{"gene":"BSG","run_date":"2026-06-09T22:02:45","timeline":{"discoveries":[{"year":2004,"finding":"CD147 associates specifically with caveolin-1 on the cell surface in a cholesterol-dependent manner within intermediate-density sucrose gradient fractions (distinct from the bulk caveolin-1 in low-density fractions). Mutagenesis showed CD147 Ig domain 2 is required for caveolin-1 association. Overexpression of caveolin-1 reduces CD147 cell-surface clustering; a CD147 mutant deficient in caveolin-1 binding shows enhanced spontaneous clustering and elevated MMP-1 induction. Thus caveolin-1 negatively regulates CD147 clustering and CD147-dependent MMP-1 induction.","method":"Co-immunoprecipitation, sucrose density gradient fractionation, cholesterol depletion, site-directed mutagenesis of CD147, caveolin-1 overexpression, cluster-specific mAb staining, MMP-1 induction assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (mutagenesis, fractionation, co-IP, functional MMP assay) in a single rigorous study","pmids":["14707126"],"is_preprint":false},{"year":2005,"finding":"CD147 selectively associates with three major transporter types at the cell surface: CD98 heavy chain (CD98hc)–L-type amino acid transporter complexes, ASCT2, and monocarboxylate transporters, as well as with epithelial cell adhesion molecule. CD147 and CD98hc play a central organizing role in these multicomponent complexes. siRNA knockdown of CD147 (and CD98hc) reduces cell proliferation and activates AMP-activated protein kinase, indicating disruption of cellular energy metabolism, consistent with a role for the CD147–CD98 supercomplex in coordinating lactate and amino acid transport.","method":"Covalent crosslinking, mass spectrometric protein identification, co-immunoprecipitation, RNA interference knockdown, AMPK activity assay","journal":"Molecular & cellular proteomics","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (crosslinking-MS, co-IP, RNAi + functional metabolic readout) in a single study","pmids":["15901826"],"is_preprint":false},{"year":2005,"finding":"CD147 cell-surface expression is regulated intracellularly by cyclophilin 60 (Cyp60). CD147 co-immunoprecipitates with Cyp60 and they co-localize intracellularly by confocal microscopy. The interaction involves proline 211 of CD147; mutation of this residue abolishes co-immunoprecipitation with Cyp60 and reduces plasma membrane expression of CD147. siRNA-mediated suppression of Cyp60 phenocopies cyclosporin A treatment, reducing CD147 surface levels, indicating Cyp60 mediates CD147 translocation to the plasma membrane.","method":"Co-immunoprecipitation, confocal immunofluorescence, site-directed mutagenesis (P211 mutation), siRNA knockdown, cyclosporin A treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reciprocal co-IP, mutagenesis, and RNAi phenocopy, multiple orthogonal methods in one study","pmids":["15946952"],"is_preprint":false},{"year":2005,"finding":"Drosophila basigin (ortholog of BSG) interacts with integrin to regulate cell architecture independently of matrix metalloprotease activity. Basigin and integrin co-localize in cultured insect cells and in the visual system. Basigin-mediated cytoskeletal rearrangements (lamellipodia formation) in cultured cells require integrin-binding activity. Loss of basigin from photoreceptors causes misplaced nuclei, rough ER, mitochondria and swollen axon terminals; these defects are rescued by either fly or mouse basigin, and genetic interaction experiments confirm basigin–integrin cooperation in cell structure.","method":"Drosophila genetics (loss-of-function, rescue with fly and mouse basigin), co-localization in cultured insect cells, mutagenesis of integrin-binding activity, in vivo phenotypic analysis","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis/rescue, co-localization, mutagenesis, multiple orthogonal methods; ortholog study with cross-species rescue validates conservation","pmids":["15928045"],"is_preprint":false},{"year":2009,"finding":"Platelet glycoprotein VI (GPVI) is identified as a novel receptor for EMMPRIN/CD147. EMMPRIN-Fc immobilized on surfaces supports ADP-stimulated platelet rolling that is blocked by anti-EMMPRIN or anti-GPVI antibodies but not by anti-P-selectin, anti-α4-integrin, or anti-GPIIb/IIIa antibodies. CHO cells stably transfected with GPVI show enhanced rolling on immobilized EMMPRIN-Fc. Direct binding is confirmed by modified ELISA and surface plasmon resonance with a dissociation constant of 88 nM.","method":"Platelet perfusion assay under flow conditions, antibody blocking, CHO cell stable transfection, ELISA binding assay, surface plasmon resonance","journal":"Thrombosis and haemostasis","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct binding quantified by SPR, functional blocking, and transfection assay; multiple orthogonal methods in one study","pmids":["19350111"],"is_preprint":false},{"year":2010,"finding":"CD147/EMMPRIN functions as a functional entry receptor for measles virus (MeV) on epithelial cells independently of the known SLAM receptor. Cyclophilin B (CypB), a cellular ligand for CD147, is incorporated into MeV virions; inhibition of CypB incorporation significantly attenuates SLAM-independent infection on epithelial cells but has no effect on SLAM-dependent infection. This reveals a CD147-CypB-dependent viral entry pathway that does not require binding of the MeV hemagglutinin protein to CD147.","method":"Viral infection assays, CypB incorporation into virions (biochemical), inhibition of CypB incorporation, SLAM-positive vs. SLAM-negative cell comparison, CD147 functional characterization","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional viral entry assay with mechanistic dissection (CypB inhibition), single laboratory","pmids":["20147391"],"is_preprint":false},{"year":2011,"finding":"Monocyte EMMPRIN/CD147 mediates firm adhesion to surface-adherent platelets and monocyte recruitment to the injured arterial wall. Antibody blockade and siRNA silencing of monocyte EMMPRIN substantially reduces monocyte firm adhesion to platelets at arterial and venous shear rates in vitro. In vivo, EMMPRIN-silenced monocytes show reduced platelet-monocyte aggregate formation in circulation and reduced recruitment to the injured carotid artery. Platelet GPVI is identified as the critical corresponding counter-receptor on platelets; blocking GPVI abolishes EMMPRIN-mediated monocyte–platelet interactions.","method":"In vitro perfusion assay under flow conditions, siRNA gene silencing, intravital microscopy, flow cytometry, in vivo carotid injury model","journal":"Journal of thrombosis and haemostasis","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal functional blocking (anti-EMMPRIN and anti-GPVI), siRNA, in vitro and in vivo concordance, multiple orthogonal methods","pmids":["21320284"],"is_preprint":false},{"year":2013,"finding":"In multiple myeloma cells, CD147 protein associates with MCT1 protein (confirmed by co-immunoprecipitation); siRNA-mediated downregulation of MCT1 decreases CD147 protein (and vice versa) at the protein level without affecting mRNA, indicating reciprocal post-translational stabilization. Knockdown of MCT1 (but not MCT4) decreases myeloma cell proliferation and lactate export, demonstrating functional dependency on the CD147–MCT1 complex for glycolytic metabolism.","method":"Co-immunoprecipitation, siRNA knockdown, Western blotting, RT-PCR, lactate export assay, proliferation assay","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and reciprocal siRNA with functional readouts; single laboratory","pmids":["24013424"],"is_preprint":false},{"year":2015,"finding":"EMMPRIN/CD147 acts as a novel co-receptor for VEGFR-2, directly interacting with it and regulating VEGF-induced VEGFR-2 activation, downstream signaling, and angiogenic outcomes in vitro and in vivo. Computational docking and mutagenesis studies identified a binding site in the extracellular domain of EMMPRIN near the membrane, containing residues 195/199, required for the interaction with VEGFR-2.","method":"Co-immunoprecipitation, site-directed mutagenesis, computational docking, in vitro angiogenesis assay, in vivo tumor model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction demonstrated with mutagenesis and co-IP, supported by in vivo data; single laboratory","pmids":["25825981"],"is_preprint":false},{"year":2016,"finding":"Neuroplastin-β is identified as a receptor for S100A8 and forms homodimers and a heterodimer with EMMPRIN on the surface of normal human keratinocytes. Upon S100A8 stimulation, neuroplastin-β recruits GRB2 and activates ERK leading to keratinocyte proliferation, while EMMPRIN recruits TRAF2. Knockdown of both receptors suppresses cell proliferation and proinflammatory cytokine induction, indicating the neuroplastin-β/EMMPRIN heterodimeric receptor complex mediates S100A8/A9 signaling in skin inflammation.","method":"Co-localization, knockdown experiments, receptor-ligand stimulation assays, ERK phosphorylation measurement, GRB2/TRAF2 recruitment assays, transgenic mouse model","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-localization, knockdown with functional readout, signaling pathway dissection; single laboratory","pmids":["27388991"],"is_preprint":false},{"year":2017,"finding":"CD147 prevents extrinsic apoptosis specifically in mouse spermatocytes (but not spermatogonia) by interacting with TRAF2. Immunodepletion of CD147 triggers apoptosis via the extrinsic pathway with activation of non-canonical NFκB and suppression of canonical NFκB signaling, accompanied by decreased TRAF2. CRISPR/Cas9 deletion of CD147 in the spermatocyte cell line GC-2 reproduces this phenotype. The same manipulation had no effect on NFκB signaling or TRAF2 in spermatogonia (GC-1 cells).","method":"CD147 immunodepletion, CRISPR/Cas9 knockout, co-immunoprecipitation (CD147–TRAF2), Western blotting, apoptosis assays, NFκB signaling pathway analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO and co-IP with mechanistic pathway dissection; single laboratory","pmids":["27902973"],"is_preprint":false},{"year":2019,"finding":"CD147 endocytic recycling in liver cancer cells is controlled by ADP-ribosylation factor 6 (Arf6) through concurrent activation of Rab5 and Rab22a GTPases. YIPF2, an ER-Golgi-resident transmembrane protein, acts as a Rab-GDF regulating three trafficking steps: Rab5 and Rab22a recruitment to endomembranes, CD147 endocytic recycling, and mature processing via the ER-Golgi route. Disruption of Arf6-mediated CD147 trafficking reduces cell-matrix/cell-cell adhesion, MMPs secretion, and migration/invasion of HCC cells.","method":"GST-RBD pull-down (Rab GTPase activation), confocal imaging, flow cytometry, biotin-labeled chase assays (endocytosis/recycling), MAPPIT screening, MSP-cDNA library screen, gelatin zymography, cell adhesion/invasion assays","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (biochemical Rab activation, trafficking assays, functional invasion assays); single laboratory","pmids":["31752956","31189879"],"is_preprint":false},{"year":2021,"finding":"CD147 is di-methylated at lysine 234 (K234me2) by lysine methyltransferase KMT5A. This di-methylation promotes interaction between CD147 and monocarboxylate transporter 4 (MCT4), enhancing translocation of MCT4 from the cytoplasm to the plasma membrane. Overexpression of CD147-K234me2 and KMT5A enhances glycolysis and lactate export in NSCLC cells; the modification was detected by LC-MS/MS in patient tissues.","method":"Liquid chromatography-tandem mass spectrometry (detection of K234me2 in patient tissues), co-immunoprecipitation, subcellular fractionation, glycolysis/lactate export assays, overexpression studies","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — PTM identified by LC-MS/MS, mechanism validated by co-IP and functional metabolic assays with multiple orthogonal methods; single laboratory","pmids":["33406400"],"is_preprint":false},{"year":2021,"finding":"CD147 is required for Foxp3+ regulatory T cell (Treg) stability through cell-to-cell contact. CD147 on Tregs is stimulated by CD98 (widely expressed in the physiological environment), causing CD147's intracellular domain to bind CDK2 and retain it near the membrane, leading to Foxp3 dephosphorylation and prevention of Foxp3 degradation. Disruption of CD147–CD98 interaction destabilizes Foxp3 expression.","method":"Co-immunoprecipitation (CD147 intracellular domain–CDK2), cell contact assays, Foxp3 phosphorylation/degradation assays, in vivo Treg distribution analysis with CD98 conditional manipulation","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with mechanistic pathway elucidation; single laboratory","pmids":["34759371"],"is_preprint":false},{"year":2022,"finding":"Glycosylated CD147 promotes pathological cardiac hypertrophy via direct binding to TRAF2 and subsequent activation of TAK1 signalling. Cardiac-specific overexpression of wild-type CD147 in AAV9 mice promotes pressure overload-induced pathological remodeling, oxidative stress, and ferroptosis, whereas glycosylation-site mutants of CD147 markedly weaken these effects. This identifies glycosylation as essential for the CD147–TRAF2–TAK1 signalling axis in pathological cardiac remodeling.","method":"AAV9-mediated cardiac-specific CD147 overexpression, glycosylation-site mutagenesis, co-immunoprecipitation (CD147–TRAF2), transverse aortic constriction mouse model, Western blotting, oxidative stress and ferroptosis assays","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with mutagenesis and in vivo functional model; single laboratory","pmids":["35096272"],"is_preprint":false},{"year":2024,"finding":"Myeloid-specific CD147 promotes atherosclerotic plaque growth by driving M1 macrophage polarization via the TRAF6–IKK–IRF5 signaling pathway and by suppressing efferocytosis through inhibition of GAS6 secretion in pro-inflammatory macrophages. Myeloid-specific CD147 knockout in ApoE-/- mice ameliorates atherosclerosis, reduces iNOS-mediated late apoptosis, and enhances efferocytosis. Conversely, myeloid CD147 overexpression worsens these phenotypes.","method":"Myeloid-specific knockout and restricted overexpression mouse models (ApoE-/- background), macrophage polarization assays (LPS/IFN-γ stimulation), NO/RNS production measurement, GAS6 secretion assay, efferocytosis assays, in vivo atherosclerosis quantification, anti-CD147 antibody treatment in humanized transgenic model","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO and OE in vivo models with concordant in vitro mechanistic dissection of TRAF6–IKK–IRF5 pathway; multiple orthogonal approaches","pmids":["38166463"],"is_preprint":false},{"year":2020,"finding":"CD147 promotes collective invasion in hepatocellular carcinoma by upregulating cathepsin B expression and activity. Mechanistically, CD147 activates β-catenin signaling by reducing GSK-3β expression, which drives cathepsin B transcription. CD147 upregulation was observed at the invasive front of tumor cell groups, and cathepsin B mediated the CD147-induced invasive phenotype in a 3D invasion model.","method":"3D invasion model, RNA-sequencing, cathepsin B enzyme activity assay, Western blotting, immunostaining of human HCC specimens, siRNA knockdown","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptome analysis + enzyme assay + functional 3D model + pathway analysis; single laboratory","pmids":["32727598"],"is_preprint":false},{"year":2020,"finding":"CD147 promotes glycolytic metabolism in hepatocellular carcinoma via the PI3K/Akt/mTOR signaling pathway, with upregulated GLUT1 and MCT1 expression in CD147-overexpressing HCC cells and xenografts.","method":"CD147 gain/loss-of-function in HCC cell lines, nude mouse xenograft model, glycolysis measurement, PI3K/Akt/mTOR pathway inhibition, immunohistochemistry","journal":"Cancer immunology, immunotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss/gain of function with pathway inhibitor confirmation in vitro and in vivo; single laboratory","pmids":["31965268"],"is_preprint":false},{"year":2018,"finding":"CD147 regulates CXCL1 secretion from hepatic stellate cells (HSCs) via the PI3K/AKT signaling pathway, promoting HSC activation and liver fibrosis. Conditional knockout of CD147 in HSCs in mice alleviates CCl4-induced liver fibrosis and reduces HSC activation. Overexpression of CD147 upregulates CXCL1, which acts in an autocrine manner to further activate HSCs.","method":"HSC-specific CD147 conditional knockout mice, CCl4 liver fibrosis model, CXCL1 secretion measurement, PI3K/AKT inhibitor treatment, overexpression studies","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO in vivo with pathway inhibitor mechanistic follow-up; single laboratory","pmids":["29642635"],"is_preprint":false},{"year":2023,"finding":"CD147 interacts with GLUT1 and is required for glucose uptake and glycolytic reprogramming in keratinocytes in psoriasis pathogenesis. Epidermal CD147 knockout in mice blocks glucose uptake and glycolysis, increases oxidative phosphorylation, and elevates carnitine and α-KG production. The elevated α-KG inhibits H3K9me3, increasing BBOX1 transcription, defining a CD147–α-KG–H3K9me3–BBOX1 metabolic axis.","method":"Epidermal-specific CD147 knockout mice, IMQ-induced psoriasis model, co-immunoprecipitation (CD147–GLUT1), non-targeted and targeted metabolomics, chromatin immunoprecipitation (H3K9me3), glucose uptake and glycolysis assays","journal":"Research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — conditional KO in vivo, co-IP, metabolomics, and ChIP providing multiple orthogonal mechanistic insights; single laboratory","pmids":["37303600"],"is_preprint":false},{"year":2023,"finding":"CD147 and CD98 define a subpopulation of extracellular vesicles (CD147+ EVs) with substantially higher microRNA content than classical tetraspanin+ EVs. CD147 interacts with heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1) to selectively enrich miRNAs into these vesicles. CD147+ EVs predominantly derive from cancer cells in mouse xenograft models.","method":"EV subpopulation isolation, miRNA content comparison, co-immunoprecipitation (CD147–hnRNPA2B1), mouse xenograft models, clinical sample analysis","journal":"Journal of extracellular vesicles","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP binding partner identification with functional miRNA enrichment assay; single laboratory","pmids":["36973758"],"is_preprint":false},{"year":2021,"finding":"SARS-CoV-2 infection and CD147 regulate ACE2 levels, and both CD147 blocking antibody and CD147 knockdown attenuate SARS-CoV-2 infection of host cells. However, CD147 binding to CyPA does not play a role in SARS-CoV-2 entry via CD147. CD147 regulates ACE2 levels and both receptors are affected by virus infection.","method":"CD147 blocking antibody treatment, siRNA knockdown, ACE2 level measurement, viral infection assay","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional blocking and knockdown data; single laboratory, mechanism partially unresolved","pmids":["34201214"],"is_preprint":false},{"year":2021,"finding":"NEGATIVE FINDING: Human basigin (CD147) does not directly interact with the SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD) or full-length spike. Using recombinant proteins, size exclusion chromatography, and surface plasmon resonance, no binding was detected between RBD/spike and recombinant human basigin expressed in E. coli or mammalian cells. Polyclonal anti-basigin IgG did not block SARS-CoV-2 infection of Vero E6 cells.","method":"Size exclusion chromatography, surface plasmon resonance, polyclonal antibody blocking of viral infection, recombinant protein binding assay","journal":"mSphere","confidence":"High","confidence_rationale":"Tier 1 / Moderate — rigorous in vitro binding assay with SPR and SEC using purified recombinant proteins with positive control (RH5-basigin); directly refutes a prior claim","pmids":["34378982"],"is_preprint":false},{"year":2023,"finding":"NEGATIVE FINDING: CRISPR/Cas9-mediated knockout of CD147 in ER-Hoxb8 monocytes had no effect on S100A8- or S100A9-induced cytokine release, in contrast to TLR4 knockout which abolished the S100-induced inflammatory response. TLR4, not CD147, is the dominant receptor for S100-triggered inflammatory activation of monocytes.","method":"CRISPR/Cas9 gene deletion in monocytes, S100A8/S100A9 stimulation, cytokine release measurement","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean CRISPR KO with functional assay; single laboratory negative result","pmids":["37056775"],"is_preprint":false}],"current_model":"BSG/CD147/EMMPRIN is a multifunctional transmembrane glycoprotein that acts as a cell-surface scaffold: it stimulates MMP production in neighboring cells via homophilic interactions; serves as the plasma membrane chaperone for monocarboxylate transporters (MCT1/4) and organizes a metabolic supercomplex with CD98hc to coordinate lactate and amino acid transport; binds cyclophilins (CypA, CypB) as a signaling receptor to mediate chemotaxis and inflammatory responses; interacts with caveolin-1 (negatively regulating CD147 clustering and MMP induction), integrins, and GPVI on platelets; co-receptors VEGFR-2 to potentiate angiogenic signaling; undergoes post-translational regulation by glycosylation (which governs TRAF2–TAK1 signaling in cardiac remodeling) and KMT5A-mediated di-methylation at K234 (enhancing MCT4 membrane translocation and lactate export); its surface trafficking is controlled intracellularly by cyclophilin 60 (Cyp60) and Arf6/Rab GTPase-dependent endocytic recycling; in the immune system it stabilizes Foxp3 in regulatory T cells via CD98-stimulated CDK2 retention and prevents spermatocyte apoptosis through TRAF2-dependent NFκB modulation; and in macrophages myeloid CD147 drives M1 polarization via TRAF6–IKK–IRF5 and suppresses efferocytosis by inhibiting GAS6 secretion, collectively establishing CD147 as a central hub integrating extracellular matrix remodeling, cellular metabolism, immune regulation, and intracellular trafficking."},"narrative":{"mechanistic_narrative":"BSG (CD147/EMMPRIN) is a multifunctional transmembrane glycoprotein that operates as a cell-surface scaffold coupling metabolite transport, matrix remodeling, and inflammatory signaling [PMID:15901826, PMID:31752956, PMID:31189879]. It serves as the plasma-membrane organizer of metabolite transporters: it associates with CD98hc–amino acid transporter complexes, ASCT2, and monocarboxylate transporters, where loss of CD147 disrupts cellular energy metabolism and activates AMPK [PMID:15901826], and it reciprocally stabilizes MCT1 at the protein level to sustain lactate export and glycolysis [PMID:24013424]. This transporter-organizing role is tuned post-translationally: KMT5A-mediated di-methylation of CD147 at K234 promotes MCT4 binding and its translocation to the membrane to enhance lactate export [PMID:33406400], while CD147 binding to GLUT1 supports glucose uptake and glycolytic reprogramming [PMID:37303600]. CD147 drives matrix-degrading and invasive programs through MMP induction, which is negatively regulated by caveolin-1 binding via CD147 Ig domain 2 that limits CD147 surface clustering [PMID:14707126], and through β-catenin/GSK-3β-dependent induction of cathepsin B [PMID:32727598]. As a receptor and co-receptor it engages platelet GPVI to mediate cell adhesion under flow [PMID:19350111, PMID:21320284], partners with VEGFR-2 to potentiate angiogenic signaling [PMID:25825981], and forms a heterodimer with neuroplastin-β in keratinocyte inflammatory signaling [PMID:27388991]. CD147 transduces signals chiefly through TRAF adaptors: glycosylation-dependent TRAF2–TAK1 signaling promotes pathological cardiac remodeling [PMID:35096272], TRAF2 engagement prevents spermatocyte apoptosis via NFκB modulation [PMID:27902973], and myeloid CD147 drives M1 macrophage polarization through TRAF6–IKK–IRF5 while suppressing efferocytosis [PMID:38166463]. Its surface availability is set intracellularly by cyclophilin 60-dependent trafficking [PMID:15946952] and Arf6/Rab5/Rab22a-dependent endocytic recycling [PMID:31752956, PMID:31189879]. CD147 also stabilizes Foxp3 in regulatory T cells through CD98-stimulated CDK2 retention [PMID:34759371]. Reported roles in viral entry are mixed: CD147 supports a CypB-dependent measles-virus entry pathway [PMID:20147391] and influences SARS-CoV-2 infection via ACE2 regulation [PMID:34201214], but direct binding of human basigin to the SARS-CoV-2 spike RBD was not detected [PMID:34378982], and CD147 is dispensable for S100-triggered monocyte cytokine release [PMID:37056775].","teleology":[{"year":2004,"claim":"Established that CD147-driven MMP induction is constrained by its surface organization, identifying caveolin-1 as a negative regulator of CD147 clustering.","evidence":"Co-IP, sucrose gradient fractionation, cholesterol depletion, CD147 mutagenesis, and MMP-1 induction assay","pmids":["14707126"],"confidence":"High","gaps":["Does not define the downstream signaling triggered by CD147 clustering","Mechanism of cluster-dependent MMP induction in target cells not resolved"]},{"year":2005,"claim":"Defined CD147 as the organizing hub of a cell-surface metabolite-transport supercomplex, linking it directly to cellular energy metabolism.","evidence":"Crosslinking-MS, co-IP, and siRNA knockdown with AMPK and proliferation readouts","pmids":["15901826"],"confidence":"High","gaps":["Does not establish whether CD147 is required for transporter folding versus surface retention","Individual transporter dependencies not separated"]},{"year":2005,"claim":"Showed that CD147 surface delivery is controlled intracellularly, identifying cyclophilin 60 and Pro211 as required for membrane translocation.","evidence":"Reciprocal co-IP, P211 mutagenesis, confocal co-localization, siRNA, and cyclosporin A treatment","pmids":["15946952"],"confidence":"High","gaps":["Trafficking compartments involved not fully mapped","Relationship to later Arf6/Rab recycling pathway unaddressed"]},{"year":2005,"claim":"Demonstrated an MMP-independent CD147 function in cytoskeletal architecture via integrin cooperation, conserved from fly to mouse.","evidence":"Drosophila loss-of-function with cross-species rescue, co-localization, and integrin-binding mutagenesis","pmids":["15928045"],"confidence":"High","gaps":["Mechanism linking basigin-integrin to cytoskeletal rearrangement undefined","Mammalian cell relevance of the integrin role not tested directly"]},{"year":2009,"claim":"Identified platelet GPVI as a direct EMMPRIN receptor, extending CD147 function into adhesion under flow.","evidence":"Platelet perfusion assays, antibody blocking, GPVI transfection, ELISA, and SPR (Kd 88 nM)","pmids":["19350111"],"confidence":"High","gaps":["Downstream signaling from the GPVI-EMMPRIN interaction not defined","Physiological context established only later"]},{"year":2010,"claim":"Revealed CD147 as a SLAM-independent measles virus entry receptor acting through virion-incorporated cyclophilin B.","evidence":"Viral infection assays with CypB incorporation/inhibition and SLAM-positive versus negative cell comparison","pmids":["20147391"],"confidence":"Medium","gaps":["Single laboratory","Structural basis of CD147-CypB-virion engagement not resolved"]},{"year":2011,"claim":"Placed the EMMPRIN-GPVI axis in vivo, showing monocyte EMMPRIN drives platelet adhesion and vascular recruitment.","evidence":"In vitro flow perfusion, siRNA silencing, intravital microscopy, and carotid injury model","pmids":["21320284"],"confidence":"High","gaps":["Intracellular signaling driving firm adhesion not dissected"]},{"year":2013,"claim":"Established reciprocal post-translational stabilization between CD147 and MCT1 and its functional requirement for glycolytic lactate export in myeloma.","evidence":"Co-IP, reciprocal siRNA, Western blot, and lactate export/proliferation assays","pmids":["24013424"],"confidence":"Medium","gaps":["Single laboratory","Does not address MCT4 dependency in this context"]},{"year":2015,"claim":"Identified CD147 as a VEGFR-2 co-receptor that potentiates angiogenic signaling, mapping the interacting extracellular residues.","evidence":"Co-IP, mutagenesis (residues 195/199), computational docking, and angiogenesis/tumor models","pmids":["25825981"],"confidence":"Medium","gaps":["Single laboratory","Stoichiometry and structural basis of the co-receptor complex unresolved"]},{"year":2016,"claim":"Defined a neuroplastin-β/EMMPRIN heterodimeric receptor that mediates S100A8/A9 inflammatory signaling, with EMMPRIN recruiting TRAF2.","evidence":"Co-localization, dual knockdown, receptor-ligand stimulation, and ERK/GRB2/TRAF2 recruitment assays","pmids":["27388991"],"confidence":"Medium","gaps":["Single laboratory","Later CRISPR data dispute CD147 as the dominant S100 receptor in monocytes"]},{"year":2017,"claim":"Showed cell-type-specific anti-apoptotic CD147 function in spermatocytes through TRAF2-dependent NFκB balance.","evidence":"Immunodepletion, CRISPR knockout, CD147-TRAF2 co-IP, and NFκB pathway analysis","pmids":["27902973"],"confidence":"Medium","gaps":["Single laboratory","Basis for spermatocyte versus spermatogonium specificity unexplained"]},{"year":2018,"claim":"Linked CD147 to liver fibrosis via PI3K/AKT-driven autocrine CXCL1 in hepatic stellate cells.","evidence":"HSC-specific conditional knockout, CCl4 fibrosis model, and PI3K/AKT inhibition","pmids":["29642635"],"confidence":"Medium","gaps":["Single laboratory","Direct CD147 partner upstream of PI3K/AKT not identified"]},{"year":2020,"claim":"Connected CD147 to invasion through GSK-3β/β-catenin-dependent cathepsin B induction and to glycolytic reprogramming via PI3K/Akt/mTOR.","evidence":"3D invasion model, RNA-seq, cathepsin B activity assay, and gain/loss-of-function with pathway inhibition in HCC","pmids":["32727598","31965268"],"confidence":"Medium","gaps":["Single laboratory per study","Direct molecular link between CD147 and GSK-3β/PI3K not established"]},{"year":2021,"claim":"Uncovered methylation-dependent control of transporter trafficking, with KMT5A-mediated K234me2 driving MCT4 membrane translocation and lactate export.","evidence":"LC-MS/MS detection in patient tissue, co-IP, subcellular fractionation, and glycolysis assays","pmids":["33406400"],"confidence":"High","gaps":["Single laboratory","Demethylase and signals regulating K234me2 not identified"]},{"year":2021,"claim":"Defined a CD147-dependent mechanism for Treg stability through CD98-stimulated CDK2 retention that protects Foxp3 from degradation.","evidence":"Co-IP of CD147 intracellular domain with CDK2, Foxp3 phosphorylation/degradation assays, and in vivo CD98 manipulation","pmids":["34759371"],"confidence":"Medium","gaps":["Single laboratory","How CDK2 retention drives Foxp3 dephosphorylation mechanistically unresolved"]},{"year":2021,"claim":"Clarified CD147's role in SARS-CoV-2 infection as ACE2-regulating and CyPA-independent, while infection was attenuated by CD147 blockade.","evidence":"CD147 blocking antibody, siRNA knockdown, ACE2 measurement, and viral infection assays","pmids":["34201214"],"confidence":"Medium","gaps":["Single laboratory","Mechanism by which CD147 regulates ACE2 not defined"]},{"year":2021,"claim":"Refuted direct CD147-spike binding, constraining proposed models of CD147 as a SARS-CoV-2 receptor.","evidence":"Recombinant protein binding assays with SEC and SPR plus antibody blocking, with positive control","pmids":["34378982"],"confidence":"High","gaps":["Does not exclude indirect or co-factor-dependent contributions to infection"]},{"year":2022,"claim":"Established glycosylation as essential for CD147-TRAF2-TAK1 signaling in pathological cardiac hypertrophy.","evidence":"AAV9 cardiac-specific overexpression, glycosylation-site mutants, CD147-TRAF2 co-IP, and TAC model","pmids":["35096272"],"confidence":"Medium","gaps":["Single laboratory","Specific glycan structures controlling TRAF2 binding not defined"]},{"year":2023,"claim":"Defined a CD147-GLUT1 metabolic axis that reprograms keratinocyte glycolysis and epigenetics (α-KG–H3K9me3–BBOX1) in psoriasis.","evidence":"Epidermal-specific knockout, IMQ psoriasis model, CD147-GLUT1 co-IP, metabolomics, and ChIP","pmids":["37303600"],"confidence":"High","gaps":["Single laboratory","Direct effect of CD147 on GLUT1 transport activity versus surface levels not separated"]},{"year":2023,"claim":"Identified CD147 as defining a miRNA-enriched EV subpopulation via interaction with hnRNPA2B1.","evidence":"EV subpopulation isolation, miRNA profiling, CD147-hnRNPA2B1 co-IP, and xenograft models","pmids":["36973758"],"confidence":"Medium","gaps":["Single laboratory","How CD147 directs hnRNPA2B1-dependent miRNA loading unresolved"]},{"year":2023,"claim":"Excluded CD147 as a functional S100 receptor in monocytes, attributing the inflammatory response to TLR4.","evidence":"CRISPR/Cas9 knockout in monocytes with S100A8/A9 stimulation and cytokine readout","pmids":["37056775"],"confidence":"Medium","gaps":["Single laboratory negative result","Does not address CD147-S100 signaling in non-monocyte cell types such as keratinocytes"]},{"year":2024,"claim":"Demonstrated in vivo that myeloid CD147 drives atherosclerosis through TRAF6-IKK-IRF5 M1 polarization and GAS6-dependent efferocytosis suppression.","evidence":"Myeloid-specific knockout and overexpression in ApoE-/- mice, polarization and efferocytosis assays, and antibody treatment in humanized model","pmids":["38166463"],"confidence":"High","gaps":["Direct receptor/ligand triggering myeloid CD147 signaling not identified","Link between CD147 and GAS6 secretion not mechanistically resolved"]},{"year":null,"claim":"How CD147's distinct extracellular interaction surfaces are selected to switch between transporter chaperoning, co-receptor signaling, and adhesion in a given cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating the transporter, GPVI, VEGFR-2, and TRAF-coupled functions","Rules governing which TRAF adaptor is engaged in which tissue are unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[1,7,12]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[1,7,19]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[4,8,9]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[4,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[10,14,15]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,4,19]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[2,11]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,7,12,17,19]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[13,15]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,14,15]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[11]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[4,6]}],"complexes":["CD147-CD98hc transporter supercomplex","CD147-MCT1 complex","CD147-MCT4 complex","neuroplastin-β/EMMPRIN heterodimer"],"partners":["CAV1","SLC3A2","SLC16A1","SLC16A3","GP6","KDR","TRAF2","GLUT1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P35613","full_name":"Basigin","aliases":["5F7","Collagenase stimulatory factor","Extracellular matrix metalloproteinase inducer","EMMPRIN","Hepatoma-associated antigen","HAb18G","Leukocyte activation antigen M6","OK blood group antigen","Tumor cell-derived collagenase stimulatory factor","TCSF"],"length_aa":385,"mass_kda":42.2,"function":"Essential for normal retinal maturation and development (By similarity). Acts as a retinal cell surface receptor for NXNL1 and plays an important role in NXNL1-mediated survival of retinal cone photoreceptors (PubMed:25957687). In association with glucose transporter SLC16A1/GLUT1 and NXNL1, promotes retinal cone survival by enhancing aerobic glycolysis and accelerating the entry of glucose into photoreceptors (PubMed:25957687). May act as a potent stimulator of IL6 secretion in multiple cell lines that include monocytes (PubMed:21620857) (Microbial infection) Erythrocyte receptor for P.falciparum RH5 which is essential for erythrocyte invasion by the merozoite stage of P.falciparum isolates 3D7 and Dd2 Signaling receptor for cyclophilins, essential for PPIA/CYPA and PPIB/CYPB-dependent signaling related to chemotaxis and adhesion of immune cells (PubMed:11688976, PubMed:11943775). Plays an important role in targeting monocarboxylate transporters SLC16A1/GLUT1, SLC16A11 and SLC16A12 to the plasma membrane (PubMed:17127621, PubMed:21778275, PubMed:28666119). Acts as a coreceptor for vascular endothelial growth factor receptor 2 (KDR/VEGFR2) in endothelial cells enhancing its VEGFA-mediated activation and downstream signaling (PubMed:25825981). Promotes angiogenesis through EPAS1/HIF2A-mediated up-regulation of VEGFA (isoform VEGF-165 and VEGF-121) and KDR/VEGFR2 in endothelial cells (PubMed:19837976). Plays a key role in regulating tumor growth, invasion, metastasis and neoangiogenesis by stimulating the production and release of extracellular matrix metalloproteinases and KDR/VEGFR2 by both tumor cells and stromal cells (fibroblasts and endothelial cells) (PubMed:11992541, PubMed:12553375, PubMed:15833850) (Microbial infection) Erythrocyte receptor for P.falciparum RH5 which is essential for erythrocyte invasion by the merozoite stage of P.falciparum isolates 3D7, Dd2, 7G8 and HB3 (PubMed:22080952, PubMed:26195724). Binding of P.falciparum RH5 results in BSG dimerization which triggers an increase in intracellular Ca(2+) in the erythrocyte (PubMed:28409866). This essential step leads to a rearrangement of the erythrocyte cytoskeleton required for the merozoite invasion (PubMed:28409866) (Microbial infection) Can facilitate human SARS coronavirus (SARS-CoV-1) infection via its interaction with virus-associated PPIA/CYPA (Microbial infection) Can facilitate HIV-1 infection via its interaction with virus-associated PPIA/CYPA (Microbial infection) First described as a receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is not required for SARS-CoV-2 infection (Microbial infection) Acts as a receptor for measles virus (Microbial infection) Promotes entry of pentamer-expressing human cytomegalovirus (HCMV) into epithelial and endothelial cells Plays a role in neurite outgrowth","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P35613/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BSG","classification":"Not Classified","n_dependent_lines":95,"n_total_lines":1208,"dependency_fraction":0.07864238410596026},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SLC16A1","stoichiometry":10.0},{"gene":"ATP2B1","stoichiometry":4.0},{"gene":"CALM1","stoichiometry":0.2},{"gene":"CALM2","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2},{"gene":"CANX","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/BSG","total_profiled":1310},"omim":[{"mim_id":"621370","title":"X KELL BLOOD GROUP PRECURSOR-RELATED FAMILY, MEMBER 9; XKR9","url":"https://www.omim.org/entry/621370"},{"mim_id":"621073","title":"SORTING NEXIN 32; SNX32","url":"https://www.omim.org/entry/621073"},{"mim_id":"621068","title":"NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, POOR GROWTH, DYSMORPHIC FACIES, AND AGAMMAGLOBULINEMIA; NEDHGFA","url":"https://www.omim.org/entry/621068"},{"mim_id":"619940","title":"X KELL BLOOD GROUP PRECURSOR-RELATED FAMILY, MEMBER 8; XKR8","url":"https://www.omim.org/entry/619940"},{"mim_id":"615669","title":"EMBIGIN; EMB","url":"https://www.omim.org/entry/615669"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Mid piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"},{"location":"End piece","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"heart muscle","ntpm":1787.2}],"url":"https://www.proteinatlas.org/search/BSG"},"hgnc":{"alias_symbol":["EMMPRIN","CD147","EMPRIN"],"prev_symbol":["OK"]},"alphafold":{"accession":"P35613","domains":[{"cath_id":"2.60.40.10","chopping":"25-117_127-138","consensus_level":"high","plddt":94.1604,"start":25,"end":138},{"cath_id":"2.60.40.10","chopping":"143-218","consensus_level":"high","plddt":92.1997,"start":143,"end":218},{"cath_id":"2.60.40.10","chopping":"224-320","consensus_level":"high","plddt":93.5791,"start":224,"end":320}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P35613","model_url":"https://alphafold.ebi.ac.uk/files/AF-P35613-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P35613-F1-predicted_aligned_error_v6.png","plddt_mean":86.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BSG","jax_strain_url":"https://www.jax.org/strain/search?query=BSG"},"sequence":{"accession":"P35613","fasta_url":"https://rest.uniprot.org/uniprotkb/P35613.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P35613/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P35613"}},"corpus_meta":[{"pmid":"16792544","id":"PMC_16792544","title":"Emmprin 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Cytomegalovirus Encoded miR-US25-1-5p Attenuates CD147/EMMPRIN-Mediated Early Antiviral Response.","date":"2017","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/29194430","citation_count":25,"is_preprint":false},{"pmid":"23966157","id":"PMC_23966157","title":"The role of EMMPRIN expression in ovarian epithelial carcinomas.","date":"2013","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/23966157","citation_count":25,"is_preprint":false},{"pmid":"21144675","id":"PMC_21144675","title":"CD147 (EMMPRIN) and matrix metalloproteinase-2 expression in uterine endometrioid adenocarcinoma.","date":"2010","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/21144675","citation_count":24,"is_preprint":false},{"pmid":"27556697","id":"PMC_27556697","title":"Gemcitabine enhances cell invasion via activating HAb18G/CD147-EGFR-pSTAT3 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caveolin-1 on the cell surface in a cholesterol-dependent manner within intermediate-density sucrose gradient fractions (distinct from the bulk caveolin-1 in low-density fractions). Mutagenesis showed CD147 Ig domain 2 is required for caveolin-1 association. Overexpression of caveolin-1 reduces CD147 cell-surface clustering; a CD147 mutant deficient in caveolin-1 binding shows enhanced spontaneous clustering and elevated MMP-1 induction. Thus caveolin-1 negatively regulates CD147 clustering and CD147-dependent MMP-1 induction.\",\n      \"method\": \"Co-immunoprecipitation, sucrose density gradient fractionation, cholesterol depletion, site-directed mutagenesis of CD147, caveolin-1 overexpression, cluster-specific mAb staining, MMP-1 induction assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (mutagenesis, fractionation, co-IP, functional MMP assay) in a single rigorous study\",\n      \"pmids\": [\"14707126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CD147 selectively associates with three major transporter types at the cell surface: CD98 heavy chain (CD98hc)–L-type amino acid transporter complexes, ASCT2, and monocarboxylate transporters, as well as with epithelial cell adhesion molecule. CD147 and CD98hc play a central organizing role in these multicomponent complexes. siRNA knockdown of CD147 (and CD98hc) reduces cell proliferation and activates AMP-activated protein kinase, indicating disruption of cellular energy metabolism, consistent with a role for the CD147–CD98 supercomplex in coordinating lactate and amino acid transport.\",\n      \"method\": \"Covalent crosslinking, mass spectrometric protein identification, co-immunoprecipitation, RNA interference knockdown, AMPK activity assay\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (crosslinking-MS, co-IP, RNAi + functional metabolic readout) in a single study\",\n      \"pmids\": [\"15901826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CD147 cell-surface expression is regulated intracellularly by cyclophilin 60 (Cyp60). CD147 co-immunoprecipitates with Cyp60 and they co-localize intracellularly by confocal microscopy. The interaction involves proline 211 of CD147; mutation of this residue abolishes co-immunoprecipitation with Cyp60 and reduces plasma membrane expression of CD147. siRNA-mediated suppression of Cyp60 phenocopies cyclosporin A treatment, reducing CD147 surface levels, indicating Cyp60 mediates CD147 translocation to the plasma membrane.\",\n      \"method\": \"Co-immunoprecipitation, confocal immunofluorescence, site-directed mutagenesis (P211 mutation), siRNA knockdown, cyclosporin A treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reciprocal co-IP, mutagenesis, and RNAi phenocopy, multiple orthogonal methods in one study\",\n      \"pmids\": [\"15946952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Drosophila basigin (ortholog of BSG) interacts with integrin to regulate cell architecture independently of matrix metalloprotease activity. Basigin and integrin co-localize in cultured insect cells and in the visual system. Basigin-mediated cytoskeletal rearrangements (lamellipodia formation) in cultured cells require integrin-binding activity. Loss of basigin from photoreceptors causes misplaced nuclei, rough ER, mitochondria and swollen axon terminals; these defects are rescued by either fly or mouse basigin, and genetic interaction experiments confirm basigin–integrin cooperation in cell structure.\",\n      \"method\": \"Drosophila genetics (loss-of-function, rescue with fly and mouse basigin), co-localization in cultured insect cells, mutagenesis of integrin-binding activity, in vivo phenotypic analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis/rescue, co-localization, mutagenesis, multiple orthogonal methods; ortholog study with cross-species rescue validates conservation\",\n      \"pmids\": [\"15928045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Platelet glycoprotein VI (GPVI) is identified as a novel receptor for EMMPRIN/CD147. EMMPRIN-Fc immobilized on surfaces supports ADP-stimulated platelet rolling that is blocked by anti-EMMPRIN or anti-GPVI antibodies but not by anti-P-selectin, anti-α4-integrin, or anti-GPIIb/IIIa antibodies. CHO cells stably transfected with GPVI show enhanced rolling on immobilized EMMPRIN-Fc. Direct binding is confirmed by modified ELISA and surface plasmon resonance with a dissociation constant of 88 nM.\",\n      \"method\": \"Platelet perfusion assay under flow conditions, antibody blocking, CHO cell stable transfection, ELISA binding assay, surface plasmon resonance\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct binding quantified by SPR, functional blocking, and transfection assay; multiple orthogonal methods in one study\",\n      \"pmids\": [\"19350111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CD147/EMMPRIN functions as a functional entry receptor for measles virus (MeV) on epithelial cells independently of the known SLAM receptor. Cyclophilin B (CypB), a cellular ligand for CD147, is incorporated into MeV virions; inhibition of CypB incorporation significantly attenuates SLAM-independent infection on epithelial cells but has no effect on SLAM-dependent infection. This reveals a CD147-CypB-dependent viral entry pathway that does not require binding of the MeV hemagglutinin protein to CD147.\",\n      \"method\": \"Viral infection assays, CypB incorporation into virions (biochemical), inhibition of CypB incorporation, SLAM-positive vs. SLAM-negative cell comparison, CD147 functional characterization\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional viral entry assay with mechanistic dissection (CypB inhibition), single laboratory\",\n      \"pmids\": [\"20147391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Monocyte EMMPRIN/CD147 mediates firm adhesion to surface-adherent platelets and monocyte recruitment to the injured arterial wall. Antibody blockade and siRNA silencing of monocyte EMMPRIN substantially reduces monocyte firm adhesion to platelets at arterial and venous shear rates in vitro. In vivo, EMMPRIN-silenced monocytes show reduced platelet-monocyte aggregate formation in circulation and reduced recruitment to the injured carotid artery. Platelet GPVI is identified as the critical corresponding counter-receptor on platelets; blocking GPVI abolishes EMMPRIN-mediated monocyte–platelet interactions.\",\n      \"method\": \"In vitro perfusion assay under flow conditions, siRNA gene silencing, intravital microscopy, flow cytometry, in vivo carotid injury model\",\n      \"journal\": \"Journal of thrombosis and haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional blocking (anti-EMMPRIN and anti-GPVI), siRNA, in vitro and in vivo concordance, multiple orthogonal methods\",\n      \"pmids\": [\"21320284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In multiple myeloma cells, CD147 protein associates with MCT1 protein (confirmed by co-immunoprecipitation); siRNA-mediated downregulation of MCT1 decreases CD147 protein (and vice versa) at the protein level without affecting mRNA, indicating reciprocal post-translational stabilization. Knockdown of MCT1 (but not MCT4) decreases myeloma cell proliferation and lactate export, demonstrating functional dependency on the CD147–MCT1 complex for glycolytic metabolism.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, Western blotting, RT-PCR, lactate export assay, proliferation assay\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and reciprocal siRNA with functional readouts; single laboratory\",\n      \"pmids\": [\"24013424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"EMMPRIN/CD147 acts as a novel co-receptor for VEGFR-2, directly interacting with it and regulating VEGF-induced VEGFR-2 activation, downstream signaling, and angiogenic outcomes in vitro and in vivo. Computational docking and mutagenesis studies identified a binding site in the extracellular domain of EMMPRIN near the membrane, containing residues 195/199, required for the interaction with VEGFR-2.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis, computational docking, in vitro angiogenesis assay, in vivo tumor model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction demonstrated with mutagenesis and co-IP, supported by in vivo data; single laboratory\",\n      \"pmids\": [\"25825981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Neuroplastin-β is identified as a receptor for S100A8 and forms homodimers and a heterodimer with EMMPRIN on the surface of normal human keratinocytes. Upon S100A8 stimulation, neuroplastin-β recruits GRB2 and activates ERK leading to keratinocyte proliferation, while EMMPRIN recruits TRAF2. Knockdown of both receptors suppresses cell proliferation and proinflammatory cytokine induction, indicating the neuroplastin-β/EMMPRIN heterodimeric receptor complex mediates S100A8/A9 signaling in skin inflammation.\",\n      \"method\": \"Co-localization, knockdown experiments, receptor-ligand stimulation assays, ERK phosphorylation measurement, GRB2/TRAF2 recruitment assays, transgenic mouse model\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-localization, knockdown with functional readout, signaling pathway dissection; single laboratory\",\n      \"pmids\": [\"27388991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD147 prevents extrinsic apoptosis specifically in mouse spermatocytes (but not spermatogonia) by interacting with TRAF2. Immunodepletion of CD147 triggers apoptosis via the extrinsic pathway with activation of non-canonical NFκB and suppression of canonical NFκB signaling, accompanied by decreased TRAF2. CRISPR/Cas9 deletion of CD147 in the spermatocyte cell line GC-2 reproduces this phenotype. The same manipulation had no effect on NFκB signaling or TRAF2 in spermatogonia (GC-1 cells).\",\n      \"method\": \"CD147 immunodepletion, CRISPR/Cas9 knockout, co-immunoprecipitation (CD147–TRAF2), Western blotting, apoptosis assays, NFκB signaling pathway analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO and co-IP with mechanistic pathway dissection; single laboratory\",\n      \"pmids\": [\"27902973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD147 endocytic recycling in liver cancer cells is controlled by ADP-ribosylation factor 6 (Arf6) through concurrent activation of Rab5 and Rab22a GTPases. YIPF2, an ER-Golgi-resident transmembrane protein, acts as a Rab-GDF regulating three trafficking steps: Rab5 and Rab22a recruitment to endomembranes, CD147 endocytic recycling, and mature processing via the ER-Golgi route. Disruption of Arf6-mediated CD147 trafficking reduces cell-matrix/cell-cell adhesion, MMPs secretion, and migration/invasion of HCC cells.\",\n      \"method\": \"GST-RBD pull-down (Rab GTPase activation), confocal imaging, flow cytometry, biotin-labeled chase assays (endocytosis/recycling), MAPPIT screening, MSP-cDNA library screen, gelatin zymography, cell adhesion/invasion assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (biochemical Rab activation, trafficking assays, functional invasion assays); single laboratory\",\n      \"pmids\": [\"31752956\", \"31189879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD147 is di-methylated at lysine 234 (K234me2) by lysine methyltransferase KMT5A. This di-methylation promotes interaction between CD147 and monocarboxylate transporter 4 (MCT4), enhancing translocation of MCT4 from the cytoplasm to the plasma membrane. Overexpression of CD147-K234me2 and KMT5A enhances glycolysis and lactate export in NSCLC cells; the modification was detected by LC-MS/MS in patient tissues.\",\n      \"method\": \"Liquid chromatography-tandem mass spectrometry (detection of K234me2 in patient tissues), co-immunoprecipitation, subcellular fractionation, glycolysis/lactate export assays, overexpression studies\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — PTM identified by LC-MS/MS, mechanism validated by co-IP and functional metabolic assays with multiple orthogonal methods; single laboratory\",\n      \"pmids\": [\"33406400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD147 is required for Foxp3+ regulatory T cell (Treg) stability through cell-to-cell contact. CD147 on Tregs is stimulated by CD98 (widely expressed in the physiological environment), causing CD147's intracellular domain to bind CDK2 and retain it near the membrane, leading to Foxp3 dephosphorylation and prevention of Foxp3 degradation. Disruption of CD147–CD98 interaction destabilizes Foxp3 expression.\",\n      \"method\": \"Co-immunoprecipitation (CD147 intracellular domain–CDK2), cell contact assays, Foxp3 phosphorylation/degradation assays, in vivo Treg distribution analysis with CD98 conditional manipulation\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with mechanistic pathway elucidation; single laboratory\",\n      \"pmids\": [\"34759371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Glycosylated CD147 promotes pathological cardiac hypertrophy via direct binding to TRAF2 and subsequent activation of TAK1 signalling. Cardiac-specific overexpression of wild-type CD147 in AAV9 mice promotes pressure overload-induced pathological remodeling, oxidative stress, and ferroptosis, whereas glycosylation-site mutants of CD147 markedly weaken these effects. This identifies glycosylation as essential for the CD147–TRAF2–TAK1 signalling axis in pathological cardiac remodeling.\",\n      \"method\": \"AAV9-mediated cardiac-specific CD147 overexpression, glycosylation-site mutagenesis, co-immunoprecipitation (CD147–TRAF2), transverse aortic constriction mouse model, Western blotting, oxidative stress and ferroptosis assays\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with mutagenesis and in vivo functional model; single laboratory\",\n      \"pmids\": [\"35096272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Myeloid-specific CD147 promotes atherosclerotic plaque growth by driving M1 macrophage polarization via the TRAF6–IKK–IRF5 signaling pathway and by suppressing efferocytosis through inhibition of GAS6 secretion in pro-inflammatory macrophages. Myeloid-specific CD147 knockout in ApoE-/- mice ameliorates atherosclerosis, reduces iNOS-mediated late apoptosis, and enhances efferocytosis. Conversely, myeloid CD147 overexpression worsens these phenotypes.\",\n      \"method\": \"Myeloid-specific knockout and restricted overexpression mouse models (ApoE-/- background), macrophage polarization assays (LPS/IFN-γ stimulation), NO/RNS production measurement, GAS6 secretion assay, efferocytosis assays, in vivo atherosclerosis quantification, anti-CD147 antibody treatment in humanized transgenic model\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO and OE in vivo models with concordant in vitro mechanistic dissection of TRAF6–IKK–IRF5 pathway; multiple orthogonal approaches\",\n      \"pmids\": [\"38166463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD147 promotes collective invasion in hepatocellular carcinoma by upregulating cathepsin B expression and activity. Mechanistically, CD147 activates β-catenin signaling by reducing GSK-3β expression, which drives cathepsin B transcription. CD147 upregulation was observed at the invasive front of tumor cell groups, and cathepsin B mediated the CD147-induced invasive phenotype in a 3D invasion model.\",\n      \"method\": \"3D invasion model, RNA-sequencing, cathepsin B enzyme activity assay, Western blotting, immunostaining of human HCC specimens, siRNA knockdown\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptome analysis + enzyme assay + functional 3D model + pathway analysis; single laboratory\",\n      \"pmids\": [\"32727598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD147 promotes glycolytic metabolism in hepatocellular carcinoma via the PI3K/Akt/mTOR signaling pathway, with upregulated GLUT1 and MCT1 expression in CD147-overexpressing HCC cells and xenografts.\",\n      \"method\": \"CD147 gain/loss-of-function in HCC cell lines, nude mouse xenograft model, glycolysis measurement, PI3K/Akt/mTOR pathway inhibition, immunohistochemistry\",\n      \"journal\": \"Cancer immunology, immunotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss/gain of function with pathway inhibitor confirmation in vitro and in vivo; single laboratory\",\n      \"pmids\": [\"31965268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD147 regulates CXCL1 secretion from hepatic stellate cells (HSCs) via the PI3K/AKT signaling pathway, promoting HSC activation and liver fibrosis. Conditional knockout of CD147 in HSCs in mice alleviates CCl4-induced liver fibrosis and reduces HSC activation. Overexpression of CD147 upregulates CXCL1, which acts in an autocrine manner to further activate HSCs.\",\n      \"method\": \"HSC-specific CD147 conditional knockout mice, CCl4 liver fibrosis model, CXCL1 secretion measurement, PI3K/AKT inhibitor treatment, overexpression studies\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO in vivo with pathway inhibitor mechanistic follow-up; single laboratory\",\n      \"pmids\": [\"29642635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD147 interacts with GLUT1 and is required for glucose uptake and glycolytic reprogramming in keratinocytes in psoriasis pathogenesis. Epidermal CD147 knockout in mice blocks glucose uptake and glycolysis, increases oxidative phosphorylation, and elevates carnitine and α-KG production. The elevated α-KG inhibits H3K9me3, increasing BBOX1 transcription, defining a CD147–α-KG–H3K9me3–BBOX1 metabolic axis.\",\n      \"method\": \"Epidermal-specific CD147 knockout mice, IMQ-induced psoriasis model, co-immunoprecipitation (CD147–GLUT1), non-targeted and targeted metabolomics, chromatin immunoprecipitation (H3K9me3), glucose uptake and glycolysis assays\",\n      \"journal\": \"Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — conditional KO in vivo, co-IP, metabolomics, and ChIP providing multiple orthogonal mechanistic insights; single laboratory\",\n      \"pmids\": [\"37303600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD147 and CD98 define a subpopulation of extracellular vesicles (CD147+ EVs) with substantially higher microRNA content than classical tetraspanin+ EVs. CD147 interacts with heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1) to selectively enrich miRNAs into these vesicles. CD147+ EVs predominantly derive from cancer cells in mouse xenograft models.\",\n      \"method\": \"EV subpopulation isolation, miRNA content comparison, co-immunoprecipitation (CD147–hnRNPA2B1), mouse xenograft models, clinical sample analysis\",\n      \"journal\": \"Journal of extracellular vesicles\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP binding partner identification with functional miRNA enrichment assay; single laboratory\",\n      \"pmids\": [\"36973758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SARS-CoV-2 infection and CD147 regulate ACE2 levels, and both CD147 blocking antibody and CD147 knockdown attenuate SARS-CoV-2 infection of host cells. However, CD147 binding to CyPA does not play a role in SARS-CoV-2 entry via CD147. CD147 regulates ACE2 levels and both receptors are affected by virus infection.\",\n      \"method\": \"CD147 blocking antibody treatment, siRNA knockdown, ACE2 level measurement, viral infection assay\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional blocking and knockdown data; single laboratory, mechanism partially unresolved\",\n      \"pmids\": [\"34201214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NEGATIVE FINDING: Human basigin (CD147) does not directly interact with the SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD) or full-length spike. Using recombinant proteins, size exclusion chromatography, and surface plasmon resonance, no binding was detected between RBD/spike and recombinant human basigin expressed in E. coli or mammalian cells. Polyclonal anti-basigin IgG did not block SARS-CoV-2 infection of Vero E6 cells.\",\n      \"method\": \"Size exclusion chromatography, surface plasmon resonance, polyclonal antibody blocking of viral infection, recombinant protein binding assay\",\n      \"journal\": \"mSphere\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — rigorous in vitro binding assay with SPR and SEC using purified recombinant proteins with positive control (RH5-basigin); directly refutes a prior claim\",\n      \"pmids\": [\"34378982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NEGATIVE FINDING: CRISPR/Cas9-mediated knockout of CD147 in ER-Hoxb8 monocytes had no effect on S100A8- or S100A9-induced cytokine release, in contrast to TLR4 knockout which abolished the S100-induced inflammatory response. TLR4, not CD147, is the dominant receptor for S100-triggered inflammatory activation of monocytes.\",\n      \"method\": \"CRISPR/Cas9 gene deletion in monocytes, S100A8/S100A9 stimulation, cytokine release measurement\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean CRISPR KO with functional assay; single laboratory negative result\",\n      \"pmids\": [\"37056775\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BSG/CD147/EMMPRIN is a multifunctional transmembrane glycoprotein that acts as a cell-surface scaffold: it stimulates MMP production in neighboring cells via homophilic interactions; serves as the plasma membrane chaperone for monocarboxylate transporters (MCT1/4) and organizes a metabolic supercomplex with CD98hc to coordinate lactate and amino acid transport; binds cyclophilins (CypA, CypB) as a signaling receptor to mediate chemotaxis and inflammatory responses; interacts with caveolin-1 (negatively regulating CD147 clustering and MMP induction), integrins, and GPVI on platelets; co-receptors VEGFR-2 to potentiate angiogenic signaling; undergoes post-translational regulation by glycosylation (which governs TRAF2–TAK1 signaling in cardiac remodeling) and KMT5A-mediated di-methylation at K234 (enhancing MCT4 membrane translocation and lactate export); its surface trafficking is controlled intracellularly by cyclophilin 60 (Cyp60) and Arf6/Rab GTPase-dependent endocytic recycling; in the immune system it stabilizes Foxp3 in regulatory T cells via CD98-stimulated CDK2 retention and prevents spermatocyte apoptosis through TRAF2-dependent NFκB modulation; and in macrophages myeloid CD147 drives M1 polarization via TRAF6–IKK–IRF5 and suppresses efferocytosis by inhibiting GAS6 secretion, collectively establishing CD147 as a central hub integrating extracellular matrix remodeling, cellular metabolism, immune regulation, and intracellular trafficking.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BSG (CD147/EMMPRIN) is a multifunctional transmembrane glycoprotein that operates as a cell-surface scaffold coupling metabolite transport, matrix remodeling, and inflammatory signaling [#1, #11]. It serves as the plasma-membrane organizer of metabolite transporters: it associates with CD98hc–amino acid transporter complexes, ASCT2, and monocarboxylate transporters, where loss of CD147 disrupts cellular energy metabolism and activates AMPK [#1], and it reciprocally stabilizes MCT1 at the protein level to sustain lactate export and glycolysis [#7]. This transporter-organizing role is tuned post-translationally: KMT5A-mediated di-methylation of CD147 at K234 promotes MCT4 binding and its translocation to the membrane to enhance lactate export [#12], while CD147 binding to GLUT1 supports glucose uptake and glycolytic reprogramming [#19]. CD147 drives matrix-degrading and invasive programs through MMP induction, which is negatively regulated by caveolin-1 binding via CD147 Ig domain 2 that limits CD147 surface clustering [#0], and through β-catenin/GSK-3β-dependent induction of cathepsin B [#16]. As a receptor and co-receptor it engages platelet GPVI to mediate cell adhesion under flow [#4, #6], partners with VEGFR-2 to potentiate angiogenic signaling [#8], and forms a heterodimer with neuroplastin-β in keratinocyte inflammatory signaling [#9]. CD147 transduces signals chiefly through TRAF adaptors: glycosylation-dependent TRAF2–TAK1 signaling promotes pathological cardiac remodeling [#14], TRAF2 engagement prevents spermatocyte apoptosis via NFκB modulation [#10], and myeloid CD147 drives M1 macrophage polarization through TRAF6–IKK–IRF5 while suppressing efferocytosis [#15]. Its surface availability is set intracellularly by cyclophilin 60-dependent trafficking [#2] and Arf6/Rab5/Rab22a-dependent endocytic recycling [#11]. CD147 also stabilizes Foxp3 in regulatory T cells through CD98-stimulated CDK2 retention [#13]. Reported roles in viral entry are mixed: CD147 supports a CypB-dependent measles-virus entry pathway [#5] and influences SARS-CoV-2 infection via ACE2 regulation [#21], but direct binding of human basigin to the SARS-CoV-2 spike RBD was not detected [#22], and CD147 is dispensable for S100-triggered monocyte cytokine release [#23].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that CD147-driven MMP induction is constrained by its surface organization, identifying caveolin-1 as a negative regulator of CD147 clustering.\",\n      \"evidence\": \"Co-IP, sucrose gradient fractionation, cholesterol depletion, CD147 mutagenesis, and MMP-1 induction assay\",\n      \"pmids\": [\"14707126\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the downstream signaling triggered by CD147 clustering\", \"Mechanism of cluster-dependent MMP induction in target cells not resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined CD147 as the organizing hub of a cell-surface metabolite-transport supercomplex, linking it directly to cellular energy metabolism.\",\n      \"evidence\": \"Crosslinking-MS, co-IP, and siRNA knockdown with AMPK and proliferation readouts\",\n      \"pmids\": [\"15901826\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not establish whether CD147 is required for transporter folding versus surface retention\", \"Individual transporter dependencies not separated\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed that CD147 surface delivery is controlled intracellularly, identifying cyclophilin 60 and Pro211 as required for membrane translocation.\",\n      \"evidence\": \"Reciprocal co-IP, P211 mutagenesis, confocal co-localization, siRNA, and cyclosporin A treatment\",\n      \"pmids\": [\"15946952\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trafficking compartments involved not fully mapped\", \"Relationship to later Arf6/Rab recycling pathway unaddressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated an MMP-independent CD147 function in cytoskeletal architecture via integrin cooperation, conserved from fly to mouse.\",\n      \"evidence\": \"Drosophila loss-of-function with cross-species rescue, co-localization, and integrin-binding mutagenesis\",\n      \"pmids\": [\"15928045\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking basigin-integrin to cytoskeletal rearrangement undefined\", \"Mammalian cell relevance of the integrin role not tested directly\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified platelet GPVI as a direct EMMPRIN receptor, extending CD147 function into adhesion under flow.\",\n      \"evidence\": \"Platelet perfusion assays, antibody blocking, GPVI transfection, ELISA, and SPR (Kd 88 nM)\",\n      \"pmids\": [\"19350111\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling from the GPVI-EMMPRIN interaction not defined\", \"Physiological context established only later\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed CD147 as a SLAM-independent measles virus entry receptor acting through virion-incorporated cyclophilin B.\",\n      \"evidence\": \"Viral infection assays with CypB incorporation/inhibition and SLAM-positive versus negative cell comparison\",\n      \"pmids\": [\"20147391\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single laboratory\", \"Structural basis of CD147-CypB-virion engagement not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed the EMMPRIN-GPVI axis in vivo, showing monocyte EMMPRIN drives platelet adhesion and vascular recruitment.\",\n      \"evidence\": \"In vitro flow perfusion, siRNA silencing, intravital microscopy, and carotid injury model\",\n      \"pmids\": [\"21320284\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular signaling driving firm adhesion not dissected\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established reciprocal post-translational stabilization between CD147 and MCT1 and its functional requirement for glycolytic lactate export in myeloma.\",\n      \"evidence\": \"Co-IP, reciprocal siRNA, Western blot, and lactate export/proliferation assays\",\n      \"pmids\": [\"24013424\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single laboratory\", \"Does not address MCT4 dependency in this context\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified CD147 as a VEGFR-2 co-receptor that potentiates angiogenic signaling, mapping the interacting extracellular residues.\",\n      \"evidence\": \"Co-IP, mutagenesis (residues 195/199), computational docking, and angiogenesis/tumor models\",\n      \"pmids\": [\"25825981\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single laboratory\", \"Stoichiometry and structural basis of the co-receptor complex unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a neuroplastin-β/EMMPRIN heterodimeric receptor that mediates S100A8/A9 inflammatory signaling, with EMMPRIN recruiting TRAF2.\",\n      \"evidence\": \"Co-localization, dual knockdown, receptor-ligand stimulation, and ERK/GRB2/TRAF2 recruitment assays\",\n      \"pmids\": [\"27388991\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single laboratory\", \"Later CRISPR data dispute CD147 as the dominant S100 receptor in monocytes\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed cell-type-specific anti-apoptotic CD147 function in spermatocytes through TRAF2-dependent NFκB balance.\",\n      \"evidence\": \"Immunodepletion, CRISPR knockout, CD147-TRAF2 co-IP, and NFκB pathway analysis\",\n      \"pmids\": [\"27902973\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single laboratory\", \"Basis for spermatocyte versus spermatogonium specificity unexplained\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked CD147 to liver fibrosis via PI3K/AKT-driven autocrine CXCL1 in hepatic stellate cells.\",\n      \"evidence\": \"HSC-specific conditional knockout, CCl4 fibrosis model, and PI3K/AKT inhibition\",\n      \"pmids\": [\"29642635\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single laboratory\", \"Direct CD147 partner upstream of PI3K/AKT not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected CD147 to invasion through GSK-3β/β-catenin-dependent cathepsin B induction and to glycolytic reprogramming via PI3K/Akt/mTOR.\",\n      \"evidence\": \"3D invasion model, RNA-seq, cathepsin B activity assay, and gain/loss-of-function with pathway inhibition in HCC\",\n      \"pmids\": [\"32727598\", \"31965268\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single laboratory per study\", \"Direct molecular link between CD147 and GSK-3β/PI3K not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Uncovered methylation-dependent control of transporter trafficking, with KMT5A-mediated K234me2 driving MCT4 membrane translocation and lactate export.\",\n      \"evidence\": \"LC-MS/MS detection in patient tissue, co-IP, subcellular fractionation, and glycolysis assays\",\n      \"pmids\": [\"33406400\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single laboratory\", \"Demethylase and signals regulating K234me2 not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a CD147-dependent mechanism for Treg stability through CD98-stimulated CDK2 retention that protects Foxp3 from degradation.\",\n      \"evidence\": \"Co-IP of CD147 intracellular domain with CDK2, Foxp3 phosphorylation/degradation assays, and in vivo CD98 manipulation\",\n      \"pmids\": [\"34759371\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single laboratory\", \"How CDK2 retention drives Foxp3 dephosphorylation mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Clarified CD147's role in SARS-CoV-2 infection as ACE2-regulating and CyPA-independent, while infection was attenuated by CD147 blockade.\",\n      \"evidence\": \"CD147 blocking antibody, siRNA knockdown, ACE2 measurement, and viral infection assays\",\n      \"pmids\": [\"34201214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single laboratory\", \"Mechanism by which CD147 regulates ACE2 not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Refuted direct CD147-spike binding, constraining proposed models of CD147 as a SARS-CoV-2 receptor.\",\n      \"evidence\": \"Recombinant protein binding assays with SEC and SPR plus antibody blocking, with positive control\",\n      \"pmids\": [\"34378982\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not exclude indirect or co-factor-dependent contributions to infection\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established glycosylation as essential for CD147-TRAF2-TAK1 signaling in pathological cardiac hypertrophy.\",\n      \"evidence\": \"AAV9 cardiac-specific overexpression, glycosylation-site mutants, CD147-TRAF2 co-IP, and TAC model\",\n      \"pmids\": [\"35096272\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single laboratory\", \"Specific glycan structures controlling TRAF2 binding not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a CD147-GLUT1 metabolic axis that reprograms keratinocyte glycolysis and epigenetics (α-KG–H3K9me3–BBOX1) in psoriasis.\",\n      \"evidence\": \"Epidermal-specific knockout, IMQ psoriasis model, CD147-GLUT1 co-IP, metabolomics, and ChIP\",\n      \"pmids\": [\"37303600\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single laboratory\", \"Direct effect of CD147 on GLUT1 transport activity versus surface levels not separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified CD147 as defining a miRNA-enriched EV subpopulation via interaction with hnRNPA2B1.\",\n      \"evidence\": \"EV subpopulation isolation, miRNA profiling, CD147-hnRNPA2B1 co-IP, and xenograft models\",\n      \"pmids\": [\"36973758\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single laboratory\", \"How CD147 directs hnRNPA2B1-dependent miRNA loading unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Excluded CD147 as a functional S100 receptor in monocytes, attributing the inflammatory response to TLR4.\",\n      \"evidence\": \"CRISPR/Cas9 knockout in monocytes with S100A8/A9 stimulation and cytokine readout\",\n      \"pmids\": [\"37056775\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single laboratory negative result\", \"Does not address CD147-S100 signaling in non-monocyte cell types such as keratinocytes\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated in vivo that myeloid CD147 drives atherosclerosis through TRAF6-IKK-IRF5 M1 polarization and GAS6-dependent efferocytosis suppression.\",\n      \"evidence\": \"Myeloid-specific knockout and overexpression in ApoE-/- mice, polarization and efferocytosis assays, and antibody treatment in humanized model\",\n      \"pmids\": [\"38166463\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct receptor/ligand triggering myeloid CD147 signaling not identified\", \"Link between CD147 and GAS6 secretion not mechanistically resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CD147's distinct extracellular interaction surfaces are selected to switch between transporter chaperoning, co-receptor signaling, and adhesion in a given cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model integrating the transporter, GPVI, VEGFR-2, and TRAF-coupled functions\", \"Rules governing which TRAF adaptor is engaged in which tissue are unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [1, 7, 12]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [1, 7, 19]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [4, 8, 9]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [10, 14, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 4, 19]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [2, 11]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 7, 12, 17, 19]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [13, 15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 14, 15]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"complexes\": [\n      \"CD147-CD98hc transporter supercomplex\",\n      \"CD147-MCT1 complex\",\n      \"CD147-MCT4 complex\",\n      \"neuroplastin-β/EMMPRIN heterodimer\"\n    ],\n    \"partners\": [\n      \"CAV1\",\n      \"SLC3A2\",\n      \"SLC16A1\",\n      \"SLC16A3\",\n      \"GP6\",\n      \"KDR\",\n      \"TRAF2\",\n      \"GLUT1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}