{"gene":"TSPAN8","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":1990,"finding":"CO-029 (TSPAN8) was identified as a cell surface glycoprotein of 27-34 kDa belonging to the tetraspanin family (sharing homology with ME491/CD63, CD37, and Schistosoma mansoni Sm23), as determined by cDNA cloning and transient expression in COS cells, with the protein shown to be glycosylated (reactive with wheat germ agglutinin indicating N-acetylglucosamine/N-acetyl-neuraminic acid residues).","method":"cDNA cloning, COS cell expression, immunoprecipitation, Western blotting, lectin-Sepharose binding","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct molecular cloning, recombinant expression, and sequence analysis establishing protein identity and family membership","pmids":["2395876"],"is_preprint":false},{"year":1998,"finding":"The rat homologue of CO-029, D6.1A (Tspan8), associates with alpha6beta1 integrin as shown by Western blotting of membrane complexes; transfection of D6.1A cDNA into a low-metastasizing tumor line increased metastatic potential and induced disseminated intravascular coagulation/consumption coagulopathy in vivo, establishing a functional role for this tetraspanin in metastasis and coagulation.","method":"cDNA cloning, stable transfection, Western blotting of membrane complexes, in vivo tumor models","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct gain-of-function transfection with defined phenotypic readout (metastasis, coagulopathy) plus co-complex identification, single lab","pmids":["9531564"],"is_preprint":false},{"year":2005,"finding":"CO-029 (TSPAN8) coimmunoprecipitates with alpha6beta4 integrin in human pancreatic adenocarcinoma cells; protein kinase C activation strengthens the CO-029/alpha6beta4 colocalization and is accompanied by internalization of the integrin-tetraspanin complex, decreased laminin-5 adhesion, and increased cell migration.","method":"Co-immunoprecipitation, confocal colocalization, PKC activation assays, cell migration assays","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with functional migration readout, single lab, two orthogonal methods","pmids":["15837731"],"is_preprint":false},{"year":2006,"finding":"D6.1A/CO-029 (Tspan8) overexpression in tumor cells stimulates angiogenic factor transcription including increased MMP and uPA secretion, increased VEGF expression in fibroblasts, and upregulation of VEGFR; D6.1A is abundantly present in tumor-derived exosomes and induces systemic angiogenesis that could be fully blocked by a D6.1A-specific antibody targeting sprouting endothelium.","method":"In vitro endothelial branching assay, in vivo angiogenesis models, antibody blocking, RT-PCR, ELISA","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional readouts (in vitro and in vivo angiogenesis, gene expression), single lab","pmids":["16849554"],"is_preprint":false},{"year":2010,"finding":"Exosomal Tspan8 contributes to selective recruitment of specific proteins (CD106, CD49d) and mRNAs into exosomes; endothelial cells preferentially internalize Tspan8-CD49d complex-containing exosomes, which induces VEGF-independent upregulation of angiogenesis-related genes (von Willebrand factor, Tspan8, CXCL5, MIF, CCR1, VEGFR2) and enhanced EC proliferation, migration, sprouting, and progenitor maturation.","method":"Exosome isolation, protein/mRNA profiling, flow cytometry, EC uptake assays, gene expression analysis, in vitro angiogenesis assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct exosome functional assays with multiple orthogonal readouts, single lab","pmids":["20124479"],"is_preprint":false},{"year":2010,"finding":"Tspan8-internalization upon activation proceeds faster than CD9 internalization and relies on association of the Tspan8 N-terminal region with intersectin-2 (a clathrin-coated pit component); PMA-induced activation drives formation of a Tspan8-intersectin2-CD49d-clathrin complex in cholesterol-depletion-resistant membrane microdomains, promotes cell migration, but reduces matrix and cell adhesion. Use of Tspan8-CD9 and Tspan8-CD151 chimeras established that the N- and C-terminal regions determine differential internalization routes.","method":"Chimeric protein constructs (N/C-terminal swaps), co-immunoprecipitation, cholesterol depletion assays, internalization kinetics, cell migration and adhesion assays","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chimeric mutagenesis approach combined with co-IP and functional assays, single lab","pmids":["20937409"],"is_preprint":false},{"year":2010,"finding":"Co-029/Tspan8 directly interacts with E-cadherin (established by chemical cross-linking and co-immunoprecipitation); silencing E-cadherin or p120-catenin unmasks a Co-029-dependent cell motility mechanism involving a switch between collagen-binding integrins alpha1beta1 and alpha2beta1; antibody-mediated disruption of Co-029 reduced motility only when p120-catenin was silenced.","method":"Chemical cross-linking, co-immunoprecipitation, siRNA silencing, cell motility assays, antibody blocking","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction documented by two orthogonal methods (cross-linking + co-IP) with functional epistasis, single lab","pmids":["20858717"],"is_preprint":false},{"year":2013,"finding":"Tspan8 knockdown in metastatic ASML cells leads to pronounced adhesion (due to CD151 associating with alpha3 integrin), while Tspan8 normally recruits beta4 integrin into motility-promoting complexes accompanied by beta4 phosphorylation, Src recruitment, and FAK/Ras activation. CD151 associates more readily with MMP9 and MMP13 than Tspan8 does, establishing distinct functional roles for the two tetraspanins in metastasis.","method":"Stable knockdown, co-immunoprecipitation, phosphorylation assays, invasion/migration assays, in vivo metastasis models","journal":"European journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — stable KD with multiple biochemical and functional readouts, single lab","pmids":["23683890"],"is_preprint":false},{"year":2008,"finding":"TM4SF3 (TSPAN8) overexpression in low-invasive esophageal carcinoma cells promotes migration, invasion, and in vivo metastasis; mechanistically, TM4SF3 upregulates ADAM12m expression, and siRNA-mediated abrogation of ADAM12m significantly suppresses TM4SF3-mediated invasion, placing ADAM12m downstream of TM4SF3 in an invasion pathway.","method":"Stable overexpression, siRNA knockdown, migration/invasion assays, xenograft spontaneous metastasis model, Western blotting","journal":"Clinical & experimental metastasis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function and loss-of-function with epistasis (ADAM12m siRNA rescue), in vivo validation, single lab","pmids":["18365756"],"is_preprint":false},{"year":2009,"finding":"In Xenopus laevis, tm4sf3 (ortholog of TSPAN8/TM4SF3) is expressed specifically in the ventral pancreas; morpholino-mediated knockdown inhibits dorsal-ventral pancreatic bud fusion and acinar cell differentiation, while overexpression promotes annular pancreas formation, establishing a role for this tetraspanin in pancreatic morphogenesis.","method":"Morpholino knockdown, mRNA overexpression, in situ hybridization, transgenic GFP chimeric embryos, Xenopus developmental model","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain- and loss-of-function in a developmental model with defined morphogenetic phenotype, single lab","pmids":["19403659"],"is_preprint":false},{"year":2012,"finding":"CO-029 (TSPAN8) knockdown in HT29 colon cancer cells significantly reduces cell migration, accompanied by upregulation of integrin-dependent cell-matrix adhesion on laminin and increased calcium-dependent cell-cell adhesion; cell surface levels of laminin-binding integrin alpha3beta1 and fibronectin-binding alpha5beta1 are increased while CD44 is decreased; MelCAM levels are reduced contributing to altered cell-cell adhesion.","method":"siRNA knockdown, cell migration assays, flow cytometry for surface integrins, adhesion assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple biochemical readouts (integrin levels, adhesion, migration), single lab","pmids":["22679508"],"is_preprint":false},{"year":2015,"finding":"Exosomal CD151 and Tspan8 contribute to host matrix remodeling through tetraspanin-integrin and tetraspanin-protease associations; CD151/Tspan8-competent exosomes support stroma cell activation (upregulation of cytokines, cytokine receptors, and proteases), promote inflammatory cytokine expression in hematopoietic cells, and drive EMT gene expression in poorly metastatic cells. Knockdown of both tetraspanins severely reduces exosome binding/uptake.","method":"Knockdown cell lines, exosome isolation, co-culture assays, binding/uptake assays, gene expression profiling, in vivo metastasis models","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal knockdown/rescue experiments with multiple functional readouts, single lab","pmids":["25544774"],"is_preprint":false},{"year":2015,"finding":"TM4SF3 (TSPAN8) forms a physical complex with androgen receptor (AR) in prostate cancer cells; androgen inhibits proteasome-dependent degradation of TM4SF3, stabilizing the protein; TM4SF3 nuclear localization depends on androgen-induced AR nuclear translocation; direct TM4SF3-AR interaction leads to mutual stabilization (knockdown of TM4SF3 reduces AR protein levels); TM4SF3 regulates androgen-dependent gene expression and PCa cell proliferation.","method":"Co-immunoprecipitation, in vitro binding assay, nuclear fractionation, proteasome inhibitor experiments, siRNA knockdown, gene expression assays","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct interaction confirmed in vitro and in cells, nuclear localization experiments, mutual stabilization demonstrated by KD, multiple orthogonal methods","pmids":["26649804"],"is_preprint":false},{"year":2015,"finding":"TSPAN8 large extracellular loop (LEL, amino acids 140-205) is identified as a key domain for regulating metastatic colorectal cancer invasion; a human anti-TSPAN8-LEL antibody specifically reduces invasion of TSPAN8-expressing metastatic CRC cells.","method":"Phage display antibody generation, in vitro invasion assays, domain mapping","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single antibody functional assay without full mechanistic dissection, single lab","pmids":["26562525"],"is_preprint":false},{"year":2015,"finding":"LSD1 epigenetically regulates TSPAN8 expression by reducing H3K9me2 occupancy on the TSPAN8 promoter in colorectal cancer cells, thereby upregulating TSPAN8; TSPAN8 promotes EMT in a LSD1-dependent manner.","method":"ChIP assay for H3K9me2 at TSPAN8 promoter, siRNA knockdown of LSD1, RT-PCR, Western blotting, EMT marker analysis","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrates epigenetic mechanism, KD experiments, single lab, two orthogonal methods","pmids":["31790687"],"is_preprint":false},{"year":2017,"finding":"p53 acts as a direct transcriptional repressor of TSPAN8; the TSPAN8 promoter contains consensus p53-binding sites; p53 silencing is sufficient to activate Tspan8 expression in non-invasive melanoma cells; p53 modulates matrigel invasion in a TSPAN8-dependent manner.","method":"Promoter analysis, siRNA silencing of p53, luciferase reporter assays (implied), invasion assays, epistasis via TSPAN8 rescue","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptional repression established by p53 KD with TSPAN8-dependent invasion phenotype, single lab","pmids":["28368391"],"is_preprint":false},{"year":2016,"finding":"An RNAi screen identified LCMR1 as a transcriptional activator of Tspan8 in melanoma; LCMR1 modulation positively regulates endogenous Tspan8 expression with concomitant phenotypic changes (loss of cell-matrix adherence, increased invasion); GSK3β, PTEN, and IQGAP1 were identified as Tspan8 repressors. Both LCMR1 and Tspan8 can be downregulated by vemurafenib (a BRAF inhibitor), placing Tspan8 downstream of RAF-MEK-ERK signaling.","method":"Large-scale RNAi screen, siRNA knockdown, overexpression, invasion assays, in vivo tumorigenicity","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — large-scale screen with functional validation, multiple regulators identified, single lab","pmids":["27375018"],"is_preprint":false},{"year":2019,"finding":"TSPAN8 interacts with PTCH1 and inhibits degradation of the SHH/PTCH1 complex through recruitment of deubiquitinating enzyme ATXN3; this results in SMO translocation to cilia, downstream Hedgehog gene expression, enhanced stemness (NANOG, OCT4, ALDHA1), chemoresistance, and tumor formation in mice.","method":"Co-immunoprecipitation, ubiquitination assays, confocal microscopy (SMO cilia localization), siRNA/shRNA knockdown, in vivo tumor formation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mechanistic dissection of protein complex (TSPAN8-PTCH1-ATXN3), ubiquitination assay, SMO localization readout, in vivo validation, multiple orthogonal methods","pmids":["31253779"],"is_preprint":false},{"year":2019,"finding":"Tspan8 expression induces beta-catenin stabilization in melanoma cells; beta-catenin in turn directly transcriptionally activates Tspan8 expression, forming a positive feedback loop that sustains invasive properties. Beta-catenin activation correlates with high Tspan8 in transgenic melanoma mouse lesions and human pre-melanoma neoplasms.","method":"Overexpression/knockdown, Western blotting for beta-catenin, luciferase reporter assays (beta-catenin target), in vivo transgenic mouse melanoma model, immunohistochemistry","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional regulatory loop established by KD/OE and transcriptional assays in vitro and in vivo, single lab","pmids":["30679790"],"is_preprint":false},{"year":2020,"finding":"Tspan8+ melanoma cells cooperate with surrounding keratinocytes to promote keratinocyte-derived proMMP-9 activation, collagen IV degradation, and dermal colonization (cell non-autonomous mechanism); this is associated with elevated active MMP-3 and low TIMP-1 levels; a Tspan8-blocking antibody reduces proMMP-9 activation and dermal invasion.","method":"Skin reconstruct model, proMMP-9 activation assay, collagen IV immunostaining, antibody blocking, overexpression in melanoma cells","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reconstitution in skin model with defined molecular mechanism (proMMP-9 activation), antibody blocking confirms specificity, single lab","pmids":["32455575"],"is_preprint":false},{"year":2021,"finding":"SOX9 is identified as a key transcriptional regulator of TSPAN8 expression in response to EGF stimulation in pancreatic cancer; SOX9 modulation positively regulates endogenous TSPAN8 with concomitant loss of cell-matrix adherence and increased invasion; EGFR tyrosine kinase inhibitors downregulate both SOX9 and TSPAN8 in vitro.","method":"ChIP or reporter assays (implied for SOX9-TSPAN8), siRNA/shRNA knockdown, overexpression, invasion assays, EGF stimulation, EGFR inhibitor treatment","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptional regulation with functional phenotype, pharmacological validation, single lab","pmids":["34163029"],"is_preprint":false},{"year":2022,"finding":"EGFR signaling induces TSPAN8 nuclear translocation by activating AKT, which directly phosphorylates TSPAN8 at Ser129; this phosphorylation is essential for TSPAN8 binding with 14-3-3θ and importin-β1. In the nucleus, phosphorylated TSPAN8 interacts with STAT3 to enhance its chromatin occupancy and transcription of downstream genes (MYC, BCL2, MMP9). TSPAN8 palmitoylation and cholesterol association are required for its extraction from the plasma membrane prior to nuclear import.","method":"In vitro kinase assay (AKT phosphorylation of TSPAN8 Ser129), site-directed mutagenesis (S129A), co-immunoprecipitation (14-3-3θ, importin-β1, STAT3), ChIP-seq for STAT3 occupancy, nuclear fractionation, palmitoylation assays, humanized monoclonal antibody functional studies in vitro and in vivo","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay plus mutagenesis, multiple co-IP interactions, ChIP-seq, nuclear fractionation, in vivo antibody validation; multiple orthogonal methods in one study","pmids":["35197608"],"is_preprint":false},{"year":2023,"finding":"TM4SF3 (TSPAN8) physically interacts with AR-V7 (castration-resistant prostate cancer splice variant) in addition to full-length AR; TM4SF3 interaction with AR or AR-V7 results in mutual deubiquitination and stabilization of both proteins; nuclear TM4SF3 is co-recruited to promoters of AR/AR-V7-regulated genes and is required for their expression. The interaction domains within AR and TM4SF3 were mapped.","method":"Co-immunoprecipitation, ubiquitination assays, ChIP (promoter recruitment), siRNA knockdown, domain mapping by truncation constructs","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (co-IP, ubiquitination, ChIP), interaction domain mapping, replicated and extended from prior TM4SF3-AR study","pmids":["36951301"],"is_preprint":false},{"year":2023,"finding":"Tspan8 associates with endothelin-converting enzyme ECE1 and amplifies its enzymatic activity (conversion of bigET1 to endothelin-1), as shown in Tspan8-transduced colon carcinoma cells and in ileum tissue fragments from Tspan8 knockout vs. wild-type mice.","method":"Mass spectrometry (co-purification), Western blotting, ECE1 enzymatic activity assay (bigET1 to ET1 conversion), Tspan8 knockout mouse tissue comparison","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry identification + enzymatic activity assay validated in KO mouse tissue, two orthogonal methods, single lab","pmids":["37835445"],"is_preprint":false},{"year":2023,"finding":"Tspan8 colocalizes with lipid rafts and facilitates IFN-γR1 localization at or near lipid rafts; Tspan8 silencing impairs lipid raft-mediated but promotes clathrin-mediated endocytosis of IFN-γR1, leading to increased STAT1 signaling; Tspan8 removal increases intestinal epithelial permeability and upregulates IFN-γ-STAT1 signaling, establishing Tspan8 as a regulator of IFN-γR1 endocytic routing and intestinal barrier function.","method":"Lipid raft fractionation, siRNA knockdown, IFN-γR1 endocytosis assays (clathrin vs. lipid raft pathway), STAT1 signaling assay, intestinal permeability measurement, mouse UC model","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic dissection of endocytic routing with functional barrier readout, KO mouse model, multiple orthogonal methods, single lab","pmids":["37204469"],"is_preprint":false},{"year":2024,"finding":"MDM2 is identified as a common E3 ubiquitin ligase for AR, AR-V7, and TM4SF3 (TSPAN8) in prostate cancer cells; MDM2 inhibition (siRNA or pharmacological inhibitor) elevates all three proteins by reducing their ubiquitination; MDM2 affects TM4SF3 protein stability independently of AR (shown in AR-negative PC-3 cells).","method":"siRNA screen for E3 ligases, siRNA knockdown of MDM2, pharmacological MDM2 inhibitor, ubiquitination assays, Western blotting, AR-negative PC-3 cell control","journal":"Endocrine oncology (Bristol, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — E3 ligase screen with validation, ubiquitination assay, AR-independent control experiment, single lab","pmids":["38410785"],"is_preprint":false},{"year":2024,"finding":"TSPAN8+ myCAFs promote cancer cell stemness through secretion of SASP factors IL-6 and IL-8; mechanistically, TSPAN8 recruits MAPK11 to phosphorylate ubiquitin E3 ligase RBBP6 at Ser772, inducing SIRT6 protein destruction; SIRT6 downregulation upregulates GLS1 and PYCR1, causing myCAFs to secrete aspartate and proline as nutritional support for breast cancer outgrowth.","method":"Co-immunoprecipitation (TSPAN8-MAPK11-RBBP6 complex), phosphorylation assays, SIRT6 protein stability assays, metabolite secretion assays, siRNA knockdown, single-cell flow cytometry","journal":"Science translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of complex, phosphorylation assay, downstream metabolic readouts, single lab with multiple orthogonal methods","pmids":["38569015"],"is_preprint":false},{"year":2021,"finding":"TSPAN8-blocking antibodies diminish SARS-CoV-2 infection of lung organoids; TSPAN8 surface levels prior to infection strongly correlate with infection rate, identifying TSPAN8 as a mediator of SARS-CoV-2 infection in lung epithelial cells.","method":"Lung organoid infection model, antibody blocking experiments, correlation of TSPAN8 levels with infection rate","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, antibody blocking in organoid model without full mechanistic dissection of how TSPAN8 mediates viral entry","pmids":["34100012"],"is_preprint":true},{"year":2016,"finding":"TSPAN8-high spermatogonia in the prepubertal mouse testis are enriched for spermatogonial stem cell (SSC) activity, as demonstrated by transplantation assays; TSPAN8-high and TSPAN8-low subpopulations show differential gene expression and DNA methylation patterns in promoters of differentially expressed genes.","method":"FACS sorting by TSPAN8 surface expression, spermatogonial transplantation assays, RNA-seq, methyl-seq, ChIP-seq","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transplantation assay provides definitive functional evidence for SSC enrichment, multiple orthogonal molecular analyses, single lab","pmids":["27733379"],"is_preprint":false},{"year":2019,"finding":"TSPAN8 directly interacts with beta-catenin in colorectal cancer cells (Co-IP) and enhances its protein expression; beta-catenin in turn directly binds to the TSPAN8 promoter (ChIP) and enhances TSPAN8 transcription, forming a positive regulatory loop that promotes colorectal cancer stemness and sphere-forming capacity.","method":"Co-immunoprecipitation, ChIP assay, knockdown, sphere formation assay","journal":"Medical science monitor","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein interaction (co-IP) and direct transcriptional regulation (ChIP) established with functional stemness readout, single lab","pmids":["31838484"],"is_preprint":false},{"year":2022,"finding":"GATA6 transcription factor binds the TSPAN8 promoter to promote TSPAN8 expression downstream of lncRNA SOX21-AS1; SOX21-AS1 interacts with GATA6 (RNA pull-down, RIP); TSPAN8 expression activates ERK signaling pathway; this SOX21-AS1/GATA6/TSPAN8/ERK axis promotes lung adenocarcinoma invasion and migration.","method":"RNA pull-down, RIP, ChIP on TSPAN8 promoter, dual-luciferase reporter assay, siRNA/overexpression, ERK pathway analysis, in vivo xenograft","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding (ChIP + luciferase), RNA-protein interaction assays, multiple orthogonal methods, single lab","pmids":["32698071"],"is_preprint":false},{"year":2015,"finding":"TSPAN8 activates the ERK MAPK pathway in gastric cancer cells; MEK-ERK inhibition (U0126) reverses the effects of TSPAN8 overexpression on cell proliferation and invasion, placing ERK MAPK downstream of TSPAN8 in a proliferation/invasion pathway.","method":"Plasmid overexpression, siRNA knockdown, MEK inhibitor (U0126), MTT proliferation assay, Transwell invasion assay, Western blotting for ERK phosphorylation","journal":"International journal of clinical and experimental medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological inhibitor rescue experiment without more direct mechanistic link between TSPAN8 and ERK activation, single lab single method","pmids":["26309511"],"is_preprint":false},{"year":2023,"finding":"TSPAN8 overexpression promotes EGFR phosphorylation and AKT phosphorylation in gastric cancer cells, activating the EGFR/AKT signaling pathway to promote migration and invasion; TSPAN8 knockdown suppresses lung metastasis in nude mice.","method":"siRNA knockdown, overexpression, Western blotting for pEGFR and pAKT, migration/invasion assays, in vivo metastasis model","journal":"Molecular biology reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway activation by Western blot without direct mechanistic link (e.g., binding or phosphorylation assay), single lab","pmids":["37535246"],"is_preprint":false},{"year":2022,"finding":"TSPAN8 can form a complex with Rictor (mTORC2 component); TSPAN8 overexpression suppresses high glucose-induced autophagy and apoptosis in kidney tubular cells (HK-2) in an mTOR activity-dependent manner.","method":"Co-immunoprecipitation (TSPAN8-Rictor), overexpression plasmid, mTOR inhibitor, flow cytometry (apoptosis), autophagy markers","journal":"Cell biology international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP without mechanistic follow-up on how TSPAN8 modulates mTORC2, single lab","pmids":["35904232"],"is_preprint":false},{"year":2021,"finding":"TSPAN8 high expression in small extracellular vesicles (sEVs) promotes their binding to target cells via confined diffusion (single-particle tracking); TSPAN8-sEVs increase cancer cell motility and EMT in recipient cells; in vivo, TSPAN8-sEVs promote uptake in liver, lung, and spleen.","method":"Single-particle tracking, genetically engineered TSPAN8-overexpressing breast cancer cells, functional motility assays, in vivo sEV uptake imaging","journal":"Journal of extracellular vesicles","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single-particle tracking quantifies biophysical mechanism, functional in vitro and in vivo validation, single lab","pmids":["34796683"],"is_preprint":false}],"current_model":"TSPAN8 is a tetraspanin that organizes membrane microdomains and associates with multiple partners including integrins (alpha6beta4, alpha6beta1), E-cadherin, AR/AR-V7, PTCH1, ATXN3, ECE1, mTORC2/Rictor, STAT3, and intersectin-2; it is internalized via a clathrin pathway requiring its N-terminal region and intersectin-2, traffics selectively into exosomes to mediate angiogenesis and pre-metastatic niche formation, and can translocate to the nucleus following AKT-mediated phosphorylation at Ser129 (driven by EGFR signaling) where it binds 14-3-3θ and importin-β1 to enter the nucleus and enhance STAT3 chromatin occupancy and transcription of oncogenes (MYC, BCL2, MMP9); in the nucleus it also stabilizes AR/AR-V7 through mutual deubiquitination, regulated by MDM2 as a common E3 ligase; at the cell surface Tspan8 promotes invasion through a cell non-autonomous mechanism involving keratinocyte-derived proMMP-9 activation, and it activates Hedgehog signaling by recruiting ATXN3 to prevent SHH/PTCH1 complex degradation, enabling SMO translocation to cilia and downstream stemness gene expression."},"narrative":{"mechanistic_narrative":"TSPAN8 (CO-029/D6.1A/TM4SF3/TM4SF3) is a glycosylated cell-surface tetraspanin that organizes membrane microdomains to drive tumor invasion, metastasis, angiogenesis, and cancer stemness [PMID:2395876, PMID:9531564, PMID:16849554]. At the plasma membrane it partitions into tetraspanin-enriched microdomains where it associates with integrins (alpha6beta1, alpha6beta4, beta4) and E-cadherin, switching cells from an adhesive to a migratory state: it recruits beta4 integrin into motility-promoting complexes accompanied by beta4 phosphorylation, Src recruitment and FAK/Ras activation, and its activation-dependent internalization via clathrin-coated pits requires its N-terminal region and intersectin-2 [PMID:15837731, PMID:20858717, PMID:23683890, PMID:20937409]. TSPAN8 is selectively sorted into exosomes/small extracellular vesicles together with integrin and protease partners, where it mediates vesicle binding to recipient endothelial and stromal cells and promotes systemic angiogenesis, matrix remodeling, and EMT-associated pre-metastatic conditioning [PMID:16849554, PMID:20124479, PMID:25544774, PMID:34796683]. Beyond its surface scaffolding role, EGFR-AKT signaling phosphorylates TSPAN8 at Ser129, enabling its extraction from cholesterol-rich membrane (requiring palmitoylation), binding to 14-3-3theta and importin-beta1, and nuclear import, where it interacts with STAT3 to enhance STAT3 chromatin occupancy and transcription of MYC, BCL2 and MMP9 [PMID:35197608]. In prostate cancer it physically binds androgen receptor and the AR-V7 splice variant, driving mutual deubiquitination and stabilization of both proteins and co-recruitment to AR-target promoters, a stability axis controlled by the shared E3 ligase MDM2 [PMID:26649804, PMID:36951301, PMID:38410785]. TSPAN8 also activates Hedgehog signaling by binding PTCH1 and recruiting the deubiquitinase ATXN3 to block SHH/PTCH1 complex degradation, permitting SMO ciliary translocation and expression of stemness genes [PMID:31253779]. TSPAN8 expression is itself a tightly regulated node, induced by LSD1, SOX9, GATA6 and a beta-catenin positive-feedback loop and repressed by p53 [PMID:31790687, PMID:28368391, PMID:30679790, PMID:34163029, PMID:31838484, PMID:32698071].","teleology":[{"year":1990,"claim":"Established the molecular identity of TSPAN8 as a glycosylated cell-surface tetraspanin, providing the structural framework for all subsequent functional work.","evidence":"cDNA cloning, COS cell expression, and lectin-binding analysis of CO-029","pmids":["2395876"],"confidence":"High","gaps":["No function assigned at identification","No interaction partners defined"]},{"year":1998,"claim":"Linked TSPAN8 to metastasis for the first time and identified integrin association as a mechanistic basis, framing it as a pro-metastatic membrane organizer.","evidence":"Stable transfection of rat D6.1A into low-metastatic tumor cells, membrane complex Western blotting, in vivo metastasis/coagulation models","pmids":["9531564"],"confidence":"Medium","gaps":["Causal contribution of alpha6beta1 association to metastasis not isolated","Coagulopathy mechanism unresolved"]},{"year":2005,"claim":"Showed that TSPAN8-integrin complexes are dynamically regulated, with PKC-driven internalization converting cells from laminin adhesion to migration.","evidence":"Reciprocal co-IP with alpha6beta4, confocal colocalization, PKC activation and migration assays in pancreatic carcinoma cells","pmids":["15837731"],"confidence":"Medium","gaps":["Direct vs. indirect TSPAN8-integrin contact not distinguished","PKC substrate within the complex unknown"]},{"year":2006,"claim":"Defined TSPAN8 as an exosome-borne angiogenic factor acting systemically, extending its role beyond the producing cell.","evidence":"In vitro endothelial branching, in vivo angiogenesis, antibody blocking, RT-PCR/ELISA of angiogenic factors","pmids":["16849554"],"confidence":"Medium","gaps":["Endothelial receptor for exosomal TSPAN8 not identified","Mechanism of selective exosomal sorting unaddressed"]},{"year":2008,"claim":"Placed ADAM12m downstream of TSPAN8 in an invasion pathway, providing an early effector for its pro-invasive activity.","evidence":"Overexpression, ADAM12m siRNA rescue, xenograft metastasis in esophageal carcinoma","pmids":["18365756"],"confidence":"Medium","gaps":["How TSPAN8 upregulates ADAM12m not defined","Direct interaction not tested"]},{"year":2009,"claim":"Demonstrated a developmental, non-oncogenic role in pancreatic morphogenesis, showing TSPAN8 function in tissue patterning.","evidence":"Morpholino knockdown and mRNA overexpression in Xenopus with in situ hybridization","pmids":["19403659"],"confidence":"Medium","gaps":["Molecular partners in pancreatic bud fusion unknown","Relevance to mammalian development untested"]},{"year":2010,"claim":"Resolved how TSPAN8 selectively loads exosomes and conditions recipient endothelium, and dissected its distinct internalization route via intersectin-2.","evidence":"Exosome protein/mRNA profiling and EC uptake assays; chimeric N/C-terminal swaps, co-IP and internalization kinetics","pmids":["20124479","20937409"],"confidence":"Medium","gaps":["Sorting determinant for specific cargo (CD49d, mRNAs) not fully mapped","Functional difference of internalization routes in vivo unclear"]},{"year":2010,"claim":"Identified E-cadherin as a direct TSPAN8 partner and showed TSPAN8 controls an integrin switch that becomes motility-driving when adherens-junction signaling is lost.","evidence":"Chemical cross-linking and co-IP, p120-catenin/E-cadherin silencing, motility and antibody-blocking assays","pmids":["20858717"],"confidence":"Medium","gaps":["Structural basis of TSPAN8-E-cadherin contact unknown","Regulation of alpha1beta1/alpha2beta1 switch mechanistically incomplete"]},{"year":2013,"claim":"Distinguished TSPAN8 from the related tetraspanin CD151, defining how TSPAN8 specifically recruits beta4 integrin into a Src-FAK-Ras motility module.","evidence":"Stable knockdown, co-IP, phosphorylation and invasion assays, in vivo metastasis in ASML cells","pmids":["23683890"],"confidence":"Medium","gaps":["Direct kinase recruited by TSPAN8 to beta4 not defined","Generalizability across tumor types untested"]},{"year":2015,"claim":"Discovered a nuclear function: TSPAN8 binds androgen receptor, undergoes androgen-dependent stabilization, and co-regulates AR target genes, reframing it as a transcriptional cofactor.","evidence":"Co-IP, in vitro binding, nuclear fractionation, proteasome inhibitor and knockdown experiments in prostate cancer cells","pmids":["26649804"],"confidence":"High","gaps":["Mechanism of nuclear import not yet defined (resolved later)","Domain mediating AR binding not mapped at this stage"]},{"year":2015,"claim":"Mapped the TSPAN8 large extracellular loop as a functional invasion domain and a therapeutic antibody target.","evidence":"Phage-display anti-LEL antibody, domain mapping and invasion assays in colorectal cancer","pmids":["26562525"],"confidence":"Low","gaps":["Single antibody functional assay without mechanistic dissection","Binding partner engaged via the LEL not identified"]},{"year":2015,"claim":"Established upstream transcriptional control of TSPAN8 by LSD1 epigenetic derepression and identified ERK MAPK as a downstream effector.","evidence":"ChIP for H3K9me2 at the TSPAN8 promoter and LSD1 knockdown; separately, MEK inhibitor rescue in gastric cancer","pmids":["31790687","26309511"],"confidence":"Medium","gaps":["How TSPAN8 activates ERK mechanistically unresolved (Low-confidence link)","Direct LSD1 vs. indirect effect on promoter not separated"]},{"year":2016,"claim":"Defined a transcriptional regulatory network (LCMR1 activator; GSK3beta/PTEN/IQGAP1 repressors) placing TSPAN8 downstream of RAF-MEK-ERK signaling, and identified a TSPAN8-high spermatogonial stem cell population, broadening its stem-cell relevance.","evidence":"RNAi screen with vemurafenib in melanoma; FACS sorting, spermatogonial transplantation, RNA/methyl/ChIP-seq in mouse testis","pmids":["27375018","27733379"],"confidence":"Medium","gaps":["Direct vs. indirect regulation by each modulator not resolved","Functional requirement of TSPAN8 itself in SSC maintenance not directly tested"]},{"year":2017,"claim":"Identified p53 as a direct transcriptional repressor of TSPAN8, integrating it into tumor-suppressor control of invasion.","evidence":"Promoter analysis, p53 silencing, and TSPAN8-dependent invasion rescue in melanoma","pmids":["28368391"],"confidence":"Medium","gaps":["Direct p53 occupancy not confirmed by ChIP","Context dependence across p53-mutant tumors unknown"]},{"year":2019,"claim":"Revealed TSPAN8 as a Hedgehog-pathway activator that recruits the deubiquitinase ATXN3 to stabilize SHH/PTCH1, driving SMO ciliary translocation and stemness.","evidence":"Co-IP, ubiquitination assays, SMO ciliary localization imaging, knockdown and in vivo tumor formation","pmids":["31253779"],"confidence":"High","gaps":["Whether TSPAN8 directly recruits ATXN3 or via an adaptor unclear","How a surface tetraspanin engages the PTCH1 complex spatially unresolved"]},{"year":2019,"claim":"Established beta-catenin positive-feedback loops in melanoma and colorectal cancer that lock in TSPAN8 expression and sustain invasive/stem phenotypes.","evidence":"Co-IP, luciferase/ChIP for beta-catenin at the TSPAN8 promoter, KD/OE, sphere formation, transgenic mouse melanoma","pmids":["30679790","31838484"],"confidence":"Medium","gaps":["Mechanism by which TSPAN8 stabilizes beta-catenin not defined","Direct TSPAN8-beta-catenin contact topology unresolved"]},{"year":2020,"claim":"Defined a cell non-autonomous invasion mechanism whereby TSPAN8+ tumor cells license keratinocyte-derived proMMP-9 activation and matrix degradation.","evidence":"Skin reconstruct model, proMMP-9 activation and collagen IV assays, antibody blocking","pmids":["32455575"],"confidence":"Medium","gaps":["Signal from TSPAN8+ cells to keratinocytes not identified","Direct molecular trigger of proMMP-9 activation unknown"]},{"year":2021,"claim":"Quantified the biophysical basis of TSPAN8-sEV docking and extended its conditioning role to distant organs; flagged TSPAN8 as a potential SARS-CoV-2 entry mediator.","evidence":"Single-particle tracking of sEV binding, in vivo uptake imaging; antibody blocking in lung organoid infection (preprint)","pmids":["34796683","34100012"],"confidence":"Medium","gaps":["Receptor mediating confined-diffusion docking unknown","SARS-CoV-2 link is a preprint with no entry mechanism defined"]},{"year":2022,"claim":"Resolved the long-standing question of how a membrane tetraspanin reaches the nucleus: EGFR-AKT phosphorylation at Ser129 enables 14-3-3theta/importin-beta1 binding and STAT3-dependent oncogenic transcription.","evidence":"In vitro AKT kinase assay, S129A mutagenesis, co-IP, ChIP-seq, nuclear fractionation, palmitoylation assays, in vivo antibody","pmids":["35197608"],"confidence":"High","gaps":["How phosphorylated TSPAN8 physically detaches from the bilayer mechanistically incomplete","Direct vs. STAT3-bridged DNA contact not established"]},{"year":2022,"claim":"Identified GATA6 (downstream of lncRNA SOX21-AS1) as a TSPAN8 activator coupling to ERK, and a Rictor/mTORC2 association in renal cells, expanding the upstream and signaling network.","evidence":"RNA pull-down/RIP, ChIP/luciferase at TSPAN8 promoter, ERK analysis; separately co-IP of TSPAN8-Rictor with mTOR-dependent autophagy assays","pmids":["32698071","35904232"],"confidence":"Medium","gaps":["TSPAN8-Rictor interaction supported by single co-IP (Low confidence)","Mechanism of ERK activation downstream of TSPAN8 unresolved"]},{"year":2023,"claim":"Extended the AR axis to castration-resistant AR-V7 with mutual deubiquitination and promoter co-recruitment, and identified ECE1 amplification and IFN-gammaR1 endocytic routing as additional TSPAN8 surface functions.","evidence":"Co-IP/ubiquitination/ChIP with AR/AR-V7 domain mapping; MS co-purification and ECE1 activity in KO tissue; lipid-raft fractionation and IFN-gammaR1 endocytosis with KO mouse colitis model","pmids":["36951301","37835445","37204469"],"confidence":"Medium","gaps":["Whether TSPAN8 carries intrinsic deubiquitinating function or recruits a DUB for AR is unresolved","Direct vs. scaffold role in ECE1 activation undefined"]},{"year":2024,"claim":"Identified MDM2 as the shared E3 ligase controlling TSPAN8/AR/AR-V7 stability and defined a TSPAN8-MAPK11-RBBP6-SIRT6 axis in cancer-associated fibroblasts feeding tumor stemness via metabolite secretion.","evidence":"E3 ligase siRNA screen, ubiquitination and AR-negative control; co-IP of TSPAN8-MAPK11-RBBP6, phosphorylation, SIRT6 stability and metabolite assays in myCAFs","pmids":["38410785","38569015"],"confidence":"Medium","gaps":["How TSPAN8 selects MDM2 substrates not defined","Direct TSPAN8-MAPK11 binding interface not mapped"]},{"year":null,"claim":"The structural basis for how a four-pass membrane tetraspanin is extracted from the bilayer, imported to the nucleus, and engages chromatin-associated transcription factors versus its canonical surface microdomain scaffolding remains mechanistically incomplete.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of nuclear TSPAN8 complexes","Membrane-to-nucleus extraction mechanism unresolved","Receptor(s) mediating exosome/sEV docking on recipient cells unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,6,7,17,21,22]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[17,22,23,25]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[12,21,22]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,5,24]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[12,21,22]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3,4,11,34]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[17]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[17,21,32]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,3,8,11]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[21,22,12]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[3,4,11,34]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[17,22,25]}],"complexes":["TSPAN8-alpha6beta4 integrin complex","TSPAN8-intersectin2-CD49d-clathrin complex","TSPAN8-PTCH1-ATXN3 complex","TSPAN8-MAPK11-RBBP6 complex"],"partners":["ITGB4","CDH1","AR","PTCH1","ATXN3","STAT3","MDM2","RICTOR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P19075","full_name":"Tetraspanin-8","aliases":["Transmembrane 4 superfamily member 3","Tumor-associated antigen CO-029"],"length_aa":237,"mass_kda":26.0,"function":"Structural component of specialized membrane microdomains known as tetraspanin-enriched microdomains (TERMs), which act as platforms for receptor clustering and signaling (PubMed:27180357, PubMed:36078095). Participates thereby in diverse biological functions such as cell signal transduction, migration and protein trafficking (PubMed:25761241). Promotes ADAM17-mediated TNF processing through recruitment of ADAM17 to tetraspanin-enriched micro-domains (TEMs) (PubMed:36078095). Forms a complex with RICTOR and integrin alpha3/ITGA3 to mediate mTORC2 activation and AKT1 phosphorylation leading to cell migration (PubMed:25761241). Reduces apoptosis and autophagy induced by high glucose levels through forming a complex with mTOR and RICTOR (PubMed:35904232). Contributes to the maintenance of intestinal epithelial barrier and plays a role in the regulation of intestine inflammation by switching interferon gamma receptor 1/IFNGR1 from clathrin-dependent to lipid raft-dependent endocytosis route to limit STAT1 activation magnitude and duration (PubMed:37204469). Acts as a modulator of the endothelin axis by associating with endothelin converting enzyme ECE1 and regulating its activity of conversion of the endothelin-1 precursor to endothelin (PubMed:37835445)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P19075/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TSPAN8","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TSPAN8","total_profiled":1310},"omim":[{"mim_id":"608212","title":"IMMUNITY-RELATED GTPase M; IRGM","url":"https://www.omim.org/entry/608212"},{"mim_id":"600769","title":"TETRASPANIN 8; TSPAN8","url":"https://www.omim.org/entry/600769"},{"mim_id":"222100","title":"TYPE 1 DIABETES MELLITUS; T1D","url":"https://www.omim.org/entry/222100"},{"mim_id":"180300","title":"RHEUMATOID ARTHRITIS; RA","url":"https://www.omim.org/entry/180300"},{"mim_id":"125853","title":"TYPE 2 DIABETES MELLITUS; T2D","url":"https://www.omim.org/entry/125853"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":891.6},{"tissue":"stomach 1","ntpm":595.5}],"url":"https://www.proteinatlas.org/search/TSPAN8"},"hgnc":{"alias_symbol":["CO-029"],"prev_symbol":["TM4SF3"]},"alphafold":{"accession":"P19075","domains":[{"cath_id":"-","chopping":"2-237","consensus_level":"medium","plddt":88.2386,"start":2,"end":237}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P19075","model_url":"https://alphafold.ebi.ac.uk/files/AF-P19075-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P19075-F1-predicted_aligned_error_v6.png","plddt_mean":87.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TSPAN8","jax_strain_url":"https://www.jax.org/strain/search?query=TSPAN8"},"sequence":{"accession":"P19075","fasta_url":"https://rest.uniprot.org/uniprotkb/P19075.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P19075/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P19075"}},"corpus_meta":[{"pmid":"20124479","id":"PMC_20124479","title":"Cell surface tetraspanin Tspan8 contributes 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TSPAN8.","date":"2024","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/38275818","citation_count":8,"is_preprint":false},{"pmid":"28274157","id":"PMC_28274157","title":"HNF1B, TSPAN8 and NOTCH2 gene polymorphisms in women with gestational diabetes.","date":"2017","source":"The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians","url":"https://pubmed.ncbi.nlm.nih.gov/28274157","citation_count":7,"is_preprint":false},{"pmid":"37204469","id":"PMC_37204469","title":"Tetraspanin Tspan8 restrains interferon signaling to stabilize intestinal epithelium by directing endocytosis of interferon receptor.","date":"2023","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/37204469","citation_count":7,"is_preprint":false},{"pmid":"34401672","id":"PMC_34401672","title":"Signatures of TSPAN8 variants associated with human metabolic regulation and diseases.","date":"2021","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/34401672","citation_count":7,"is_preprint":false},{"pmid":"38410785","id":"PMC_38410785","title":"MDM2 regulates the stability of AR, AR-V7, and TM4SF3 proteins in prostate cancer.","date":"2024","source":"Endocrine oncology (Bristol, England)","url":"https://pubmed.ncbi.nlm.nih.gov/38410785","citation_count":6,"is_preprint":false},{"pmid":"37535246","id":"PMC_37535246","title":"TSPAN8 regulates EGFR/AKT pathway to enhance metastasis in gastric cancer.","date":"2023","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/37535246","citation_count":5,"is_preprint":false},{"pmid":"35904232","id":"PMC_35904232","title":"TSPAN8 alleviates high glucose-induced apoptosis and autophagy via targeting mTORC2.","date":"2022","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/35904232","citation_count":5,"is_preprint":false},{"pmid":"36084547","id":"PMC_36084547","title":"Histone demethylase KDM2A suppresses EGF-TSPAN8 pathway to inhibit breast cancer cell migration and invasion in vitro.","date":"2022","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/36084547","citation_count":5,"is_preprint":false},{"pmid":"36951301","id":"PMC_36951301","title":"The Transmembrane Protein TM4SF3 Interacts With AR and AR-V7 and is Recruited to AR Target Genes.","date":"2023","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/36951301","citation_count":4,"is_preprint":false},{"pmid":"38398085","id":"PMC_38398085","title":"Cancer Cell Biomechanical Properties Accompany Tspan8-Dependent Cutaneous Melanoma Invasion.","date":"2024","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/38398085","citation_count":3,"is_preprint":false},{"pmid":"38861838","id":"PMC_38861838","title":"Overexpression of TSPAN8 in consensus molecular subtype 3 colorectal cancer.","date":"2024","source":"Experimental and molecular pathology","url":"https://pubmed.ncbi.nlm.nih.gov/38861838","citation_count":3,"is_preprint":false},{"pmid":"40251391","id":"PMC_40251391","title":"Cancer stem cells-derived exosomal TSPAN8 enhances non-stem cancer cells stemness and promotes malignant progression in PDAC.","date":"2025","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/40251391","citation_count":2,"is_preprint":false},{"pmid":"37835445","id":"PMC_37835445","title":"The Tetraspanin Tspan8 Associates with Endothelin Converting Enzyme ECE1 and Regulates Its 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England)","url":"https://pubmed.ncbi.nlm.nih.gov/37822366","citation_count":0,"is_preprint":false},{"pmid":"38430035","id":"PMC_38430035","title":"miR-378a-5p represses Barrett's esophagus cells proliferation, migration and invasion through targeting TSPAN8.","date":"2024","source":"Cellular and molecular biology (Noisy-le-Grand, France)","url":"https://pubmed.ncbi.nlm.nih.gov/38430035","citation_count":0,"is_preprint":false},{"pmid":"37572802","id":"PMC_37572802","title":"Regional expression differences of SERT and TSPAN8 in hippocampus, cerebellum and cortex of wild-type young, adult and middle-aged rats.","date":"2023","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/37572802","citation_count":0,"is_preprint":false},{"pmid":"42097620","id":"PMC_42097620","title":"TSPAN8-mediated Epithelial-mesenchymal Transition Drives Acquired Radioresistance in Cervical Cancer.","date":"2026","source":"Radiation research","url":"https://pubmed.ncbi.nlm.nih.gov/42097620","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.27.672753","title":"A Spatially Resolved Atlas of Alternative Polyadenylation Across 18 Human Tissues and 76 Disease States","date":"2025-09-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.27.672753","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":37117,"output_tokens":9220,"usd":0.124826,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19370,"output_tokens":6956,"usd":0.135375,"stage2_stop_reason":"end_turn"},"total_usd":0.260201,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1990,\n      \"finding\": \"CO-029 (TSPAN8) was identified as a cell surface glycoprotein of 27-34 kDa belonging to the tetraspanin family (sharing homology with ME491/CD63, CD37, and Schistosoma mansoni Sm23), as determined by cDNA cloning and transient expression in COS cells, with the protein shown to be glycosylated (reactive with wheat germ agglutinin indicating N-acetylglucosamine/N-acetyl-neuraminic acid residues).\",\n      \"method\": \"cDNA cloning, COS cell expression, immunoprecipitation, Western blotting, lectin-Sepharose binding\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct molecular cloning, recombinant expression, and sequence analysis establishing protein identity and family membership\",\n      \"pmids\": [\"2395876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The rat homologue of CO-029, D6.1A (Tspan8), associates with alpha6beta1 integrin as shown by Western blotting of membrane complexes; transfection of D6.1A cDNA into a low-metastasizing tumor line increased metastatic potential and induced disseminated intravascular coagulation/consumption coagulopathy in vivo, establishing a functional role for this tetraspanin in metastasis and coagulation.\",\n      \"method\": \"cDNA cloning, stable transfection, Western blotting of membrane complexes, in vivo tumor models\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct gain-of-function transfection with defined phenotypic readout (metastasis, coagulopathy) plus co-complex identification, single lab\",\n      \"pmids\": [\"9531564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CO-029 (TSPAN8) coimmunoprecipitates with alpha6beta4 integrin in human pancreatic adenocarcinoma cells; protein kinase C activation strengthens the CO-029/alpha6beta4 colocalization and is accompanied by internalization of the integrin-tetraspanin complex, decreased laminin-5 adhesion, and increased cell migration.\",\n      \"method\": \"Co-immunoprecipitation, confocal colocalization, PKC activation assays, cell migration assays\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with functional migration readout, single lab, two orthogonal methods\",\n      \"pmids\": [\"15837731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"D6.1A/CO-029 (Tspan8) overexpression in tumor cells stimulates angiogenic factor transcription including increased MMP and uPA secretion, increased VEGF expression in fibroblasts, and upregulation of VEGFR; D6.1A is abundantly present in tumor-derived exosomes and induces systemic angiogenesis that could be fully blocked by a D6.1A-specific antibody targeting sprouting endothelium.\",\n      \"method\": \"In vitro endothelial branching assay, in vivo angiogenesis models, antibody blocking, RT-PCR, ELISA\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional readouts (in vitro and in vivo angiogenesis, gene expression), single lab\",\n      \"pmids\": [\"16849554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Exosomal Tspan8 contributes to selective recruitment of specific proteins (CD106, CD49d) and mRNAs into exosomes; endothelial cells preferentially internalize Tspan8-CD49d complex-containing exosomes, which induces VEGF-independent upregulation of angiogenesis-related genes (von Willebrand factor, Tspan8, CXCL5, MIF, CCR1, VEGFR2) and enhanced EC proliferation, migration, sprouting, and progenitor maturation.\",\n      \"method\": \"Exosome isolation, protein/mRNA profiling, flow cytometry, EC uptake assays, gene expression analysis, in vitro angiogenesis assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct exosome functional assays with multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"20124479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Tspan8-internalization upon activation proceeds faster than CD9 internalization and relies on association of the Tspan8 N-terminal region with intersectin-2 (a clathrin-coated pit component); PMA-induced activation drives formation of a Tspan8-intersectin2-CD49d-clathrin complex in cholesterol-depletion-resistant membrane microdomains, promotes cell migration, but reduces matrix and cell adhesion. Use of Tspan8-CD9 and Tspan8-CD151 chimeras established that the N- and C-terminal regions determine differential internalization routes.\",\n      \"method\": \"Chimeric protein constructs (N/C-terminal swaps), co-immunoprecipitation, cholesterol depletion assays, internalization kinetics, cell migration and adhesion assays\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chimeric mutagenesis approach combined with co-IP and functional assays, single lab\",\n      \"pmids\": [\"20937409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Co-029/Tspan8 directly interacts with E-cadherin (established by chemical cross-linking and co-immunoprecipitation); silencing E-cadherin or p120-catenin unmasks a Co-029-dependent cell motility mechanism involving a switch between collagen-binding integrins alpha1beta1 and alpha2beta1; antibody-mediated disruption of Co-029 reduced motility only when p120-catenin was silenced.\",\n      \"method\": \"Chemical cross-linking, co-immunoprecipitation, siRNA silencing, cell motility assays, antibody blocking\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction documented by two orthogonal methods (cross-linking + co-IP) with functional epistasis, single lab\",\n      \"pmids\": [\"20858717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Tspan8 knockdown in metastatic ASML cells leads to pronounced adhesion (due to CD151 associating with alpha3 integrin), while Tspan8 normally recruits beta4 integrin into motility-promoting complexes accompanied by beta4 phosphorylation, Src recruitment, and FAK/Ras activation. CD151 associates more readily with MMP9 and MMP13 than Tspan8 does, establishing distinct functional roles for the two tetraspanins in metastasis.\",\n      \"method\": \"Stable knockdown, co-immunoprecipitation, phosphorylation assays, invasion/migration assays, in vivo metastasis models\",\n      \"journal\": \"European journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — stable KD with multiple biochemical and functional readouts, single lab\",\n      \"pmids\": [\"23683890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TM4SF3 (TSPAN8) overexpression in low-invasive esophageal carcinoma cells promotes migration, invasion, and in vivo metastasis; mechanistically, TM4SF3 upregulates ADAM12m expression, and siRNA-mediated abrogation of ADAM12m significantly suppresses TM4SF3-mediated invasion, placing ADAM12m downstream of TM4SF3 in an invasion pathway.\",\n      \"method\": \"Stable overexpression, siRNA knockdown, migration/invasion assays, xenograft spontaneous metastasis model, Western blotting\",\n      \"journal\": \"Clinical & experimental metastasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function and loss-of-function with epistasis (ADAM12m siRNA rescue), in vivo validation, single lab\",\n      \"pmids\": [\"18365756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In Xenopus laevis, tm4sf3 (ortholog of TSPAN8/TM4SF3) is expressed specifically in the ventral pancreas; morpholino-mediated knockdown inhibits dorsal-ventral pancreatic bud fusion and acinar cell differentiation, while overexpression promotes annular pancreas formation, establishing a role for this tetraspanin in pancreatic morphogenesis.\",\n      \"method\": \"Morpholino knockdown, mRNA overexpression, in situ hybridization, transgenic GFP chimeric embryos, Xenopus developmental model\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain- and loss-of-function in a developmental model with defined morphogenetic phenotype, single lab\",\n      \"pmids\": [\"19403659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CO-029 (TSPAN8) knockdown in HT29 colon cancer cells significantly reduces cell migration, accompanied by upregulation of integrin-dependent cell-matrix adhesion on laminin and increased calcium-dependent cell-cell adhesion; cell surface levels of laminin-binding integrin alpha3beta1 and fibronectin-binding alpha5beta1 are increased while CD44 is decreased; MelCAM levels are reduced contributing to altered cell-cell adhesion.\",\n      \"method\": \"siRNA knockdown, cell migration assays, flow cytometry for surface integrins, adhesion assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple biochemical readouts (integrin levels, adhesion, migration), single lab\",\n      \"pmids\": [\"22679508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Exosomal CD151 and Tspan8 contribute to host matrix remodeling through tetraspanin-integrin and tetraspanin-protease associations; CD151/Tspan8-competent exosomes support stroma cell activation (upregulation of cytokines, cytokine receptors, and proteases), promote inflammatory cytokine expression in hematopoietic cells, and drive EMT gene expression in poorly metastatic cells. Knockdown of both tetraspanins severely reduces exosome binding/uptake.\",\n      \"method\": \"Knockdown cell lines, exosome isolation, co-culture assays, binding/uptake assays, gene expression profiling, in vivo metastasis models\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal knockdown/rescue experiments with multiple functional readouts, single lab\",\n      \"pmids\": [\"25544774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TM4SF3 (TSPAN8) forms a physical complex with androgen receptor (AR) in prostate cancer cells; androgen inhibits proteasome-dependent degradation of TM4SF3, stabilizing the protein; TM4SF3 nuclear localization depends on androgen-induced AR nuclear translocation; direct TM4SF3-AR interaction leads to mutual stabilization (knockdown of TM4SF3 reduces AR protein levels); TM4SF3 regulates androgen-dependent gene expression and PCa cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assay, nuclear fractionation, proteasome inhibitor experiments, siRNA knockdown, gene expression assays\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct interaction confirmed in vitro and in cells, nuclear localization experiments, mutual stabilization demonstrated by KD, multiple orthogonal methods\",\n      \"pmids\": [\"26649804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TSPAN8 large extracellular loop (LEL, amino acids 140-205) is identified as a key domain for regulating metastatic colorectal cancer invasion; a human anti-TSPAN8-LEL antibody specifically reduces invasion of TSPAN8-expressing metastatic CRC cells.\",\n      \"method\": \"Phage display antibody generation, in vitro invasion assays, domain mapping\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single antibody functional assay without full mechanistic dissection, single lab\",\n      \"pmids\": [\"26562525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LSD1 epigenetically regulates TSPAN8 expression by reducing H3K9me2 occupancy on the TSPAN8 promoter in colorectal cancer cells, thereby upregulating TSPAN8; TSPAN8 promotes EMT in a LSD1-dependent manner.\",\n      \"method\": \"ChIP assay for H3K9me2 at TSPAN8 promoter, siRNA knockdown of LSD1, RT-PCR, Western blotting, EMT marker analysis\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrates epigenetic mechanism, KD experiments, single lab, two orthogonal methods\",\n      \"pmids\": [\"31790687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"p53 acts as a direct transcriptional repressor of TSPAN8; the TSPAN8 promoter contains consensus p53-binding sites; p53 silencing is sufficient to activate Tspan8 expression in non-invasive melanoma cells; p53 modulates matrigel invasion in a TSPAN8-dependent manner.\",\n      \"method\": \"Promoter analysis, siRNA silencing of p53, luciferase reporter assays (implied), invasion assays, epistasis via TSPAN8 rescue\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptional repression established by p53 KD with TSPAN8-dependent invasion phenotype, single lab\",\n      \"pmids\": [\"28368391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"An RNAi screen identified LCMR1 as a transcriptional activator of Tspan8 in melanoma; LCMR1 modulation positively regulates endogenous Tspan8 expression with concomitant phenotypic changes (loss of cell-matrix adherence, increased invasion); GSK3β, PTEN, and IQGAP1 were identified as Tspan8 repressors. Both LCMR1 and Tspan8 can be downregulated by vemurafenib (a BRAF inhibitor), placing Tspan8 downstream of RAF-MEK-ERK signaling.\",\n      \"method\": \"Large-scale RNAi screen, siRNA knockdown, overexpression, invasion assays, in vivo tumorigenicity\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — large-scale screen with functional validation, multiple regulators identified, single lab\",\n      \"pmids\": [\"27375018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TSPAN8 interacts with PTCH1 and inhibits degradation of the SHH/PTCH1 complex through recruitment of deubiquitinating enzyme ATXN3; this results in SMO translocation to cilia, downstream Hedgehog gene expression, enhanced stemness (NANOG, OCT4, ALDHA1), chemoresistance, and tumor formation in mice.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, confocal microscopy (SMO cilia localization), siRNA/shRNA knockdown, in vivo tumor formation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mechanistic dissection of protein complex (TSPAN8-PTCH1-ATXN3), ubiquitination assay, SMO localization readout, in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"31253779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Tspan8 expression induces beta-catenin stabilization in melanoma cells; beta-catenin in turn directly transcriptionally activates Tspan8 expression, forming a positive feedback loop that sustains invasive properties. Beta-catenin activation correlates with high Tspan8 in transgenic melanoma mouse lesions and human pre-melanoma neoplasms.\",\n      \"method\": \"Overexpression/knockdown, Western blotting for beta-catenin, luciferase reporter assays (beta-catenin target), in vivo transgenic mouse melanoma model, immunohistochemistry\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional regulatory loop established by KD/OE and transcriptional assays in vitro and in vivo, single lab\",\n      \"pmids\": [\"30679790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Tspan8+ melanoma cells cooperate with surrounding keratinocytes to promote keratinocyte-derived proMMP-9 activation, collagen IV degradation, and dermal colonization (cell non-autonomous mechanism); this is associated with elevated active MMP-3 and low TIMP-1 levels; a Tspan8-blocking antibody reduces proMMP-9 activation and dermal invasion.\",\n      \"method\": \"Skin reconstruct model, proMMP-9 activation assay, collagen IV immunostaining, antibody blocking, overexpression in melanoma cells\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reconstitution in skin model with defined molecular mechanism (proMMP-9 activation), antibody blocking confirms specificity, single lab\",\n      \"pmids\": [\"32455575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SOX9 is identified as a key transcriptional regulator of TSPAN8 expression in response to EGF stimulation in pancreatic cancer; SOX9 modulation positively regulates endogenous TSPAN8 with concomitant loss of cell-matrix adherence and increased invasion; EGFR tyrosine kinase inhibitors downregulate both SOX9 and TSPAN8 in vitro.\",\n      \"method\": \"ChIP or reporter assays (implied for SOX9-TSPAN8), siRNA/shRNA knockdown, overexpression, invasion assays, EGF stimulation, EGFR inhibitor treatment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptional regulation with functional phenotype, pharmacological validation, single lab\",\n      \"pmids\": [\"34163029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EGFR signaling induces TSPAN8 nuclear translocation by activating AKT, which directly phosphorylates TSPAN8 at Ser129; this phosphorylation is essential for TSPAN8 binding with 14-3-3θ and importin-β1. In the nucleus, phosphorylated TSPAN8 interacts with STAT3 to enhance its chromatin occupancy and transcription of downstream genes (MYC, BCL2, MMP9). TSPAN8 palmitoylation and cholesterol association are required for its extraction from the plasma membrane prior to nuclear import.\",\n      \"method\": \"In vitro kinase assay (AKT phosphorylation of TSPAN8 Ser129), site-directed mutagenesis (S129A), co-immunoprecipitation (14-3-3θ, importin-β1, STAT3), ChIP-seq for STAT3 occupancy, nuclear fractionation, palmitoylation assays, humanized monoclonal antibody functional studies in vitro and in vivo\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay plus mutagenesis, multiple co-IP interactions, ChIP-seq, nuclear fractionation, in vivo antibody validation; multiple orthogonal methods in one study\",\n      \"pmids\": [\"35197608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TM4SF3 (TSPAN8) physically interacts with AR-V7 (castration-resistant prostate cancer splice variant) in addition to full-length AR; TM4SF3 interaction with AR or AR-V7 results in mutual deubiquitination and stabilization of both proteins; nuclear TM4SF3 is co-recruited to promoters of AR/AR-V7-regulated genes and is required for their expression. The interaction domains within AR and TM4SF3 were mapped.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, ChIP (promoter recruitment), siRNA knockdown, domain mapping by truncation constructs\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (co-IP, ubiquitination, ChIP), interaction domain mapping, replicated and extended from prior TM4SF3-AR study\",\n      \"pmids\": [\"36951301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Tspan8 associates with endothelin-converting enzyme ECE1 and amplifies its enzymatic activity (conversion of bigET1 to endothelin-1), as shown in Tspan8-transduced colon carcinoma cells and in ileum tissue fragments from Tspan8 knockout vs. wild-type mice.\",\n      \"method\": \"Mass spectrometry (co-purification), Western blotting, ECE1 enzymatic activity assay (bigET1 to ET1 conversion), Tspan8 knockout mouse tissue comparison\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry identification + enzymatic activity assay validated in KO mouse tissue, two orthogonal methods, single lab\",\n      \"pmids\": [\"37835445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Tspan8 colocalizes with lipid rafts and facilitates IFN-γR1 localization at or near lipid rafts; Tspan8 silencing impairs lipid raft-mediated but promotes clathrin-mediated endocytosis of IFN-γR1, leading to increased STAT1 signaling; Tspan8 removal increases intestinal epithelial permeability and upregulates IFN-γ-STAT1 signaling, establishing Tspan8 as a regulator of IFN-γR1 endocytic routing and intestinal barrier function.\",\n      \"method\": \"Lipid raft fractionation, siRNA knockdown, IFN-γR1 endocytosis assays (clathrin vs. lipid raft pathway), STAT1 signaling assay, intestinal permeability measurement, mouse UC model\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic dissection of endocytic routing with functional barrier readout, KO mouse model, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"37204469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MDM2 is identified as a common E3 ubiquitin ligase for AR, AR-V7, and TM4SF3 (TSPAN8) in prostate cancer cells; MDM2 inhibition (siRNA or pharmacological inhibitor) elevates all three proteins by reducing their ubiquitination; MDM2 affects TM4SF3 protein stability independently of AR (shown in AR-negative PC-3 cells).\",\n      \"method\": \"siRNA screen for E3 ligases, siRNA knockdown of MDM2, pharmacological MDM2 inhibitor, ubiquitination assays, Western blotting, AR-negative PC-3 cell control\",\n      \"journal\": \"Endocrine oncology (Bristol, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — E3 ligase screen with validation, ubiquitination assay, AR-independent control experiment, single lab\",\n      \"pmids\": [\"38410785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TSPAN8+ myCAFs promote cancer cell stemness through secretion of SASP factors IL-6 and IL-8; mechanistically, TSPAN8 recruits MAPK11 to phosphorylate ubiquitin E3 ligase RBBP6 at Ser772, inducing SIRT6 protein destruction; SIRT6 downregulation upregulates GLS1 and PYCR1, causing myCAFs to secrete aspartate and proline as nutritional support for breast cancer outgrowth.\",\n      \"method\": \"Co-immunoprecipitation (TSPAN8-MAPK11-RBBP6 complex), phosphorylation assays, SIRT6 protein stability assays, metabolite secretion assays, siRNA knockdown, single-cell flow cytometry\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of complex, phosphorylation assay, downstream metabolic readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"38569015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TSPAN8-blocking antibodies diminish SARS-CoV-2 infection of lung organoids; TSPAN8 surface levels prior to infection strongly correlate with infection rate, identifying TSPAN8 as a mediator of SARS-CoV-2 infection in lung epithelial cells.\",\n      \"method\": \"Lung organoid infection model, antibody blocking experiments, correlation of TSPAN8 levels with infection rate\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, antibody blocking in organoid model without full mechanistic dissection of how TSPAN8 mediates viral entry\",\n      \"pmids\": [\"34100012\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TSPAN8-high spermatogonia in the prepubertal mouse testis are enriched for spermatogonial stem cell (SSC) activity, as demonstrated by transplantation assays; TSPAN8-high and TSPAN8-low subpopulations show differential gene expression and DNA methylation patterns in promoters of differentially expressed genes.\",\n      \"method\": \"FACS sorting by TSPAN8 surface expression, spermatogonial transplantation assays, RNA-seq, methyl-seq, ChIP-seq\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transplantation assay provides definitive functional evidence for SSC enrichment, multiple orthogonal molecular analyses, single lab\",\n      \"pmids\": [\"27733379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TSPAN8 directly interacts with beta-catenin in colorectal cancer cells (Co-IP) and enhances its protein expression; beta-catenin in turn directly binds to the TSPAN8 promoter (ChIP) and enhances TSPAN8 transcription, forming a positive regulatory loop that promotes colorectal cancer stemness and sphere-forming capacity.\",\n      \"method\": \"Co-immunoprecipitation, ChIP assay, knockdown, sphere formation assay\",\n      \"journal\": \"Medical science monitor\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein interaction (co-IP) and direct transcriptional regulation (ChIP) established with functional stemness readout, single lab\",\n      \"pmids\": [\"31838484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GATA6 transcription factor binds the TSPAN8 promoter to promote TSPAN8 expression downstream of lncRNA SOX21-AS1; SOX21-AS1 interacts with GATA6 (RNA pull-down, RIP); TSPAN8 expression activates ERK signaling pathway; this SOX21-AS1/GATA6/TSPAN8/ERK axis promotes lung adenocarcinoma invasion and migration.\",\n      \"method\": \"RNA pull-down, RIP, ChIP on TSPAN8 promoter, dual-luciferase reporter assay, siRNA/overexpression, ERK pathway analysis, in vivo xenograft\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding (ChIP + luciferase), RNA-protein interaction assays, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"32698071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TSPAN8 activates the ERK MAPK pathway in gastric cancer cells; MEK-ERK inhibition (U0126) reverses the effects of TSPAN8 overexpression on cell proliferation and invasion, placing ERK MAPK downstream of TSPAN8 in a proliferation/invasion pathway.\",\n      \"method\": \"Plasmid overexpression, siRNA knockdown, MEK inhibitor (U0126), MTT proliferation assay, Transwell invasion assay, Western blotting for ERK phosphorylation\",\n      \"journal\": \"International journal of clinical and experimental medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological inhibitor rescue experiment without more direct mechanistic link between TSPAN8 and ERK activation, single lab single method\",\n      \"pmids\": [\"26309511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TSPAN8 overexpression promotes EGFR phosphorylation and AKT phosphorylation in gastric cancer cells, activating the EGFR/AKT signaling pathway to promote migration and invasion; TSPAN8 knockdown suppresses lung metastasis in nude mice.\",\n      \"method\": \"siRNA knockdown, overexpression, Western blotting for pEGFR and pAKT, migration/invasion assays, in vivo metastasis model\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway activation by Western blot without direct mechanistic link (e.g., binding or phosphorylation assay), single lab\",\n      \"pmids\": [\"37535246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TSPAN8 can form a complex with Rictor (mTORC2 component); TSPAN8 overexpression suppresses high glucose-induced autophagy and apoptosis in kidney tubular cells (HK-2) in an mTOR activity-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation (TSPAN8-Rictor), overexpression plasmid, mTOR inhibitor, flow cytometry (apoptosis), autophagy markers\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP without mechanistic follow-up on how TSPAN8 modulates mTORC2, single lab\",\n      \"pmids\": [\"35904232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TSPAN8 high expression in small extracellular vesicles (sEVs) promotes their binding to target cells via confined diffusion (single-particle tracking); TSPAN8-sEVs increase cancer cell motility and EMT in recipient cells; in vivo, TSPAN8-sEVs promote uptake in liver, lung, and spleen.\",\n      \"method\": \"Single-particle tracking, genetically engineered TSPAN8-overexpressing breast cancer cells, functional motility assays, in vivo sEV uptake imaging\",\n      \"journal\": \"Journal of extracellular vesicles\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single-particle tracking quantifies biophysical mechanism, functional in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"34796683\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TSPAN8 is a tetraspanin that organizes membrane microdomains and associates with multiple partners including integrins (alpha6beta4, alpha6beta1), E-cadherin, AR/AR-V7, PTCH1, ATXN3, ECE1, mTORC2/Rictor, STAT3, and intersectin-2; it is internalized via a clathrin pathway requiring its N-terminal region and intersectin-2, traffics selectively into exosomes to mediate angiogenesis and pre-metastatic niche formation, and can translocate to the nucleus following AKT-mediated phosphorylation at Ser129 (driven by EGFR signaling) where it binds 14-3-3θ and importin-β1 to enter the nucleus and enhance STAT3 chromatin occupancy and transcription of oncogenes (MYC, BCL2, MMP9); in the nucleus it also stabilizes AR/AR-V7 through mutual deubiquitination, regulated by MDM2 as a common E3 ligase; at the cell surface Tspan8 promotes invasion through a cell non-autonomous mechanism involving keratinocyte-derived proMMP-9 activation, and it activates Hedgehog signaling by recruiting ATXN3 to prevent SHH/PTCH1 complex degradation, enabling SMO translocation to cilia and downstream stemness gene expression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TSPAN8 (CO-029/D6.1A/TM4SF3/TM4SF3) is a glycosylated cell-surface tetraspanin that organizes membrane microdomains to drive tumor invasion, metastasis, angiogenesis, and cancer stemness [#0, #1, #3]. At the plasma membrane it partitions into tetraspanin-enriched microdomains where it associates with integrins (alpha6beta1, alpha6beta4, beta4) and E-cadherin, switching cells from an adhesive to a migratory state: it recruits beta4 integrin into motility-promoting complexes accompanied by beta4 phosphorylation, Src recruitment and FAK/Ras activation, and its activation-dependent internalization via clathrin-coated pits requires its N-terminal region and intersectin-2 [#2, #6, #7, #5]. TSPAN8 is selectively sorted into exosomes/small extracellular vesicles together with integrin and protease partners, where it mediates vesicle binding to recipient endothelial and stromal cells and promotes systemic angiogenesis, matrix remodeling, and EMT-associated pre-metastatic conditioning [#3, #4, #11, #34]. Beyond its surface scaffolding role, EGFR-AKT signaling phosphorylates TSPAN8 at Ser129, enabling its extraction from cholesterol-rich membrane (requiring palmitoylation), binding to 14-3-3theta and importin-beta1, and nuclear import, where it interacts with STAT3 to enhance STAT3 chromatin occupancy and transcription of MYC, BCL2 and MMP9 [#21]. In prostate cancer it physically binds androgen receptor and the AR-V7 splice variant, driving mutual deubiquitination and stabilization of both proteins and co-recruitment to AR-target promoters, a stability axis controlled by the shared E3 ligase MDM2 [#12, #22, #25]. TSPAN8 also activates Hedgehog signaling by binding PTCH1 and recruiting the deubiquitinase ATXN3 to block SHH/PTCH1 complex degradation, permitting SMO ciliary translocation and expression of stemness genes [#17]. TSPAN8 expression is itself a tightly regulated node, induced by LSD1, SOX9, GATA6 and a beta-catenin positive-feedback loop and repressed by p53 [#14, #15, #18, #20, #29, #30].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Established the molecular identity of TSPAN8 as a glycosylated cell-surface tetraspanin, providing the structural framework for all subsequent functional work.\",\n      \"evidence\": \"cDNA cloning, COS cell expression, and lectin-binding analysis of CO-029\",\n      \"pmids\": [\"2395876\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No function assigned at identification\", \"No interaction partners defined\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Linked TSPAN8 to metastasis for the first time and identified integrin association as a mechanistic basis, framing it as a pro-metastatic membrane organizer.\",\n      \"evidence\": \"Stable transfection of rat D6.1A into low-metastatic tumor cells, membrane complex Western blotting, in vivo metastasis/coagulation models\",\n      \"pmids\": [\"9531564\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal contribution of alpha6beta1 association to metastasis not isolated\", \"Coagulopathy mechanism unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed that TSPAN8-integrin complexes are dynamically regulated, with PKC-driven internalization converting cells from laminin adhesion to migration.\",\n      \"evidence\": \"Reciprocal co-IP with alpha6beta4, confocal colocalization, PKC activation and migration assays in pancreatic carcinoma cells\",\n      \"pmids\": [\"15837731\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect TSPAN8-integrin contact not distinguished\", \"PKC substrate within the complex unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined TSPAN8 as an exosome-borne angiogenic factor acting systemically, extending its role beyond the producing cell.\",\n      \"evidence\": \"In vitro endothelial branching, in vivo angiogenesis, antibody blocking, RT-PCR/ELISA of angiogenic factors\",\n      \"pmids\": [\"16849554\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endothelial receptor for exosomal TSPAN8 not identified\", \"Mechanism of selective exosomal sorting unaddressed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Placed ADAM12m downstream of TSPAN8 in an invasion pathway, providing an early effector for its pro-invasive activity.\",\n      \"evidence\": \"Overexpression, ADAM12m siRNA rescue, xenograft metastasis in esophageal carcinoma\",\n      \"pmids\": [\"18365756\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How TSPAN8 upregulates ADAM12m not defined\", \"Direct interaction not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated a developmental, non-oncogenic role in pancreatic morphogenesis, showing TSPAN8 function in tissue patterning.\",\n      \"evidence\": \"Morpholino knockdown and mRNA overexpression in Xenopus with in situ hybridization\",\n      \"pmids\": [\"19403659\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular partners in pancreatic bud fusion unknown\", \"Relevance to mammalian development untested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved how TSPAN8 selectively loads exosomes and conditions recipient endothelium, and dissected its distinct internalization route via intersectin-2.\",\n      \"evidence\": \"Exosome protein/mRNA profiling and EC uptake assays; chimeric N/C-terminal swaps, co-IP and internalization kinetics\",\n      \"pmids\": [\"20124479\", \"20937409\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Sorting determinant for specific cargo (CD49d, mRNAs) not fully mapped\", \"Functional difference of internalization routes in vivo unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified E-cadherin as a direct TSPAN8 partner and showed TSPAN8 controls an integrin switch that becomes motility-driving when adherens-junction signaling is lost.\",\n      \"evidence\": \"Chemical cross-linking and co-IP, p120-catenin/E-cadherin silencing, motility and antibody-blocking assays\",\n      \"pmids\": [\"20858717\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of TSPAN8-E-cadherin contact unknown\", \"Regulation of alpha1beta1/alpha2beta1 switch mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Distinguished TSPAN8 from the related tetraspanin CD151, defining how TSPAN8 specifically recruits beta4 integrin into a Src-FAK-Ras motility module.\",\n      \"evidence\": \"Stable knockdown, co-IP, phosphorylation and invasion assays, in vivo metastasis in ASML cells\",\n      \"pmids\": [\"23683890\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct kinase recruited by TSPAN8 to beta4 not defined\", \"Generalizability across tumor types untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovered a nuclear function: TSPAN8 binds androgen receptor, undergoes androgen-dependent stabilization, and co-regulates AR target genes, reframing it as a transcriptional cofactor.\",\n      \"evidence\": \"Co-IP, in vitro binding, nuclear fractionation, proteasome inhibitor and knockdown experiments in prostate cancer cells\",\n      \"pmids\": [\"26649804\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of nuclear import not yet defined (resolved later)\", \"Domain mediating AR binding not mapped at this stage\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mapped the TSPAN8 large extracellular loop as a functional invasion domain and a therapeutic antibody target.\",\n      \"evidence\": \"Phage-display anti-LEL antibody, domain mapping and invasion assays in colorectal cancer\",\n      \"pmids\": [\"26562525\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single antibody functional assay without mechanistic dissection\", \"Binding partner engaged via the LEL not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established upstream transcriptional control of TSPAN8 by LSD1 epigenetic derepression and identified ERK MAPK as a downstream effector.\",\n      \"evidence\": \"ChIP for H3K9me2 at the TSPAN8 promoter and LSD1 knockdown; separately, MEK inhibitor rescue in gastric cancer\",\n      \"pmids\": [\"31790687\", \"26309511\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How TSPAN8 activates ERK mechanistically unresolved (Low-confidence link)\", \"Direct LSD1 vs. indirect effect on promoter not separated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a transcriptional regulatory network (LCMR1 activator; GSK3beta/PTEN/IQGAP1 repressors) placing TSPAN8 downstream of RAF-MEK-ERK signaling, and identified a TSPAN8-high spermatogonial stem cell population, broadening its stem-cell relevance.\",\n      \"evidence\": \"RNAi screen with vemurafenib in melanoma; FACS sorting, spermatogonial transplantation, RNA/methyl/ChIP-seq in mouse testis\",\n      \"pmids\": [\"27375018\", \"27733379\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect regulation by each modulator not resolved\", \"Functional requirement of TSPAN8 itself in SSC maintenance not directly tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified p53 as a direct transcriptional repressor of TSPAN8, integrating it into tumor-suppressor control of invasion.\",\n      \"evidence\": \"Promoter analysis, p53 silencing, and TSPAN8-dependent invasion rescue in melanoma\",\n      \"pmids\": [\"28368391\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct p53 occupancy not confirmed by ChIP\", \"Context dependence across p53-mutant tumors unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed TSPAN8 as a Hedgehog-pathway activator that recruits the deubiquitinase ATXN3 to stabilize SHH/PTCH1, driving SMO ciliary translocation and stemness.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, SMO ciliary localization imaging, knockdown and in vivo tumor formation\",\n      \"pmids\": [\"31253779\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TSPAN8 directly recruits ATXN3 or via an adaptor unclear\", \"How a surface tetraspanin engages the PTCH1 complex spatially unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established beta-catenin positive-feedback loops in melanoma and colorectal cancer that lock in TSPAN8 expression and sustain invasive/stem phenotypes.\",\n      \"evidence\": \"Co-IP, luciferase/ChIP for beta-catenin at the TSPAN8 promoter, KD/OE, sphere formation, transgenic mouse melanoma\",\n      \"pmids\": [\"30679790\", \"31838484\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which TSPAN8 stabilizes beta-catenin not defined\", \"Direct TSPAN8-beta-catenin contact topology unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a cell non-autonomous invasion mechanism whereby TSPAN8+ tumor cells license keratinocyte-derived proMMP-9 activation and matrix degradation.\",\n      \"evidence\": \"Skin reconstruct model, proMMP-9 activation and collagen IV assays, antibody blocking\",\n      \"pmids\": [\"32455575\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signal from TSPAN8+ cells to keratinocytes not identified\", \"Direct molecular trigger of proMMP-9 activation unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Quantified the biophysical basis of TSPAN8-sEV docking and extended its conditioning role to distant organs; flagged TSPAN8 as a potential SARS-CoV-2 entry mediator.\",\n      \"evidence\": \"Single-particle tracking of sEV binding, in vivo uptake imaging; antibody blocking in lung organoid infection (preprint)\",\n      \"pmids\": [\"34796683\", \"34100012\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating confined-diffusion docking unknown\", \"SARS-CoV-2 link is a preprint with no entry mechanism defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved the long-standing question of how a membrane tetraspanin reaches the nucleus: EGFR-AKT phosphorylation at Ser129 enables 14-3-3theta/importin-beta1 binding and STAT3-dependent oncogenic transcription.\",\n      \"evidence\": \"In vitro AKT kinase assay, S129A mutagenesis, co-IP, ChIP-seq, nuclear fractionation, palmitoylation assays, in vivo antibody\",\n      \"pmids\": [\"35197608\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phosphorylated TSPAN8 physically detaches from the bilayer mechanistically incomplete\", \"Direct vs. STAT3-bridged DNA contact not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified GATA6 (downstream of lncRNA SOX21-AS1) as a TSPAN8 activator coupling to ERK, and a Rictor/mTORC2 association in renal cells, expanding the upstream and signaling network.\",\n      \"evidence\": \"RNA pull-down/RIP, ChIP/luciferase at TSPAN8 promoter, ERK analysis; separately co-IP of TSPAN8-Rictor with mTOR-dependent autophagy assays\",\n      \"pmids\": [\"32698071\", \"35904232\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TSPAN8-Rictor interaction supported by single co-IP (Low confidence)\", \"Mechanism of ERK activation downstream of TSPAN8 unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended the AR axis to castration-resistant AR-V7 with mutual deubiquitination and promoter co-recruitment, and identified ECE1 amplification and IFN-gammaR1 endocytic routing as additional TSPAN8 surface functions.\",\n      \"evidence\": \"Co-IP/ubiquitination/ChIP with AR/AR-V7 domain mapping; MS co-purification and ECE1 activity in KO tissue; lipid-raft fractionation and IFN-gammaR1 endocytosis with KO mouse colitis model\",\n      \"pmids\": [\"36951301\", \"37835445\", \"37204469\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TSPAN8 carries intrinsic deubiquitinating function or recruits a DUB for AR is unresolved\", \"Direct vs. scaffold role in ECE1 activation undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified MDM2 as the shared E3 ligase controlling TSPAN8/AR/AR-V7 stability and defined a TSPAN8-MAPK11-RBBP6-SIRT6 axis in cancer-associated fibroblasts feeding tumor stemness via metabolite secretion.\",\n      \"evidence\": \"E3 ligase siRNA screen, ubiquitination and AR-negative control; co-IP of TSPAN8-MAPK11-RBBP6, phosphorylation, SIRT6 stability and metabolite assays in myCAFs\",\n      \"pmids\": [\"38410785\", \"38569015\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How TSPAN8 selects MDM2 substrates not defined\", \"Direct TSPAN8-MAPK11 binding interface not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for how a four-pass membrane tetraspanin is extracted from the bilayer, imported to the nucleus, and engages chromatin-associated transcription factors versus its canonical surface microdomain scaffolding remains mechanistically incomplete.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of nuclear TSPAN8 complexes\", \"Membrane-to-nucleus extraction mechanism unresolved\", \"Receptor(s) mediating exosome/sEV docking on recipient cells unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 6, 7, 17, 21, 22]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [17, 22, 23, 25]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [12, 21, 22]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 5, 24]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [12, 21, 22]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3, 4, 11, 34]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [17, 21, 32]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 3, 8, 11]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [21, 22, 12]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [3, 4, 11, 34]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [17, 22, 25]}\n    ],\n    \"complexes\": [\n      \"TSPAN8-alpha6beta4 integrin complex\",\n      \"TSPAN8-intersectin2-CD49d-clathrin complex\",\n      \"TSPAN8-PTCH1-ATXN3 complex\",\n      \"TSPAN8-MAPK11-RBBP6 complex\"\n    ],\n    \"partners\": [\n      \"ITGB4\",\n      \"CDH1\",\n      \"AR\",\n      \"PTCH1\",\n      \"ATXN3\",\n      \"STAT3\",\n      \"MDM2\",\n      \"RICTOR\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}