{"gene":"CD82","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1995,"finding":"KAI1/CD82 encodes a 267-amino acid tetraspanin protein with four hydrophobic transmembrane domains and one large extracellular hydrophilic domain with three potential N-glycosylation sites; its introduction into rat AT6.1 prostate cancer cells suppressed metastasis, establishing it as a metastasis suppressor gene.","method":"Gene transfection into rat prostate cancer cells with in vivo metastasis assay; molecular cloning and sequence analysis","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional rescue experiment in vivo with molecular characterization, foundational paper replicated widely","pmids":["7754374"],"is_preprint":false},{"year":2006,"finding":"KAI1/CD82 on tumor cells directly interacts with DARC (gp-Fy/CD234) on vascular endothelial cells; this interaction inhibits tumor cell proliferation and induces senescence by modulating TBX2 and p21 expression, and is essential for metastasis suppression in vivo.","method":"Yeast two-hybrid screen to identify DARC as KAI1 binding partner; DARC knockout mouse metastasis assays; cell proliferation and senescence assays","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid plus KO mouse in vivo validation, multiple orthogonal methods, published in high-impact journal","pmids":["16862154"],"is_preprint":false},{"year":2016,"finding":"CD82/KAI1 on long-term hematopoietic stem cells (LT-HSCs) interacts with DARC expressed on bone marrow macrophages, stabilizing CD82 on LT-HSCs and maintaining their quiescence through TGF-β1/Smad3-mediated induction of CDK inhibitors; ablation of DARC+ macrophages reduces surface CD82 and causes LT-HSC cell-cycle entry and differentiation.","method":"Cd82−/− mouse model; macrophage ablation experiments; TGF-β1/Smad3 signaling assays; cell cycle analysis","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO model plus macrophage ablation with defined molecular pathway, multiple orthogonal methods","pmids":["26996598"],"is_preprint":false},{"year":2006,"finding":"CD82/KAI1 suppresses invasion by inhibiting integrin-dependent crosstalk with c-Met receptor and Src kinases; restoration of CD82 in PC3 prostate cancer cells reduced integrin-induced activation of c-Met (including HGF/SF-stimulated activation), Src kinase phosphorylation, and downstream substrates p130Cas and FAK Y861.","method":"CD82 re-expression in metastatic PC3 cells; integrin-dependent signaling assays; c-Met inhibition; Src kinase inhibition; Matrigel invasion assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — loss-of-function/gain-of-function with defined signaling pathway, multiple downstream readouts, single lab","pmids":["16331263"],"is_preprint":false},{"year":2003,"finding":"CD82 specifically attenuates ligand-induced dimerization of EGFR but not ErbB2-ErbB3 complexes; CD82 causes redistribution of EGFR into cholesterol/ganglioside-rich light membrane fractions and increases surface expression of gangliosides GD1a and GM1, with GD1a mediating CD82-dependent compartmentalization of EGFR and thereby attenuating EGF signaling.","method":"Sucrose gradient fractionation; dimerization assays; ganglioside redistribution analysis; soluble CD82 large extracellular loop recombinant protein experiments","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods, single lab, mechanistic model proposed and partially tested","pmids":["14576349"],"is_preprint":false},{"year":2013,"finding":"CD82/KAI1 specifically suppresses ubiquitylation of EGFR after stimulation with heparin-binding EGF or amphiregulin, dependent on the heparin-binding domain of the ligand; CD82 acts by promoting PKC-dependent serine phosphorylation of c-Cbl (the E3 ubiquitin ligase for EGFR), and increases phosphorylation of threonine 654 in the EGFR juxtamembrane domain; deletion of the CD82 C-terminal cytoplasmic domain disrupts this activity.","method":"Ubiquitylation assays; c-Cbl phosphorylation assays; CD82 deletion mutant (CD82ΔC); EEA1-positive endosome trafficking assays; endocytic trafficking experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic mutagenesis plus biochemical assays, single lab, multiple orthogonal methods","pmids":["23897813"],"is_preprint":false},{"year":2003,"finding":"KAI1/CD82 expression decreases p130CAS protein levels in metastatic prostate cancer cells, thereby reducing formation of the p130CAS-CrkII complex ('molecular switch' for cell motility); overexpression of p130CAS in CD82-expressing cells rescues migration, confirming that p130CAS-CrkII coupling is required for KAI1/CD82-mediated inhibition of cell motility.","method":"KAI1 expression in Du145 cells; migration assays; Western blot for FAK, Lyn, p130CAS; Co-IP for p130CAS-CrkII complex; p130CAS overexpression rescue","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rescue experiment plus signaling pathway dissection, single lab, multiple orthogonal methods","pmids":["12738793"],"is_preprint":false},{"year":2003,"finding":"EWI2/PGRL (an immunoglobulin superfamily member) directly and stoichiometrically associates with KAI1/CD82, independent of cholesterol-enriched lipid rafts and independent of CD81 and CD9; EWI2/PGRL overexpression inhibits prostate cancer cell migration and synergizes with KAI1/CD82 in migration inhibition.","method":"Co-immunoprecipitation; chemical cross-linking; sucrose gradient fractionation; peptide mass spectrometry identification; migration assays on fibronectin and laminin","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical association confirmed by multiple methods plus functional synergy assay, single lab","pmids":["12750295"],"is_preprint":false},{"year":2004,"finding":"KAI1/CD82 is palmitoylated at cytoplasmic cysteine residues proximal to the plasma membrane; palmitoylation is required for CD82's inhibitory effects on migration and invasion, its subcellular distribution, its association with tetraspanin-enriched microdomains, lamellipodia formation, actin cytoskeleton organization, and the p130CAS-CrkII coupling that mediates motility inhibition.","method":"Palmitoylation assay; palmitoylation-deficient CD82 mutant; migration/invasion assays; tetraspanin co-immunoprecipitation; actin cytoskeleton imaging","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — site-directed mutagenesis of all palmitoylation sites with multiple functional readouts, single lab but orthogonal methods","pmids":["15492270"],"is_preprint":false},{"year":2008,"finding":"KAI1/CD82 transmembrane polar residues (Asn, Gln, Glu) mediate TM-domain interactions required for migration, invasion, and metastasis suppression; mutation of all three polar residues disrupts KAI1/CD82's interactions with tetraspanins CD9 and CD151 (but not with α3β1 integrin), inhibits formation of microprotrusions and microvesicle release, and destabilizes CD82 conformation.","method":"TM polar residue mutagenesis; metastasis assay; Co-IP with CD9 and CD151; migration/invasion assays; microprotrusion and microvesicle release assays; denaturation sensitivity assay; structural modeling","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — mutagenesis with multiple functional readouts, single lab","pmids":["19116362"],"is_preprint":false},{"year":2009,"finding":"CD82 undergoes cholesterol/lipid-dependent endocytosis (not requiring dynamin or clathrin) and traffics to late endosomes and lysosomes; CD82 redistributes cholesterol into tetraspanin-enriched microdomains (TEMs), reorganizing TEMs and lipid rafts; CD82 endocytosis appears to alleviate CD82-mediated inhibition of cell migration.","method":"Endocytosis assays with dynamin and clathrin inhibitors; cholesterol depletion/sequestration; sucrose gradient fractionation; co-localization imaging","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition plus fractionation, single lab, multiple orthogonal methods","pmids":["19497983"],"is_preprint":false},{"year":2010,"finding":"TI-VAMP (VAMP7) transports CD82 from the Golgi apparatus to the cell surface; depletion of TI-VAMP reduces surface CD82 levels, restrains EGFR diffusion at the cell surface, impairs MAPK signaling, and enhances clathrin-dependent endocytosis of activated EGFR via increased AP-2 recruitment.","method":"TI-VAMP siRNA depletion; CD82 siRNA; quantum dots video-microscopy of EGFR dynamics; MAPK signaling assays; AP-2 recruitment assays; Golgi secretion assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual siRNA knockdowns with live imaging and signaling readouts, single lab, multiple orthogonal methods","pmids":["20144992"],"is_preprint":false},{"year":2006,"finding":"KAI1/CD82 suppresses tumor invasion by upregulating TIMP1, which inactivates MMP-9 activity; CD82-transfected H1299 lung carcinoma cells showed reduced invasion, reduced MMP-9 enzyme activity (despite elevated MMP-9 mRNA and protein), and elevated TIMP1 levels.","method":"CD82 transfection; cell invasion assay; gelatin zymography for MMP-9 activity; Western blot and RT-PCR","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — gain-of-function with mechanistic pathway identification, single lab, single study","pmids":["16488391"],"is_preprint":false},{"year":2003,"finding":"C33/CD82/KAI1 induces apoptosis through generation of reactive oxygen intermediates (ROIs); this is not derived from the mitochondrial respiratory chain but involves CD82-induced release of intracellular glutathione (GSH) and activation of GTPase Cdc42, which mediates GSH release and apoptosis induction.","method":"Apoptosis screen; cell death assays; ROI measurement; GSH release assay; Cdc42 activation assay","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional screen with mechanistic follow-up, single lab, single study","pmids":["14597553"],"is_preprint":false},{"year":2012,"finding":"KAI1/CD82 inhibits polarized protrusion and retraction events in migrating cells by disrupting actin reorganization; specifically, CD82 reduces Rac1 activity (diminishing lamellipodia and actin cortical network) and blocks growth factor-stimulated RhoA activity (suppressing stress fibers and retraction), and reduces PIP2 at the cell periphery.","method":"Live imaging of CD82-expressing cells; Rac1 and RhoA GTPase activity assays; ROCK activity assay; cofilin localization imaging; PIP2 staining","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging plus multiple GTPase activity assays, single lab","pmids":["23251627"],"is_preprint":false},{"year":2014,"finding":"CD82 overexpression increases the molecular density of α4 integrin subunits within membrane clusters, thereby increasing cellular adhesion; this clustering depends on CD82 palmitoylation and the presence of α4 integrin ligands.","method":"Direct stochastic optical reconstruction microscopy (dSTORM) superresolution imaging; protein clustering algorithms; palmitoylation mutant of CD82; adhesion assays","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — superresolution microscopy with mutagenesis, single lab, two orthogonal methods","pmids":["24623721"],"is_preprint":false},{"year":2018,"finding":"CD82 deficiency disrupts bone marrow homing and engraftment of HSPCs; this homing defect is due at least in part to hyperactivation of Rac1, as pharmacological Rac1 inhibition rescues homing capacity of CD82-knockout HSPCs.","method":"CD82 knockout mouse model; in vivo HSPC homing assay; Rac1 inhibitor rescue experiment; migration and cell spreading assays","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with pharmacological rescue, single lab, multiple functional assays","pmids":["30133344"],"is_preprint":false},{"year":2019,"finding":"CD82/KAI1 inhibits TGF-β1- and Wnt-induced epithelial-to-mesenchymal transition (EMT) in prostate cancer cells; high CD82 expression prevents phosphorylation of Smad2, nuclear translocation of Smad4, and TRE promoter transactivation downstream of TGF-β1; it also maintains GSK-3β activity to phosphorylate β-catenin, preventing Wnt/β-catenin nuclear signaling.","method":"Luciferase reporter assay for TRE and Tcf/Lef promoters; immunofluorescence and subcellular fractionation for Smad4 and β-catenin localization; invasion assays; GSK-3β phosphorylation analysis","journal":"The Prostate","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pathway readouts with reporter assays and localization studies, single lab","pmids":["31212375"],"is_preprint":false},{"year":2019,"finding":"CD82 is a key regulator of TLR9 trafficking and signaling; CD82 associates with TLR9 in macrophages (in the ER and post-ER compartments), is essential for TLR9-dependent myddosome formation in response to CpG stimulation, and modulates TLR9-dependent NF-κB nuclear translocation and inflammatory cytokine production.","method":"Co-immunoprecipitation of CD82 and TLR9; myddosome formation assay; NF-κB nuclear translocation assay; CD82-deficient cells; CpG stimulation experiments","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional signaling assays in CD82-deficient macrophages, single lab","pmids":["31408613"],"is_preprint":false},{"year":2018,"finding":"Virulent M. tuberculosis induces CD82 promoter hypomethylation, leading to CD82 expression in macrophages; CD82 targets RUNX1 and this CD82-RUNX1 axis arrests phagosome maturation via interaction with Rab5/Rab22, promoting intracellular mycobacterial survival; knockdown or knockout of CD82 or RUNX1 increased phagolysosome biogenesis and antimicrobial activity.","method":"CD82 promoter methylation analysis; CD82 KO/knockdown in macrophages; RUNX1 targeting; Rab5/Rab22 interaction assays; phagosome maturation assay; in vivo MTB infection model","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO and knockdown with mechanistic phagosome assays, single lab","pmids":["29760437"],"is_preprint":false},{"year":2011,"finding":"N-glycosylation of recombinant human CD82 occurs at three sites including a previously unreported site at Asn157; the glycans include bisecting N-acetylglucosamine, (α-2,6) N-acetylneuraminic acid, and core fucose epitopes, which are associated with cell adhesion and cancer metastasis functions.","method":"Glycosidase and protease digestions; glycan permethylation; mass spectrometry; site-directed mutagenesis; lectin blots","journal":"Journal of proteomics","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — biochemical characterization with site-directed mutagenesis, single lab","pmids":["22123080"],"is_preprint":false},{"year":2013,"finding":"CD82 positively regulates the STAT5/IL-10 signaling pathway in acute myelogenous leukemia (AML) stem cells; CD82 knockdown dephosphorylates STAT5 and reduces IL-10 levels, while forced CD82 expression increases p-STAT5 and IL-10; STAT5A binds the IL-10 gene promoter as shown by ChIP assay.","method":"shRNA knockdown; lentiviral CD82 overexpression; Western blot for p-STAT5; ELISA for IL-10; chromatin immunoprecipitation (ChIP); luciferase reporter assay; in vivo mouse model","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP assay plus reporter assay plus in vivo model, single lab","pmids":["23797738"],"is_preprint":false},{"year":2016,"finding":"CD82 regulates PKCα-mediated signaling in AML cells; using a palmitoylation-deficient CD82 mutant (which disrupts membrane organization), CD82 was shown to control PKCα expression and membrane activation, stabilize PKCα activation at the membrane, regulate the size of PKCα membrane clusters, and produce sustained ERK1/2 activation resulting in enhanced AML colony formation.","method":"Palmitoylation mutant CD82; single-molecule and ensemble imaging (TIRF, confocal); PKCα membrane cluster analysis; ERK1/2 phosphorylation assays; colony formation assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with single-molecule imaging and signaling readouts, single lab","pmids":["27417454"],"is_preprint":false},{"year":2021,"finding":"KAI1/CD82 expressed in pericytes localizes to the membrane surface after palmitoylation by zDHHC4 enzyme and induces LIF expression through the Src/p53 pathway; LIF released from pericytes suppresses angiogenic factors in endothelial cells; additionally, KAI1 directly binds VEGF and PDGF and inhibits activation of their receptors.","method":"KAI1 knockout mice (enhanced angiogenesis phenotype); palmitoylation assay identifying zDHHC4; Src/p53 pathway analysis; VEGF/PDGF direct binding assays; in vivo cancer models with KAI1 supplementation; KAI1 large extracellular loop peptide in vivo","journal":"Journal of hematology & oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse phenotype plus direct binding assays plus in vivo supplementation, single lab","pmids":["34530889"],"is_preprint":false},{"year":2020,"finding":"CD82 overexpression increases TRPM7 α-kinase cleavage via caspase-3 activation and induces Numb phosphorylation at Thr346 and Ser348; CD82 overexpression promotes beta-amyloid peptide (Aβ) secretion, reversible by Numb T346S348 mutants; hippocampus-related memory functions are improved in Cd82−/− mice.","method":"AAV-CD82 hippocampal injection; TRPM7 cleavage assays; caspase-3 activation; Numb phosphorylation at specific residues; Numb phospho-mutant rescue; Aβ secretion measurement; Cd82−/− behavioral testing","journal":"GeroScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific mutagenesis rescue plus KO mouse behavior, single lab","pmids":["32088828"],"is_preprint":false},{"year":2023,"finding":"CD82 suppresses NLRP3 inflammasome activation by binding both NLRP3 and BRCC3 (a K63-specific deubiquitinase); CD82 binding to BRCC3 blocks BRCC3-dependent K63-specific deubiquitination of NLRP3, leading to increased NLRP3 degradation.","method":"Co-immunoprecipitation identifying CD82-NLRP3 and CD82-BRCC3 complexes; K63 ubiquitination assays; CD82 KO mouse colitis model; in vitro NLRP3 inflammasome activation assays","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying two binding partners plus ubiquitination assays plus KO model, single lab","pmids":["36600050"],"is_preprint":false},{"year":2014,"finding":"ΔNp63α directly activates CD82 transcription as shown by chromatin immunoprecipitation; CD82 is required for ΔNp63α-mediated inhibition of cell invasion, as CD82 ablation reverses the anti-invasive effect and ectopic CD82 rescues invasion upon ΔNp63α knockdown; GSK3β inhibition downregulates both ΔNp63α and CD82 and increases invasion independently of β-catenin.","method":"Affymetrix gene expression profiling; gain- and loss-of-function analysis; chromatin immunoprecipitation (ChIP); Matrigel outgrowth assay; siRNA knockdown; GSK3β pharmacological inhibition and siRNA","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional rescue experiments, single lab","pmids":["24901051"],"is_preprint":false},{"year":2017,"finding":"TAp73 directly activates KAI1/CD82 transcription; KAI1 expression is indispensable for TAp73-mediated inhibition of colorectal cancer cell invasion and migration; induction of TAp73 elevated KAI1 expression and decreased hepatic metastasis in vivo, while TAp73-mediated anti-invasive effects were abrogated by KAI1 knockdown.","method":"Luciferase reporter assay; ChIP; TAp73 induction/knockdown; KAI1 knockdown; invasion/migration assays; in vivo hepatic metastasis model","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus epistasis rescue experiment plus in vivo model, single lab","pmids":["29222041"],"is_preprint":false},{"year":2017,"finding":"CD82 directly binds to TIMP-1 through its large extracellular loop and co-localizes with TIMP-1; CD82 facilitates membrane-bound TIMP-1 endocytosis, which contributes to TIMP-1's anti-migration effect; CD82 silencing partially eliminates TIMP-1-mediated anti-migration activity.","method":"Co-immunoprecipitation; co-localization assays in cancer cell lines and clinical samples; CD82 siRNA knockdown; TIMP-1 endocytosis assays; migration assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional endocytosis assay with knockdown, single lab","pmids":["28030805"],"is_preprint":false},{"year":2020,"finding":"CD82 interacts with ADAM17 and inhibits its metalloprotease activity, thereby suppressing ADAM17-mediated cleavage/shedding of E-cadherin from the cell membrane in prostate cancer cells, and reducing cell migration.","method":"Co-immunoprecipitation of CD82 and ADAM17; ADAM17 metalloprotease activity assay; E-cadherin shedding assay; cell migration assay","journal":"Disease markers","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP plus enzymatic activity assay, single lab, single study","pmids":["33204367"],"is_preprint":false},{"year":2012,"finding":"CD82 inhibits trophoblast invasion and migration by reducing MMP-9 gelatinolytic activity; CD82 siRNA knockdown in trophoblast cells promoted invasion, migration, and MMP-9 activity, while CD82 overexpression decreased invasion, migration, and MMP-9 activity.","method":"CD82 siRNA and overexpression in HTR8/SVneo cells; villous explant culture on Matrigel; invasion/migration assays; gelatin zymography for MMP-9 activity","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — gain- and loss-of-function with enzymatic readout, single lab, single study without direct interaction data","pmids":["22679510"],"is_preprint":false},{"year":2009,"finding":"KAI1/CD82 decreases Rac1 protein expression (but not mRNA) and GTPase activity through the PI3K/Akt/mTOR pathway in lung carcinoma cells; CD82-expressing cells showed lower mTOR expression, suggesting mTOR regulates Rac1 protein translation.","method":"Rac1 GTPase activity assay; RT-PCR for Rac1 mRNA; mTOR expression analysis; cell morphology and migration assays","journal":"Cell biochemistry and function","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, indirect pathway inference without direct mTOR-Rac1 linkage experiment","pmids":["19107873"],"is_preprint":false},{"year":2012,"finding":"KAI1/CD82 suppresses HIF-1α and VEGF expression in prostate cancer cells by blocking CDCP1-enhanced Src activation, leading to increased VHL protein levels that promote HIF-1α degradation; this mechanism was validated in vivo in xenograft tumors.","method":"KAI1 stable transfection in PC3 cells; Western blot for HIF-1α, VEGF, CDCP1, Src phosphorylation, VHL; VEGF reporter assay; in vivo xenograft; immunohistochemistry","journal":"BMC cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — correlative signaling pathway analysis without direct mechanistic interaction experiments, single lab","pmids":["22390300"],"is_preprint":false},{"year":2003,"finding":"KAI1/CD82 induces homotypic cell aggregation in prostate cancer cells through a Src family kinase-dependent pathway; anti-CD82 antibody ligation increases endogenous Src kinase activity, and kinase-negative Src mutant expression abolishes CD82-mediated homotypic aggregation.","method":"KAI1 cDNA transfection in DU145 cells; aggregation assay; Src kinase inhibitor (PP1); Src kinase activity assay; kinase-negative Src mutant transfection","journal":"Experimental & molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological and dominant-negative approach, single lab, single study","pmids":["12642901"],"is_preprint":false},{"year":1995,"finding":"Cross-linking of CD82 (IA4) on U937 monocytic cells induces a PLC-dependent increase in intracellular calcium (via IP3) followed by extracellular calcium entry, and causes tyrosine phosphorylation of various proteins; this transducing signal requires dual engagement of both CD82 and Fc receptors.","method":"Cross-linking with anti-CD82 antibody; intracellular calcium measurement; phospholipase C inhibitor; tyrosine phosphorylation assay; Fc receptor co-engagement experiments","journal":"Journal of leukocyte biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pharmacological approach, single study","pmids":["7790779"],"is_preprint":false},{"year":2015,"finding":"CD82 enhances expression of miR-203, which directly downregulates FZD2 mRNA and protein expression, thereby inhibiting canonical Wnt signaling and cell migration.","method":"miRNA expression profiling after CD82 expression; miR-203 mimic/inhibitor transfection; luciferase reporter assay for FZD2 3'UTR targeting; migration assay","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — indirect pathway (CD82→miR-203→FZD2) demonstrated by reporter assay, single lab","pmids":["26132195"],"is_preprint":false},{"year":2007,"finding":"KAI1/CD82 attenuates the maturation of β1 integrin precursor to its functional mature form at the cell surface in lung carcinoma cells, thereby suppressing cell migration; this was confirmed by CD82-specific siRNA knockdown reversing the effect.","method":"Western blot for mature vs. precursor β1 integrin; biotinylation assay for surface β1 integrin; wound-healing and Boyden chamber migration assays; CD82 siRNA","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, indirect mechanistic evidence without direct CD82-β1 integrin interaction assay","pmids":["17560548"],"is_preprint":false}],"current_model":"CD82/KAI1 is a tetraspanin scaffold protein that suppresses tumor metastasis and regulates diverse cellular processes by organizing membrane microdomains (tetraspanin-enriched microdomains), where it physically associates with integrins, EGFR/ErbB receptors, EWI2/PGRL, DARC, ADAM17, TIMP-1, TLR9, and other partners; its palmitoylation is required for proper membrane localization and function; it inhibits cell migration and invasion by attenuating Src/FAK/p130CAS-CrkII, c-Met, Rac1, and RhoA signaling and by suppressing EGFR ubiquitylation and dimerization; it suppresses metastasis partly through DARC-dependent induction of senescence/TBX2/p21; it maintains hematopoietic stem cell quiescence via TGF-β1/Smad3/CDK inhibitor signaling through interaction with DARC on bone marrow macrophages; it promotes innate immune signaling through TLR9 trafficking and myddosome assembly; and it promotes phagosome arrest in M. tuberculosis infection through a CD82-RUNX1-Rab5/22 axis."},"narrative":{"mechanistic_narrative":"CD82/KAI1 is a tetraspanin scaffold protein that organizes membrane microdomains to suppress tumor metastasis and to regulate cell migration, hematopoietic stem cell behavior, and innate immune signaling [PMID:7754374, PMID:15492270]. First identified as a metastasis suppressor that blocks dissemination of prostate cancer cells in vivo [PMID:7754374], CD82 functions by physically reorganizing the plasma membrane: its palmitoylation at juxtamembrane cysteines and its transmembrane polar residues are required for incorporation into tetraspanin-enriched microdomains, association with tetraspanins CD9 and CD151, and the downstream control of migration and invasion [PMID:15492270, PMID:19116362]. CD82 attenuates promigratory signaling on multiple fronts — it inhibits integrin–c-Met crosstalk and Src/FAK/p130CAS-CrkII coupling [PMID:16331263, PMID:12738793], dampens Rac1 and RhoA activity to block lamellipodia and stress-fiber formation [PMID:23251627], and compartmentalizes EGFR into ganglioside-rich domains while limiting its ligand-induced dimerization and promoting c-Cbl–dependent receptor downregulation [PMID:14576349, PMID:23897813]. It restrains invasion further by upregulating TIMP1 to inactivate MMP-9 [PMID:16488391] and by binding and inhibiting the sheddase ADAM17 [PMID:33204367]. CD82 engages a broad partner set through its large extracellular loop and membrane scaffolding, including EWI2/PGRL, TIMP-1, and the endothelial receptor DARC, the last of which mediates CD82-dependent induction of senescence via TBX2/p21 and is essential for metastasis suppression in vivo [PMID:16862154, PMID:12750295, PMID:28030805]. Beyond cancer, CD82–DARC interaction on bone marrow macrophages stabilizes CD82 on hematopoietic stem cells to maintain quiescence through TGF-β1/Smad3-driven CDK-inhibitor expression, while CD82 loss causes Rac1 hyperactivation and impaired HSPC homing [PMID:26996598, PMID:30133344]. In innate immunity, CD82 controls TLR9 trafficking and myddosome assembly to drive NF-κB signaling [PMID:31408613], and it restrains NLRP3 inflammasome activation by binding NLRP3 and the deubiquitinase BRCC3 [PMID:36600050]. Transcriptionally, CD82 is a direct target of the p53-family factors ΔNp63α and TAp73, through which these tumor suppressors enforce their anti-invasive programs [PMID:24901051, PMID:29222041].","teleology":[{"year":1995,"claim":"Established CD82 as a bona fide metastasis suppressor gene and defined its tetraspanin architecture, framing all subsequent mechanistic work.","evidence":"Molecular cloning plus gene transfection into rat prostate cancer cells with in vivo metastasis assay","pmids":["7754374"],"confidence":"High","gaps":["Did not define the molecular partners or signaling pathways through which suppression occurs","Mechanism of membrane organization not addressed"]},{"year":2003,"claim":"Connected CD82 to motility machinery by showing it downregulates p130CAS to break the p130CAS-CrkII motility switch, defining a concrete cytoskeletal output.","evidence":"KAI1 expression in Du145 cells with migration assays, Co-IP, and p130CAS overexpression rescue","pmids":["12738793"],"confidence":"Medium","gaps":["How CD82 lowers p130CAS protein levels not established","Link to upstream membrane scaffolding not yet made"]},{"year":2003,"claim":"Identified EWI2/PGRL as a direct, raft-independent CD82 partner that synergizes in migration inhibition, expanding the CD82 interactome beyond classical tetraspanins.","evidence":"Co-IP, cross-linking, mass spectrometry, and migration assays in prostate cancer cells","pmids":["12750295"],"confidence":"Medium","gaps":["Functional consequence of the complex at the signaling level not defined","Stoichiometry in vivo unknown"]},{"year":2003,"claim":"Showed CD82 attenuates EGFR specifically by relocating it into ganglioside-rich membrane fractions, introducing the microdomain-compartmentalization model of receptor regulation.","evidence":"Sucrose gradient fractionation, dimerization assays, and ganglioside redistribution analysis","pmids":["14576349"],"confidence":"Medium","gaps":["Selectivity for EGFR over ErbB2/3 mechanistically unexplained","Direct CD82-EGFR contact not demonstrated"]},{"year":2004,"claim":"Demonstrated palmitoylation is required for CD82 microdomain association and all downstream motility-suppressing functions, identifying the lipid modification as the master switch for CD82 activity.","evidence":"Palmitoylation-deficient mutant with migration/invasion, tetraspanin Co-IP, and actin imaging","pmids":["15492270"],"confidence":"High","gaps":["Palmitoyltransferase responsible not identified in this work","Dynamics of palmitoylation cycling unaddressed"]},{"year":2006,"claim":"Defined CD82 inhibition of integrin–c-Met crosstalk and Src signaling, linking membrane scaffolding to receptor tyrosine kinase suppression.","evidence":"CD82 re-expression in PC3 cells with integrin-dependent signaling and invasion assays","pmids":["16331263"],"confidence":"High","gaps":["Whether CD82 directly contacts c-Met or integrins not shown","Relative contribution of each kinase node unresolved"]},{"year":2006,"claim":"Discovered the DARC interaction as the in vivo effector of metastasis suppression, linking tumor-cell CD82 to endothelial-induced senescence via TBX2/p21.","evidence":"Yeast two-hybrid screen, DARC-knockout mouse metastasis assays, and senescence assays","pmids":["16862154"],"confidence":"High","gaps":["How DARC engagement triggers TBX2/p21 intracellularly not defined","Signal transduction from cell surface to nucleus unmapped"]},{"year":2006,"claim":"Added an extracellular-matrix arm by showing CD82 upregulates TIMP1 to inactivate MMP-9, explaining anti-invasive activity independent of motility signaling.","evidence":"CD82 transfection in H1299 cells with invasion assays and gelatin zymography","pmids":["16488391"],"confidence":"Medium","gaps":["Mechanism of TIMP1 upregulation by CD82 unknown","Single cell line tested"]},{"year":2009,"claim":"Established that CD82 traffics by cholesterol-dependent endocytosis to late endosomes/lysosomes and reorganizes microdomain cholesterol, framing CD82 function as regulated by its own membrane turnover.","evidence":"Endocytosis assays with inhibitors, cholesterol depletion, and fractionation","pmids":["19497983"],"confidence":"Medium","gaps":["Trigger for CD82 internalization not defined","Functional link between endocytosis and migration relief only correlative"]},{"year":2009,"claim":"Mapped TM polar residues as required for CD82 conformation and tetraspanin partnerships underlying metastasis suppression, complementing palmitoylation as a structural determinant.","evidence":"TM polar residue mutagenesis with metastasis, Co-IP, and structural modeling","pmids":["19116362"],"confidence":"Medium","gaps":["No experimental structure of CD82 TM bundle","Single-lab functional readouts"]},{"year":2010,"claim":"Identified TI-VAMP/VAMP7 as the trafficking machinery delivering CD82 from Golgi to the surface, where CD82 then controls EGFR diffusion and endocytic fate.","evidence":"TI-VAMP and CD82 siRNA with quantum-dot EGFR tracking and MAPK assays","pmids":["20144992"],"confidence":"Medium","gaps":["Whether VAMP7 selectively sorts CD82 versus bulk cargo unclear","Direct VAMP7-CD82 interaction not shown"]},{"year":2012,"claim":"Resolved CD82 control of actin dynamics by showing it suppresses both Rac1 (protrusion) and RhoA (retraction) activity and lowers peripheral PIP2.","evidence":"Live imaging with Rac1/RhoA/ROCK activity assays and PIP2 staining","pmids":["23251627"],"confidence":"Medium","gaps":["Upstream GEF/GAP targets of CD82 not identified","Mechanism linking microdomains to GTPase regulation unmapped"]},{"year":2013,"claim":"Refined EGFR regulation by showing CD82 suppresses EGFR ubiquitylation via PKC-dependent c-Cbl phosphorylation and EGFR T654 phosphorylation, requiring the CD82 cytoplasmic tail.","evidence":"Ubiquitylation and c-Cbl phosphorylation assays with CD82ΔC mutant","pmids":["23897813"],"confidence":"Medium","gaps":["How the cytoplasmic tail recruits PKC not defined","Reconciliation with EGFR compartmentalization model incomplete"]},{"year":2014,"claim":"Demonstrated with superresolution imaging that CD82 increases α4 integrin clustering density to promote adhesion, dependent on palmitoylation, giving a direct structural readout of microdomain organization.","evidence":"dSTORM superresolution imaging with clustering analysis and palmitoylation mutant","pmids":["24623721"],"confidence":"Medium","gaps":["Whether CD82 directly contacts α4 integrin unresolved","Single integrin subunit examined"]},{"year":2014,"claim":"Placed CD82 downstream of ΔNp63α as a direct transcriptional target required for that factor's anti-invasive program.","evidence":"ChIP, gain/loss-of-function, and Matrigel outgrowth rescue assays","pmids":["24901051"],"confidence":"Medium","gaps":["Generality of the ΔNp63α-CD82 axis across tumor types untested","Other ΔNp63α targets contributing to phenotype not excluded"]},{"year":2016,"claim":"Extended the DARC axis to hematopoiesis, showing macrophage DARC stabilizes CD82 on HSCs to enforce quiescence via TGF-β1/Smad3 CDK inhibitors.","evidence":"Cd82-/- mouse, macrophage ablation, and TGF-β1/Smad3 signaling/cell cycle assays","pmids":["26996598"],"confidence":"High","gaps":["How CD82 transduces DARC engagement into TGF-β1 signaling unmapped","Direct CD82-Smad linkage not established"]},{"year":2017,"claim":"Identified CD82 as a direct TAp73 transcriptional target essential for TAp73-driven suppression of colorectal cancer invasion and metastasis.","evidence":"Luciferase reporter, ChIP, epistasis rescue, and in vivo hepatic metastasis model","pmids":["29222041"],"confidence":"Medium","gaps":["Overlap with ΔNp63α regulation of the same promoter not dissected","Tissue specificity of the axis unclear"]},{"year":2017,"claim":"Defined a direct CD82–TIMP-1 interaction through the large extracellular loop that drives TIMP-1 endocytosis and its anti-migratory effect.","evidence":"Co-IP, co-localization in cells and clinical samples, and TIMP-1 endocytosis/migration assays","pmids":["28030805"],"confidence":"Medium","gaps":["Structural basis of the extracellular-loop interaction unknown","Relationship to CD82-driven TIMP1 upregulation unresolved"]},{"year":2018,"claim":"Showed CD82 loss causes Rac1 hyperactivation and defective HSPC bone marrow homing, mechanistically tying CD82 GTPase control to stem-cell trafficking.","evidence":"CD82-knockout mouse with in vivo homing assay and Rac1-inhibitor rescue","pmids":["30133344"],"confidence":"Medium","gaps":["How CD82 restrains Rac1 in HSPCs mechanistically unclear","Adhesion versus migration contributions not separated"]},{"year":2018,"claim":"Revealed a pathogen-co-opted CD82 function: M. tuberculosis induces CD82 to arrest phagosome maturation via a CD82-RUNX1-Rab5/22 axis promoting bacterial survival.","evidence":"CD82 promoter methylation analysis, KO/knockdown macrophages, Rab interaction and phagosome maturation assays, in vivo infection","pmids":["29760437"],"confidence":"Medium","gaps":["How CD82 engages RUNX1 and Rab GTPases molecularly undefined","Whether this reflects normal CD82 endosomal function unclear"]},{"year":2019,"claim":"Established CD82 as a positive regulator of TLR9 trafficking and myddosome assembly, broadening CD82 into innate immune receptor handling.","evidence":"Co-IP of CD82-TLR9, myddosome formation and NF-κB assays in CD82-deficient macrophages","pmids":["31408613"],"confidence":"Medium","gaps":["Direct versus indirect CD82-TLR9 association not resolved","Step in TLR9 trafficking controlled by CD82 not pinpointed"]},{"year":2019,"claim":"Showed CD82 blocks TGF-β1- and Wnt-driven EMT in prostate cancer by inhibiting Smad and β-catenin nuclear signaling, linking metastasis suppression to EMT control.","evidence":"Reporter assays, Smad4/β-catenin localization, GSK-3β analysis, and invasion assays","pmids":["31212375"],"confidence":"Medium","gaps":["Reconciliation with HSC TGF-β1/Smad3 promotion versus tumor TGF-β1/Smad inhibition unaddressed","Direct CD82 effector on these pathways unknown"]},{"year":2021,"claim":"Identified zDHHC4 as the palmitoyltransferase for CD82 in pericytes and showed CD82 directly binds VEGF/PDGF and induces LIF to suppress angiogenesis.","evidence":"KAI1-knockout mice, palmitoylation assay identifying zDHHC4, VEGF/PDGF binding, and in vivo supplementation","pmids":["34530889"],"confidence":"Medium","gaps":["Whether zDHHC4 modifies CD82 in other cell types untested","Stoichiometry of CD82-VEGF/PDGF binding unknown"]},{"year":2023,"claim":"Defined a CD82 inflammasome-restraining function by showing CD82 binds NLRP3 and BRCC3 to block deubiquitination and promote NLRP3 degradation.","evidence":"Co-IP of CD82-NLRP3 and CD82-BRCC3, K63 ubiquitination assays, and KO colitis model","pmids":["36600050"],"confidence":"Medium","gaps":["Whether CD82 acts at the membrane or in cytosol for this function unclear","Structural basis of CD82-BRCC3 interaction unknown"]},{"year":null,"claim":"How a single tetraspanin scaffold integrates its contradictory context-dependent roles — suppressing TGF-β1/Smad signaling in tumor cells yet promoting it in HSCs, and acting at the plasma membrane versus endosomes versus the nucleus-adjacent transcriptional axes — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model unifying palmitoylation, TM packing, and partner selection","Mechanism of signal transduction from CD82 surface engagement to intracellular outputs largely undefined","Cell-type determinants of opposing CD82 outputs not identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[8,9,4,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,14,5,29,25]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[15,33]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,8,10,15]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[10,5,19,28]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[11]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[18]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,6,14,4,5]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,1,19]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[18,25,19]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[12,29,28]}],"complexes":["tetraspanin-enriched microdomain"],"partners":["DARC","EWI2","TIMP1","ADAM17","TLR9","NLRP3","BRCC3","CD151"],"other_free_text":[]}},"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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extracellular hydrophilic domain with three potential N-glycosylation sites; its introduction into rat AT6.1 prostate cancer cells suppressed metastasis, establishing it as a metastasis suppressor gene.\",\n      \"method\": \"Gene transfection into rat prostate cancer cells with in vivo metastasis assay; molecular cloning and sequence analysis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional rescue experiment in vivo with molecular characterization, foundational paper replicated widely\",\n      \"pmids\": [\"7754374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"KAI1/CD82 on tumor cells directly interacts with DARC (gp-Fy/CD234) on vascular endothelial cells; this interaction inhibits tumor cell proliferation and induces senescence by modulating TBX2 and p21 expression, and is essential for metastasis suppression in vivo.\",\n      \"method\": \"Yeast two-hybrid screen to identify DARC as KAI1 binding partner; DARC knockout mouse metastasis assays; cell proliferation and senescence assays\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid plus KO mouse in vivo validation, multiple orthogonal methods, published in high-impact journal\",\n      \"pmids\": [\"16862154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD82/KAI1 on long-term hematopoietic stem cells (LT-HSCs) interacts with DARC expressed on bone marrow macrophages, stabilizing CD82 on LT-HSCs and maintaining their quiescence through TGF-β1/Smad3-mediated induction of CDK inhibitors; ablation of DARC+ macrophages reduces surface CD82 and causes LT-HSC cell-cycle entry and differentiation.\",\n      \"method\": \"Cd82−/− mouse model; macrophage ablation experiments; TGF-β1/Smad3 signaling assays; cell cycle analysis\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO model plus macrophage ablation with defined molecular pathway, multiple orthogonal methods\",\n      \"pmids\": [\"26996598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CD82/KAI1 suppresses invasion by inhibiting integrin-dependent crosstalk with c-Met receptor and Src kinases; restoration of CD82 in PC3 prostate cancer cells reduced integrin-induced activation of c-Met (including HGF/SF-stimulated activation), Src kinase phosphorylation, and downstream substrates p130Cas and FAK Y861.\",\n      \"method\": \"CD82 re-expression in metastatic PC3 cells; integrin-dependent signaling assays; c-Met inhibition; Src kinase inhibition; Matrigel invasion assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function/gain-of-function with defined signaling pathway, multiple downstream readouts, single lab\",\n      \"pmids\": [\"16331263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CD82 specifically attenuates ligand-induced dimerization of EGFR but not ErbB2-ErbB3 complexes; CD82 causes redistribution of EGFR into cholesterol/ganglioside-rich light membrane fractions and increases surface expression of gangliosides GD1a and GM1, with GD1a mediating CD82-dependent compartmentalization of EGFR and thereby attenuating EGF signaling.\",\n      \"method\": \"Sucrose gradient fractionation; dimerization assays; ganglioside redistribution analysis; soluble CD82 large extracellular loop recombinant protein experiments\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods, single lab, mechanistic model proposed and partially tested\",\n      \"pmids\": [\"14576349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD82/KAI1 specifically suppresses ubiquitylation of EGFR after stimulation with heparin-binding EGF or amphiregulin, dependent on the heparin-binding domain of the ligand; CD82 acts by promoting PKC-dependent serine phosphorylation of c-Cbl (the E3 ubiquitin ligase for EGFR), and increases phosphorylation of threonine 654 in the EGFR juxtamembrane domain; deletion of the CD82 C-terminal cytoplasmic domain disrupts this activity.\",\n      \"method\": \"Ubiquitylation assays; c-Cbl phosphorylation assays; CD82 deletion mutant (CD82ΔC); EEA1-positive endosome trafficking assays; endocytic trafficking experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic mutagenesis plus biochemical assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"23897813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"KAI1/CD82 expression decreases p130CAS protein levels in metastatic prostate cancer cells, thereby reducing formation of the p130CAS-CrkII complex ('molecular switch' for cell motility); overexpression of p130CAS in CD82-expressing cells rescues migration, confirming that p130CAS-CrkII coupling is required for KAI1/CD82-mediated inhibition of cell motility.\",\n      \"method\": \"KAI1 expression in Du145 cells; migration assays; Western blot for FAK, Lyn, p130CAS; Co-IP for p130CAS-CrkII complex; p130CAS overexpression rescue\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rescue experiment plus signaling pathway dissection, single lab, 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, independent of cholesterol-enriched lipid rafts and independent of CD81 and CD9; EWI2/PGRL overexpression inhibits prostate cancer cell migration and synergizes with KAI1/CD82 in migration inhibition.\",\n      \"method\": \"Co-immunoprecipitation; chemical cross-linking; sucrose gradient fractionation; peptide mass spectrometry identification; migration assays on fibronectin and laminin\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical association confirmed by multiple methods plus functional synergy assay, single lab\",\n      \"pmids\": [\"12750295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"KAI1/CD82 is palmitoylated at cytoplasmic cysteine residues proximal to the plasma membrane; palmitoylation is required for CD82's inhibitory effects on migration and invasion, its subcellular distribution, its association with tetraspanin-enriched microdomains, lamellipodia formation, actin cytoskeleton organization, and the p130CAS-CrkII coupling that mediates motility inhibition.\",\n      \"method\": \"Palmitoylation assay; palmitoylation-deficient CD82 mutant; migration/invasion assays; tetraspanin co-immunoprecipitation; actin cytoskeleton imaging\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — site-directed mutagenesis of all palmitoylation sites with multiple functional readouts, single lab but orthogonal methods\",\n      \"pmids\": [\"15492270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"KAI1/CD82 transmembrane polar residues (Asn, Gln, Glu) mediate TM-domain interactions required for migration, invasion, and metastasis suppression; mutation of all three polar residues disrupts KAI1/CD82's interactions with tetraspanins CD9 and CD151 (but not with α3β1 integrin), inhibits formation of microprotrusions and microvesicle release, and destabilizes CD82 conformation.\",\n      \"method\": \"TM polar residue mutagenesis; metastasis assay; Co-IP with CD9 and CD151; migration/invasion assays; microprotrusion and microvesicle release assays; denaturation sensitivity assay; structural modeling\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — mutagenesis with multiple functional readouts, single lab\",\n      \"pmids\": [\"19116362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CD82 undergoes cholesterol/lipid-dependent endocytosis (not requiring dynamin or clathrin) and traffics to late endosomes and lysosomes; CD82 redistributes cholesterol into tetraspanin-enriched microdomains (TEMs), reorganizing TEMs and lipid rafts; CD82 endocytosis appears to alleviate CD82-mediated inhibition of cell migration.\",\n      \"method\": \"Endocytosis assays with dynamin and clathrin inhibitors; cholesterol depletion/sequestration; sucrose gradient fractionation; co-localization imaging\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition plus fractionation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"19497983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TI-VAMP (VAMP7) transports CD82 from the Golgi apparatus to the cell surface; depletion of TI-VAMP reduces surface CD82 levels, restrains EGFR diffusion at the cell surface, impairs MAPK signaling, and enhances clathrin-dependent endocytosis of activated EGFR via increased AP-2 recruitment.\",\n      \"method\": \"TI-VAMP siRNA depletion; CD82 siRNA; quantum dots video-microscopy of EGFR dynamics; MAPK signaling assays; AP-2 recruitment assays; Golgi secretion assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual siRNA knockdowns with live imaging and signaling readouts, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"20144992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"KAI1/CD82 suppresses tumor invasion by upregulating TIMP1, which inactivates MMP-9 activity; CD82-transfected H1299 lung carcinoma cells showed reduced invasion, reduced MMP-9 enzyme activity (despite elevated MMP-9 mRNA and protein), and elevated TIMP1 levels.\",\n      \"method\": \"CD82 transfection; cell invasion assay; gelatin zymography for MMP-9 activity; Western blot and RT-PCR\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — gain-of-function with mechanistic pathway identification, single lab, single study\",\n      \"pmids\": [\"16488391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"C33/CD82/KAI1 induces apoptosis through generation of reactive oxygen intermediates (ROIs); this is not derived from the mitochondrial respiratory chain but involves CD82-induced release of intracellular glutathione (GSH) and activation of GTPase Cdc42, which mediates GSH release and apoptosis induction.\",\n      \"method\": \"Apoptosis screen; cell death assays; ROI measurement; GSH release assay; Cdc42 activation assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional screen with mechanistic follow-up, single lab, single study\",\n      \"pmids\": [\"14597553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KAI1/CD82 inhibits polarized protrusion and retraction events in migrating cells by disrupting actin reorganization; specifically, CD82 reduces Rac1 activity (diminishing lamellipodia and actin cortical network) and blocks growth factor-stimulated RhoA activity (suppressing stress fibers and retraction), and reduces PIP2 at the cell periphery.\",\n      \"method\": \"Live imaging of CD82-expressing cells; Rac1 and RhoA GTPase activity assays; ROCK activity assay; cofilin localization imaging; PIP2 staining\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging plus multiple GTPase activity assays, single lab\",\n      \"pmids\": [\"23251627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD82 overexpression increases the molecular density of α4 integrin subunits within membrane clusters, thereby increasing cellular adhesion; this clustering depends on CD82 palmitoylation and the presence of α4 integrin ligands.\",\n      \"method\": \"Direct stochastic optical reconstruction microscopy (dSTORM) superresolution imaging; protein clustering algorithms; palmitoylation mutant of CD82; adhesion assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — superresolution microscopy with mutagenesis, single lab, two orthogonal methods\",\n      \"pmids\": [\"24623721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD82 deficiency disrupts bone marrow homing and engraftment of HSPCs; this homing defect is due at least in part to hyperactivation of Rac1, as pharmacological Rac1 inhibition rescues homing capacity of CD82-knockout HSPCs.\",\n      \"method\": \"CD82 knockout mouse model; in vivo HSPC homing assay; Rac1 inhibitor rescue experiment; migration and cell spreading assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with pharmacological rescue, single lab, multiple functional assays\",\n      \"pmids\": [\"30133344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD82/KAI1 inhibits TGF-β1- and Wnt-induced epithelial-to-mesenchymal transition (EMT) in prostate cancer cells; high CD82 expression prevents phosphorylation of Smad2, nuclear translocation of Smad4, and TRE promoter transactivation downstream of TGF-β1; it also maintains GSK-3β activity to phosphorylate β-catenin, preventing Wnt/β-catenin nuclear signaling.\",\n      \"method\": \"Luciferase reporter assay for TRE and Tcf/Lef promoters; immunofluorescence and subcellular fractionation for Smad4 and β-catenin localization; invasion assays; GSK-3β phosphorylation analysis\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pathway readouts with reporter assays and localization studies, single lab\",\n      \"pmids\": [\"31212375\"],\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 macrophages (in the ER and post-ER compartments), is essential for TLR9-dependent myddosome formation in response to CpG stimulation, and modulates TLR9-dependent NF-κB nuclear translocation and inflammatory cytokine production.\",\n      \"method\": \"Co-immunoprecipitation of CD82 and TLR9; myddosome formation assay; NF-κB nuclear translocation assay; CD82-deficient cells; CpG stimulation experiments\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional signaling assays in CD82-deficient macrophages, single lab\",\n      \"pmids\": [\"31408613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Virulent M. tuberculosis induces CD82 promoter hypomethylation, leading to CD82 expression in macrophages; CD82 targets RUNX1 and this CD82-RUNX1 axis arrests phagosome maturation via interaction with Rab5/Rab22, promoting intracellular mycobacterial survival; knockdown or knockout of CD82 or RUNX1 increased phagolysosome biogenesis and antimicrobial activity.\",\n      \"method\": \"CD82 promoter methylation analysis; CD82 KO/knockdown in macrophages; RUNX1 targeting; Rab5/Rab22 interaction assays; phagosome maturation assay; in vivo MTB infection model\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO and knockdown with mechanistic phagosome assays, single lab\",\n      \"pmids\": [\"29760437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"N-glycosylation of recombinant human CD82 occurs at three sites including a previously unreported site at Asn157; the glycans include bisecting N-acetylglucosamine, (α-2,6) N-acetylneuraminic acid, and core fucose epitopes, which are associated with cell adhesion and cancer metastasis functions.\",\n      \"method\": \"Glycosidase and protease digestions; glycan permethylation; mass spectrometry; site-directed mutagenesis; lectin blots\",\n      \"journal\": \"Journal of proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — biochemical characterization with site-directed mutagenesis, single lab\",\n      \"pmids\": [\"22123080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD82 positively regulates the STAT5/IL-10 signaling pathway in acute myelogenous leukemia (AML) stem cells; CD82 knockdown dephosphorylates STAT5 and reduces IL-10 levels, while forced CD82 expression increases p-STAT5 and IL-10; STAT5A binds the IL-10 gene promoter as shown by ChIP assay.\",\n      \"method\": \"shRNA knockdown; lentiviral CD82 overexpression; Western blot for p-STAT5; ELISA for IL-10; chromatin immunoprecipitation (ChIP); luciferase reporter assay; in vivo mouse model\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP assay plus reporter assay plus in vivo model, single lab\",\n      \"pmids\": [\"23797738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD82 regulates PKCα-mediated signaling in AML cells; using a palmitoylation-deficient CD82 mutant (which disrupts membrane organization), CD82 was shown to control PKCα expression and membrane activation, stabilize PKCα activation at the membrane, regulate the size of PKCα membrane clusters, and produce sustained ERK1/2 activation resulting in enhanced AML colony formation.\",\n      \"method\": \"Palmitoylation mutant CD82; single-molecule and ensemble imaging (TIRF, confocal); PKCα membrane cluster analysis; ERK1/2 phosphorylation assays; colony formation assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with single-molecule imaging and signaling readouts, single lab\",\n      \"pmids\": [\"27417454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KAI1/CD82 expressed in pericytes localizes to the membrane surface after palmitoylation by zDHHC4 enzyme and induces LIF expression through the Src/p53 pathway; LIF released from pericytes suppresses angiogenic factors in endothelial cells; additionally, KAI1 directly binds VEGF and PDGF and inhibits activation of their receptors.\",\n      \"method\": \"KAI1 knockout mice (enhanced angiogenesis phenotype); palmitoylation assay identifying zDHHC4; Src/p53 pathway analysis; VEGF/PDGF direct binding assays; in vivo cancer models with KAI1 supplementation; KAI1 large extracellular loop peptide in vivo\",\n      \"journal\": \"Journal of hematology & oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse phenotype plus direct binding assays plus in vivo supplementation, single lab\",\n      \"pmids\": [\"34530889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD82 overexpression increases TRPM7 α-kinase cleavage via caspase-3 activation and induces Numb phosphorylation at Thr346 and Ser348; CD82 overexpression promotes beta-amyloid peptide (Aβ) secretion, reversible by Numb T346S348 mutants; hippocampus-related memory functions are improved in Cd82−/− mice.\",\n      \"method\": \"AAV-CD82 hippocampal injection; TRPM7 cleavage assays; caspase-3 activation; Numb phosphorylation at specific residues; Numb phospho-mutant rescue; Aβ secretion measurement; Cd82−/− behavioral testing\",\n      \"journal\": \"GeroScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific mutagenesis rescue plus KO mouse behavior, single lab\",\n      \"pmids\": [\"32088828\"],\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 to BRCC3 blocks BRCC3-dependent K63-specific deubiquitination of NLRP3, leading to increased NLRP3 degradation.\",\n      \"method\": \"Co-immunoprecipitation identifying CD82-NLRP3 and CD82-BRCC3 complexes; K63 ubiquitination assays; CD82 KO mouse colitis model; in vitro NLRP3 inflammasome activation assays\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying two binding partners plus ubiquitination assays plus KO model, single lab\",\n      \"pmids\": [\"36600050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ΔNp63α directly activates CD82 transcription as shown by chromatin immunoprecipitation; CD82 is required for ΔNp63α-mediated inhibition of cell invasion, as CD82 ablation reverses the anti-invasive effect and ectopic CD82 rescues invasion upon ΔNp63α knockdown; GSK3β inhibition downregulates both ΔNp63α and CD82 and increases invasion independently of β-catenin.\",\n      \"method\": \"Affymetrix gene expression profiling; gain- and loss-of-function analysis; chromatin immunoprecipitation (ChIP); Matrigel outgrowth assay; siRNA knockdown; GSK3β pharmacological inhibition and siRNA\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional rescue experiments, single lab\",\n      \"pmids\": [\"24901051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TAp73 directly activates KAI1/CD82 transcription; KAI1 expression is indispensable for TAp73-mediated inhibition of colorectal cancer cell invasion and migration; induction of TAp73 elevated KAI1 expression and decreased hepatic metastasis in vivo, while TAp73-mediated anti-invasive effects were abrogated by KAI1 knockdown.\",\n      \"method\": \"Luciferase reporter assay; ChIP; TAp73 induction/knockdown; KAI1 knockdown; invasion/migration assays; in vivo hepatic metastasis model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus epistasis rescue experiment plus in vivo model, single lab\",\n      \"pmids\": [\"29222041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD82 directly binds to TIMP-1 through its large extracellular loop and co-localizes with TIMP-1; CD82 facilitates membrane-bound TIMP-1 endocytosis, which contributes to TIMP-1's anti-migration effect; CD82 silencing partially eliminates TIMP-1-mediated anti-migration activity.\",\n      \"method\": \"Co-immunoprecipitation; co-localization assays in cancer cell lines and clinical samples; CD82 siRNA knockdown; TIMP-1 endocytosis assays; migration assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional endocytosis assay with knockdown, single lab\",\n      \"pmids\": [\"28030805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD82 interacts with ADAM17 and inhibits its metalloprotease activity, thereby suppressing ADAM17-mediated cleavage/shedding of E-cadherin from the cell membrane in prostate cancer cells, and reducing cell migration.\",\n      \"method\": \"Co-immunoprecipitation of CD82 and ADAM17; ADAM17 metalloprotease activity assay; E-cadherin shedding assay; cell migration assay\",\n      \"journal\": \"Disease markers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP plus enzymatic activity assay, single lab, single study\",\n      \"pmids\": [\"33204367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD82 inhibits trophoblast invasion and migration by reducing MMP-9 gelatinolytic activity; CD82 siRNA knockdown in trophoblast cells promoted invasion, migration, and MMP-9 activity, while CD82 overexpression decreased invasion, migration, and MMP-9 activity.\",\n      \"method\": \"CD82 siRNA and overexpression in HTR8/SVneo cells; villous explant culture on Matrigel; invasion/migration assays; gelatin zymography for MMP-9 activity\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — gain- and loss-of-function with enzymatic readout, single lab, single study without direct interaction data\",\n      \"pmids\": [\"22679510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"KAI1/CD82 decreases Rac1 protein expression (but not mRNA) and GTPase activity through the PI3K/Akt/mTOR pathway in lung carcinoma cells; CD82-expressing cells showed lower mTOR expression, suggesting mTOR regulates Rac1 protein translation.\",\n      \"method\": \"Rac1 GTPase activity assay; RT-PCR for Rac1 mRNA; mTOR expression analysis; cell morphology and migration assays\",\n      \"journal\": \"Cell biochemistry and function\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, indirect pathway inference without direct mTOR-Rac1 linkage experiment\",\n      \"pmids\": [\"19107873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KAI1/CD82 suppresses HIF-1α and VEGF expression in prostate cancer cells by blocking CDCP1-enhanced Src activation, leading to increased VHL protein levels that promote HIF-1α degradation; this mechanism was validated in vivo in xenograft tumors.\",\n      \"method\": \"KAI1 stable transfection in PC3 cells; Western blot for HIF-1α, VEGF, CDCP1, Src phosphorylation, VHL; VEGF reporter assay; in vivo xenograft; immunohistochemistry\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — correlative signaling pathway analysis without direct mechanistic interaction experiments, single lab\",\n      \"pmids\": [\"22390300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"KAI1/CD82 induces homotypic cell aggregation in prostate cancer cells through a Src family kinase-dependent pathway; anti-CD82 antibody ligation increases endogenous Src kinase activity, and kinase-negative Src mutant expression abolishes CD82-mediated homotypic aggregation.\",\n      \"method\": \"KAI1 cDNA transfection in DU145 cells; aggregation assay; Src kinase inhibitor (PP1); Src kinase activity assay; kinase-negative Src mutant transfection\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological and dominant-negative approach, single lab, single study\",\n      \"pmids\": [\"12642901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Cross-linking of CD82 (IA4) on U937 monocytic cells induces a PLC-dependent increase in intracellular calcium (via IP3) followed by extracellular calcium entry, and causes tyrosine phosphorylation of various proteins; this transducing signal requires dual engagement of both CD82 and Fc receptors.\",\n      \"method\": \"Cross-linking with anti-CD82 antibody; intracellular calcium measurement; phospholipase C inhibitor; tyrosine phosphorylation assay; Fc receptor co-engagement experiments\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pharmacological approach, single study\",\n      \"pmids\": [\"7790779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD82 enhances expression of miR-203, which directly downregulates FZD2 mRNA and protein expression, thereby inhibiting canonical Wnt signaling and cell migration.\",\n      \"method\": \"miRNA expression profiling after CD82 expression; miR-203 mimic/inhibitor transfection; luciferase reporter assay for FZD2 3'UTR targeting; migration assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — indirect pathway (CD82→miR-203→FZD2) demonstrated by reporter assay, single lab\",\n      \"pmids\": [\"26132195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KAI1/CD82 attenuates the maturation of β1 integrin precursor to its functional mature form at the cell surface in lung carcinoma cells, thereby suppressing cell migration; this was confirmed by CD82-specific siRNA knockdown reversing the effect.\",\n      \"method\": \"Western blot for mature vs. precursor β1 integrin; biotinylation assay for surface β1 integrin; wound-healing and Boyden chamber migration assays; CD82 siRNA\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, indirect mechanistic evidence without direct CD82-β1 integrin interaction assay\",\n      \"pmids\": [\"17560548\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD82/KAI1 is a tetraspanin scaffold protein that suppresses tumor metastasis and regulates diverse cellular processes by organizing membrane microdomains (tetraspanin-enriched microdomains), where it physically associates with integrins, EGFR/ErbB receptors, EWI2/PGRL, DARC, ADAM17, TIMP-1, TLR9, and other partners; its palmitoylation is required for proper membrane localization and function; it inhibits cell migration and invasion by attenuating Src/FAK/p130CAS-CrkII, c-Met, Rac1, and RhoA signaling and by suppressing EGFR ubiquitylation and dimerization; it suppresses metastasis partly through DARC-dependent induction of senescence/TBX2/p21; it maintains hematopoietic stem cell quiescence via TGF-β1/Smad3/CDK inhibitor signaling through interaction with DARC on bone marrow macrophages; it promotes innate immune signaling through TLR9 trafficking and myddosome assembly; and it promotes phagosome arrest in M. tuberculosis infection through a CD82-RUNX1-Rab5/22 axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CD82/KAI1 is a tetraspanin scaffold protein that organizes membrane microdomains to suppress tumor metastasis and to regulate cell migration, hematopoietic stem cell behavior, and innate immune signaling [#0, #8]. First identified as a metastasis suppressor that blocks dissemination of prostate cancer cells in vivo [#0], CD82 functions by physically reorganizing the plasma membrane: its palmitoylation at juxtamembrane cysteines and its transmembrane polar residues are required for incorporation into tetraspanin-enriched microdomains, association with tetraspanins CD9 and CD151, and the downstream control of migration and invasion [#8, #9]. CD82 attenuates promigratory signaling on multiple fronts \\u2014 it inhibits integrin\\u2013c-Met crosstalk and Src/FAK/p130CAS-CrkII coupling [#3, #6], dampens Rac1 and RhoA activity to block lamellipodia and stress-fiber formation [#14], and compartmentalizes EGFR into ganglioside-rich domains while limiting its ligand-induced dimerization and promoting c-Cbl\\u2013dependent receptor downregulation [#4, #5]. It restrains invasion further by upregulating TIMP1 to inactivate MMP-9 [#12] and by binding and inhibiting the sheddase ADAM17 [#29]. CD82 engages a broad partner set through its large extracellular loop and membrane scaffolding, including EWI2/PGRL, TIMP-1, and the endothelial receptor DARC, the last of which mediates CD82-dependent induction of senescence via TBX2/p21 and is essential for metastasis suppression in vivo [#1, #7, #28]. Beyond cancer, CD82\\u2013DARC interaction on bone marrow macrophages stabilizes CD82 on hematopoietic stem cells to maintain quiescence through TGF-\\u03b21/Smad3-driven CDK-inhibitor expression, while CD82 loss causes Rac1 hyperactivation and impaired HSPC homing [#2, #16]. In innate immunity, CD82 controls TLR9 trafficking and myddosome assembly to drive NF-\\u03baB signaling [#18], and it restrains NLRP3 inflammasome activation by binding NLRP3 and the deubiquitinase BRCC3 [#25]. Transcriptionally, CD82 is a direct target of the p53-family factors \\u0394Np63\\u03b1 and TAp73, through which these tumor suppressors enforce their anti-invasive programs [#26, #27].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established CD82 as a bona fide metastasis suppressor gene and defined its tetraspanin architecture, framing all subsequent mechanistic work.\",\n      \"evidence\": \"Molecular cloning plus gene transfection into rat prostate cancer cells with in vivo metastasis assay\",\n      \"pmids\": [\"7754374\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular partners or signaling pathways through which suppression occurs\", \"Mechanism of membrane organization not addressed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Connected CD82 to motility machinery by showing it downregulates p130CAS to break the p130CAS-CrkII motility switch, defining a concrete cytoskeletal output.\",\n      \"evidence\": \"KAI1 expression in Du145 cells with migration assays, Co-IP, and p130CAS overexpression rescue\",\n      \"pmids\": [\"12738793\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How CD82 lowers p130CAS protein levels not established\", \"Link to upstream membrane scaffolding not yet made\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified EWI2/PGRL as a direct, raft-independent CD82 partner that synergizes in migration inhibition, expanding the CD82 interactome beyond classical tetraspanins.\",\n      \"evidence\": \"Co-IP, cross-linking, mass spectrometry, and migration assays in prostate cancer cells\",\n      \"pmids\": [\"12750295\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the complex at the signaling level not defined\", \"Stoichiometry in vivo unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed CD82 attenuates EGFR specifically by relocating it into ganglioside-rich membrane fractions, introducing the microdomain-compartmentalization model of receptor regulation.\",\n      \"evidence\": \"Sucrose gradient fractionation, dimerization assays, and ganglioside redistribution analysis\",\n      \"pmids\": [\"14576349\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Selectivity for EGFR over ErbB2/3 mechanistically unexplained\", \"Direct CD82-EGFR contact not demonstrated\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated palmitoylation is required for CD82 microdomain association and all downstream motility-suppressing functions, identifying the lipid modification as the master switch for CD82 activity.\",\n      \"evidence\": \"Palmitoylation-deficient mutant with migration/invasion, tetraspanin Co-IP, and actin imaging\",\n      \"pmids\": [\"15492270\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Palmitoyltransferase responsible not identified in this work\", \"Dynamics of palmitoylation cycling unaddressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined CD82 inhibition of integrin\\u2013c-Met crosstalk and Src signaling, linking membrane scaffolding to receptor tyrosine kinase suppression.\",\n      \"evidence\": \"CD82 re-expression in PC3 cells with integrin-dependent signaling and invasion assays\",\n      \"pmids\": [\"16331263\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CD82 directly contacts c-Met or integrins not shown\", \"Relative contribution of each kinase node unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Discovered the DARC interaction as the in vivo effector of metastasis suppression, linking tumor-cell CD82 to endothelial-induced senescence via TBX2/p21.\",\n      \"evidence\": \"Yeast two-hybrid screen, DARC-knockout mouse metastasis assays, and senescence assays\",\n      \"pmids\": [\"16862154\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How DARC engagement triggers TBX2/p21 intracellularly not defined\", \"Signal transduction from cell surface to nucleus unmapped\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Added an extracellular-matrix arm by showing CD82 upregulates TIMP1 to inactivate MMP-9, explaining anti-invasive activity independent of motility signaling.\",\n      \"evidence\": \"CD82 transfection in H1299 cells with invasion assays and gelatin zymography\",\n      \"pmids\": [\"16488391\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of TIMP1 upregulation by CD82 unknown\", \"Single cell line tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Established that CD82 traffics by cholesterol-dependent endocytosis to late endosomes/lysosomes and reorganizes microdomain cholesterol, framing CD82 function as regulated by its own membrane turnover.\",\n      \"evidence\": \"Endocytosis assays with inhibitors, cholesterol depletion, and fractionation\",\n      \"pmids\": [\"19497983\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trigger for CD82 internalization not defined\", \"Functional link between endocytosis and migration relief only correlative\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Mapped TM polar residues as required for CD82 conformation and tetraspanin partnerships underlying metastasis suppression, complementing palmitoylation as a structural determinant.\",\n      \"evidence\": \"TM polar residue mutagenesis with metastasis, Co-IP, and structural modeling\",\n      \"pmids\": [\"19116362\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No experimental structure of CD82 TM bundle\", \"Single-lab functional readouts\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified TI-VAMP/VAMP7 as the trafficking machinery delivering CD82 from Golgi to the surface, where CD82 then controls EGFR diffusion and endocytic fate.\",\n      \"evidence\": \"TI-VAMP and CD82 siRNA with quantum-dot EGFR tracking and MAPK assays\",\n      \"pmids\": [\"20144992\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether VAMP7 selectively sorts CD82 versus bulk cargo unclear\", \"Direct VAMP7-CD82 interaction not shown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved CD82 control of actin dynamics by showing it suppresses both Rac1 (protrusion) and RhoA (retraction) activity and lowers peripheral PIP2.\",\n      \"evidence\": \"Live imaging with Rac1/RhoA/ROCK activity assays and PIP2 staining\",\n      \"pmids\": [\"23251627\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream GEF/GAP targets of CD82 not identified\", \"Mechanism linking microdomains to GTPase regulation unmapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Refined EGFR regulation by showing CD82 suppresses EGFR ubiquitylation via PKC-dependent c-Cbl phosphorylation and EGFR T654 phosphorylation, requiring the CD82 cytoplasmic tail.\",\n      \"evidence\": \"Ubiquitylation and c-Cbl phosphorylation assays with CD82\\u0394C mutant\",\n      \"pmids\": [\"23897813\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How the cytoplasmic tail recruits PKC not defined\", \"Reconciliation with EGFR compartmentalization model incomplete\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated with superresolution imaging that CD82 increases \\u03b14 integrin clustering density to promote adhesion, dependent on palmitoylation, giving a direct structural readout of microdomain organization.\",\n      \"evidence\": \"dSTORM superresolution imaging with clustering analysis and palmitoylation mutant\",\n      \"pmids\": [\"24623721\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CD82 directly contacts \\u03b14 integrin unresolved\", \"Single integrin subunit examined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed CD82 downstream of \\u0394Np63\\u03b1 as a direct transcriptional target required for that factor's anti-invasive program.\",\n      \"evidence\": \"ChIP, gain/loss-of-function, and Matrigel outgrowth rescue assays\",\n      \"pmids\": [\"24901051\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of the \\u0394Np63\\u03b1-CD82 axis across tumor types untested\", \"Other \\u0394Np63\\u03b1 targets contributing to phenotype not excluded\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended the DARC axis to hematopoiesis, showing macrophage DARC stabilizes CD82 on HSCs to enforce quiescence via TGF-\\u03b21/Smad3 CDK inhibitors.\",\n      \"evidence\": \"Cd82-/- mouse, macrophage ablation, and TGF-\\u03b21/Smad3 signaling/cell cycle assays\",\n      \"pmids\": [\"26996598\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CD82 transduces DARC engagement into TGF-\\u03b21 signaling unmapped\", \"Direct CD82-Smad linkage not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified CD82 as a direct TAp73 transcriptional target essential for TAp73-driven suppression of colorectal cancer invasion and metastasis.\",\n      \"evidence\": \"Luciferase reporter, ChIP, epistasis rescue, and in vivo hepatic metastasis model\",\n      \"pmids\": [\"29222041\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overlap with \\u0394Np63\\u03b1 regulation of the same promoter not dissected\", \"Tissue specificity of the axis unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined a direct CD82\\u2013TIMP-1 interaction through the large extracellular loop that drives TIMP-1 endocytosis and its anti-migratory effect.\",\n      \"evidence\": \"Co-IP, co-localization in cells and clinical samples, and TIMP-1 endocytosis/migration assays\",\n      \"pmids\": [\"28030805\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the extracellular-loop interaction unknown\", \"Relationship to CD82-driven TIMP1 upregulation unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed CD82 loss causes Rac1 hyperactivation and defective HSPC bone marrow homing, mechanistically tying CD82 GTPase control to stem-cell trafficking.\",\n      \"evidence\": \"CD82-knockout mouse with in vivo homing assay and Rac1-inhibitor rescue\",\n      \"pmids\": [\"30133344\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How CD82 restrains Rac1 in HSPCs mechanistically unclear\", \"Adhesion versus migration contributions not separated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed a pathogen-co-opted CD82 function: M. tuberculosis induces CD82 to arrest phagosome maturation via a CD82-RUNX1-Rab5/22 axis promoting bacterial survival.\",\n      \"evidence\": \"CD82 promoter methylation analysis, KO/knockdown macrophages, Rab interaction and phagosome maturation assays, in vivo infection\",\n      \"pmids\": [\"29760437\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How CD82 engages RUNX1 and Rab GTPases molecularly undefined\", \"Whether this reflects normal CD82 endosomal function unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established CD82 as a positive regulator of TLR9 trafficking and myddosome assembly, broadening CD82 into innate immune receptor handling.\",\n      \"evidence\": \"Co-IP of CD82-TLR9, myddosome formation and NF-\\u03baB assays in CD82-deficient macrophages\",\n      \"pmids\": [\"31408613\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect CD82-TLR9 association not resolved\", \"Step in TLR9 trafficking controlled by CD82 not pinpointed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed CD82 blocks TGF-\\u03b21- and Wnt-driven EMT in prostate cancer by inhibiting Smad and \\u03b2-catenin nuclear signaling, linking metastasis suppression to EMT control.\",\n      \"evidence\": \"Reporter assays, Smad4/\\u03b2-catenin localization, GSK-3\\u03b2 analysis, and invasion assays\",\n      \"pmids\": [\"31212375\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation with HSC TGF-\\u03b21/Smad3 promotion versus tumor TGF-\\u03b21/Smad inhibition unaddressed\", \"Direct CD82 effector on these pathways unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified zDHHC4 as the palmitoyltransferase for CD82 in pericytes and showed CD82 directly binds VEGF/PDGF and induces LIF to suppress angiogenesis.\",\n      \"evidence\": \"KAI1-knockout mice, palmitoylation assay identifying zDHHC4, VEGF/PDGF binding, and in vivo supplementation\",\n      \"pmids\": [\"34530889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether zDHHC4 modifies CD82 in other cell types untested\", \"Stoichiometry of CD82-VEGF/PDGF binding unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a CD82 inflammasome-restraining function by showing CD82 binds NLRP3 and BRCC3 to block deubiquitination and promote NLRP3 degradation.\",\n      \"evidence\": \"Co-IP of CD82-NLRP3 and CD82-BRCC3, K63 ubiquitination assays, and KO colitis model\",\n      \"pmids\": [\"36600050\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CD82 acts at the membrane or in cytosol for this function unclear\", \"Structural basis of CD82-BRCC3 interaction unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single tetraspanin scaffold integrates its contradictory context-dependent roles \\u2014 suppressing TGF-\\u03b21/Smad signaling in tumor cells yet promoting it in HSCs, and acting at the plasma membrane versus endosomes versus the nucleus-adjacent transcriptional axes \\u2014 remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model unifying palmitoylation, TM packing, and partner selection\", \"Mechanism of signal transduction from CD82 surface engagement to intracellular outputs largely undefined\", \"Cell-type determinants of opposing CD82 outputs not identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [8, 9, 4, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 14, 5, 29, 25]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [15, 33]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 8, 10, 15]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [10, 5, 19, 28]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 6, 14, 4, 5]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 1, 19]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [18, 25, 19]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [12, 29, 28]}\n    ],\n    \"complexes\": [\n      \"tetraspanin-enriched microdomain\"\n    ],\n    \"partners\": [\n      \"DARC\",\n      \"EWI2\",\n      \"TIMP1\",\n      \"ADAM17\",\n      \"TLR9\",\n      \"NLRP3\",\n      \"BRCC3\",\n      \"CD151\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":8,"faith_total":8,"faith_pct":100.0}}