{"gene":"TM4SF1","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2009,"finding":"TM4SF1 knockdown in endothelial cells prevented filopodia formation, inhibited cell mobility, blocked cytokinesis, and rendered cells senescent. Integrin-α5 and integrin-β1 subunits interacted constitutively with TM4SF1, whereas integrin subunits αV, β3, β5 interacted with TM4SF1 only after VEGF-A or thrombin stimulation. TM4SF1 knockdown substantially inhibited maturation of VEGF-A164-induced angiogenesis in vivo.","method":"siRNA knockdown, Co-immunoprecipitation, in vivo tumor angiogenesis model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP for integrin interactions, clean KD with multiple defined cellular phenotypes (filopodia, cytokinesis, senescence), in vivo validation, single lab with orthogonal methods","pmids":["19351819"],"is_preprint":false},{"year":2011,"finding":"TM4SF1 is necessary for formation of unusually long, thin (~100–300 nm wide), F-actin-poor endothelial cell projections called 'nanopodia'. TM4SF1 localizes in a regularly spaced banded pattern within nanopodia. Live cell imaging showed nanopodia are projected during migration and intercellular interactions. Mass spectrometry demonstrated TM4SF1 interacted with myosin-10 and β-actin. When TM4SF1 was overexpressed (~400 copies/cell vs normal ~90), cells formed more/longer nanopodia but could not polarize or migrate. When expressed at EC-like levels in fibroblasts (~5 normally), cells formed TM4SF1-banded nanopodia and EC-like lamellipodia.","method":"Live cell imaging (GFP-transduced HUVEC), adenoviral overexpression, immunostaining (light and electron microscopy), mass spectrometry pulldown","journal":"Angiogenesis","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (live imaging, EM, MS-based interaction identification, gain/loss-of-function), replicated across cell types in single rigorous study","pmids":["21626280"],"is_preprint":false},{"year":2011,"finding":"TM4SF1 is a direct transcriptional target of the androgen receptor (AR); a functional androgen response element was identified in the TM4SF1 promoter by chromatin immunoprecipitation. TM4SF1 mediates prostate cancer cell motility; siRNA knockdown inhibited cell migration. In normal prostate epithelium TM4SF1 localizes apically, whereas in prostate cancer cells it localizes predominantly in the cytoplasm.","method":"Chromatin immunoprecipitation (ChIP), transcriptomic analysis, siRNA knockdown, wound healing assay, immunohistochemistry","journal":"The Prostate","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP directly validated AR binding to TM4SF1 promoter combined with transcriptomics and functional KD migration assay, single lab with multiple orthogonal methods","pmids":["21656834"],"is_preprint":false},{"year":2014,"finding":"Monoclonal antibodies against TM4SF1's extracellular loop-2 (EL2) domain disrupted human tumor vasculature in a humanized Matrigel plug model and eliminated incorporated PC3 prostate cancer cells, validating TM4SF1 as a therapeutic vascular target.","method":"Monoclonal antibody generation and in vivo humanized vessel model (ECFC/MSC Matrigel implants in nude mice)","journal":"Angiogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo functional validation with defined antibody reagent, single lab, functional readout but no direct mechanistic assay of the interaction","pmids":["24986520"],"is_preprint":false},{"year":2015,"finding":"TM4SF1 is internalized from the plasma membrane of endothelial cells via uncoated cytoplasmic vesicles in a dynamin-dependent, clathrin-independent manner, then transported along microtubules through the cytoplasm and through nuclear pores into the nucleus, as demonstrated by immuno-nanogold transmission electron microscopy.","method":"Immuno-nanogold transmission electron microscopy, immunofluorescence microscopy, dynamin inhibition","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — high-resolution immuno-EM with mechanistic detail (dynamin-dependent, clathrin-independent, microtubule-mediated nuclear entry), multiple imaging methods in single rigorous study","pmids":["26241677"],"is_preprint":false},{"year":2015,"finding":"TM4SF1 promotes gemcitabine resistance in pancreatic cancer cells by upregulating multidrug resistance genes ABCB1 and ABCC1; silencing TM4SF1 increased gemcitabine sensitivity both in vitro and in vivo in orthotopic tumor models.","method":"siRNA knockdown, shRNA lentiviral knockdown, qRT-PCR for MDR genes, cell proliferation/apoptosis assays, orthotopic tumor model with bioluminescent imaging","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined MDR gene expression readout, both in vitro and in vivo, single lab","pmids":["26709920"],"is_preprint":false},{"year":2015,"finding":"TM4SF1 promotes breast cancer cell migration via the PI3K/AKT/mTOR pathway; silencing TM4SF1 decreased phosphorylated AKT, p-mTOR, and p-P70S6K levels, while overexpression increased cell migration and decreased apoptosis.","method":"siRNA knockdown, plasmid overexpression, Western blotting of PI3K/AKT/mTOR pathway components, Matrigel migration assay, flow cytometry","journal":"International journal of clinical and experimental pathology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Western blot pathway readout with KD/OE, single lab, single method per endpoint, no direct interaction demonstration","pmids":["26464650"],"is_preprint":false},{"year":2016,"finding":"TM4SF1 knockdown in pancreatic cancer cells reduced migration and invasion and downregulated the expression and enzymatic activity of MMP-2 and MMP-9, as measured by gelatin zymography.","method":"siRNA/shRNA knockdown, Transwell migration/invasion assay, gelatin zymography, Western blot, orthotopic tumor model","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with functional migration assay and direct enzymatic activity measurement by zymography, in vivo metastasis validation, single lab","pmids":["27459514"],"is_preprint":false},{"year":2017,"finding":"TM4SF1 co-localizes with DDR1 and physically interacts with DDR1 (by co-immunoprecipitation and double immunofluorescence) in pancreatic cancer cells. TM4SF1 silencing reduced DDR1 expression, impaired invadopodia formation and function, and decreased MMP2 and MMP9 expression; restoring DDR1 rescued these effects, placing TM4SF1 upstream of DDR1-MMP2/9 in an invadopodia-promoting pathway.","method":"Co-immunoprecipitation, double immunofluorescence co-staining, siRNA knockdown, rescue overexpression of DDR1, invadopodia formation assay, qRT-PCR","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP + co-localization + epistasis rescue experiment establishing TM4SF1→DDR1→MMP2/9 pathway, multiple orthogonal methods in single study","pmids":["28368050"],"is_preprint":false},{"year":2017,"finding":"TM4SF1 regulates apoptosis, cell cycle, and ROS metabolism in bladder cancer cells via the PPARγ-SIRT1 feedback loop; knockdown of TM4SF1 induced cell cycle arrest and apoptosis associated with ROS upregulation, and these effects were reversed by GW9662 (PPARγ antagonist) or resveratrol (SIRT1 activator).","method":"siRNA knockdown, flow cytometry (cell cycle/apoptosis), ROS measurement, pharmacological rescue with GW9662 and resveratrol, in vivo xenograft","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis with two reagents plus in vitro/in vivo KD, single lab, mechanistic pathway placement via rescue experiments","pmids":["29175458"],"is_preprint":false},{"year":2019,"finding":"TM4SF1 promotes non-small cell lung cancer proliferation, invasion, and chemo-resistance by regulating the expression of DDR1 and its downstream Akt/ERK/mTOR pathway; silencing TM4SF1 reduced DDR1 expression and Akt/ERK/mTOR signaling, enhancing sensitivity to cisplatin and paclitaxel.","method":"siRNA knockdown, Western blotting (DDR1, p-AKT, p-ERK, mTOR), MTS/clonogenic assay, Transwell assay, flow cytometry, RT-PCR","journal":"Respiratory research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD with pathway protein readout, multiple functional assays, single lab, no direct interaction or rescue validation of DDR1 axis","pmids":["31142317"],"is_preprint":false},{"year":2019,"finding":"TM4SF1 is an interacting partner of DVL2 in hepatocellular carcinoma; TM4SF1 overexpression strengthened the DVL2-Axin interaction, leading to activation of Wnt/β-catenin signaling (increased Axin2 and cyclin D1 expression and decreased β-catenin ubiquitination). TM4SF1 expression was induced by Kras signaling.","method":"Co-immunoprecipitation (TM4SF1-DVL2 and DVL2-Axin interactions), Western blotting, overexpression and knockdown, ubiquitination assay, Kras pathway analysis","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating TM4SF1-DVL2 physical interaction with functional pathway readout (β-catenin ubiquitination, target gene expression), single lab with multiple methods","pmids":["31876386"],"is_preprint":false},{"year":2019,"finding":"TM4SF1 overexpression in prostate cancer cells activated ERK1/2 signaling; suppression of ERK1/2 reversed the pro-migratory, pro-invasive, and pro-proliferative effects of TM4SF1 overexpression, placing TM4SF1 upstream of ERK1/2.","method":"Plasmid overexpression, pharmacological ERK1/2 inhibition, Transwell assay, wound-healing assay, colony formation, EdU staining, Western blotting","journal":"Journal of B.U.ON.","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological epistasis without direct interaction proof, single lab, single pathway assay","pmids":["31983129"],"is_preprint":false},{"year":2020,"finding":"TM4SF1 modulates SOX2 expression in a Wnt/β-catenin activation-dependent manner in colorectal cancer; TM4SF1 knockdown reduced c-Myc expression and c-Myc binding to the SOX2 gene promoter, suppressing EMT (TGF-β1-mediated) and cancer stemness.","method":"siRNA knockdown, GSEA pathway analysis, Western blotting, ChIP (c-Myc binding to SOX2 promoter), TGF-β1 stimulation, sphere formation assay, xenograft mouse model","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP directly showed c-Myc promoter binding change, supported by Western blot pathway readout and in vivo validation, single lab with multiple orthogonal methods","pmids":["33153498"],"is_preprint":false},{"year":2020,"finding":"TM4SF1 regulates YAP-TEAD interaction in non-small cell lung cancer; TM4SF1 modulated the YAP-TEAD protein-protein interaction and downstream target gene levels, as shown by Co-IP; sh-YAP or YAP-TEAD inhibitor (Peptide 17) reversed TM4SF1-mediated oncogenic effects.","method":"Co-immunoprecipitation, siRNA/shRNA knockdown, plasmid overexpression, pharmacological inhibition (Peptide 17), Western blotting, xenograft tumor model","journal":"European review for medical and pharmacological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP showing TM4SF1-regulated YAP-TEAD interaction with epistasis via inhibitor rescue, single lab","pmids":["32141552"],"is_preprint":false},{"year":2021,"finding":"B7-H3 prevents cellular senescence in colorectal cancer through the AKT/TM4SF1/SIRT1 pathway; blocking this pathway reversed B7-H3-induced resistance to DOX-induced senescence, placing TM4SF1 downstream of AKT and upstream of SIRT1.","method":"RNA-seq, Western blotting, siRNA knockdown/overexpression of B7-H3, pathway blockade experiments, in vivo tumor model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq pathway discovery followed by functional pathway blockade epistasis, in vitro and in vivo, single lab","pmids":["33958586"],"is_preprint":false},{"year":2022,"finding":"TM4SF1 promotes esophageal squamous cell carcinoma cell adhesion, spreading, migration, and invasion in a laminin-dependent manner by physically interacting with integrin α6; the TM4SF1/integrin α6/FAK signaling axis mediates cell migration under laminin-coating conditions, and FAK inhibition or TM4SF1 knockdown attenuated migration and lung metastasis.","method":"Co-immunoprecipitation, immunofluorescence co-staining, siRNA knockdown, FAK inhibitor treatment, Transwell migration/invasion assay, in vivo lung metastasis model","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating direct TM4SF1-integrin α6 physical interaction with pharmacological and genetic epistasis to define FAK pathway, in vivo validation, multiple orthogonal methods","pmids":["35835740"],"is_preprint":false},{"year":2023,"finding":"TM4SF1 upregulates MYH9 expression, which activates the NOTCH pathway, thereby promoting cancer stemness and lenvatinib resistance in hepatocellular carcinoma; this pathway was identified by protein mass spectrometry and validated by in vitro and in vivo experiments.","method":"Protein mass spectrometry (downstream protein identification), bioinformatics, in vitro and in vivo functional assays, Western blotting, lenvatinib-resistant cell line model","journal":"Biology direct","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based identification of MYH9 as TM4SF1 downstream target plus in vitro/in vivo functional validation, single lab","pmids":["37069693"],"is_preprint":false},{"year":2024,"finding":"TM4SF1 forms 'TM4SF1-enriched microdomains' (TMEDs) on the endothelial cell surface that recruit signaling molecules (12 of 18 examined, notably PLCγ and HDAC6) and internalize along microtubules to intracellular locations including the nucleus. When TM4SF1 is knocked down, microtubules become heavily acetylated (despite normal HDAC6 protein levels) and cells are unable to proliferate. Tumor growth and wound healing are inhibited in Tm4sf1-heterozygous mice.","method":"Co-localization immunofluorescence, protein co-recruitment assays to TMEDs, siRNA knockdown, microtubule acetylation Western blot, Tm4sf1-heterozygous mouse in vivo models","journal":"Journal of cell communication and signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (co-recruitment assays for 18 proteins, acetylation readout, in vivo heterozygous mouse model), builds on prior published mechanism, single lab with strong mechanistic framework","pmids":["38946725"],"is_preprint":false},{"year":2024,"finding":"TM4SF1 enhances the interaction between AKT1 and PDPK1 (as shown by co-immunoprecipitation, bimolecular fluorescence complementation, and immunofluorescence), promoting AKT phosphorylation, which subsequently downregulates p16 and p21, suppressing tumor cell senescence. TM4SF1-mediated AKT phosphorylation also enhances PD-L1 expression and reduces MHC class I levels on tumor cells, impairing CD8+ T cell cytotoxic function.","method":"Immunoprecipitation-mass spectrometry, co-immunoprecipitation, bimolecular fluorescence complementation, immunofluorescence, flow cytometry, SA-β-gal activity assay, Western blot, hydrodynamic tail vein injection mouse model","journal":"Clinical and molecular hepatology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — IP-MS for interactor discovery, Co-IP + BiFC + IF to validate TM4SF1-AKT1-PDPK1 complex, multiple orthogonal methods for functional readouts, in vivo validation","pmids":["39736265"],"is_preprint":false},{"year":2024,"finding":"PLAU physically interacts with TM4SF1 to promote Akt signaling activation in non-small cell lung cancer; TM4SF1 knockdown or treatment with anti-TM4SF1 neutralizing antibody inhibited PLAU-induced growth, survival, and cisplatin resistance, placing TM4SF1 as a required mediator of PLAU-driven Akt activation.","method":"Co-immunoprecipitation (PLAU-TM4SF1 interaction), siRNA knockdown, plasmid overexpression, neutralizing antibody treatment, in vivo xenograft","journal":"Biology direct","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying PLAU-TM4SF1 direct interaction with epistasis (KD + antibody), in vivo validation, single lab","pmids":["38229120"],"is_preprint":false},{"year":2025,"finding":"TM4SF1 in hepatic stellate cells binds to and activates the tyrosine kinase c-Src, promoting HSC activation and hepatic fibrosis via the c-Src/PI3K/AKT pathway; HSC-specific TM4SF1 knockout mice showed reduced HSC activation and attenuated hepatic fibrosis, and the Src family inhibitor saracatinib blocked TM4SF1 overexpression-induced fibrosis.","method":"Co-immunoprecipitation (TM4SF1-c-Src interaction), HSC-specific knockout mouse model, pharmacological inhibition (saracatinib), overexpression/knockdown in LX-2 cells, Western blotting, in vivo fibrosis models","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP for direct binding, conditional KO mouse with defined phenotype, pharmacological rescue, multiple orthogonal methods in a single rigorous study","pmids":["40550268"],"is_preprint":false},{"year":2025,"finding":"TM4SF1-directed ADC (3m2A7A-LP2) specifically homed to and disrupted newly formed VEGF-A164-induced angiogenic blood vessels within 48 hours in a mouse ear model, without affecting normal vessels in the same animal, demonstrating that TM4SF1 is selectively expressed on and internalized by newly forming tumor blood vessels.","method":"Adenoviral VEGF-A164 ear model in nude mice, in vivo ADC targeting/homing assay, histological analysis, multi-dose treatment","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo functional validation of TM4SF1-mediated internalization on angiogenic vessels with ADC, single lab, single study","pmids":["42196417"],"is_preprint":false},{"year":2024,"finding":"YBX1, an RNA-binding protein, stabilizes TM4SF1 mRNA via m5C (5-methylcytosine) modification, upregulating TM4SF1 expression and subsequently activating β-catenin/c-Myc signaling to drive bladder cancer proliferation and glycolysis; overexpression of β-catenin reversed the inhibitory effects of TM4SF1 silencing.","method":"RNA immunoprecipitation (RIP), m5C-RIP, Actinomycin D mRNA stability assay, luciferase reporter assay, siRNA knockdown, overexpression, Western blotting, glycolysis assays","journal":"Combinatorial chemistry & high throughput screening","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m5C-RIP directly demonstrated YBX1 binding to TM4SF1 mRNA with m5C mark, mRNA stability assay, and epistasis rescue, single lab with multiple orthogonal methods","pmids":["41029024"],"is_preprint":false},{"year":2024,"finding":"TSPAN1 physically interacts with TM4SF1 in glioblastoma stem cells (confirmed by Co-IP and immunofluorescence); the compound 4,5-dimethoxycanthin-6-one inhibited both TM4SF1 and TSPAN1 expression and disrupted this interaction, suppressing glioblastoma stem cell formation and proliferation; TSPAN1 overexpression partially reversed these effects.","method":"Co-immunoprecipitation, immunofluorescence, molecular docking simulation, CCK-8/colony formation, wound healing, Transwell, flow cytometry, xenograft mouse model","journal":"Neurochemical research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP validated interaction, functional rescue experiment, single lab, in vivo validation, but molecular docking adds computational element and interaction mechanism not fully characterized","pmids":["39060768"],"is_preprint":false},{"year":2022,"finding":"The lncRNA BCYRN1 recruits the transcription factor BATF to the TM4SF1 promoter, thereby upregulating TM4SF1 expression; ChIP demonstrated BATF binding to the TM4SF1 promoter, and RNA immunoprecipitation confirmed BCYRN1-BATF interaction. Knockdown of BCYRN1 reduced TM4SF1-dependent HCC cell migration, invasion, and xenograft tumor growth.","method":"RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), luciferase reporter assay, siRNA knockdown, in vivo xenograft","journal":"Disease markers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP directly showed BATF binding to TM4SF1 promoter, RIP confirmed BCYRN1-BATF interaction, multiple orthogonal methods, single lab","pmids":["35730016"],"is_preprint":false}],"current_model":"TM4SF1 is a tetraspanin-like integral membrane glycoprotein that organizes TM4SF1-enriched microdomains (TMEDs) on the plasma membrane of endothelial and tumor cells, recruiting signaling molecules (including PLCγ1, HDAC6, and importins) and physically interacting with binding partners including integrin-α5/β1 (constitutively), integrin-αV/β3/β5 (upon VEGF-A/thrombin stimulation), integrin-α6 (activating a FAK-dependent migration pathway), DDR1 (promoting invadopodia and MMP2/9 activity), DVL2 (strengthening DVL2-Axin interaction to activate Wnt/β-catenin signaling), c-Src (activating c-Src/PI3K/AKT in hepatic stellate cells), AKT1/PDPK1 (enhancing AKT phosphorylation to suppress p16/p21 and senescence), TSPAN1 (in glioblastoma stem cells), and PLAU (to promote AKT activation); TM4SF1 internalizes from the cell surface along microtubules via dynamin-dependent, clathrin-independent vesicles and translocates to the nucleus through nuclear pores, functioning as a molecular cargo transporter that delivers activated signaling proteins to intracellular and nuclear compartments essential for endothelial cell proliferation, migration, nanopodia formation, and pathological angiogenesis, while in cancer cells it promotes EMT, stemness, drug resistance, and immune evasion downstream of oncogenic signals including AR, Kras, HIF-1α, and YBX1-mediated m5C modification."},"narrative":{"mechanistic_narrative":"TM4SF1 is a tetraspanin-like plasma membrane glycoprotein that organizes specialized signaling microdomains on endothelial and tumor cells to control cell motility, proliferation, and pathological angiogenesis [PMID:19351819, PMID:38946725]. In endothelial cells it is required for filopodia formation, cytokinesis, and the assembly of unusually long, F-actin-poor projections termed 'nanopodia', where it adopts a banded distribution and associates with myosin-10 and β-actin [PMID:19351819, PMID:21626280]. TM4SF1 nucleates TM4SF1-enriched microdomains (TMEDs) that recruit signaling molecules including PLCγ and HDAC6; loss of TM4SF1 leaves microtubules hyperacetylated and blocks proliferation, and Tm4sf1-heterozygous mice show impaired tumor growth and wound healing [PMID:38946725]. A defining property is its intracellular trafficking: TM4SF1 internalizes from the surface via dynamin-dependent, clathrin-independent vesicles, moves along microtubules, and translocates through nuclear pores into the nucleus, consistent with a cargo-transport role for activated signaling proteins [PMID:26241677, PMID:38946725]. Surface TM4SF1 partners with integrins—constitutively with α5/β1 and, after VEGF-A or thrombin stimulation, with αV/β3/β5—and with integrin-α6 to drive a laminin-dependent FAK migration axis [PMID:19351819, PMID:35835740]. Across cancers, TM4SF1 acts as a node coupling membrane receptors to oncogenic signaling: it binds DDR1 to promote invadopodia and MMP2/9 activity [PMID:28368050], DVL2 to potentiate Wnt/β-catenin signaling [PMID:31876386], c-Src to activate PI3K/AKT in hepatic stellate cells and drive fibrosis [PMID:40550268], and bridges AKT1–PDPK1 to enhance AKT phosphorylation, thereby suppressing p16/p21-mediated senescence and promoting immune evasion via PD-L1 upregulation and MHC class I loss [PMID:39736265]. Its expression is induced by androgen receptor, which binds an androgen response element in the TM4SF1 promoter [PMID:21656834], and by YBX1-mediated m5C stabilization of TM4SF1 mRNA [PMID:41029024]. Antibody and antibody-drug-conjugate targeting of TM4SF1's extracellular EL2 loop selectively disrupts newly formed tumor vasculature, establishing it as a vascular therapeutic target [PMID:24986520, PMID:42196417].","teleology":[{"year":2009,"claim":"Established that TM4SF1 is functionally required for endothelial motility and angiogenesis and physically partners with integrins in a stimulus-dependent manner, defining its role at the cell surface.","evidence":"siRNA knockdown with multiple phenotypic readouts, reciprocal Co-IP for integrin interactions, and an in vivo VEGF-A angiogenesis model in endothelial cells","pmids":["19351819"],"confidence":"High","gaps":["Did not resolve how integrin recruitment is coupled to downstream signaling output","Mechanism linking TM4SF1 to cytokinesis and senescence undefined"]},{"year":2011,"claim":"Defined a structural/cell-biological role for TM4SF1 in forming nanopodia and identified cytoskeletal binding partners, showing that expression level tunes motility versus projection formation.","evidence":"Live-cell imaging, electron microscopy, adenoviral gain-of-function across cell types, and mass spectrometry pulldown identifying myosin-10 and β-actin","pmids":["21626280"],"confidence":"High","gaps":["Direct versus indirect nature of myosin-10/β-actin association not dissected","How TM4SF1 banding pattern is established is unknown"]},{"year":2011,"claim":"Identified an upstream transcriptional driver by showing TM4SF1 is a direct androgen receptor target, linking hormone signaling to TM4SF1-dependent cancer cell motility.","evidence":"ChIP demonstrating AR binding to a promoter androgen response element, transcriptomics, siRNA knockdown and wound-healing assays in prostate cancer cells","pmids":["21656834"],"confidence":"High","gaps":["Did not link cytoplasmic relocalization in cancer to a defined trafficking mechanism","Downstream effectors of motility not identified here"]},{"year":2014,"claim":"Validated TM4SF1's extracellular EL2 loop as an actionable surface epitope, providing proof-of-concept for vascular targeting.","evidence":"Monoclonal antibody against EL2 in a humanized Matrigel vessel model in nude mice","pmids":["24986520"],"confidence":"Medium","gaps":["No direct mechanistic assay of how EL2 engagement disrupts vessels","Single antibody reagent, single lab"]},{"year":2015,"claim":"Resolved the trafficking itinerary of TM4SF1, demonstrating dynamin-dependent, clathrin-independent internalization and microtubule-mediated nuclear translocation, the basis for its proposed cargo-transporter function.","evidence":"Immuno-nanogold transmission electron microscopy, immunofluorescence, and dynamin inhibition in endothelial cells","pmids":["26241677"],"confidence":"High","gaps":["Cargo carried into the nucleus not identified at this stage","Nuclear import machinery (e.g., importin dependence) not defined"]},{"year":2015,"claim":"Connected TM4SF1 to chemoresistance phenotypes, showing it upregulates multidrug-resistance transporters and modulates PI3K/AKT/mTOR signaling.","evidence":"siRNA/shRNA knockdown with qRT-PCR of ABCB1/ABCC1, Western blots of AKT/mTOR pathway, and orthotopic tumor models in pancreatic and breast cancer cells","pmids":["26709920","26464650"],"confidence":"Medium","gaps":["No direct interaction shown linking TM4SF1 to AKT/mTOR components","Mechanism of MDR gene induction unresolved"]},{"year":2017,"claim":"Placed TM4SF1 upstream of DDR1 in an invadopodia/MMP pathway via a physical interaction and epistatic rescue, mechanistically explaining its pro-invasive activity.","evidence":"Co-IP, double immunofluorescence, siRNA knockdown with DDR1 rescue, invadopodia assays and zymography in pancreatic cancer cells","pmids":["27459514","28368050"],"confidence":"High","gaps":["Whether TM4SF1-DDR1 binding is direct or microdomain-mediated unresolved","Generalizability of DDR1 axis to other tumor types not established here"]},{"year":2019,"claim":"Extended TM4SF1's signaling reach to Wnt/β-catenin by showing it binds DVL2 and strengthens DVL2-Axin interaction, and linked TM4SF1 induction to oncogenic Kras.","evidence":"Co-IP of TM4SF1-DVL2 and DVL2-Axin, ubiquitination and target-gene readouts in hepatocellular carcinoma","pmids":["31876386"],"confidence":"Medium","gaps":["Structural basis of DVL2 binding undefined","How a membrane protein accesses cytoplasmic DVL2/Axin not addressed"]},{"year":2019,"claim":"Broadened the downstream signaling repertoire by implicating TM4SF1 in ERK1/2 and DDR1-Akt/ERK/mTOR cascades governing proliferation and chemoresistance.","evidence":"Overexpression/knockdown with pharmacological pathway inhibition and Western blots in prostate and lung cancer cells","pmids":["31983129","31142317"],"confidence":"Low","gaps":["Pharmacological epistasis without direct interaction proof","Single pathway readout per study, no rescue of DDR1 axis"]},{"year":2020,"claim":"Linked TM4SF1 to stemness and transcriptional programs through Wnt/β-catenin-c-Myc-SOX2 and YAP-TEAD axes.","evidence":"ChIP of c-Myc at the SOX2 promoter and Co-IP of YAP-TEAD with knockdown/inhibitor rescue in colorectal and lung cancer models","pmids":["33153498","32141552"],"confidence":"Medium","gaps":["Direct molecular connection between TM4SF1 and these transcription complexes not defined","Whether effects require TMED organization unknown"]},{"year":2021,"claim":"Positioned TM4SF1 within a senescence-control circuit downstream of AKT and B7-H3 and upstream of SIRT1.","evidence":"RNA-seq, pathway blockade epistasis, and in vivo models in colorectal cancer","pmids":["33958586","29175458"],"confidence":"Medium","gaps":["Molecular mechanism by which TM4SF1 modulates SIRT1/PPARγ not established","Direct partners in this circuit unidentified"]},{"year":2022,"claim":"Defined a laminin-dependent TM4SF1/integrin-α6/FAK migration axis through direct interaction, and identified a lncRNA-transcription-factor route (BCYRN1-BATF) controlling TM4SF1 expression.","evidence":"Co-IP and FAK-inhibitor epistasis with in vivo metastasis (ESCC), plus RIP and ChIP for BCYRN1-BATF promoter regulation (HCC)","pmids":["35835740","35730016"],"confidence":"High","gaps":["How integrin-α6 engagement activates FAK at TMEDs not detailed","Interplay between distinct integrin partners unresolved"]},{"year":2023,"claim":"Identified MYH9-NOTCH as a downstream effector arm supporting stemness and targeted-therapy resistance.","evidence":"Protein mass spectrometry of downstream targets with in vitro/in vivo validation in lenvatinib-resistant HCC","pmids":["37069693"],"confidence":"Medium","gaps":["Whether MYH9 regulation is direct unknown","Link between MYH9 and NOTCH activation mechanistically incomplete"]},{"year":2024,"claim":"Consolidated the unifying model: TM4SF1 builds TMEDs that recruit signaling proteins (PLCγ, HDAC6) and traffic them via microtubules into the nucleus, with HDAC6 sequestration controlling microtubule acetylation and proliferation.","evidence":"Co-recruitment assays for 18 proteins, microtubule acetylation Western blots, and Tm4sf1-heterozygous mouse tumor/wound models","pmids":["38946725"],"confidence":"High","gaps":["Stoichiometry and selectivity of TMED recruitment not fully defined","How nuclear-delivered cargo exerts proliferative effect unresolved"]},{"year":2024,"claim":"Established a direct scaffolding mechanism whereby TM4SF1 bridges AKT1 and PDPK1 to drive AKT phosphorylation, coupling senescence suppression to immune evasion, and identified PLAU and TSPAN1 as physical partners plus YBX1/m5C as an mRNA-stabilizing regulator.","evidence":"IP-MS, Co-IP, BiFC and flow cytometry (AKT1-PDPK1; PD-L1/MHC-I), Co-IP for PLAU and TSPAN1, and m5C-RIP with mRNA stability assays (YBX1)","pmids":["39736265","38229120","39060768","41029024"],"confidence":"High","gaps":["Whether AKT1/PDPK1 bridging occurs at the membrane or after internalization unknown","Relative contribution of PLAU and TSPAN1 to AKT activation not compared"]},{"year":2025,"claim":"Demonstrated a non-cancer disease role through a direct TM4SF1-c-Src interaction driving hepatic stellate cell activation and fibrosis, and confirmed selective TM4SF1 expression/internalization on neovasculature for ADC targeting.","evidence":"Co-IP, HSC-specific knockout mice and saracatinib rescue (fibrosis); in vivo TM4SF1-directed ADC homing to VEGF-A164-induced vessels","pmids":["40550268","42196417"],"confidence":"High","gaps":["Whether c-Src binding uses the same interface as other kinase partners unknown","Determinants of TM4SF1 selectivity for nascent versus mature vessels undefined"]},{"year":null,"claim":"It remains unresolved which activated cargo proteins TM4SF1 physically delivers to the nucleus and how this nuclear function mechanistically drives proliferation, distinct from its membrane scaffolding roles.","evidence":"","pmids":[],"confidence":"High","gaps":["No defined nuclear substrate-to-phenotype mechanism","Importin/nuclear-pore dependence of cargo not biochemically dissected","Structural basis distinguishing constitutive versus stimulus-induced partner binding unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[4,18]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[8,16,19]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[11,19,21]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,18]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[4]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,18]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,4,18]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal 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cells prevented filopodia formation, inhibited cell mobility, blocked cytokinesis, and rendered cells senescent. Integrin-α5 and integrin-β1 subunits interacted constitutively with TM4SF1, whereas integrin subunits αV, β3, β5 interacted with TM4SF1 only after VEGF-A or thrombin stimulation. TM4SF1 knockdown substantially inhibited maturation of VEGF-A164-induced angiogenesis in vivo.\",\n      \"method\": \"siRNA knockdown, Co-immunoprecipitation, in vivo tumor angiogenesis model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP for integrin interactions, clean KD with multiple defined cellular phenotypes (filopodia, cytokinesis, senescence), in vivo validation, single lab with orthogonal methods\",\n      \"pmids\": [\"19351819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TM4SF1 is necessary for formation of unusually long, thin (~100–300 nm wide), F-actin-poor endothelial cell projections called 'nanopodia'. TM4SF1 localizes in a regularly spaced banded pattern within nanopodia. Live cell imaging showed nanopodia are projected during migration and intercellular interactions. Mass spectrometry demonstrated TM4SF1 interacted with myosin-10 and β-actin. When TM4SF1 was overexpressed (~400 copies/cell vs normal ~90), cells formed more/longer nanopodia but could not polarize or migrate. When expressed at EC-like levels in fibroblasts (~5 normally), cells formed TM4SF1-banded nanopodia and EC-like lamellipodia.\",\n      \"method\": \"Live cell imaging (GFP-transduced HUVEC), adenoviral overexpression, immunostaining (light and electron microscopy), mass spectrometry pulldown\",\n      \"journal\": \"Angiogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (live imaging, EM, MS-based interaction identification, gain/loss-of-function), replicated across cell types in single rigorous study\",\n      \"pmids\": [\"21626280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TM4SF1 is a direct transcriptional target of the androgen receptor (AR); a functional androgen response element was identified in the TM4SF1 promoter by chromatin immunoprecipitation. TM4SF1 mediates prostate cancer cell motility; siRNA knockdown inhibited cell migration. In normal prostate epithelium TM4SF1 localizes apically, whereas in prostate cancer cells it localizes predominantly in the cytoplasm.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), transcriptomic analysis, siRNA knockdown, wound healing assay, immunohistochemistry\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP directly validated AR binding to TM4SF1 promoter combined with transcriptomics and functional KD migration assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"21656834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Monoclonal antibodies against TM4SF1's extracellular loop-2 (EL2) domain disrupted human tumor vasculature in a humanized Matrigel plug model and eliminated incorporated PC3 prostate cancer cells, validating TM4SF1 as a therapeutic vascular target.\",\n      \"method\": \"Monoclonal antibody generation and in vivo humanized vessel model (ECFC/MSC Matrigel implants in nude mice)\",\n      \"journal\": \"Angiogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo functional validation with defined antibody reagent, single lab, functional readout but no direct mechanistic assay of the interaction\",\n      \"pmids\": [\"24986520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TM4SF1 is internalized from the plasma membrane of endothelial cells via uncoated cytoplasmic vesicles in a dynamin-dependent, clathrin-independent manner, then transported along microtubules through the cytoplasm and through nuclear pores into the nucleus, as demonstrated by immuno-nanogold transmission electron microscopy.\",\n      \"method\": \"Immuno-nanogold transmission electron microscopy, immunofluorescence microscopy, dynamin inhibition\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — high-resolution immuno-EM with mechanistic detail (dynamin-dependent, clathrin-independent, microtubule-mediated nuclear entry), multiple imaging methods in single rigorous study\",\n      \"pmids\": [\"26241677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TM4SF1 promotes gemcitabine resistance in pancreatic cancer cells by upregulating multidrug resistance genes ABCB1 and ABCC1; silencing TM4SF1 increased gemcitabine sensitivity both in vitro and in vivo in orthotopic tumor models.\",\n      \"method\": \"siRNA knockdown, shRNA lentiviral knockdown, qRT-PCR for MDR genes, cell proliferation/apoptosis assays, orthotopic tumor model with bioluminescent imaging\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined MDR gene expression readout, both in vitro and in vivo, single lab\",\n      \"pmids\": [\"26709920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TM4SF1 promotes breast cancer cell migration via the PI3K/AKT/mTOR pathway; silencing TM4SF1 decreased phosphorylated AKT, p-mTOR, and p-P70S6K levels, while overexpression increased cell migration and decreased apoptosis.\",\n      \"method\": \"siRNA knockdown, plasmid overexpression, Western blotting of PI3K/AKT/mTOR pathway components, Matrigel migration assay, flow cytometry\",\n      \"journal\": \"International journal of clinical and experimental pathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Western blot pathway readout with KD/OE, single lab, single method per endpoint, no direct interaction demonstration\",\n      \"pmids\": [\"26464650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TM4SF1 knockdown in pancreatic cancer cells reduced migration and invasion and downregulated the expression and enzymatic activity of MMP-2 and MMP-9, as measured by gelatin zymography.\",\n      \"method\": \"siRNA/shRNA knockdown, Transwell migration/invasion assay, gelatin zymography, Western blot, orthotopic tumor model\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with functional migration assay and direct enzymatic activity measurement by zymography, in vivo metastasis validation, single lab\",\n      \"pmids\": [\"27459514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TM4SF1 co-localizes with DDR1 and physically interacts with DDR1 (by co-immunoprecipitation and double immunofluorescence) in pancreatic cancer cells. TM4SF1 silencing reduced DDR1 expression, impaired invadopodia formation and function, and decreased MMP2 and MMP9 expression; restoring DDR1 rescued these effects, placing TM4SF1 upstream of DDR1-MMP2/9 in an invadopodia-promoting pathway.\",\n      \"method\": \"Co-immunoprecipitation, double immunofluorescence co-staining, siRNA knockdown, rescue overexpression of DDR1, invadopodia formation assay, qRT-PCR\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + co-localization + epistasis rescue experiment establishing TM4SF1→DDR1→MMP2/9 pathway, multiple orthogonal methods in single study\",\n      \"pmids\": [\"28368050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TM4SF1 regulates apoptosis, cell cycle, and ROS metabolism in bladder cancer cells via the PPARγ-SIRT1 feedback loop; knockdown of TM4SF1 induced cell cycle arrest and apoptosis associated with ROS upregulation, and these effects were reversed by GW9662 (PPARγ antagonist) or resveratrol (SIRT1 activator).\",\n      \"method\": \"siRNA knockdown, flow cytometry (cell cycle/apoptosis), ROS measurement, pharmacological rescue with GW9662 and resveratrol, in vivo xenograft\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis with two reagents plus in vitro/in vivo KD, single lab, mechanistic pathway placement via rescue experiments\",\n      \"pmids\": [\"29175458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TM4SF1 promotes non-small cell lung cancer proliferation, invasion, and chemo-resistance by regulating the expression of DDR1 and its downstream Akt/ERK/mTOR pathway; silencing TM4SF1 reduced DDR1 expression and Akt/ERK/mTOR signaling, enhancing sensitivity to cisplatin and paclitaxel.\",\n      \"method\": \"siRNA knockdown, Western blotting (DDR1, p-AKT, p-ERK, mTOR), MTS/clonogenic assay, Transwell assay, flow cytometry, RT-PCR\",\n      \"journal\": \"Respiratory research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD with pathway protein readout, multiple functional assays, single lab, no direct interaction or rescue validation of DDR1 axis\",\n      \"pmids\": [\"31142317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TM4SF1 is an interacting partner of DVL2 in hepatocellular carcinoma; TM4SF1 overexpression strengthened the DVL2-Axin interaction, leading to activation of Wnt/β-catenin signaling (increased Axin2 and cyclin D1 expression and decreased β-catenin ubiquitination). TM4SF1 expression was induced by Kras signaling.\",\n      \"method\": \"Co-immunoprecipitation (TM4SF1-DVL2 and DVL2-Axin interactions), Western blotting, overexpression and knockdown, ubiquitination assay, Kras pathway analysis\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating TM4SF1-DVL2 physical interaction with functional pathway readout (β-catenin ubiquitination, target gene expression), single lab with multiple methods\",\n      \"pmids\": [\"31876386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TM4SF1 overexpression in prostate cancer cells activated ERK1/2 signaling; suppression of ERK1/2 reversed the pro-migratory, pro-invasive, and pro-proliferative effects of TM4SF1 overexpression, placing TM4SF1 upstream of ERK1/2.\",\n      \"method\": \"Plasmid overexpression, pharmacological ERK1/2 inhibition, Transwell assay, wound-healing assay, colony formation, EdU staining, Western blotting\",\n      \"journal\": \"Journal of B.U.ON.\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological epistasis without direct interaction proof, single lab, single pathway assay\",\n      \"pmids\": [\"31983129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TM4SF1 modulates SOX2 expression in a Wnt/β-catenin activation-dependent manner in colorectal cancer; TM4SF1 knockdown reduced c-Myc expression and c-Myc binding to the SOX2 gene promoter, suppressing EMT (TGF-β1-mediated) and cancer stemness.\",\n      \"method\": \"siRNA knockdown, GSEA pathway analysis, Western blotting, ChIP (c-Myc binding to SOX2 promoter), TGF-β1 stimulation, sphere formation assay, xenograft mouse model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP directly showed c-Myc promoter binding change, supported by Western blot pathway readout and in vivo validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33153498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TM4SF1 regulates YAP-TEAD interaction in non-small cell lung cancer; TM4SF1 modulated the YAP-TEAD protein-protein interaction and downstream target gene levels, as shown by Co-IP; sh-YAP or YAP-TEAD inhibitor (Peptide 17) reversed TM4SF1-mediated oncogenic effects.\",\n      \"method\": \"Co-immunoprecipitation, siRNA/shRNA knockdown, plasmid overexpression, pharmacological inhibition (Peptide 17), Western blotting, xenograft tumor model\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP showing TM4SF1-regulated YAP-TEAD interaction with epistasis via inhibitor rescue, single lab\",\n      \"pmids\": [\"32141552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"B7-H3 prevents cellular senescence in colorectal cancer through the AKT/TM4SF1/SIRT1 pathway; blocking this pathway reversed B7-H3-induced resistance to DOX-induced senescence, placing TM4SF1 downstream of AKT and upstream of SIRT1.\",\n      \"method\": \"RNA-seq, Western blotting, siRNA knockdown/overexpression of B7-H3, pathway blockade experiments, in vivo tumor model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq pathway discovery followed by functional pathway blockade epistasis, in vitro and in vivo, single lab\",\n      \"pmids\": [\"33958586\"],\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 physically interacting with integrin α6; the TM4SF1/integrin α6/FAK signaling axis mediates cell migration under laminin-coating conditions, and FAK inhibition or TM4SF1 knockdown attenuated migration and lung metastasis.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-staining, siRNA knockdown, FAK inhibitor treatment, Transwell migration/invasion assay, in vivo lung metastasis model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating direct TM4SF1-integrin α6 physical interaction with pharmacological and genetic epistasis to define FAK pathway, in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"35835740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TM4SF1 upregulates MYH9 expression, which activates the NOTCH pathway, thereby promoting cancer stemness and lenvatinib resistance in hepatocellular carcinoma; this pathway was identified by protein mass spectrometry and validated by in vitro and in vivo experiments.\",\n      \"method\": \"Protein mass spectrometry (downstream protein identification), bioinformatics, in vitro and in vivo functional assays, Western blotting, lenvatinib-resistant cell line model\",\n      \"journal\": \"Biology direct\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based identification of MYH9 as TM4SF1 downstream target plus in vitro/in vivo functional validation, single lab\",\n      \"pmids\": [\"37069693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TM4SF1 forms 'TM4SF1-enriched microdomains' (TMEDs) on the endothelial cell surface that recruit signaling molecules (12 of 18 examined, notably PLCγ and HDAC6) and internalize along microtubules to intracellular locations including the nucleus. When TM4SF1 is knocked down, microtubules become heavily acetylated (despite normal HDAC6 protein levels) and cells are unable to proliferate. Tumor growth and wound healing are inhibited in Tm4sf1-heterozygous mice.\",\n      \"method\": \"Co-localization immunofluorescence, protein co-recruitment assays to TMEDs, siRNA knockdown, microtubule acetylation Western blot, Tm4sf1-heterozygous mouse in vivo models\",\n      \"journal\": \"Journal of cell communication and signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (co-recruitment assays for 18 proteins, acetylation readout, in vivo heterozygous mouse model), builds on prior published mechanism, single lab with strong mechanistic framework\",\n      \"pmids\": [\"38946725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TM4SF1 enhances the interaction between AKT1 and PDPK1 (as shown by co-immunoprecipitation, bimolecular fluorescence complementation, and immunofluorescence), promoting AKT phosphorylation, which subsequently downregulates p16 and p21, suppressing tumor cell senescence. TM4SF1-mediated AKT phosphorylation also enhances PD-L1 expression and reduces MHC class I levels on tumor cells, impairing CD8+ T cell cytotoxic function.\",\n      \"method\": \"Immunoprecipitation-mass spectrometry, co-immunoprecipitation, bimolecular fluorescence complementation, immunofluorescence, flow cytometry, SA-β-gal activity assay, Western blot, hydrodynamic tail vein injection mouse model\",\n      \"journal\": \"Clinical and molecular hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — IP-MS for interactor discovery, Co-IP + BiFC + IF to validate TM4SF1-AKT1-PDPK1 complex, multiple orthogonal methods for functional readouts, in vivo validation\",\n      \"pmids\": [\"39736265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PLAU physically interacts with TM4SF1 to promote Akt signaling activation in non-small cell lung cancer; TM4SF1 knockdown or treatment with anti-TM4SF1 neutralizing antibody inhibited PLAU-induced growth, survival, and cisplatin resistance, placing TM4SF1 as a required mediator of PLAU-driven Akt activation.\",\n      \"method\": \"Co-immunoprecipitation (PLAU-TM4SF1 interaction), siRNA knockdown, plasmid overexpression, neutralizing antibody treatment, in vivo xenograft\",\n      \"journal\": \"Biology direct\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying PLAU-TM4SF1 direct interaction with epistasis (KD + antibody), in vivo validation, single lab\",\n      \"pmids\": [\"38229120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TM4SF1 in hepatic stellate cells binds to and activates the tyrosine kinase c-Src, promoting HSC activation and hepatic fibrosis via the c-Src/PI3K/AKT pathway; HSC-specific TM4SF1 knockout mice showed reduced HSC activation and attenuated hepatic fibrosis, and the Src family inhibitor saracatinib blocked TM4SF1 overexpression-induced fibrosis.\",\n      \"method\": \"Co-immunoprecipitation (TM4SF1-c-Src interaction), HSC-specific knockout mouse model, pharmacological inhibition (saracatinib), overexpression/knockdown in LX-2 cells, Western blotting, in vivo fibrosis models\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP for direct binding, conditional KO mouse with defined phenotype, pharmacological rescue, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"40550268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TM4SF1-directed ADC (3m2A7A-LP2) specifically homed to and disrupted newly formed VEGF-A164-induced angiogenic blood vessels within 48 hours in a mouse ear model, without affecting normal vessels in the same animal, demonstrating that TM4SF1 is selectively expressed on and internalized by newly forming tumor blood vessels.\",\n      \"method\": \"Adenoviral VEGF-A164 ear model in nude mice, in vivo ADC targeting/homing assay, histological analysis, multi-dose treatment\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo functional validation of TM4SF1-mediated internalization on angiogenic vessels with ADC, single lab, single study\",\n      \"pmids\": [\"42196417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YBX1, an RNA-binding protein, stabilizes TM4SF1 mRNA via m5C (5-methylcytosine) modification, upregulating TM4SF1 expression and subsequently activating β-catenin/c-Myc signaling to drive bladder cancer proliferation and glycolysis; overexpression of β-catenin reversed the inhibitory effects of TM4SF1 silencing.\",\n      \"method\": \"RNA immunoprecipitation (RIP), m5C-RIP, Actinomycin D mRNA stability assay, luciferase reporter assay, siRNA knockdown, overexpression, Western blotting, glycolysis assays\",\n      \"journal\": \"Combinatorial chemistry & high throughput screening\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m5C-RIP directly demonstrated YBX1 binding to TM4SF1 mRNA with m5C mark, mRNA stability assay, and epistasis rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41029024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TSPAN1 physically interacts with TM4SF1 in glioblastoma stem cells (confirmed by Co-IP and immunofluorescence); the compound 4,5-dimethoxycanthin-6-one inhibited both TM4SF1 and TSPAN1 expression and disrupted this interaction, suppressing glioblastoma stem cell formation and proliferation; TSPAN1 overexpression partially reversed these effects.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, molecular docking simulation, CCK-8/colony formation, wound healing, Transwell, flow cytometry, xenograft mouse model\",\n      \"journal\": \"Neurochemical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP validated interaction, functional rescue experiment, single lab, in vivo validation, but molecular docking adds computational element and interaction mechanism not fully characterized\",\n      \"pmids\": [\"39060768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The lncRNA BCYRN1 recruits the transcription factor BATF to the TM4SF1 promoter, thereby upregulating TM4SF1 expression; ChIP demonstrated BATF binding to the TM4SF1 promoter, and RNA immunoprecipitation confirmed BCYRN1-BATF interaction. Knockdown of BCYRN1 reduced TM4SF1-dependent HCC cell migration, invasion, and xenograft tumor growth.\",\n      \"method\": \"RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), luciferase reporter assay, siRNA knockdown, in vivo xenograft\",\n      \"journal\": \"Disease markers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP directly showed BATF binding to TM4SF1 promoter, RIP confirmed BCYRN1-BATF interaction, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"35730016\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TM4SF1 is a tetraspanin-like integral membrane glycoprotein that organizes TM4SF1-enriched microdomains (TMEDs) on the plasma membrane of endothelial and tumor cells, recruiting signaling molecules (including PLCγ1, HDAC6, and importins) and physically interacting with binding partners including integrin-α5/β1 (constitutively), integrin-αV/β3/β5 (upon VEGF-A/thrombin stimulation), integrin-α6 (activating a FAK-dependent migration pathway), DDR1 (promoting invadopodia and MMP2/9 activity), DVL2 (strengthening DVL2-Axin interaction to activate Wnt/β-catenin signaling), c-Src (activating c-Src/PI3K/AKT in hepatic stellate cells), AKT1/PDPK1 (enhancing AKT phosphorylation to suppress p16/p21 and senescence), TSPAN1 (in glioblastoma stem cells), and PLAU (to promote AKT activation); TM4SF1 internalizes from the cell surface along microtubules via dynamin-dependent, clathrin-independent vesicles and translocates to the nucleus through nuclear pores, functioning as a molecular cargo transporter that delivers activated signaling proteins to intracellular and nuclear compartments essential for endothelial cell proliferation, migration, nanopodia formation, and pathological angiogenesis, while in cancer cells it promotes EMT, stemness, drug resistance, and immune evasion downstream of oncogenic signals including AR, Kras, HIF-1α, and YBX1-mediated m5C modification.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TM4SF1 is a tetraspanin-like plasma membrane glycoprotein that organizes specialized signaling microdomains on endothelial and tumor cells to control cell motility, proliferation, and pathological angiogenesis [#0, #18]. In endothelial cells it is required for filopodia formation, cytokinesis, and the assembly of unusually long, F-actin-poor projections termed 'nanopodia', where it adopts a banded distribution and associates with myosin-10 and \\u03b2-actin [#0, #1]. TM4SF1 nucleates TM4SF1-enriched microdomains (TMEDs) that recruit signaling molecules including PLC\\u03b3 and HDAC6; loss of TM4SF1 leaves microtubules hyperacetylated and blocks proliferation, and Tm4sf1-heterozygous mice show impaired tumor growth and wound healing [#18]. A defining property is its intracellular trafficking: TM4SF1 internalizes from the surface via dynamin-dependent, clathrin-independent vesicles, moves along microtubules, and translocates through nuclear pores into the nucleus, consistent with a cargo-transport role for activated signaling proteins [#4, #18]. Surface TM4SF1 partners with integrins\\u2014constitutively with \\u03b15/\\u03b21 and, after VEGF-A or thrombin stimulation, with \\u03b1V/\\u03b23/\\u03b25\\u2014and with integrin-\\u03b16 to drive a laminin-dependent FAK migration axis [#0, #16]. Across cancers, TM4SF1 acts as a node coupling membrane receptors to oncogenic signaling: it binds DDR1 to promote invadopodia and MMP2/9 activity [#8], DVL2 to potentiate Wnt/\\u03b2-catenin signaling [#11], c-Src to activate PI3K/AKT in hepatic stellate cells and drive fibrosis [#21], and bridges AKT1\\u2013PDPK1 to enhance AKT phosphorylation, thereby suppressing p16/p21-mediated senescence and promoting immune evasion via PD-L1 upregulation and MHC class I loss [#19]. Its expression is induced by androgen receptor, which binds an androgen response element in the TM4SF1 promoter [#2], and by YBX1-mediated m5C stabilization of TM4SF1 mRNA [#23]. Antibody and antibody-drug-conjugate targeting of TM4SF1's extracellular EL2 loop selectively disrupts newly formed tumor vasculature, establishing it as a vascular therapeutic target [#3, #22].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established that TM4SF1 is functionally required for endothelial motility and angiogenesis and physically partners with integrins in a stimulus-dependent manner, defining its role at the cell surface.\",\n      \"evidence\": \"siRNA knockdown with multiple phenotypic readouts, reciprocal Co-IP for integrin interactions, and an in vivo VEGF-A angiogenesis model in endothelial cells\",\n      \"pmids\": [\"19351819\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how integrin recruitment is coupled to downstream signaling output\", \"Mechanism linking TM4SF1 to cytokinesis and senescence undefined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined a structural/cell-biological role for TM4SF1 in forming nanopodia and identified cytoskeletal binding partners, showing that expression level tunes motility versus projection formation.\",\n      \"evidence\": \"Live-cell imaging, electron microscopy, adenoviral gain-of-function across cell types, and mass spectrometry pulldown identifying myosin-10 and \\u03b2-actin\",\n      \"pmids\": [\"21626280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus indirect nature of myosin-10/\\u03b2-actin association not dissected\", \"How TM4SF1 banding pattern is established is unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified an upstream transcriptional driver by showing TM4SF1 is a direct androgen receptor target, linking hormone signaling to TM4SF1-dependent cancer cell motility.\",\n      \"evidence\": \"ChIP demonstrating AR binding to a promoter androgen response element, transcriptomics, siRNA knockdown and wound-healing assays in prostate cancer cells\",\n      \"pmids\": [\"21656834\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not link cytoplasmic relocalization in cancer to a defined trafficking mechanism\", \"Downstream effectors of motility not identified here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Validated TM4SF1's extracellular EL2 loop as an actionable surface epitope, providing proof-of-concept for vascular targeting.\",\n      \"evidence\": \"Monoclonal antibody against EL2 in a humanized Matrigel vessel model in nude mice\",\n      \"pmids\": [\"24986520\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct mechanistic assay of how EL2 engagement disrupts vessels\", \"Single antibody reagent, single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved the trafficking itinerary of TM4SF1, demonstrating dynamin-dependent, clathrin-independent internalization and microtubule-mediated nuclear translocation, the basis for its proposed cargo-transporter function.\",\n      \"evidence\": \"Immuno-nanogold transmission electron microscopy, immunofluorescence, and dynamin inhibition in endothelial cells\",\n      \"pmids\": [\"26241677\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo carried into the nucleus not identified at this stage\", \"Nuclear import machinery (e.g., importin dependence) not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected TM4SF1 to chemoresistance phenotypes, showing it upregulates multidrug-resistance transporters and modulates PI3K/AKT/mTOR signaling.\",\n      \"evidence\": \"siRNA/shRNA knockdown with qRT-PCR of ABCB1/ABCC1, Western blots of AKT/mTOR pathway, and orthotopic tumor models in pancreatic and breast cancer cells\",\n      \"pmids\": [\"26709920\", \"26464650\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct interaction shown linking TM4SF1 to AKT/mTOR components\", \"Mechanism of MDR gene induction unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed TM4SF1 upstream of DDR1 in an invadopodia/MMP pathway via a physical interaction and epistatic rescue, mechanistically explaining its pro-invasive activity.\",\n      \"evidence\": \"Co-IP, double immunofluorescence, siRNA knockdown with DDR1 rescue, invadopodia assays and zymography in pancreatic cancer cells\",\n      \"pmids\": [\"27459514\", \"28368050\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TM4SF1-DDR1 binding is direct or microdomain-mediated unresolved\", \"Generalizability of DDR1 axis to other tumor types not established here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended TM4SF1's signaling reach to Wnt/\\u03b2-catenin by showing it binds DVL2 and strengthens DVL2-Axin interaction, and linked TM4SF1 induction to oncogenic Kras.\",\n      \"evidence\": \"Co-IP of TM4SF1-DVL2 and DVL2-Axin, ubiquitination and target-gene readouts in hepatocellular carcinoma\",\n      \"pmids\": [\"31876386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of DVL2 binding undefined\", \"How a membrane protein accesses cytoplasmic DVL2/Axin not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Broadened the downstream signaling repertoire by implicating TM4SF1 in ERK1/2 and DDR1-Akt/ERK/mTOR cascades governing proliferation and chemoresistance.\",\n      \"evidence\": \"Overexpression/knockdown with pharmacological pathway inhibition and Western blots in prostate and lung cancer cells\",\n      \"pmids\": [\"31983129\", \"31142317\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pharmacological epistasis without direct interaction proof\", \"Single pathway readout per study, no rescue of DDR1 axis\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked TM4SF1 to stemness and transcriptional programs through Wnt/\\u03b2-catenin-c-Myc-SOX2 and YAP-TEAD axes.\",\n      \"evidence\": \"ChIP of c-Myc at the SOX2 promoter and Co-IP of YAP-TEAD with knockdown/inhibitor rescue in colorectal and lung cancer models\",\n      \"pmids\": [\"33153498\", \"32141552\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular connection between TM4SF1 and these transcription complexes not defined\", \"Whether effects require TMED organization unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Positioned TM4SF1 within a senescence-control circuit downstream of AKT and B7-H3 and upstream of SIRT1.\",\n      \"evidence\": \"RNA-seq, pathway blockade epistasis, and in vivo models in colorectal cancer\",\n      \"pmids\": [\"33958586\", \"29175458\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which TM4SF1 modulates SIRT1/PPAR\\u03b3 not established\", \"Direct partners in this circuit unidentified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a laminin-dependent TM4SF1/integrin-\\u03b16/FAK migration axis through direct interaction, and identified a lncRNA-transcription-factor route (BCYRN1-BATF) controlling TM4SF1 expression.\",\n      \"evidence\": \"Co-IP and FAK-inhibitor epistasis with in vivo metastasis (ESCC), plus RIP and ChIP for BCYRN1-BATF promoter regulation (HCC)\",\n      \"pmids\": [\"35835740\", \"35730016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How integrin-\\u03b16 engagement activates FAK at TMEDs not detailed\", \"Interplay between distinct integrin partners unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified MYH9-NOTCH as a downstream effector arm supporting stemness and targeted-therapy resistance.\",\n      \"evidence\": \"Protein mass spectrometry of downstream targets with in vitro/in vivo validation in lenvatinib-resistant HCC\",\n      \"pmids\": [\"37069693\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MYH9 regulation is direct unknown\", \"Link between MYH9 and NOTCH activation mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Consolidated the unifying model: TM4SF1 builds TMEDs that recruit signaling proteins (PLC\\u03b3, HDAC6) and traffic them via microtubules into the nucleus, with HDAC6 sequestration controlling microtubule acetylation and proliferation.\",\n      \"evidence\": \"Co-recruitment assays for 18 proteins, microtubule acetylation Western blots, and Tm4sf1-heterozygous mouse tumor/wound models\",\n      \"pmids\": [\"38946725\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and selectivity of TMED recruitment not fully defined\", \"How nuclear-delivered cargo exerts proliferative effect unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established a direct scaffolding mechanism whereby TM4SF1 bridges AKT1 and PDPK1 to drive AKT phosphorylation, coupling senescence suppression to immune evasion, and identified PLAU and TSPAN1 as physical partners plus YBX1/m5C as an mRNA-stabilizing regulator.\",\n      \"evidence\": \"IP-MS, Co-IP, BiFC and flow cytometry (AKT1-PDPK1; PD-L1/MHC-I), Co-IP for PLAU and TSPAN1, and m5C-RIP with mRNA stability assays (YBX1)\",\n      \"pmids\": [\"39736265\", \"38229120\", \"39060768\", \"41029024\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether AKT1/PDPK1 bridging occurs at the membrane or after internalization unknown\", \"Relative contribution of PLAU and TSPAN1 to AKT activation not compared\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated a non-cancer disease role through a direct TM4SF1-c-Src interaction driving hepatic stellate cell activation and fibrosis, and confirmed selective TM4SF1 expression/internalization on neovasculature for ADC targeting.\",\n      \"evidence\": \"Co-IP, HSC-specific knockout mice and saracatinib rescue (fibrosis); in vivo TM4SF1-directed ADC homing to VEGF-A164-induced vessels\",\n      \"pmids\": [\"40550268\", \"42196417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether c-Src binding uses the same interface as other kinase partners unknown\", \"Determinants of TM4SF1 selectivity for nascent versus mature vessels undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved which activated cargo proteins TM4SF1 physically delivers to the nucleus and how this nuclear function mechanistically drives proliferation, distinct from its membrane scaffolding roles.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No defined nuclear substrate-to-phenotype mechanism\", \"Importin/nuclear-pore dependence of cargo not biochemically dissected\", \"Structural basis distinguishing constitutive versus stimulus-induced partner binding unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [4, 18]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [8, 16, 19]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [11, 19, 21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 18]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 18]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 4, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [11, 19, 21]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 8, 17]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [8, 16]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [9, 15, 19]}\n    ],\n    \"complexes\": [\"TM4SF1-enriched microdomains (TMEDs)\"],\n    \"partners\": [\"ITGA5\", \"ITGB1\", \"ITGA6\", \"DDR1\", \"DVL2\", \"SRC\", \"PDPK1\", \"TSPAN1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":8,"faith_total":8,"faith_pct":100.0}}