes EMT and cancer stemness in colorectal cancer via the Wnt/β-catenin/c-Myc/SOX2 axis; TM4SF1 knockdown suppresses Wnt/β-catenin activation and reduces c-Myc binding to the SOX2 promoter; TM4SF1 modulates SOX2 expression in a Wnt/β-catenin-dependent manner.\",\n      \"method\": \"siRNA/shRNA knockdown; GSEA pathway analysis; Western blotting; chromatin immunoprecipitation (c-Myc binding to SOX2 promoter); xenograft mouse model; sphere formation assay\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus Western blot pathway validation plus in vivo model; single lab\",\n      \"pmids\": [\"33153498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TM4SF1 promotes NSCLC proliferation, invasion, and chemo-resistance by regulating DDR1 expression and its downstream Akt/ERK/mTOR pathway; TM4SF1 silencing induced G2/M arrest and apoptosis, and sensitized cells to cisplatin and paclitaxel.\",\n      \"method\": \"siRNA knockdown; Western blotting; flow cytometry; MTS/clonogenic assay; Transwell assay\",\n      \"journal\": \"Respiratory research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — KD with defined phenotype and pathway readout; single lab, no direct protein interaction validation\",\n      \"pmids\": [\"31142317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TM4SF1 physically interacts with DVL2 in hepatocellular carcinoma cells, strengthening the DVL2-Axin interaction and thereby activating Wnt/β-catenin signaling; TM4SF1 knockdown promotes β-catenin ubiquitination and reduces Axin2 and cyclin D1 expression.\",\n      \"method\": \"Co-immunoprecipitation; Western blotting; siRNA knockdown; ubiquitination assay; reporter gene assay\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP identifying binding partner plus ubiquitination and downstream signaling readouts; single lab\",\n      \"pmids\": [\"31876386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TM4SF1 promotes esophageal squamous cell carcinoma cell adhesion, spreading, migration, and invasion in a laminin-dependent manner by directly interacting with integrin α6; the TM4SF1/integrin α6/FAK signaling axis mediates cell migration; inhibiting FAK or knocking down TM4SF1 attenuates migration and lung metastasis.\",\n      \"method\": \"Co-immunoprecipitation; siRNA knockdown; FAK inhibitor treatment; laminin-coated Transwell assay; in vivo lung metastasis model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP identifying integrin α6 as binding partner plus FAK pathway epistasis with in vivo validation; single lab\",\n      \"pmids\": [\"35835740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TM4SF1 is internalized upon antibody binding; anti-TM4SF1 antibody-drug conjugates selectively kill TM4SF1-expressing tumor and endothelial cells in vitro and induce tumor regression in vivo, demonstrating that antibody-induced internalization of TM4SF1 is sufficient to deliver cytotoxic payload intracellularly.\",\n      \"method\": \"ADC internalization assay; cell viability assay; xenograft mouse tumor models\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct internalization functional assay with in vivo efficacy data; single lab\",\n      \"pmids\": [\"26089370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TM4SF1 regulates apoptosis, cell cycle progression, and ROS metabolism in bladder cancer cells via the PPARγ-SIRT1 feedback loop; knockdown of TM4SF1 upregulates ROS, induces cell cycle arrest and apoptosis, and these effects are reversed by the PPARγ antagonist GW9662 or the SIRT1 activator resveratrol.\",\n      \"method\": \"siRNA knockdown; flow cytometry (cell cycle and apoptosis); ROS measurement; pharmacological rescue with GW9662 and resveratrol; xenograft model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — pharmacological rescue supports pathway placement but no direct binding/interaction demonstrated; single lab\",\n      \"pmids\": [\"29175458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TM4SF1 upregulates MYH9, which in turn activates the NOTCH pathway, promoting cancer stemness and lenvatinib resistance in hepatocellular carcinoma; protein mass spectrometry identified MYH9 as a downstream interactor of TM4SF1.\",\n      \"method\": \"Protein mass spectrometry; bioinformatics; Western blotting; in vitro and in vivo functional assays; lenvatinib-resistant cell line generation\",\n      \"journal\": \"Biology direct\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — MS identifies interaction but no direct Co-IP validation of TM4SF1-MYH9; single lab\",\n      \"pmids\": [\"37069693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"B7-H3 prevents DOX-induced cellular senescence through the AKT/TM4SF1/SIRT1 pathway in colorectal cancer; blocking TM4SF1 (downstream of AKT) reverses B7-H3-mediated resistance to senescence, positioning TM4SF1 as an effector in this anti-senescence signaling cascade.\",\n      \"method\": \"RNA-seq; Western blotting; pathway inhibition experiments; siRNA knockdown; senescence assay; in vivo xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — TM4SF1 placed in pathway by RNA-seq + Western blot + knockdown; no direct TM4SF1 biochemical mechanism elucidated\",\n      \"pmids\": [\"33958586\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TM4SF1 is a tetraspanin-like four-transmembrane plasma membrane glycoprotein that functions as a molecular organizer in endothelial cell filopodia/nanopodia (forming banded domains), constitutively interacts with integrins α5/β1 (and conditionally with αV/β3/β5 upon VEGF-A or thrombin stimulation), interacts with myosin-10 and β-actin to regulate actin-based cell protrusions, associates with tetraspanin-enriched microdomains via its cytoplasmic regions, undergoes ubiquitylation required for its pro-migratory function, is internalized via a biosynthetic route to late endosomes, and in cancer contexts signals through DDR1/MMP2/MMP9, Wnt/β-catenin/c-Myc/SOX2, and integrin α6/FAK axes to promote invasion, metastasis, and stemness.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TM4SF1 is a tetraspanin-like four-transmembrane glycoprotein that functions as a molecular organizer of membrane–cytoskeleton interactions to drive cell protrusion, polarization, migration, and invasion. On endothelial cells it localizes in a periodic banded pattern along filopodia and nanopodia, constitutively interacts with integrins α5/β1 (and conditionally with αV/β3/β5 upon VEGF-A or thrombin stimulation), and associates with myosin-10 and β-actin; knockdown abolishes nanopodia formation, blocks cytokinesis, induces senescence, and inhibits VEGF-A–driven angiogenesis in vivo [PMID:19351819, PMID:21626280]. TM4SF1 resides in tetraspanin-enriched microdomains via its cytoplasmic domains, undergoes ubiquitylation required for pro-migratory function, and is internalized through a biosynthetic route to late endosomes [PMID:18270265]. In cancer cells, TM4SF1 promotes invasion and metastasis by physically engaging DDR1 to sustain MMP2/MMP9 expression and invadopodia function, by interacting with DVL2 to activate Wnt/β-catenin signaling, and by coupling with integrin α6 to activate FAK-dependent migration [PMID:28368050, PMID:31876386, PMID:35835740].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Molecular cloning established TM4SF1 as a four-transmembrane surface glycoprotein with topology resembling the tetraspanin superfamily, providing the structural framework for all subsequent functional studies.\",\n      \"evidence\": \"Expression cloning in COS cells with antibody validation and hydropathy analysis\",\n      \"pmids\": [\"1565644\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No function assigned beyond predicted membrane topology\",\n        \"Post-translational modifications not characterized\",\n        \"Binding partners unknown\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Forced expression and antibody-clustering experiments demonstrated that TM4SF1 directly enhances tumor cell invasiveness and experimental metastasis, establishing it as a functionally pro-invasive membrane protein.\",\n      \"evidence\": \"TM4SF1 overexpression in lung carcinoma cells; Transwell invasion assays; SCID mouse metastasis model; antibody clustering\",\n      \"pmids\": [\"12855661\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Downstream signaling pathways uncharacterized\",\n        \"Mechanism by which antibody clustering blocks invasion unknown\",\n        \"Endogenous loss-of-function data not yet available for cancer context\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Subcellular trafficking and post-translational modification studies revealed that TM4SF1 is recruited to tetraspanin-enriched microdomains via its cytoplasmic domains, is ubiquitylated, and that both TERM association and ubiquitylation are required for its pro-migratory activity.\",\n      \"evidence\": \"Antibody internalization tracking, subcellular fractionation, domain-deletion mapping, ubiquitylation assays, and migration readouts in multiple cell lines\",\n      \"pmids\": [\"18270265\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"E3 ligase mediating TM4SF1 ubiquitylation not identified\",\n        \"Structural basis for TERM recruitment unknown\",\n        \"Relationship between late-endosomal targeting and signaling unclear\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identification of integrin partners and in vivo angiogenesis requirement showed that TM4SF1 constitutively binds integrins α5/β1, conditionally binds αV/β3/β5 upon VEGF-A or thrombin stimulation, and is essential for endothelial filopodia formation, cytokinesis, and VEGF-A–driven angiogenesis.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation; siRNA knockdown; live imaging; in vivo Matrigel angiogenesis assay\",\n      \"pmids\": [\"19351819\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct versus indirect integrin interaction not resolved\",\n        \"How VEGF-A/thrombin remodel the TM4SF1 interactome mechanistically unknown\",\n        \"Cytokinesis failure mechanism not detailed\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovery of nanopodia as TM4SF1-organized structures, together with identification of myosin-10 and β-actin as interaction partners, established TM4SF1 as a membrane–cytoskeleton organizer that initiates actin-based cell protrusions and polarized migration.\",\n      \"evidence\": \"Adenoviral overexpression; live-cell GFP imaging; electron microscopy; interaction proteomics (mass spectrometry); siRNA knockdown in endothelial cells and fibroblasts\",\n      \"pmids\": [\"21626280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of periodic banding along nanopodia unresolved\",\n        \"Whether myosin-10 interaction is direct or via actin scaffolding unknown\",\n        \"In vivo nanopodia relevance beyond EC not demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"In pancreatic cancer, TM4SF1 was shown to physically interact with DDR1 and to drive invadopodia formation via a TM4SF1→DDR1→MMP2/MMP9 axis, extending its role from endothelial protrusions to cancer cell invasion machinery.\",\n      \"evidence\": \"Co-immunoprecipitation; DDR1 rescue after TM4SF1 knockdown; gelatin degradation invadopodia assay\",\n      \"pmids\": [\"28368050\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether DDR1 interaction is direct or bridged by integrins unclear\",\n        \"Not tested in non-pancreatic cancer contexts at the time\",\n        \"Collagen dependence of the TM4SF1–DDR1 axis not examined\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Two studies expanded TM4SF1's signaling repertoire: interaction with DVL2 activates Wnt/β-catenin signaling in hepatocellular carcinoma, and TM4SF1-dependent DDR1 regulation was linked to Akt/ERK/mTOR signaling and chemoresistance in NSCLC.\",\n      \"evidence\": \"Co-immunoprecipitation of TM4SF1–DVL2; ubiquitination of β-catenin upon TM4SF1 knockdown; pathway inhibition in NSCLC cells\",\n      \"pmids\": [\"31876386\", \"31142317\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct binding interface between TM4SF1 and DVL2 not mapped\",\n        \"DDR1-Akt/ERK connection in NSCLC based on Western blot without interaction data\",\n        \"Whether Wnt activation and DDR1 regulation are independent or convergent pathways unknown\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"TM4SF1 was shown to drive EMT and cancer stemness in colorectal cancer through Wnt/β-catenin–dependent c-Myc activation, with c-Myc binding the SOX2 promoter, establishing a transcriptional mechanism linking TM4SF1 to stemness reprogramming.\",\n      \"evidence\": \"ChIP for c-Myc at SOX2 promoter; shRNA knockdown; sphere formation; xenograft model\",\n      \"pmids\": [\"33153498\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How TM4SF1 activates Wnt/β-catenin upstream not mechanistically resolved\",\n        \"Direct versus indirect regulation of c-Myc/SOX2 not distinguished\",\n        \"Single cancer type examined\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of integrin α6 as a direct TM4SF1 partner and the TM4SF1/integrin α6/FAK axis as a driver of laminin-dependent migration and lung metastasis extended the integrin-partnership model beyond endothelial cells into epithelial cancer invasion.\",\n      \"evidence\": \"Co-immunoprecipitation; FAK inhibitor epistasis; laminin-coated Transwell assay; in vivo lung metastasis model in esophageal squamous cell carcinoma\",\n      \"pmids\": [\"35835740\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether integrin α6 partnership is distinct from α5/β1 in a common complex unknown\",\n        \"Laminin isoform specificity not examined\",\n        \"Structural basis of TM4SF1–integrin interaction unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of TM4SF1's interactions with integrins and cytoskeletal partners, the identity of its E3 ubiquitin ligase, and the mechanism by which it selectively activates multiple signaling pathways in different cellular contexts remain unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No atomic-resolution structure of TM4SF1 or any TM4SF1–partner complex\",\n        \"E3 ligase responsible for ubiquitylation not identified\",\n        \"Whether TM4SF1 functions as a passive scaffold or has intrinsic signaling activity unresolved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 3, 5, 8, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 5, 6, 7, 8, 9]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [5, 9]}\n    ],\n    \"complexes\": [\n      \"tetraspanin-enriched microdomains (TERM)\"\n    ],\n    \"partners\": [\n      \"ITGA5\",\n      \"ITGB1\",\n      \"MYO10\",\n      \"DDR1\",\n      \"DVL2\",\n      \"ITGA6\",\n      \"ACTB\",\n      \"ITGB3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}