{"gene":"CD82","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":1995,"finding":"KAI1/CD82 was identified as a metastasis suppressor gene encoding a 267-amino acid protein with four transmembrane domains and one large extracellular hydrophilic domain with N-glycosylation sites, belonging to the tetraspanin/transmembrane 4 superfamily; introduction of KAI1 into metastatic rat prostate cancer cells suppressed metastasis in vivo.","method":"Gene transfer into rat AT6.1 prostate cancer cells, in vivo metastasis assay, molecular cloning","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — original functional discovery with in vivo loss/gain-of-function, replicated across many subsequent studies","pmids":["7754374"],"is_preprint":false},{"year":1998,"finding":"The tumor suppressor p53 directly activates KAI1/CD82 transcription by binding to a tandem p53 consensus sequence ~860 bp upstream of the transcriptional initiation site, as demonstrated by gel-shift mobility assay with purified p53 protein and mutational analysis of the binding sequence.","method":"Gel-shift mobility assay (EMSA), promoter-reporter assay, site-directed mutagenesis, immunohistochemistry","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — in vitro binding with purified protein plus mutagenesis confirming functional binding site","pmids":["9736732"],"is_preprint":false},{"year":2003,"finding":"CD82 specifically attenuates ligand-induced dimerization of EGFR and causes redistribution of EGFR into lipid raft-like light sucrose gradient fractions enriched in gangliosides GD1a and GM1; the large extracellular loop of CD82 alone is insufficient for this effect, implicating other domains. CD82 is also associated with ErbB2 and ErbB3 but does not affect ErbB2-ErbB3 dimerization.","method":"Sucrose gradient fractionation, co-immunoprecipitation, confocal microscopy, expression of recombinant CD82 domains","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods in one study establishing mechanistic link between CD82, ganglioside-mediated compartmentalization, and EGFR dimerization","pmids":["14576349"],"is_preprint":false},{"year":2003,"finding":"KAI1/CD82 inhibits cancer cell migration by downregulating p130CAS protein levels, thereby reducing formation of the p130CAS-CrkII complex (a 'molecular switch' in cell motility); overexpression of p130CAS in KAI1/CD82-expressing cells restored migration, confirming the pathway.","method":"Stable transfection, Western blot, co-immunoprecipitation, migration assay, p130CAS overexpression rescue experiment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — epistasis confirmed by rescue experiment; multiple orthogonal methods","pmids":["12738793"],"is_preprint":false},{"year":2003,"finding":"EWI2/PGRL (an immunoglobulin superfamily member) directly and stoichiometrically associates with KAI1/CD82 in a cholesterol-independent, likely direct interaction; overexpression of EWI2/PGRL inhibits prostate cancer cell migration and synergizes with KAI1/CD82 in migration suppression.","method":"Chemical cross-linking, co-immunoprecipitation, mass spectrometry peptide sequencing, migration assay, cholesterol depletion","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — stoichiometric direct association confirmed by cross-linking and MS; functional synergy demonstrated","pmids":["12750295"],"is_preprint":false},{"year":2003,"finding":"C33/CD82/KAI1 induces apoptosis by generating reactive oxygen intermediates (ROIs) via a non-mitochondrial pathway; it promotes cell death by causing release of intracellular antioxidant glutathione (GSH) from cells and activates the GTPase Cdc42, which mediates GSH release and apoptosis induction.","method":"Apoptosis screen (gain-of-function), ROI detection, GSH measurement, Cdc42 activation assay","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — multiple mechanistic readouts in one lab; single study","pmids":["14597553"],"is_preprint":false},{"year":2003,"finding":"KAI1/CD82 promotes homotypic aggregation of prostate cancer cells through a Src kinase-dependent intracellular signaling pathway; ligation of CD82 increases endogenous Src kinase activity, and a kinase-negative Src mutant abolished CD82-mediated aggregation.","method":"Stable transfection, kinase-negative Src mutant re-transfection, antibody-induced CD82 cross-linking, Src kinase activity assay","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — dominant-negative epistasis with kinase assay; single lab","pmids":["12642901"],"is_preprint":false},{"year":2004,"finding":"KAI1/CD82 is palmitoylated at all cytoplasmic cysteine residues proximal to the plasma membrane; palmitoylation-deficient CD82 mutant largely reverses inhibitory effects on migration and invasion, disrupts tetraspanin web association, alters subcellular distribution, and abolishes inhibition of lamellipodia formation and p130CAS-CrkII coupling.","method":"[3H]-palmitate metabolic labeling, site-directed mutagenesis of cysteine residues, migration/invasion assay, co-immunoprecipitation, actin cytoskeleton imaging","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 — direct PTM identification by metabolic labeling plus mutagenesis with multiple functional readouts","pmids":["15492270"],"is_preprint":false},{"year":2004,"finding":"CD82 attenuates integrin α6-mediated cell adhesion and morphogenesis by associating with integrin α6 and promoting its internalization, thereby reducing α6 integrin surface expression without changing total cellular α6 protein levels.","method":"Co-immunoprecipitation, surface biotinylation, internalization assay, Matrigel morphogenesis assay, integrin-blocking antibodies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — direct physical association shown by Co-IP; mechanistic link to surface downregulation confirmed by biotinylation and internalization assays","pmids":["15557282"],"is_preprint":false},{"year":2004,"finding":"KITENIN/VANGL1, a tetraspanin family member, interacts specifically with the C-terminal cytoplasmic domain of KAI1 (identified by yeast two-hybrid); KITENIN overexpression increases tumor invasiveness and metastasis, antagonizing KAI1 metastasis suppressor function.","method":"Yeast two-hybrid screening, in vivo metastasis model, invasion and adhesion assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 3 — yeast two-hybrid identification; functional antagonism shown in vivo; no reciprocal Co-IP in mammalian cells reported","pmids":["15205336"],"is_preprint":false},{"year":2008,"finding":"Ganglioside GM2/GM3 complex (heterodimer stabilized by Ca2+) interacts with CD82 in glycosynaptic microdomains to inhibit HGF-induced cMet tyrosine kinase activity and cell motility; an antibody blocking GM2/GM3 dimer-CD82 interaction restores cell motility, confirming functional specificity.","method":"ESI mass spectrometry, cell motility assay, cMet kinase activity assay, blocking antibody (mAb 8E11), nanosphere coating with glycosphingolipids","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical characterization of heterodimer, functional rescue with blocking antibody, multiple cell systems","pmids":["18272501"],"is_preprint":false},{"year":2008,"finding":"CD82 requires polar residues (Asn, Gln, Glu) within its transmembrane domains for its migration-, invasion-, and metastasis-suppressive activities; mutation of these residues disrupts interaction with tetraspanins CD9 and CD151 (but not α3β1 integrin association), reduces conformational stability, and abolishes inhibition of microprotrusion formation and microvesicle release.","method":"Site-directed mutagenesis of TM domain polar residues, co-immunoprecipitation, in vivo metastasis assay, structural modeling, denaturation assay","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis plus multiple functional and biochemical readouts","pmids":["19116362"],"is_preprint":false},{"year":2009,"finding":"CD82 undergoes cholesterol-dependent, dynamin- and clathrin-independent endocytosis to late endosomes and lysosomes; cholesterol depletion blocks CD82 internalization. CD82 also redistributes cholesterol into tetraspanin-enriched microdomains (TEMs), reorganizing TEMs and lipid rafts. CD82 endocytosis alleviates its inhibitory effect on cell migration.","method":"Endocytosis/trafficking assays, cholesterol depletion (methyl-β-cyclodextrin), dominant-negative dynamin expression, sucrose gradient fractionation, live-cell imaging","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods; functional consequence of endocytosis on migration demonstrated","pmids":["19497983"],"is_preprint":false},{"year":2010,"finding":"The E3 ubiquitin ligase gp78 targets KAI1/CD82 for degradation via ER-associated degradation (ERAD); gp78 overexpression reduces KAI1 expression and gp78 knockdown increases KAI1 expression; gp78 regulation of cell proliferation is mediated by KAI1, demonstrated by KAI1 knockdown rescuing reduced proliferation in stable gp78 knockdown cells.","method":"MMTV-gp78 transgenic mouse model, siRNA/shRNA knockdown, Western blot, BrdU proliferation assay, epistasis rescue experiment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis rescue experiment plus in vivo transgenic model; multiple orthogonal methods","pmids":["20089858"],"is_preprint":false},{"year":2012,"finding":"KAI1/CD82 inhibits cell migration by attenuating the plasma membrane-dependent actin organization: it reduces Rac1 activity (diminishing lamellipodia and actin cortical network), blocks growth factor-stimulated RhoA activity (preventing stress fiber formation and retraction), reduces cofilin enrichment at the cell periphery, and decreases Rho kinase activity. Additionally, phosphatidylinositol 4,5-bisphosphate becomes less detectable at the cell periphery.","method":"Live imaging, Rac1/RhoA activity assays (pull-down), ROCK kinase assay, phospholipid imaging, stable transfection","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — multiple signaling readouts with live imaging; mechanistic pathway defined","pmids":["23251627"],"is_preprint":false},{"year":2013,"finding":"CD82/KAI1 suppresses ubiquitylation of EGFR after stimulation with heparin-binding EGF or amphiregulin (but not EGF itself), delays EGFR recruitment to EEA1-positive early endosomes, and increases PKC-dependent serine phosphorylation of c-Cbl E3 ubiquitin ligase; phosphorylation of EGFR Thr654 (PKC site) is also increased in CD82-expressing cells. The C-terminal cytoplasmic domain of CD82 is required for its endocytic trafficking and this regulatory function.","method":"Ubiquitylation assay, endocytic trafficking assay (EEA1 co-localization), C-terminal deletion mutant (CD82ΔC), phospho-specific antibodies, Western blot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — mechanistic dissection with deletion mutant, specific ligand discrimination, and c-Cbl phosphorylation link established","pmids":["23897813"],"is_preprint":false},{"year":2013,"finding":"CD82 positively regulates the STAT5/IL-10 signaling pathway in leukemia stem cells: CD82 knockdown dephosphorylates STAT5 and decreases IL-10 levels, while forced CD82 expression increases p-STAT5 and IL-10; ChIP assay demonstrates STAT5A binds to the IL-10 gene promoter, and reporter assay confirms transcriptional activation of IL-10 by CD82-driven STAT5.","method":"shRNA knockdown, lentiviral overexpression, ChIP assay, luciferase reporter assay, Western blot","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus reporter assay; single lab, single study","pmids":["23797738"],"is_preprint":false},{"year":2014,"finding":"CD82 overexpression increases the molecular density of α4 integrin subunits within plasma membrane clusters, thereby increasing cell adhesion; this packing depends on CD82 palmitoylation and the presence of α4 integrin ligands. CD82 regulates HSPC adhesion and homing to bone marrow through modulation of integrin membrane organization.","method":"Direct stochastic optical reconstruction microscopy (dSTORM) superresolution imaging, protein clustering algorithms, palmitoylation-deficient mutant, cell adhesion assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 — superresolution structural imaging with quantitative clustering analysis and mutagenesis; functional link established","pmids":["24623721"],"is_preprint":false},{"year":2014,"finding":"ΔNp63α directly transcriptionally activates CD82/KAI1 as a target gene to inhibit cancer cell invasion; chromatin immunoprecipitation confirmed ΔNp63α binding to the CD82 promoter; CD82 knockdown reversed ΔNp63α-mediated invasion suppression; GSK3β inhibition downregulates both ΔNp63α and CD82 independently of β-catenin.","method":"ChIP, Affymetrix gene expression profiling, siRNA knockdown rescue, Matrigel invasion assay, luciferase reporter","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP plus expression profiling plus epistasis rescue; direct transcriptional regulatory mechanism confirmed","pmids":["24901051"],"is_preprint":false},{"year":2014,"finding":"CD82 restrains angiogenesis in endothelial cells by inhibiting lipid raft clustering and CD44 membrane trafficking; CD82 ablation increases ganglioside levels and lipid raft clustering in the plasma membrane, reduces clathrin-independent endocytosis of CD44, and elevates CD44 surface expression, leading to enhanced outside-in signaling and EC migration.","method":"Cd82-null mouse model, in vivo and ex vivo angiogenesis assays, lipid raft fractionation, CD44 trafficking assay, ganglioside analysis","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 — knockout mouse model with multiple mechanistic readouts and in vivo validation","pmids":["25149363"],"is_preprint":false},{"year":2016,"finding":"CD82 suppresses U2AF2-mediated CD44 alternative splicing (specifically CD44v8-10 production) by inducing ubiquitination and degradation of the splicing factor U2AF2, thereby inhibiting melanoma metastasis; U2AF2-dependent CD44v8-10 promotes migration via Src/FAK/RhoA activation and CD44-E-selectin binding.","method":"In vivo metastasis assay, in vitro migration, ubiquitination assay, siRNA knockdown, Affymetrix expression, immunoprecipitation","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — ubiquitination assay with in vivo validation and mechanistic pathway defined","pmids":["27041584"],"is_preprint":false},{"year":2017,"finding":"CD82 inhibits fibronectin-induced epithelial-to-mesenchymal transition (EMT) in prostate cancer cells by forming lateral interactions with fibronectin-binding α3β1 and α5β1 integrins and attenuating downstream FAK-Src and ILK signaling pathways.","method":"Co-immunoprecipitation, immunofluorescence, Western blot for FAK/Src/ILK phosphorylation, invasion/migration assay, human tissue immunostaining","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus signaling assay; single lab but multiple methods","pmids":["27926483"],"is_preprint":false},{"year":2018,"finding":"CD82 deficiency in hematopoietic stem and progenitor cells (HSPCs) causes hyperactivation of Rac1, impaired bone marrow homing and engraftment, and reduced stem cell quiescence (cell cycle activation); pharmacological Rac1 inhibition rescues the homing defect of CD82KO HSPCs.","method":"CD82 knockout mouse model, Rac1 activity assay, bone marrow transplantation homing assay, cell cycle analysis, Rac1 inhibitor rescue","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — KO model with epistasis rescue by Rac1 inhibitor; multiple functional readouts","pmids":["30133344"],"is_preprint":false},{"year":2019,"finding":"CD82 is a key regulator of TLR9 trafficking and signaling: CD82 associates with TLR9 in the endoplasmic reticulum and post-ER compartments in macrophages; CD82 is essential for CpG-stimulated TLR9-dependent myddosome formation and NF-κB nuclear translocation leading to inflammatory cytokine production.","method":"Co-immunoprecipitation, confocal microscopy, myddosome formation assay, NF-κB nuclear translocation assay, cytokine measurement, CD82-deficient macrophages","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — Co-IP with subcellular localization, functional loss-of-function, and multiple downstream signaling readouts","pmids":["31408613"],"is_preprint":false},{"year":2019,"finding":"CD82 represses TGF-β1/Smad signaling and Wnt/β-catenin signaling to suppress EMT in prostate cancer: CD82 blocks Smad2 phosphorylation, Smad4 nuclear translocation, and TRE promoter transactivation; it also prevents GSK-3β inactivation downstream of Wnt3a, maintaining β-catenin phosphorylation and blocking its nuclear translocation.","method":"Luciferase reporter assay (TRE and Tcf/Lef promoters), subcellular fractionation, confocal immunofluorescence, Western blot, invasion assay","journal":"The Prostate","confidence":"Medium","confidence_rationale":"Tier 2 — reporter assay plus subcellular fractionation; single lab, multiple pathways addressed","pmids":["31212375"],"is_preprint":false},{"year":2021,"finding":"KAI1/CD82 expressed in pericytes inhibits angiogenesis through two mechanisms: (1) it localizes to the membrane surface after palmitoylation by zDHHC4 and induces LIF production through the Src/p53 pathway, with secreted LIF suppressing angiogenic factors in endothelial cells; (2) CD82 directly binds VEGF and PDGF and inhibits activation of their receptors. A peptide derived from the large extracellular loop of CD82 reproduces anti-angiogenic effects in vivo.","method":"Kai1 knockout mice, in vitro/in vivo angiogenesis assay, direct binding assay (VEGF/PDGF), palmitoylation assay, Src/p53 pathway analysis, LIF measurement","journal":"Journal of hematology & oncology","confidence":"Medium","confidence_rationale":"Tier 2 — KO model plus direct binding assay; two distinct mechanisms proposed; single study","pmids":["34530889"],"is_preprint":false},{"year":2023,"finding":"CD82 suppresses NLRP3 inflammasome activation by binding both NLRP3 and BRCC3 (a K63-specific deubiquitinase); CD82 binding blocks BRCC3-dependent K63 deubiquitination of NLRP3, promoting NLRP3 degradation. CD82 deficiency elevates NLRP3 inflammasome activation and reduces colitis severity in mice.","method":"Co-immunoprecipitation (NLRP3 and BRCC3 binding partners), CD82 KO mice, NLRP3 inflammasome activation assay, ubiquitination assay, in vivo colitis model","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP binding partners plus ubiquitination mechanistic assay; single lab","pmids":["36600050"],"is_preprint":false},{"year":2020,"finding":"CD82 interacts with ADAM17 metalloprotease and inhibits its metalloprotease activity, thereby suppressing ADAM17-mediated E-cadherin ectodomain cleavage from the cell membrane and reducing prostate cancer cell migration.","method":"Co-immunoprecipitation, ADAM17 metalloprotease activity assay, E-cadherin shedding assay, migration assay","journal":"Disease markers","confidence":"Medium","confidence_rationale":"Tier 2 — direct Co-IP plus enzyme activity assay; single lab","pmids":["33204367"],"is_preprint":false},{"year":2011,"finding":"CD82 inhibits invasiveness of endometrial stromal cells by downregulating CCL2 secretion and CCR2 expression via MAPK and integrin-β1 signaling pathways, and in turn upregulating TIMP1 and TIMP2 in an autocrine manner; TCDD and 17β-estradiol promote invasion by suppressing CD82 expression.","method":"siRNA knockdown, invasion assay, MAPK inhibition, Western blot for TIMP1/TIMP2/CCL2","journal":"Journal of molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA-based loss-of-function with multiple mechanistic readouts; single lab","pmids":["21685244"],"is_preprint":false},{"year":2006,"finding":"KAI1/CD82 overexpression in H1299 lung carcinoma cells suppresses tumor invasiveness by inducing MMP9 inactivation through upregulation of TIMP1, while MMP9 mRNA and protein levels are paradoxically elevated.","method":"Stable transfection, invasion assay, gelatin zymography, RT-PCR, Western blot","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods; mechanistic pathway (TIMP1-mediated MMP9 inhibition) established; single lab","pmids":["16488391"],"is_preprint":false},{"year":2012,"finding":"CD82 inhibits trophoblast invasion and migration by suppressing MMP9 gelatinolytic activity; CD82 siRNA enhances trophoblast invasion/migration and MMP9 activity, while CD82 overexpression decreases both, in villous explant and HTR8/SVneo trophoblast cell models.","method":"siRNA knockdown, CD82 overexpression, villous explant culture, invasion/migration assay, gelatin zymography","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — bidirectional gain/loss-of-function with enzymatic activity readout; single lab","pmids":["22679510"],"is_preprint":false},{"year":2007,"finding":"KAI1/CD82 suppresses HGF-induced cMet tyrosine kinase activation in the glycosynaptic microdomain as part of GM2/tetraspanin complex, inhibiting cell motility.","method":"cMet kinase activity assay, cell motility assay, glycosynaptic microdomain co-immunoprecipitation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — kinase activity assay in context of CD82-ganglioside complex; mechanistic but single lab","pmids":["18272501"],"is_preprint":false},{"year":2007,"finding":"KAI1/CD82-expressing tumor cells interact with Duffy antigen receptor for chemokines (DARC) on vascular endothelial cells, transmitting a senescent signal to cancer cells; cells that lost KAI1 expression escape this senescence and proliferate, enabling metastasis.","method":"In vitro cell-cell interaction assay, in vivo metastasis model, senescence assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo plus in vitro validation of KAI1-DARC interaction mechanism; single lab","pmids":["17308076"],"is_preprint":false},{"year":2008,"finding":"KAI1/CD82 transcription in prostate cancer cells is regulated by competition between a β-catenin/Reptin repressor complex and a Tip60/Pontin activator complex at the proximal promoter; phorbol ester (PMA) induces KAI1 transcription via cPKC→MEK1/2→ERK1/2 signaling, causing recruitment of Tip60/Pontin to NFκB-p50 motifs in the promoter and enhanced histone H3 acetylation.","method":"Chromatin immunoprecipitation (ChIP), kinase inhibitor studies, histone acetylation assay, PMA stimulation","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP confirmation of complex recruitment; signaling pathway defined by specific inhibitors; single lab","pmids":["19048121"],"is_preprint":false},{"year":2011,"finding":"N-glycosylation of CD82 occurs at three confirmed sites (including a novel site at Asn157); the glycans include bisecting N-acetylglucosamine, α-2,6-linked N-acetylneuraminic acid, and core fucose; these glycan epitopes are relevant to cell adhesion and cancer metastasis functions of CD82.","method":"Glycosidase and protease digestion, glycan permethylation, MS analysis, site-directed mutagenesis, lectin blot","journal":"Journal of proteomics","confidence":"Medium","confidence_rationale":"Tier 1 — direct biochemical characterization with mutagenesis confirming sites; structural glycoproteomics","pmids":["22123080"],"is_preprint":false},{"year":2012,"finding":"KAI1/CD82 suppresses HIF-1α and VEGF expression in prostate cancer by blocking CDCP1-enhanced Src kinase activation; KAI1 expression reduces CDCP1-Src signaling and increases VHL protein levels, promoting HIF-1α degradation.","method":"Stable transfection, Western blot, VEGF luciferase reporter, in vivo xenograft, immunohistochemistry","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 — reporter assay plus in vivo validation; pathway order defined; single lab","pmids":["22390300"],"is_preprint":false},{"year":1995,"finding":"Cross-linking of CD82 together with Fc receptors on U937 monocytic cells induces a PLC-dependent increase in intracellular calcium (via PtdIns(1,4,5)P3) followed by extracellular calcium entry, and tyrosine phosphorylation of various proteins; CD82 cross-linking alone is insufficient and requires co-engagement with FcR, suggesting formation of a CD82-FcR multimolecular signaling complex.","method":"Antibody cross-linking, calcium imaging (intracellular calcium measurement), tyrosine phosphorylation assay, pharmacological inhibitors (PLC inhibition)","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple biochemical readouts with pharmacological dissection; single lab","pmids":["7790779"],"is_preprint":false}],"current_model":"CD82/KAI1 is a tetraspanin transmembrane scaffold protein that suppresses tumor metastasis and cell migration by organizing plasma membrane microdomains (tetraspanin-enriched microdomains, lipid rafts, ganglioside-enriched domains): it attenuates EGFR dimerization and ubiquitylation (via c-Cbl regulation), promotes integrin internalization (α6, α4) to reduce adhesion/signaling, inhibits actin-dependent protrusion/retraction by suppressing Rac1/RhoA and their effectors, disrupts the p130CAS-CrkII motility switch, suppresses EMT by blocking TGF-β/Smad and Wnt/β-catenin pathways, promotes NLRP3 degradation by blocking BRCC3 deubiquitination, regulates TLR9 trafficking and myddosome formation, and is itself post-translationally regulated by palmitoylation (required for microdomain association and function) and by gp78-mediated ubiquitin–proteasome degradation, with its transcription directly activated by p53, ΔNp63α, and Tip60/Pontin complexes downstream of PKC-MEK-ERK signaling."},"narrative":{"teleology":[{"year":1995,"claim":"Identification of KAI1/CD82 as a metastasis suppressor gene established that a tetraspanin could directly suppress cancer dissemination in vivo, opening the question of how a transmembrane scaffold protein achieves this.","evidence":"Gene transfer into metastatic rat AT6.1 prostate cancer cells with in vivo metastasis assay","pmids":["7754374"],"confidence":"High","gaps":["Mechanism of metastasis suppression unknown","Downstream signaling pathways not identified","Relevant interacting partners not yet defined"]},{"year":1998,"claim":"Discovery that p53 directly activates KAI1/CD82 transcription linked metastasis suppression to the p53 tumor suppressor network, explaining how KAI1 is silenced in cancers with p53 loss.","evidence":"EMSA with purified p53, promoter-reporter assay, and site-directed mutagenesis of p53 binding site","pmids":["9736732"],"confidence":"High","gaps":["Other transcriptional regulators of KAI1 not yet identified","Mechanism by which CD82 protein suppresses metastasis still undefined"]},{"year":2003,"claim":"Convergent studies revealed that CD82 reorganizes plasma membrane microdomains to attenuate EGFR dimerization, disrupts the p130CAS–CrkII motility switch, and partners with EWI2/PGRL, collectively establishing membrane compartmentalization and adhesion signaling as the core mechanisms of metastasis suppression.","evidence":"Sucrose gradient fractionation and Co-IP for EGFR compartmentalization; p130CAS overexpression rescue of migration; chemical cross-linking/MS for EWI2 stoichiometric association","pmids":["14576349","12738793","12750295"],"confidence":"High","gaps":["How CD82 remodels lipid domains mechanistically (lipid species involved) not yet defined","Whether p130CAS downregulation is transcriptional or post-translational unclear"]},{"year":2004,"claim":"Palmitoylation at all cytoplasmic cysteines was shown to be essential for CD82 integration into tetraspanin-enriched microdomains and its anti-migratory and anti-invasive functions, establishing a critical post-translational regulatory mechanism.","evidence":"³H-palmitate metabolic labeling, cysteine-to-alanine mutagenesis with migration/invasion and Co-IP readouts","pmids":["15492270"],"confidence":"High","gaps":["Palmitoyltransferase responsible not yet identified (zDHHC4 identified later)","Whether palmitoylation is dynamically regulated in response to signals unknown"]},{"year":2004,"claim":"Demonstration that CD82 promotes integrin α6 internalization without altering total protein levels revealed a trafficking-based mechanism for reducing cell adhesion, extending the model beyond signaling attenuation to receptor surface regulation.","evidence":"Co-IP, surface biotinylation, and integrin internalization assay in epithelial cells","pmids":["15557282"],"confidence":"High","gaps":["Endocytic route for integrin internalization not characterized","Whether other integrins are similarly affected not systematically tested"]},{"year":2008,"claim":"Identification of the GM2/GM3 ganglioside heterodimer as a functional partner of CD82 that inhibits HGF/cMet signaling provided a molecular explanation for how glycolipid–tetraspanin interactions suppress receptor tyrosine kinase activation in glycosynaptic microdomains.","evidence":"ESI-MS of ganglioside complex, cMet kinase assay, and functional rescue with anti-GM2/GM3 blocking antibody","pmids":["18272501"],"confidence":"High","gaps":["Whether other RTKs are similarly regulated by this ganglioside complex unknown","Structural basis of CD82–ganglioside interaction unresolved"]},{"year":2008,"claim":"Polar residues within CD82 transmembrane domains were shown to be required for tetraspanin web integrity (CD9/CD151 interaction) and metastasis suppression, linking protein structural features to microdomain organization.","evidence":"TM domain polar residue mutagenesis with Co-IP, in vivo metastasis assay, and conformational stability assay","pmids":["19116362"],"confidence":"High","gaps":["No high-resolution structure of CD82 available","How TM polar residues mediate specific tetraspanin–tetraspanin contacts at atomic level unknown"]},{"year":2008,"claim":"Characterization of KAI1 promoter regulation by competing Tip60/Pontin activator and β-catenin/Reptin repressor complexes downstream of PKC–MEK–ERK signaling revealed an epigenetic switch controlling CD82 expression in prostate cancer.","evidence":"ChIP for Tip60/Pontin and Reptin at NF-κB-p50 promoter motifs, kinase inhibitor studies, histone acetylation assay","pmids":["19048121"],"confidence":"Medium","gaps":["Whether this transcriptional switch operates in non-prostate contexts unclear","Direct interaction between β-catenin/Reptin and Tip60/Pontin at the promoter not structurally resolved"]},{"year":2009,"claim":"Discovery that CD82 itself undergoes cholesterol-dependent, clathrin-independent endocytosis to late endosomes/lysosomes — and that this endocytosis relieves its migration-inhibitory effect — established that CD82 surface levels are dynamically regulated and functionally consequential.","evidence":"Endocytosis/trafficking assays with cholesterol depletion and dominant-negative dynamin, live-cell imaging","pmids":["19497983"],"confidence":"High","gaps":["Specific endocytic machinery mediating clathrin-independent CD82 uptake not identified","Signals triggering CD82 internalization in physiological contexts unknown"]},{"year":2010,"claim":"Identification of gp78 E3 ligase-mediated ERAD of CD82, with epistasis showing KAI1 knockdown rescues gp78 knockdown phenotypes, established proteasomal degradation as a key mechanism for CD82 protein level control in cancer.","evidence":"gp78 transgenic mouse, shRNA knockdown, BrdU proliferation assay, epistasis rescue","pmids":["20089858"],"confidence":"High","gaps":["Ubiquitination sites on CD82 not mapped","Whether other E3 ligases target CD82 unknown"]},{"year":2012,"claim":"Mechanistic dissection of CD82's anti-migratory action showed it suppresses both Rac1 (lamellipodia) and RhoA (stress fibers/retraction) activities while reducing PIP2 at the cell periphery, unifying the cytoskeletal phenotypes under a shared membrane signaling mechanism.","evidence":"Rac1/RhoA GTPase pull-down assays, ROCK kinase assay, PIP2 imaging, live-cell imaging","pmids":["23251627"],"confidence":"High","gaps":["How CD82 simultaneously suppresses opposing GTPases mechanistically unresolved","Direct effector linking CD82 to GTPase regulation not identified"]},{"year":2013,"claim":"CD82 was found to suppress EGFR ubiquitylation by increasing PKC-dependent c-Cbl phosphorylation in a ligand-selective manner (HB-EGF/amphiregulin but not EGF), refining understanding of how CD82 modulates RTK signaling at the post-activation level.","evidence":"Ubiquitylation assay, EEA1 endosome colocalization, C-terminal deletion mutant, phospho-specific antibodies","pmids":["23897813"],"confidence":"High","gaps":["Why ligand selectivity exists (HB-EGF vs EGF) not mechanistically explained","Whether reduced EGFR ubiquitylation promotes degradation or recycling not resolved"]},{"year":2014,"claim":"Superresolution imaging showed CD82 increases molecular packing density of α4 integrin clusters in a palmitoylation-dependent manner, providing the first nanoscale visualization of how a tetraspanin organizes integrin membrane architecture to regulate HSPC adhesion.","evidence":"dSTORM superresolution imaging, clustering algorithms, palmitoylation-deficient mutant, cell adhesion assay","pmids":["24623721"],"confidence":"High","gaps":["Whether CD82 similarly organizes other integrins at the nanoscale not tested","Structural basis for palmitoylation-dependent integrin clustering unknown"]},{"year":2014,"claim":"ΔNp63α was identified as a direct transcriptional activator of CD82, with CD82 knockdown reversing ΔNp63α-mediated invasion suppression, connecting CD82 to the p63 family of transcription factors beyond p53.","evidence":"ChIP, expression profiling, siRNA knockdown rescue, invasion assay","pmids":["24901051"],"confidence":"High","gaps":["Whether p53 and ΔNp63α compete or cooperate at the CD82 promoter unknown","Relevance in non-epithelial cell types not established"]},{"year":2018,"claim":"CD82 knockout in HSPCs revealed Rac1 hyperactivation causing defective bone marrow homing and quiescence loss, rescued by Rac1 inhibition, demonstrating that CD82's restraint of Rac1 is physiologically essential for stem cell function beyond cancer.","evidence":"CD82 KO mouse, Rac1 activity assay, bone marrow transplantation, Rac1 inhibitor rescue","pmids":["30133344"],"confidence":"High","gaps":["How CD82 restrains Rac1 activity molecularly (direct vs indirect) not defined","Whether quiescence defect contributes to long-term HSC exhaustion not tested"]},{"year":2019,"claim":"CD82 was shown to regulate innate immunity by associating with TLR9 from the ER through endosomal compartments and being required for myddosome formation and NF-κB activation, revealing a non-cancer function in immune signaling.","evidence":"Co-IP, confocal microscopy, myddosome formation assay, NF-κB translocation, CD82-deficient macrophages","pmids":["31408613"],"confidence":"High","gaps":["Whether CD82 regulates other TLRs beyond TLR9 not tested","Mechanism by which CD82 enables myddosome assembly not defined"]},{"year":2023,"claim":"CD82 was found to suppress NLRP3 inflammasome activation by binding both NLRP3 and BRCC3 deubiquitinase, blocking K63 deubiquitination and promoting NLRP3 degradation — establishing CD82 as a negative regulator of inflammasome signaling.","evidence":"Co-IP with NLRP3 and BRCC3, ubiquitination assay, CD82 KO mice with colitis model","pmids":["36600050"],"confidence":"Medium","gaps":["Whether CD82 bridges NLRP3 and BRCC3 as a ternary complex or competes for binding not resolved","Single study — independent replication needed","Structural basis of CD82–BRCC3 interaction unknown"]},{"year":null,"claim":"The molecular mechanism by which CD82 simultaneously restrains multiple GTPases (Rac1, RhoA, Cdc42), the structural basis of its tetraspanin web interactions, and the relative contributions of its diverse signaling outputs to metastasis suppression in vivo remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of CD82 in a membrane context","No systematic in vivo epistasis distinguishing contributions of individual effector pathways","How CD82 coordinates cancer-cell-autonomous vs microenvironmental (endothelial, immune) functions is unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,8,10,14,15,22,26,27]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[10,12,19]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[23,26]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,7,8,10,11,12,17,19,25]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[12,23]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[13,23]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,10,14,15,24,35]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[23,26,36]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[8,17,21]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[8,12,15]}],"complexes":["tetraspanin-enriched microdomain (TEM)","GM2/GM3-CD82 glycosynaptic complex"],"partners":["EGFR","IGSF8","ITGA6","ITGA4","NLRP3","TLR9","BRCC3","ADAM17"],"other_free_text":[]},"mechanistic_narrative":"CD82/KAI1 is a tetraspanin that functions as a metastasis suppressor and membrane microdomain organizer, controlling cell migration, invasion, adhesion, and angiogenesis by reorganizing lipid raft and ganglioside-enriched domains to modulate receptor tyrosine kinase signaling, integrin trafficking, and actin cytoskeleton dynamics. CD82 attenuates EGFR dimerization by redistributing it into ganglioside-enriched membrane fractions, suppresses HGF/cMet activation through GM2/GM3–CD82 glycosynaptic complexes, promotes integrin α6 and α4 internalization or clustering in a palmitoylation-dependent manner, and inhibits cell motility by reducing Rac1 and RhoA activity and disrupting the p130CAS–CrkII signaling switch [PMID:14576349, PMID:18272501, PMID:15557282, PMID:24623721, PMID:23251627, PMID:12738793]. Its expression is transcriptionally activated by p53, ΔNp63α, and Tip60/Pontin complexes downstream of PKC–MEK–ERK signaling, and its protein stability is regulated by palmitoylation at cytoplasmic cysteines and by gp78 E3 ligase-mediated proteasomal degradation [PMID:9736732, PMID:24901051, PMID:19048121, PMID:15492270, PMID:20089858]. Beyond its anti-metastatic role, CD82 regulates innate immune signaling by facilitating TLR9 trafficking and myddosome assembly in macrophages and suppressing NLRP3 inflammasome activation by blocking BRCC3-mediated deubiquitination of NLRP3 [PMID:31408613, PMID:36600050]."},"prefetch_data":{"uniprot":{"accession":"P27701","full_name":"CD82 antigen","aliases":["C33 antigen","IA4","Inducible membrane protein R2","Metastasis suppressor Kangai-1","Suppressor of tumorigenicity 6 protein","Tetraspanin-27","Tspan-27"],"length_aa":267,"mass_kda":29.6,"function":"Structural component of specialized membrane microdomains known as tetraspanin-enriched microdomains (TERMs), which act as platforms for receptor clustering and signaling (PubMed:19497983). Participates thereby in diverse biological functions such as cell signal transduction, adhesion, migration and protein trafficking. Acts as a attenuator of EGF signaling, facilitating ligand-induced endocytosis of the receptor and its subsequent desensitization (PubMed:10985391, PubMed:35538033). Mechanistically, modulates ligand-induced ubiquitination and trafficking of EGFR via E3 ligase CBL phosphorylation by PKC (PubMed:23897813). Increases cell-matrix adhesion by regulating the membrane organization of integrin alpha4/ITA4 (PubMed:24623721, PubMed:8757325). Modulates adhesion and suppresses cell migration through other integrins such as the alpha6/ITGA6 and beta1/ITGB1 (PubMed:15557282, PubMed:17560548). Decreases cell-associated plasminogen activation by interfering with the interaction between urokinase-type plasminogen activator/PLAU and its receptor PLAUR (PubMed:15677461). Associates with CD4 or CD8 and delivers costimulatory signals for the TCR/CD3 pathway. Plays a role in TLR9 trafficking to acidified CpG-containing compartments by controlling interaction between TLR9 and VAMP3 and subsequent myddosome assembly (By similarity). Inhibits LPS-induced inflammatory response by preventing binding of LPS to TLR4 on the cell surface (PubMed:36945827). Plays a role in the activation of macrophages into anti-inflammatory phenotypes (By similarity). Independently of Toll-like receptor (TLR) signaling, is recruited to pathogen-containing phagosomes prior to fusion with lysosomes and thereby participates in antigen presentation (By similarity). Also acts to control angiogenesis and switch angiogenic milieu to quiescent state by binding and sequestering VEGFA and PDGFB to inhibit the signaling they trigger via their respective cell surface receptor (PubMed:34530889)","subcellular_location":"Cell membrane; Cytoplasmic vesicle, phagosome","url":"https://www.uniprot.org/uniprotkb/P27701/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD82","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CD82","total_profiled":1310},"omim":[{"mim_id":"621013","title":"TETRASPANIN 11; TSPAN11","url":"https://www.omim.org/entry/621013"},{"mim_id":"613665","title":"ATYPICAL CHEMOKINE RECEPTOR 1; ACKR1","url":"https://www.omim.org/entry/613665"},{"mim_id":"603243","title":"AUTOCRINE MOTILITY FACTOR RECEPTOR; AMFR","url":"https://www.omim.org/entry/603243"},{"mim_id":"600623","title":"CD82 ANTIGEN; CD82","url":"https://www.omim.org/entry/600623"},{"mim_id":"176807","title":"PROSTATE CANCER","url":"https://www.omim.org/entry/176807"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Vesicles","reliability":"Uncertain"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CD82"},"hgnc":{"alias_symbol":["R2","IA4","TSPAN27"],"prev_symbol":["ST6","KAI1"]},"alphafold":{"accession":"P27701","domains":[{"cath_id":"-","chopping":"2-124_233-264","consensus_level":"medium","plddt":88.8417,"start":2,"end":264},{"cath_id":"-","chopping":"134-217","consensus_level":"medium","plddt":84.04,"start":134,"end":217}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P27701","model_url":"https://alphafold.ebi.ac.uk/files/AF-P27701-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P27701-F1-predicted_aligned_error_v6.png","plddt_mean":88.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CD82","jax_strain_url":"https://www.jax.org/strain/search?query=CD82"},"sequence":{"accession":"P27701","fasta_url":"https://rest.uniprot.org/uniprotkb/P27701.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P27701/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P27701"}},"corpus_meta":[{"pmid":"9311998","id":"PMC_9311998","title":"TRAIL-R2: 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haematology","url":"https://pubmed.ncbi.nlm.nih.gov/10583248","citation_count":21,"is_preprint":false},{"pmid":"19656997","id":"PMC_19656997","title":"Effect of expressional alteration of KAI1 on breast cancer cell growth, adhesion, migration and invasion.","date":"2009","source":"Cancer genomics & proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/19656997","citation_count":21,"is_preprint":false},{"pmid":"24066021","id":"PMC_24066021","title":"Evolution of the R2 retrotransposon ribozyme and its self-cleavage site.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24066021","citation_count":21,"is_preprint":false},{"pmid":"25435431","id":"PMC_25435431","title":"Alternative splicing of KAI1 abrogates its tumor-suppressive effects on integrin αvβ3-mediated ovarian cancer biology.","date":"2014","source":"Cellular 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into rat AT6.1 prostate cancer cells, in vivo metastasis assay, molecular cloning\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — original functional discovery with in vivo loss/gain-of-function, replicated across many subsequent studies\",\n      \"pmids\": [\"7754374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The tumor suppressor p53 directly activates KAI1/CD82 transcription by binding to a tandem p53 consensus sequence ~860 bp upstream of the transcriptional initiation site, as demonstrated by gel-shift mobility assay with purified p53 protein and mutational analysis of the binding sequence.\",\n      \"method\": \"Gel-shift mobility assay (EMSA), promoter-reporter assay, site-directed mutagenesis, immunohistochemistry\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro binding with purified protein plus mutagenesis confirming functional binding site\",\n      \"pmids\": [\"9736732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CD82 specifically attenuates ligand-induced dimerization of EGFR and causes redistribution of EGFR into lipid raft-like light sucrose gradient fractions enriched in gangliosides GD1a and GM1; the large extracellular loop of CD82 alone is insufficient for this effect, implicating other domains. CD82 is also associated with ErbB2 and ErbB3 but does not affect ErbB2-ErbB3 dimerization.\",\n      \"method\": \"Sucrose gradient fractionation, co-immunoprecipitation, confocal microscopy, expression of recombinant CD82 domains\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in one study establishing mechanistic link between CD82, ganglioside-mediated compartmentalization, and EGFR dimerization\",\n      \"pmids\": [\"14576349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"KAI1/CD82 inhibits cancer cell migration by downregulating p130CAS protein levels, thereby reducing formation of the p130CAS-CrkII complex (a 'molecular switch' in cell motility); overexpression of p130CAS in KAI1/CD82-expressing cells restored migration, confirming the pathway.\",\n      \"method\": \"Stable transfection, Western blot, co-immunoprecipitation, migration assay, p130CAS overexpression rescue experiment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis confirmed by rescue experiment; multiple orthogonal methods\",\n      \"pmids\": [\"12738793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"EWI2/PGRL (an immunoglobulin superfamily member) directly and stoichiometrically associates with KAI1/CD82 in a cholesterol-independent, likely direct interaction; overexpression of EWI2/PGRL inhibits prostate cancer cell migration and synergizes with KAI1/CD82 in migration suppression.\",\n      \"method\": \"Chemical cross-linking, co-immunoprecipitation, mass spectrometry peptide sequencing, migration assay, cholesterol depletion\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — stoichiometric direct association confirmed by cross-linking and MS; functional synergy demonstrated\",\n      \"pmids\": [\"12750295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"C33/CD82/KAI1 induces apoptosis by generating reactive oxygen intermediates (ROIs) via a non-mitochondrial pathway; it promotes cell death by causing release of intracellular antioxidant glutathione (GSH) from cells and activates the GTPase Cdc42, which mediates GSH release and apoptosis induction.\",\n      \"method\": \"Apoptosis screen (gain-of-function), ROI detection, GSH measurement, Cdc42 activation assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple mechanistic readouts in one lab; single study\",\n      \"pmids\": [\"14597553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"KAI1/CD82 promotes homotypic aggregation of prostate cancer cells through a Src kinase-dependent intracellular signaling pathway; ligation of CD82 increases endogenous Src kinase activity, and a kinase-negative Src mutant abolished CD82-mediated aggregation.\",\n      \"method\": \"Stable transfection, kinase-negative Src mutant re-transfection, antibody-induced CD82 cross-linking, Src kinase activity assay\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — dominant-negative epistasis with kinase assay; single lab\",\n      \"pmids\": [\"12642901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"KAI1/CD82 is palmitoylated at all cytoplasmic cysteine residues proximal to the plasma membrane; palmitoylation-deficient CD82 mutant largely reverses inhibitory effects on migration and invasion, disrupts tetraspanin web association, alters subcellular distribution, and abolishes inhibition of lamellipodia formation and p130CAS-CrkII coupling.\",\n      \"method\": \"[3H]-palmitate metabolic labeling, site-directed mutagenesis of cysteine residues, migration/invasion assay, co-immunoprecipitation, actin cytoskeleton imaging\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct PTM identification by metabolic labeling plus mutagenesis with multiple functional readouts\",\n      \"pmids\": [\"15492270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CD82 attenuates integrin α6-mediated cell adhesion and morphogenesis by associating with integrin α6 and promoting its internalization, thereby reducing α6 integrin surface expression without changing total cellular α6 protein levels.\",\n      \"method\": \"Co-immunoprecipitation, surface biotinylation, internalization assay, Matrigel morphogenesis assay, integrin-blocking antibodies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct physical association shown by Co-IP; mechanistic link to surface downregulation confirmed by biotinylation and internalization assays\",\n      \"pmids\": [\"15557282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"KITENIN/VANGL1, a tetraspanin family member, interacts specifically with the C-terminal cytoplasmic domain of KAI1 (identified by yeast two-hybrid); KITENIN overexpression increases tumor invasiveness and metastasis, antagonizing KAI1 metastasis suppressor function.\",\n      \"method\": \"Yeast two-hybrid screening, in vivo metastasis model, invasion and adhesion assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — yeast two-hybrid identification; functional antagonism shown in vivo; no reciprocal Co-IP in mammalian cells reported\",\n      \"pmids\": [\"15205336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Ganglioside GM2/GM3 complex (heterodimer stabilized by Ca2+) interacts with CD82 in glycosynaptic microdomains to inhibit HGF-induced cMet tyrosine kinase activity and cell motility; an antibody blocking GM2/GM3 dimer-CD82 interaction restores cell motility, confirming functional specificity.\",\n      \"method\": \"ESI mass spectrometry, cell motility assay, cMet kinase activity assay, blocking antibody (mAb 8E11), nanosphere coating with glycosphingolipids\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical characterization of heterodimer, functional rescue with blocking antibody, multiple cell systems\",\n      \"pmids\": [\"18272501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CD82 requires polar residues (Asn, Gln, Glu) within its transmembrane domains for its migration-, invasion-, and metastasis-suppressive activities; mutation of these residues disrupts interaction with tetraspanins CD9 and CD151 (but not α3β1 integrin association), reduces conformational stability, and abolishes inhibition of microprotrusion formation and microvesicle release.\",\n      \"method\": \"Site-directed mutagenesis of TM domain polar residues, co-immunoprecipitation, in vivo metastasis assay, structural modeling, denaturation assay\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis plus multiple functional and biochemical readouts\",\n      \"pmids\": [\"19116362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CD82 undergoes cholesterol-dependent, dynamin- and clathrin-independent endocytosis to late endosomes and lysosomes; cholesterol depletion blocks CD82 internalization. CD82 also redistributes cholesterol into tetraspanin-enriched microdomains (TEMs), reorganizing TEMs and lipid rafts. CD82 endocytosis alleviates its inhibitory effect on cell migration.\",\n      \"method\": \"Endocytosis/trafficking assays, cholesterol depletion (methyl-β-cyclodextrin), dominant-negative dynamin expression, sucrose gradient fractionation, live-cell imaging\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods; functional consequence of endocytosis on migration demonstrated\",\n      \"pmids\": [\"19497983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The E3 ubiquitin ligase gp78 targets KAI1/CD82 for degradation via ER-associated degradation (ERAD); gp78 overexpression reduces KAI1 expression and gp78 knockdown increases KAI1 expression; gp78 regulation of cell proliferation is mediated by KAI1, demonstrated by KAI1 knockdown rescuing reduced proliferation in stable gp78 knockdown cells.\",\n      \"method\": \"MMTV-gp78 transgenic mouse model, siRNA/shRNA knockdown, Western blot, BrdU proliferation assay, epistasis rescue experiment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis rescue experiment plus in vivo transgenic model; multiple orthogonal methods\",\n      \"pmids\": [\"20089858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KAI1/CD82 inhibits cell migration by attenuating the plasma membrane-dependent actin organization: it reduces Rac1 activity (diminishing lamellipodia and actin cortical network), blocks growth factor-stimulated RhoA activity (preventing stress fiber formation and retraction), reduces cofilin enrichment at the cell periphery, and decreases Rho kinase activity. Additionally, phosphatidylinositol 4,5-bisphosphate becomes less detectable at the cell periphery.\",\n      \"method\": \"Live imaging, Rac1/RhoA activity assays (pull-down), ROCK kinase assay, phospholipid imaging, stable transfection\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple signaling readouts with live imaging; mechanistic pathway defined\",\n      \"pmids\": [\"23251627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD82/KAI1 suppresses ubiquitylation of EGFR after stimulation with heparin-binding EGF or amphiregulin (but not EGF itself), delays EGFR recruitment to EEA1-positive early endosomes, and increases PKC-dependent serine phosphorylation of c-Cbl E3 ubiquitin ligase; phosphorylation of EGFR Thr654 (PKC site) is also increased in CD82-expressing cells. The C-terminal cytoplasmic domain of CD82 is required for its endocytic trafficking and this regulatory function.\",\n      \"method\": \"Ubiquitylation assay, endocytic trafficking assay (EEA1 co-localization), C-terminal deletion mutant (CD82ΔC), phospho-specific antibodies, Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mechanistic dissection with deletion mutant, specific ligand discrimination, and c-Cbl phosphorylation link established\",\n      \"pmids\": [\"23897813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD82 positively regulates the STAT5/IL-10 signaling pathway in leukemia stem cells: CD82 knockdown dephosphorylates STAT5 and decreases IL-10 levels, while forced CD82 expression increases p-STAT5 and IL-10; ChIP assay demonstrates STAT5A binds to the IL-10 gene promoter, and reporter assay confirms transcriptional activation of IL-10 by CD82-driven STAT5.\",\n      \"method\": \"shRNA knockdown, lentiviral overexpression, ChIP assay, luciferase reporter assay, Western blot\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus reporter assay; single lab, single study\",\n      \"pmids\": [\"23797738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD82 overexpression increases the molecular density of α4 integrin subunits within plasma membrane clusters, thereby increasing cell adhesion; this packing depends on CD82 palmitoylation and the presence of α4 integrin ligands. CD82 regulates HSPC adhesion and homing to bone marrow through modulation of integrin membrane organization.\",\n      \"method\": \"Direct stochastic optical reconstruction microscopy (dSTORM) superresolution imaging, protein clustering algorithms, palmitoylation-deficient mutant, cell adhesion assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — superresolution structural imaging with quantitative clustering analysis and mutagenesis; functional link established\",\n      \"pmids\": [\"24623721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ΔNp63α directly transcriptionally activates CD82/KAI1 as a target gene to inhibit cancer cell invasion; chromatin immunoprecipitation confirmed ΔNp63α binding to the CD82 promoter; CD82 knockdown reversed ΔNp63α-mediated invasion suppression; GSK3β inhibition downregulates both ΔNp63α and CD82 independently of β-catenin.\",\n      \"method\": \"ChIP, Affymetrix gene expression profiling, siRNA knockdown rescue, Matrigel invasion assay, luciferase reporter\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP plus expression profiling plus epistasis rescue; direct transcriptional regulatory mechanism confirmed\",\n      \"pmids\": [\"24901051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD82 restrains angiogenesis in endothelial cells by inhibiting lipid raft clustering and CD44 membrane trafficking; CD82 ablation increases ganglioside levels and lipid raft clustering in the plasma membrane, reduces clathrin-independent endocytosis of CD44, and elevates CD44 surface expression, leading to enhanced outside-in signaling and EC migration.\",\n      \"method\": \"Cd82-null mouse model, in vivo and ex vivo angiogenesis assays, lipid raft fractionation, CD44 trafficking assay, ganglioside analysis\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — knockout mouse model with multiple mechanistic readouts and in vivo validation\",\n      \"pmids\": [\"25149363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD82 suppresses U2AF2-mediated CD44 alternative splicing (specifically CD44v8-10 production) by inducing ubiquitination and degradation of the splicing factor U2AF2, thereby inhibiting melanoma metastasis; U2AF2-dependent CD44v8-10 promotes migration via Src/FAK/RhoA activation and CD44-E-selectin binding.\",\n      \"method\": \"In vivo metastasis assay, in vitro migration, ubiquitination assay, siRNA knockdown, Affymetrix expression, immunoprecipitation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ubiquitination assay with in vivo validation and mechanistic pathway defined\",\n      \"pmids\": [\"27041584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD82 inhibits fibronectin-induced epithelial-to-mesenchymal transition (EMT) in prostate cancer cells by forming lateral interactions with fibronectin-binding α3β1 and α5β1 integrins and attenuating downstream FAK-Src and ILK signaling pathways.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, Western blot for FAK/Src/ILK phosphorylation, invasion/migration assay, human tissue immunostaining\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus signaling assay; single lab but multiple methods\",\n      \"pmids\": [\"27926483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD82 deficiency in hematopoietic stem and progenitor cells (HSPCs) causes hyperactivation of Rac1, impaired bone marrow homing and engraftment, and reduced stem cell quiescence (cell cycle activation); pharmacological Rac1 inhibition rescues the homing defect of CD82KO HSPCs.\",\n      \"method\": \"CD82 knockout mouse model, Rac1 activity assay, bone marrow transplantation homing assay, cell cycle analysis, Rac1 inhibitor rescue\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO model with epistasis rescue by Rac1 inhibitor; multiple functional readouts\",\n      \"pmids\": [\"30133344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD82 is a key regulator of TLR9 trafficking and signaling: CD82 associates with TLR9 in the endoplasmic reticulum and post-ER compartments in macrophages; CD82 is essential for CpG-stimulated TLR9-dependent myddosome formation and NF-κB nuclear translocation leading to inflammatory cytokine production.\",\n      \"method\": \"Co-immunoprecipitation, confocal microscopy, myddosome formation assay, NF-κB nuclear translocation assay, cytokine measurement, CD82-deficient macrophages\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with subcellular localization, functional loss-of-function, and multiple downstream signaling readouts\",\n      \"pmids\": [\"31408613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD82 represses TGF-β1/Smad signaling and Wnt/β-catenin signaling to suppress EMT in prostate cancer: CD82 blocks Smad2 phosphorylation, Smad4 nuclear translocation, and TRE promoter transactivation; it also prevents GSK-3β inactivation downstream of Wnt3a, maintaining β-catenin phosphorylation and blocking its nuclear translocation.\",\n      \"method\": \"Luciferase reporter assay (TRE and Tcf/Lef promoters), subcellular fractionation, confocal immunofluorescence, Western blot, invasion assay\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter assay plus subcellular fractionation; single lab, multiple pathways addressed\",\n      \"pmids\": [\"31212375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KAI1/CD82 expressed in pericytes inhibits angiogenesis through two mechanisms: (1) it localizes to the membrane surface after palmitoylation by zDHHC4 and induces LIF production through the Src/p53 pathway, with secreted LIF suppressing angiogenic factors in endothelial cells; (2) CD82 directly binds VEGF and PDGF and inhibits activation of their receptors. A peptide derived from the large extracellular loop of CD82 reproduces anti-angiogenic effects in vivo.\",\n      \"method\": \"Kai1 knockout mice, in vitro/in vivo angiogenesis assay, direct binding assay (VEGF/PDGF), palmitoylation assay, Src/p53 pathway analysis, LIF measurement\",\n      \"journal\": \"Journal of hematology & oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO model plus direct binding assay; two distinct mechanisms proposed; single study\",\n      \"pmids\": [\"34530889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD82 suppresses NLRP3 inflammasome activation by binding both NLRP3 and BRCC3 (a K63-specific deubiquitinase); CD82 binding blocks BRCC3-dependent K63 deubiquitination of NLRP3, promoting NLRP3 degradation. CD82 deficiency elevates NLRP3 inflammasome activation and reduces colitis severity in mice.\",\n      \"method\": \"Co-immunoprecipitation (NLRP3 and BRCC3 binding partners), CD82 KO mice, NLRP3 inflammasome activation assay, ubiquitination assay, in vivo colitis model\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP binding partners plus ubiquitination mechanistic assay; single lab\",\n      \"pmids\": [\"36600050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD82 interacts with ADAM17 metalloprotease and inhibits its metalloprotease activity, thereby suppressing ADAM17-mediated E-cadherin ectodomain cleavage from the cell membrane and reducing prostate cancer cell migration.\",\n      \"method\": \"Co-immunoprecipitation, ADAM17 metalloprotease activity assay, E-cadherin shedding assay, migration assay\",\n      \"journal\": \"Disease markers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct Co-IP plus enzyme activity assay; single lab\",\n      \"pmids\": [\"33204367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD82 inhibits invasiveness of endometrial stromal cells by downregulating CCL2 secretion and CCR2 expression via MAPK and integrin-β1 signaling pathways, and in turn upregulating TIMP1 and TIMP2 in an autocrine manner; TCDD and 17β-estradiol promote invasion by suppressing CD82 expression.\",\n      \"method\": \"siRNA knockdown, invasion assay, MAPK inhibition, Western blot for TIMP1/TIMP2/CCL2\",\n      \"journal\": \"Journal of molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA-based loss-of-function with multiple mechanistic readouts; single lab\",\n      \"pmids\": [\"21685244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"KAI1/CD82 overexpression in H1299 lung carcinoma cells suppresses tumor invasiveness by inducing MMP9 inactivation through upregulation of TIMP1, while MMP9 mRNA and protein levels are paradoxically elevated.\",\n      \"method\": \"Stable transfection, invasion assay, gelatin zymography, RT-PCR, Western blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods; mechanistic pathway (TIMP1-mediated MMP9 inhibition) established; single lab\",\n      \"pmids\": [\"16488391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD82 inhibits trophoblast invasion and migration by suppressing MMP9 gelatinolytic activity; CD82 siRNA enhances trophoblast invasion/migration and MMP9 activity, while CD82 overexpression decreases both, in villous explant and HTR8/SVneo trophoblast cell models.\",\n      \"method\": \"siRNA knockdown, CD82 overexpression, villous explant culture, invasion/migration assay, gelatin zymography\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional gain/loss-of-function with enzymatic activity readout; single lab\",\n      \"pmids\": [\"22679510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KAI1/CD82 suppresses HGF-induced cMet tyrosine kinase activation in the glycosynaptic microdomain as part of GM2/tetraspanin complex, inhibiting cell motility.\",\n      \"method\": \"cMet kinase activity assay, cell motility assay, glycosynaptic microdomain co-immunoprecipitation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — kinase activity assay in context of CD82-ganglioside complex; mechanistic but single lab\",\n      \"pmids\": [\"18272501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KAI1/CD82-expressing tumor cells interact with Duffy antigen receptor for chemokines (DARC) on vascular endothelial cells, transmitting a senescent signal to cancer cells; cells that lost KAI1 expression escape this senescence and proliferate, enabling metastasis.\",\n      \"method\": \"In vitro cell-cell interaction assay, in vivo metastasis model, senescence assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo plus in vitro validation of KAI1-DARC interaction mechanism; single lab\",\n      \"pmids\": [\"17308076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"KAI1/CD82 transcription in prostate cancer cells is regulated by competition between a β-catenin/Reptin repressor complex and a Tip60/Pontin activator complex at the proximal promoter; phorbol ester (PMA) induces KAI1 transcription via cPKC→MEK1/2→ERK1/2 signaling, causing recruitment of Tip60/Pontin to NFκB-p50 motifs in the promoter and enhanced histone H3 acetylation.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), kinase inhibitor studies, histone acetylation assay, PMA stimulation\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirmation of complex recruitment; signaling pathway defined by specific inhibitors; single lab\",\n      \"pmids\": [\"19048121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"N-glycosylation of CD82 occurs at three confirmed sites (including a novel site at Asn157); the glycans include bisecting N-acetylglucosamine, α-2,6-linked N-acetylneuraminic acid, and core fucose; these glycan epitopes are relevant to cell adhesion and cancer metastasis functions of CD82.\",\n      \"method\": \"Glycosidase and protease digestion, glycan permethylation, MS analysis, site-directed mutagenesis, lectin blot\",\n      \"journal\": \"Journal of proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical characterization with mutagenesis confirming sites; structural glycoproteomics\",\n      \"pmids\": [\"22123080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KAI1/CD82 suppresses HIF-1α and VEGF expression in prostate cancer by blocking CDCP1-enhanced Src kinase activation; KAI1 expression reduces CDCP1-Src signaling and increases VHL protein levels, promoting HIF-1α degradation.\",\n      \"method\": \"Stable transfection, Western blot, VEGF luciferase reporter, in vivo xenograft, immunohistochemistry\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter assay plus in vivo validation; pathway order defined; single lab\",\n      \"pmids\": [\"22390300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Cross-linking of CD82 together with Fc receptors on U937 monocytic cells induces a PLC-dependent increase in intracellular calcium (via PtdIns(1,4,5)P3) followed by extracellular calcium entry, and tyrosine phosphorylation of various proteins; CD82 cross-linking alone is insufficient and requires co-engagement with FcR, suggesting formation of a CD82-FcR multimolecular signaling complex.\",\n      \"method\": \"Antibody cross-linking, calcium imaging (intracellular calcium measurement), tyrosine phosphorylation assay, pharmacological inhibitors (PLC inhibition)\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical readouts with pharmacological dissection; single lab\",\n      \"pmids\": [\"7790779\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD82/KAI1 is a tetraspanin transmembrane scaffold protein that suppresses tumor metastasis and cell migration by organizing plasma membrane microdomains (tetraspanin-enriched microdomains, lipid rafts, ganglioside-enriched domains): it attenuates EGFR dimerization and ubiquitylation (via c-Cbl regulation), promotes integrin internalization (α6, α4) to reduce adhesion/signaling, inhibits actin-dependent protrusion/retraction by suppressing Rac1/RhoA and their effectors, disrupts the p130CAS-CrkII motility switch, suppresses EMT by blocking TGF-β/Smad and Wnt/β-catenin pathways, promotes NLRP3 degradation by blocking BRCC3 deubiquitination, regulates TLR9 trafficking and myddosome formation, and is itself post-translationally regulated by palmitoylation (required for microdomain association and function) and by gp78-mediated ubiquitin–proteasome degradation, with its transcription directly activated by p53, ΔNp63α, and Tip60/Pontin complexes downstream of PKC-MEK-ERK signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CD82/KAI1 is a tetraspanin that functions as a metastasis suppressor and membrane microdomain organizer, controlling cell migration, invasion, adhesion, and angiogenesis by reorganizing lipid raft and ganglioside-enriched domains to modulate receptor tyrosine kinase signaling, integrin trafficking, and actin cytoskeleton dynamics. CD82 attenuates EGFR dimerization by redistributing it into ganglioside-enriched membrane fractions, suppresses HGF/cMet activation through GM2/GM3–CD82 glycosynaptic complexes, promotes integrin α6 and α4 internalization or clustering in a palmitoylation-dependent manner, and inhibits cell motility by reducing Rac1 and RhoA activity and disrupting the p130CAS–CrkII signaling switch [PMID:14576349, PMID:18272501, PMID:15557282, PMID:24623721, PMID:23251627, PMID:12738793]. Its expression is transcriptionally activated by p53, ΔNp63α, and Tip60/Pontin complexes downstream of PKC–MEK–ERK signaling, and its protein stability is regulated by palmitoylation at cytoplasmic cysteines and by gp78 E3 ligase-mediated proteasomal degradation [PMID:9736732, PMID:24901051, PMID:19048121, PMID:15492270, PMID:20089858]. Beyond its anti-metastatic role, CD82 regulates innate immune signaling by facilitating TLR9 trafficking and myddosome assembly in macrophages and suppressing NLRP3 inflammasome activation by blocking BRCC3-mediated deubiquitination of NLRP3 [PMID:31408613, PMID:36600050].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Identification of KAI1/CD82 as a metastasis suppressor gene established that a tetraspanin could directly suppress cancer dissemination in vivo, opening the question of how a transmembrane scaffold protein achieves this.\",\n      \"evidence\": \"Gene transfer into metastatic rat AT6.1 prostate cancer cells with in vivo metastasis assay\",\n      \"pmids\": [\"7754374\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of metastasis suppression unknown\", \"Downstream signaling pathways not identified\", \"Relevant interacting partners not yet defined\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Discovery that p53 directly activates KAI1/CD82 transcription linked metastasis suppression to the p53 tumor suppressor network, explaining how KAI1 is silenced in cancers with p53 loss.\",\n      \"evidence\": \"EMSA with purified p53, promoter-reporter assay, and site-directed mutagenesis of p53 binding site\",\n      \"pmids\": [\"9736732\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other transcriptional regulators of KAI1 not yet identified\", \"Mechanism by which CD82 protein suppresses metastasis still undefined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Convergent studies revealed that CD82 reorganizes plasma membrane microdomains to attenuate EGFR dimerization, disrupts the p130CAS–CrkII motility switch, and partners with EWI2/PGRL, collectively establishing membrane compartmentalization and adhesion signaling as the core mechanisms of metastasis suppression.\",\n      \"evidence\": \"Sucrose gradient fractionation and Co-IP for EGFR compartmentalization; p130CAS overexpression rescue of migration; chemical cross-linking/MS for EWI2 stoichiometric association\",\n      \"pmids\": [\"14576349\", \"12738793\", \"12750295\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CD82 remodels lipid domains mechanistically (lipid species involved) not yet defined\", \"Whether p130CAS downregulation is transcriptional or post-translational unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Palmitoylation at all cytoplasmic cysteines was shown to be essential for CD82 integration into tetraspanin-enriched microdomains and its anti-migratory and anti-invasive functions, establishing a critical post-translational regulatory mechanism.\",\n      \"evidence\": \"³H-palmitate metabolic labeling, cysteine-to-alanine mutagenesis with migration/invasion and Co-IP readouts\",\n      \"pmids\": [\"15492270\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Palmitoyltransferase responsible not yet identified (zDHHC4 identified later)\", \"Whether palmitoylation is dynamically regulated in response to signals unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstration that CD82 promotes integrin α6 internalization without altering total protein levels revealed a trafficking-based mechanism for reducing cell adhesion, extending the model beyond signaling attenuation to receptor surface regulation.\",\n      \"evidence\": \"Co-IP, surface biotinylation, and integrin internalization assay in epithelial cells\",\n      \"pmids\": [\"15557282\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endocytic route for integrin internalization not characterized\", \"Whether other integrins are similarly affected not systematically tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identification of the GM2/GM3 ganglioside heterodimer as a functional partner of CD82 that inhibits HGF/cMet signaling provided a molecular explanation for how glycolipid–tetraspanin interactions suppress receptor tyrosine kinase activation in glycosynaptic microdomains.\",\n      \"evidence\": \"ESI-MS of ganglioside complex, cMet kinase assay, and functional rescue with anti-GM2/GM3 blocking antibody\",\n      \"pmids\": [\"18272501\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other RTKs are similarly regulated by this ganglioside complex unknown\", \"Structural basis of CD82–ganglioside interaction unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Polar residues within CD82 transmembrane domains were shown to be required for tetraspanin web integrity (CD9/CD151 interaction) and metastasis suppression, linking protein structural features to microdomain organization.\",\n      \"evidence\": \"TM domain polar residue mutagenesis with Co-IP, in vivo metastasis assay, and conformational stability assay\",\n      \"pmids\": [\"19116362\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of CD82 available\", \"How TM polar residues mediate specific tetraspanin–tetraspanin contacts at atomic level unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Characterization of KAI1 promoter regulation by competing Tip60/Pontin activator and β-catenin/Reptin repressor complexes downstream of PKC–MEK–ERK signaling revealed an epigenetic switch controlling CD82 expression in prostate cancer.\",\n      \"evidence\": \"ChIP for Tip60/Pontin and Reptin at NF-κB-p50 promoter motifs, kinase inhibitor studies, histone acetylation assay\",\n      \"pmids\": [\"19048121\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this transcriptional switch operates in non-prostate contexts unclear\", \"Direct interaction between β-catenin/Reptin and Tip60/Pontin at the promoter not structurally resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Discovery that CD82 itself undergoes cholesterol-dependent, clathrin-independent endocytosis to late endosomes/lysosomes — and that this endocytosis relieves its migration-inhibitory effect — established that CD82 surface levels are dynamically regulated and functionally consequential.\",\n      \"evidence\": \"Endocytosis/trafficking assays with cholesterol depletion and dominant-negative dynamin, live-cell imaging\",\n      \"pmids\": [\"19497983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific endocytic machinery mediating clathrin-independent CD82 uptake not identified\", \"Signals triggering CD82 internalization in physiological contexts unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identification of gp78 E3 ligase-mediated ERAD of CD82, with epistasis showing KAI1 knockdown rescues gp78 knockdown phenotypes, established proteasomal degradation as a key mechanism for CD82 protein level control in cancer.\",\n      \"evidence\": \"gp78 transgenic mouse, shRNA knockdown, BrdU proliferation assay, epistasis rescue\",\n      \"pmids\": [\"20089858\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitination sites on CD82 not mapped\", \"Whether other E3 ligases target CD82 unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mechanistic dissection of CD82's anti-migratory action showed it suppresses both Rac1 (lamellipodia) and RhoA (stress fibers/retraction) activities while reducing PIP2 at the cell periphery, unifying the cytoskeletal phenotypes under a shared membrane signaling mechanism.\",\n      \"evidence\": \"Rac1/RhoA GTPase pull-down assays, ROCK kinase assay, PIP2 imaging, live-cell imaging\",\n      \"pmids\": [\"23251627\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CD82 simultaneously suppresses opposing GTPases mechanistically unresolved\", \"Direct effector linking CD82 to GTPase regulation not identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"CD82 was found to suppress EGFR ubiquitylation by increasing PKC-dependent c-Cbl phosphorylation in a ligand-selective manner (HB-EGF/amphiregulin but not EGF), refining understanding of how CD82 modulates RTK signaling at the post-activation level.\",\n      \"evidence\": \"Ubiquitylation assay, EEA1 endosome colocalization, C-terminal deletion mutant, phospho-specific antibodies\",\n      \"pmids\": [\"23897813\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why ligand selectivity exists (HB-EGF vs EGF) not mechanistically explained\", \"Whether reduced EGFR ubiquitylation promotes degradation or recycling not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Superresolution imaging showed CD82 increases molecular packing density of α4 integrin clusters in a palmitoylation-dependent manner, providing the first nanoscale visualization of how a tetraspanin organizes integrin membrane architecture to regulate HSPC adhesion.\",\n      \"evidence\": \"dSTORM superresolution imaging, clustering algorithms, palmitoylation-deficient mutant, cell adhesion assay\",\n      \"pmids\": [\"24623721\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CD82 similarly organizes other integrins at the nanoscale not tested\", \"Structural basis for palmitoylation-dependent integrin clustering unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"ΔNp63α was identified as a direct transcriptional activator of CD82, with CD82 knockdown reversing ΔNp63α-mediated invasion suppression, connecting CD82 to the p63 family of transcription factors beyond p53.\",\n      \"evidence\": \"ChIP, expression profiling, siRNA knockdown rescue, invasion assay\",\n      \"pmids\": [\"24901051\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether p53 and ΔNp63α compete or cooperate at the CD82 promoter unknown\", \"Relevance in non-epithelial cell types not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"CD82 knockout in HSPCs revealed Rac1 hyperactivation causing defective bone marrow homing and quiescence loss, rescued by Rac1 inhibition, demonstrating that CD82's restraint of Rac1 is physiologically essential for stem cell function beyond cancer.\",\n      \"evidence\": \"CD82 KO mouse, Rac1 activity assay, bone marrow transplantation, Rac1 inhibitor rescue\",\n      \"pmids\": [\"30133344\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CD82 restrains Rac1 activity molecularly (direct vs indirect) not defined\", \"Whether quiescence defect contributes to long-term HSC exhaustion not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"CD82 was shown to regulate innate immunity by associating with TLR9 from the ER through endosomal compartments and being required for myddosome formation and NF-κB activation, revealing a non-cancer function in immune signaling.\",\n      \"evidence\": \"Co-IP, confocal microscopy, myddosome formation assay, NF-κB translocation, CD82-deficient macrophages\",\n      \"pmids\": [\"31408613\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CD82 regulates other TLRs beyond TLR9 not tested\", \"Mechanism by which CD82 enables myddosome assembly not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"CD82 was found to suppress NLRP3 inflammasome activation by binding both NLRP3 and BRCC3 deubiquitinase, blocking K63 deubiquitination and promoting NLRP3 degradation — establishing CD82 as a negative regulator of inflammasome signaling.\",\n      \"evidence\": \"Co-IP with NLRP3 and BRCC3, ubiquitination assay, CD82 KO mice with colitis model\",\n      \"pmids\": [\"36600050\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CD82 bridges NLRP3 and BRCC3 as a ternary complex or competes for binding not resolved\", \"Single study — independent replication needed\", \"Structural basis of CD82–BRCC3 interaction unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular mechanism by which CD82 simultaneously restrains multiple GTPases (Rac1, RhoA, Cdc42), the structural basis of its tetraspanin web interactions, and the relative contributions of its diverse signaling outputs to metastasis suppression in vivo remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of CD82 in a membrane context\", \"No systematic in vivo epistasis distinguishing contributions of individual effector pathways\", \"How CD82 coordinates cancer-cell-autonomous vs microenvironmental (endothelial, immune) functions is unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 8, 10, 14, 15, 22, 26, 27]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [10, 12, 19]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [23, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 7, 8, 10, 11, 12, 17, 19, 25]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [12, 23]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [13, 23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 10, 14, 15, 24, 35]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [23, 26, 36]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [8, 17, 21]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [8, 12, 15]}\n    ],\n    \"complexes\": [\n      \"tetraspanin-enriched microdomain (TEM)\",\n      \"GM2/GM3-CD82 glycosynaptic complex\"\n    ],\n    \"partners\": [\n      \"EGFR\",\n      \"IGSF8\",\n      \"ITGA6\",\n      \"ITGA4\",\n      \"NLRP3\",\n      \"TLR9\",\n      \"BRCC3\",\n      \"ADAM17\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}