Affinage

TSPAN8

Tetraspanin-8 · UniProt P19075

Length
237 aa
Mass
26.0 kDa
Annotated
2026-06-10
71 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1990 High

    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

    PMID:2395876

    Open questions at the time
    • No function assigned at identification
    • No interaction partners defined
  2. 1998 Medium

    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

    PMID:9531564

    Open questions at the time
    • Causal contribution of alpha6beta1 association to metastasis not isolated
    • Coagulopathy mechanism unresolved
  3. 2005 Medium

    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

    PMID:15837731

    Open questions at the time
    • Direct vs. indirect TSPAN8-integrin contact not distinguished
    • PKC substrate within the complex unknown
  4. 2006 Medium

    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

    PMID:16849554

    Open questions at the time
    • Endothelial receptor for exosomal TSPAN8 not identified
    • Mechanism of selective exosomal sorting unaddressed
  5. 2008 Medium

    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

    PMID:18365756

    Open questions at the time
    • How TSPAN8 upregulates ADAM12m not defined
    • Direct interaction not tested
  6. 2009 Medium

    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

    PMID:19403659

    Open questions at the time
    • Molecular partners in pancreatic bud fusion unknown
    • Relevance to mammalian development untested
  7. 2010 Medium

    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

    PMID:20124479 PMID:20937409

    Open questions at the time
    • Sorting determinant for specific cargo (CD49d, mRNAs) not fully mapped
    • Functional difference of internalization routes in vivo unclear
  8. 2010 Medium

    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

    PMID:20858717

    Open questions at the time
    • Structural basis of TSPAN8-E-cadherin contact unknown
    • Regulation of alpha1beta1/alpha2beta1 switch mechanistically incomplete
  9. 2013 Medium

    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

    PMID:23683890

    Open questions at the time
    • Direct kinase recruited by TSPAN8 to beta4 not defined
    • Generalizability across tumor types untested
  10. 2015 High

    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

    PMID:26649804

    Open questions at the time
    • Mechanism of nuclear import not yet defined (resolved later)
    • Domain mediating AR binding not mapped at this stage
  11. 2015 Low

    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

    PMID:26562525

    Open questions at the time
    • Single antibody functional assay without mechanistic dissection
    • Binding partner engaged via the LEL not identified
  12. 2015 Medium

    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

    PMID:26309511 PMID:31790687

    Open questions at the time
    • How TSPAN8 activates ERK mechanistically unresolved (Low-confidence link)
    • Direct LSD1 vs. indirect effect on promoter not separated
  13. 2016 Medium

    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

    PMID:27375018 PMID:27733379

    Open questions at the time
    • Direct vs. indirect regulation by each modulator not resolved
    • Functional requirement of TSPAN8 itself in SSC maintenance not directly tested
  14. 2017 Medium

    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

    PMID:28368391

    Open questions at the time
    • Direct p53 occupancy not confirmed by ChIP
    • Context dependence across p53-mutant tumors unknown
  15. 2019 High

    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

    PMID:31253779

    Open questions at the time
    • Whether TSPAN8 directly recruits ATXN3 or via an adaptor unclear
    • How a surface tetraspanin engages the PTCH1 complex spatially unresolved
  16. 2019 Medium

    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

    PMID:30679790 PMID:31838484

    Open questions at the time
    • Mechanism by which TSPAN8 stabilizes beta-catenin not defined
    • Direct TSPAN8-beta-catenin contact topology unresolved
  17. 2020 Medium

    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

    PMID:32455575

    Open questions at the time
    • Signal from TSPAN8+ cells to keratinocytes not identified
    • Direct molecular trigger of proMMP-9 activation unknown
  18. 2021 Medium

    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)

    PMID:34100012 PMID:34796683

    Open questions at the time
    • Receptor mediating confined-diffusion docking unknown
    • SARS-CoV-2 link is a preprint with no entry mechanism defined
  19. 2022 High

    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

    PMID:35197608

    Open questions at the time
    • How phosphorylated TSPAN8 physically detaches from the bilayer mechanistically incomplete
    • Direct vs. STAT3-bridged DNA contact not established
  20. 2022 Medium

    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

    PMID:32698071 PMID:35904232

    Open questions at the time
    • TSPAN8-Rictor interaction supported by single co-IP (Low confidence)
    • Mechanism of ERK activation downstream of TSPAN8 unresolved
  21. 2023 Medium

    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

    PMID:36951301 PMID:37204469 PMID:37835445

    Open questions at the time
    • Whether TSPAN8 carries intrinsic deubiquitinating function or recruits a DUB for AR is unresolved
    • Direct vs. scaffold role in ECE1 activation undefined
  22. 2024 Medium

    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

    PMID:38410785 PMID:38569015

    Open questions at the time
    • How TSPAN8 selects MDM2 substrates not defined
    • Direct TSPAN8-MAPK11 binding interface not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 6 GO:0098772 molecular function regulator activity 4 GO:0140110 transcription regulator activity 3 GO:0005198 structural molecule activity 2
Localization
GO:0005886 plasma membrane 4 GO:0031410 cytoplasmic vesicle 4 GO:0005634 nucleus 3 GO:0005929 cilium 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
ARATXN3CDH1ITGB4MDM2PTCH1RICTORSTAT3
Complex memberships
TSPAN8-MAPK11-RBBP6 complexTSPAN8-PTCH1-ATXN3 complexTSPAN8-alpha6beta4 integrin complexTSPAN8-intersectin2-CD49d-clathrin complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 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). cDNA cloning, COS cell expression, immunoprecipitation, Western blotting, lectin-Sepharose binding Proceedings of the National Academy of Sciences of the United States of America High 2395876
1998 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. cDNA cloning, stable transfection, Western blotting of membrane complexes, in vivo tumor models The Journal of cell biology Medium 9531564
2005 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. Co-immunoprecipitation, confocal colocalization, PKC activation assays, cell migration assays Clinical cancer research Medium 15837731
2006 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. In vitro endothelial branching assay, in vivo angiogenesis models, antibody blocking, RT-PCR, ELISA Cancer research Medium 16849554
2010 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. Exosome isolation, protein/mRNA profiling, flow cytometry, EC uptake assays, gene expression analysis, in vitro angiogenesis assays Cancer research Medium 20124479
2010 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. Chimeric protein constructs (N/C-terminal swaps), co-immunoprecipitation, cholesterol depletion assays, internalization kinetics, cell migration and adhesion assays The international journal of biochemistry & cell biology Medium 20937409
2010 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. Chemical cross-linking, co-immunoprecipitation, siRNA silencing, cell motility assays, antibody blocking Cancer research Medium 20858717
2013 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. Stable knockdown, co-immunoprecipitation, phosphorylation assays, invasion/migration assays, in vivo metastasis models European journal of cancer Medium 23683890
2008 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. Stable overexpression, siRNA knockdown, migration/invasion assays, xenograft spontaneous metastasis model, Western blotting Clinical & experimental metastasis Medium 18365756
2009 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. Morpholino knockdown, mRNA overexpression, in situ hybridization, transgenic GFP chimeric embryos, Xenopus developmental model Development (Cambridge, England) Medium 19403659
2012 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. siRNA knockdown, cell migration assays, flow cytometry for surface integrins, adhesion assays PloS one Medium 22679508
2015 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. Knockdown cell lines, exosome isolation, co-culture assays, binding/uptake assays, gene expression profiling, in vivo metastasis models Oncotarget Medium 25544774
2015 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. Co-immunoprecipitation, in vitro binding assay, nuclear fractionation, proteasome inhibitor experiments, siRNA knockdown, gene expression assays Molecular endocrinology (Baltimore, Md.) High 26649804
2015 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. Phage display antibody generation, in vitro invasion assays, domain mapping Biochemical and biophysical research communications Low 26562525
2015 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. ChIP assay for H3K9me2 at TSPAN8 promoter, siRNA knockdown of LSD1, RT-PCR, Western blotting, EMT marker analysis Life sciences Medium 31790687
2017 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. Promoter analysis, siRNA silencing of p53, luciferase reporter assays (implied), invasion assays, epistasis via TSPAN8 rescue Oncogenesis Medium 28368391
2016 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. Large-scale RNAi screen, siRNA knockdown, overexpression, invasion assays, in vivo tumorigenicity Oncogene Medium 27375018
2019 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. Co-immunoprecipitation, ubiquitination assays, confocal microscopy (SMO cilia localization), siRNA/shRNA knockdown, in vivo tumor formation Nature communications High 31253779
2019 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. Overexpression/knockdown, Western blotting for beta-catenin, luciferase reporter assays (beta-catenin target), in vivo transgenic mouse melanoma model, immunohistochemistry Oncogene Medium 30679790
2020 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. Skin reconstruct model, proMMP-9 activation assay, collagen IV immunostaining, antibody blocking, overexpression in melanoma cells Cancers Medium 32455575
2021 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. ChIP or reporter assays (implied for SOX9-TSPAN8), siRNA/shRNA knockdown, overexpression, invasion assays, EGF stimulation, EGFR inhibitor treatment Oncogene Medium 34163029
2022 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. 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 Cell research High 35197608
2023 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. Co-immunoprecipitation, ubiquitination assays, ChIP (promoter recruitment), siRNA knockdown, domain mapping by truncation constructs Endocrinology High 36951301
2023 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. Mass spectrometry (co-purification), Western blotting, ECE1 enzymatic activity assay (bigET1 to ET1 conversion), Tspan8 knockout mouse tissue comparison Cancers Medium 37835445
2023 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. Lipid raft fractionation, siRNA knockdown, IFN-γR1 endocytosis assays (clathrin vs. lipid raft pathway), STAT1 signaling assay, intestinal permeability measurement, mouse UC model Cellular and molecular life sciences : CMLS Medium 37204469
2024 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). siRNA screen for E3 ligases, siRNA knockdown of MDM2, pharmacological MDM2 inhibitor, ubiquitination assays, Western blotting, AR-negative PC-3 cell control Endocrine oncology (Bristol, England) Medium 38410785
2024 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. Co-immunoprecipitation (TSPAN8-MAPK11-RBBP6 complex), phosphorylation assays, SIRT6 protein stability assays, metabolite secretion assays, siRNA knockdown, single-cell flow cytometry Science translational medicine Medium 38569015
2021 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. Lung organoid infection model, antibody blocking experiments, correlation of TSPAN8 levels with infection rate bioRxivpreprint Low 34100012
2016 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. FACS sorting by TSPAN8 surface expression, spermatogonial transplantation assays, RNA-seq, methyl-seq, ChIP-seq Biology of reproduction Medium 27733379
2019 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. Co-immunoprecipitation, ChIP assay, knockdown, sphere formation assay Medical science monitor Medium 31838484
2022 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. RNA pull-down, RIP, ChIP on TSPAN8 promoter, dual-luciferase reporter assay, siRNA/overexpression, ERK pathway analysis, in vivo xenograft International journal of biological macromolecules Medium 32698071
2015 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. Plasmid overexpression, siRNA knockdown, MEK inhibitor (U0126), MTT proliferation assay, Transwell invasion assay, Western blotting for ERK phosphorylation International journal of clinical and experimental medicine Low 26309511
2023 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. siRNA knockdown, overexpression, Western blotting for pEGFR and pAKT, migration/invasion assays, in vivo metastasis model Molecular biology reports Low 37535246
2022 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. Co-immunoprecipitation (TSPAN8-Rictor), overexpression plasmid, mTOR inhibitor, flow cytometry (apoptosis), autophagy markers Cell biology international Low 35904232
2021 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. Single-particle tracking, genetically engineered TSPAN8-overexpressing breast cancer cells, functional motility assays, in vivo sEV uptake imaging Journal of extracellular vesicles Medium 34796683

Source papers

Stage 0 corpus · 71 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Cell surface tetraspanin Tspan8 contributes to molecular pathways of exosome-induced endothelial cell activation. Cancer research 548 20124479
2006 Systemic induction of the angiogenesis switch by the tetraspanin D6.1A/CO-029. Cancer research 178 16849554
2019 TSPAN8 promotes cancer cell stemness via activation of sonic Hedgehog signaling. Nature communications 165 31253779
1990 Molecular cloning of cDNA for the human tumor-associated antigen CO-029 and identification of related transmembrane antigens. Proceedings of the National Academy of Sciences of the United States of America 150 2395876
2015 The tetraspanins CD151 and Tspan8 are essential exosome components for the crosstalk between cancer initiating cells and their surrounding. Oncotarget 147 25544774
2008 Association testing of novel type 2 diabetes risk alleles in the JAZF1, CDC123/CAMK1D, TSPAN8, THADA, ADAMTS9, and NOTCH2 loci with insulin release, insulin sensitivity, and obesity in a population-based sample of 4,516 glucose-tolerant middle-aged Danes. Diabetes 121 18567820
2005 Colocalization of the tetraspanins, CO-029 and CD151, with integrins in human pancreatic adenocarcinoma: impact on cell motility. Clinical cancer research : an official journal of the American Association for Cancer Research 109 15837731
1998 Association between the rat homologue of CO-029, a metastasis-associated tetraspanin molecule and consumption coagulopathy. The Journal of cell biology 89 9531564
2024 TSPAN8+ myofibroblastic cancer-associated fibroblasts promote chemoresistance in patients with breast cancer. Science translational medicine 78 38569015
2013 Tspan8, CD44v6 and alpha6beta4 are biomarkers of migrating pancreatic cancer-initiating cells. International journal of cancer 75 23338841
2010 E-cadherin/p120-catenin and tetraspanin Co-029 cooperate for cell motility control in human colon carcinoma. Cancer research 70 20858717
2001 Overexpression of tetraspanin CO-029 in hepatocellular carcinoma. Journal of hepatology 69 11690710
2010 Activation-induced internalization differs for the tetraspanins CD9 and Tspan8: Impact on tumor cell motility. The international journal of biochemistry & cell biology 67 20937409
2022 EGFR signaling promotes nuclear translocation of plasma membrane protein TSPAN8 to enhance tumor progression via STAT3-mediated transcription. Cell research 62 35197608
2021 Identification of CD318, TSPAN8 and CD66c as target candidates for CAR T cell based immunotherapy of pancreatic adenocarcinoma. Nature communications 61 33674603
2013 Tspan8 and CD151 promote metastasis by distinct mechanisms. European journal of cancer (Oxford, England : 1990) 57 23683890
2008 TM4SF3 promotes esophageal carcinoma metastasis via upregulating ADAM12m expression. Clinical & experimental metastasis 53 18365756
2015 TSPAN8 promotes gastric cancer growth and metastasis via ERK MAPK pathway. International journal of clinical and experimental medicine 45 26309511
2021 SOX9 is a critical regulator of TSPAN8-mediated metastasis in pancreatic cancer. Oncogene 41 34163029
2019 TSPAN8 promotes colorectal cancer cell growth and migration in LSD1-dependent manner. Life sciences 38 31790687
2003 Possible involvement of tetraspanin CO-029 in hematogenous intrahepatic metastasis of liver cancer cells. Journal of gastroenterology and hepatology 38 14535989
2019 Tspan8 is expressed in breast cancer and regulates E-cadherin/catenin signalling and metastasis accompanied by increased circulating extracellular vesicles. The Journal of pathology 37 30982971
2014 Effect of an anti-human Co-029/tspan8 mouse monoclonal antibody on tumor growth in a nude mouse model. Frontiers in physiology 36 25285080
2018 Tspan8 and Tspan8/CD151 knockout mice unravel the contribution of tumor and host exosomes to tumor progression. Journal of experimental & clinical cancer research : CR 34 30541597
2016 TSPAN8 Expression Distinguishes Spermatogonial Stem Cells in the Prepubertal Mouse Testis. Biology of reproduction 33 27733379
2015 TSPAN8, identified by Escherichia coli ampicillin secretion trap, is associated with cell growth and invasion in gastric cancer. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 33 25711980
2009 The tetraspanin Tm4sf3 is localized to the ventral pancreas and regulates fusion of the dorsal and ventral pancreatic buds. Development (Cambridge, England) 31 19403659
2012 Tetraspanin CO-029 inhibits colorectal cancer cell movement by deregulating cell-matrix and cell-cell adhesions. PloS one 29 22679508
2018 MiR-324-5p reduces viability and induces apoptosis in gastric cancer cells through modulating TSPAN8. The Journal of pharmacy and pharmacology 28 30159900
2021 High TSPAN8 expression in epithelial cancer cell-derived small extracellular vesicles promote confined diffusion and pronounced uptake. Journal of extracellular vesicles 26 34796683
2020 Colorectal cancer screening: Assessment of CEACAM6, LGALS4, TSPAN8 and COL1A2 as blood markers in faecal immunochemical test negative subjects. Journal of advanced research 26 32257432
2010 Functional variants of TSPAN8 are associated with bipolar disorder and schizophrenia. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 26 20052686
2020 TSPAN8 as a Novel Emerging Therapeutic Target in Cancer for Monoclonal Antibody Therapy. Biomolecules 25 32138170
2010 Reduced body weight in male Tspan8-deficient mice. International journal of obesity (2005) 22 20733586
2019 Tspan8-β-catenin positive feedback loop promotes melanoma invasion. Oncogene 21 30679790
2020 Tspan8-Tumor Extracellular Vesicle-Induced Endothelial Cell and Fibroblast Remodeling Relies on the Target Cell-Selective Response. Cells 20 32013145
2015 Association of JAZF1 and TSPAN8/LGR5 variants in relation to type 2 diabetes mellitus in a Saudi population. Diabetology & metabolic syndrome 20 26500707
1989 Colon carcinoma-associated glycoproteins recognized by monoclonal antibodies CO-029 and GA22-2. Hybridoma 20 2777278
2015 Generation of a human antibody that inhibits TSPAN8-mediated invasion of metastatic colorectal cancer cells. Biochemical and biophysical research communications 19 26562525
2017 p53 targets TSPAN8 to prevent invasion in melanoma cells. Oncogenesis 18 28368391
2015 CO-029 is overexpressed in gastric cancer and mediates the effects of EGF on gastric cancer cell proliferation and invasion. International journal of molecular medicine 18 25592989
2020 Tspan8 Drives Melanoma Dermal Invasion by Promoting ProMMP-9 Activation and Basement Membrane Proteolysis in a Keratinocyte-Dependent Manner. Cancers 17 32455575
2020 Silencing of long non-coding RNA SOX21-AS1 inhibits lung adenocarcinoma invasion and migration by impairing TSPAN8 via transcription factor GATA6. International journal of biological macromolecules 17 32698071
2016 A large-scale RNAi screen identifies LCMR1 as a critical regulator of Tspan8-mediated melanoma invasion. Oncogene 16 27375018
2022 miR-543 regulates high glucose-induced fibrosis and autophagy in diabetic nephropathy by targeting TSPAN8. BMC nephrology 14 35246069
2019 Comprehensive Genetic Search to Clarify the Molecular Mechanism of Drug Resistance Identifies ASCL2-LEF1/TSPAN8 Axis in Colorectal Cancer. Annals of surgical oncology 13 30706227
2021 SARS-CoV-2 infection studies in lung organoids identify TSPAN8 as novel mediator. bioRxiv : the preprint server for biology 12 34100012
2017 Joint features and complementarities of Tspan8 and CD151 revealed in knockdown and knockout models. Biochemical Society transactions 11 28408484
2017 Multi-factorial modulation of colorectal carcinoma cells motility - partial coordination by the tetraspanin Co-029/tspan8. Oncotarget 11 28418857
2015 TM4SF3 and AR: A Nuclear Complex that Stabilizes Both Proteins. Molecular endocrinology (Baltimore, Md.) 11 26649804
2019 A Positive Tetraspanin 8 (TSPAN8)/β-Catenin Regulatory Loop Enhances the Stemness of Colorectal Cancer Cells. Medical science monitor : international medical journal of experimental and clinical research 10 31838484
2016 Overexpression of TSPAN8 Promotes Tumor Cell Viability and Proliferation in Nonsmall Cell Lung Cancer. Cancer biotherapy & radiopharmaceuticals 10 27996312
2024 Molecular Regulation and Oncogenic Functions of TSPAN8. Cells 8 38275818
2023 Tetraspanin Tspan8 restrains interferon signaling to stabilize intestinal epithelium by directing endocytosis of interferon receptor. Cellular and molecular life sciences : CMLS 7 37204469
2021 Signatures of TSPAN8 variants associated with human metabolic regulation and diseases. iScience 7 34401672
2017 HNF1B, TSPAN8 and NOTCH2 gene polymorphisms in women with gestational diabetes. 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 7 28274157
2024 MDM2 regulates the stability of AR, AR-V7, and TM4SF3 proteins in prostate cancer. Endocrine oncology (Bristol, England) 6 38410785
2023 TSPAN8 regulates EGFR/AKT pathway to enhance metastasis in gastric cancer. Molecular biology reports 5 37535246
2022 TSPAN8 alleviates high glucose-induced apoptosis and autophagy via targeting mTORC2. Cell biology international 5 35904232
2022 Histone demethylase KDM2A suppresses EGF-TSPAN8 pathway to inhibit breast cancer cell migration and invasion in vitro. Biochemical and biophysical research communications 5 36084547
2023 The Transmembrane Protein TM4SF3 Interacts With AR and AR-V7 and is Recruited to AR Target Genes. Endocrinology 4 36951301
2024 Cancer Cell Biomechanical Properties Accompany Tspan8-Dependent Cutaneous Melanoma Invasion. Cancers 3 38398085
2024 Overexpression of TSPAN8 in consensus molecular subtype 3 colorectal cancer. Experimental and molecular pathology 3 38861838
2025 Cancer stem cells-derived exosomal TSPAN8 enhances non-stem cancer cells stemness and promotes malignant progression in PDAC. Oncogene 2 40251391
2023 The Tetraspanin Tspan8 Associates with Endothelin Converting Enzyme ECE1 and Regulates Its Activity. Cancers 2 37835445
2022 [TSPAN8 is involved in lipid metabolism in non-alcoholic fatty liver disease in mice]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 2 35673914
2025 Characterization of LINC00483 as a Novel Oncogene in Colorectal Cancer via Targeting miR-601/TSPAN8 Signaling Axis. Journal of biochemical and molecular toxicology 1 40059517
2026 TSPAN8-mediated Epithelial-mesenchymal Transition Drives Acquired Radioresistance in Cervical Cancer. Radiation research 0 42097620
2024 miR-378a-5p represses Barrett's esophagus cells proliferation, migration and invasion through targeting TSPAN8. Cellular and molecular biology (Noisy-le-Grand, France) 0 38430035
2023 Regional expression differences of SERT and TSPAN8 in hippocampus, cerebellum and cortex of wild-type young, adult and middle-aged rats. Gene 0 37572802
2023 Peptides disrupting TM4SF3 interaction with AR or AR-V7 block prostate cancer cell proliferation. Endocrine oncology (Bristol, England) 0 37822366

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