{"gene":"CD151","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1995,"finding":"CD151 (PETA-3) was cloned and identified as a 253 amino acid protein with four transmembrane domains, a large extracellular loop with a single N-linked glycosylation site, and structural homology to the tetraspanin/TM4SF family. Northern blot confirmed broad tissue expression.","method":"cDNA cloning, Northern blot, sequence analysis","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — molecular cloning with structural characterization but single lab, foundational identification paper","pmids":["7632941"],"is_preprint":false},{"year":1998,"finding":"CD151/PETA-3 localizes to endothelial cell-cell lateral junctions and forms molecular complexes with α3β1 integrin and other tetraspanins (CD9, CD81). Anti-CD151 antibodies inhibited endothelial cell migration in wound healing and invasion into collagen gels, and increased adhesion to ECM proteins.","method":"Immunofluorescence microscopy, biochemical co-immunoprecipitation, time-lapse video microscopy, collagen gel invasion assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus functional inhibition with antibodies, multiple orthogonal methods, replicated across cell systems","pmids":["9566977"],"is_preprint":false},{"year":1999,"finding":"CD151 associates with multiple integrin chains (β1, β3, β4, α2, α3, α5, α6) including α6β4 integrin, and is present both on the plasma membrane at cell-cell contacts and in intracellular endosomal/lysosomal compartments (co-localizing with transferrin receptor and CD63). Anti-PETA-3 antibodies inhibited endothelial cell migration and modulated in vitro angiogenesis but had no effect on neutrophil transendothelial migration.","method":"Co-immunoprecipitation, immunofluorescence confocal microscopy, immuno-electron microscopy, functional antibody inhibition assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with multiple integrin chains, immuno-EM for localization, orthogonal functional assays, single lab with multiple methods","pmids":["10036233"],"is_preprint":false},{"year":1999,"finding":"Among tetraspanins, CD151 forms digitonin-resistant (direct) complexes specifically with integrins α3β1 and α6β1, whereas other tetraspanins associate with integrins only indirectly through CD151. An anti-CD151 antibody (TS151r) epitope maps to the integrin-binding region and its binding is blocked by α3β1 or α6β1 overexpression.","method":"Reciprocal co-immunoprecipitation in multiple detergent conditions (digitonin, Brij 97, CHAPS), antibody epitope-blocking experiments, cell surface binding quantification","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — rigorous biochemical dissection using multiple detergent conditions and reciprocal immunoprecipitation across multiple cell lines","pmids":["10229664"],"is_preprint":false},{"year":1999,"finding":"CD151 (PETA-3) overexpression in HeLa cells enhanced cell migration, and anti-CD151 antibodies inhibited HEp-3 cell chemotaxis and in vivo metastasis without affecting cell adhesion or tumor growth, identifying CD151 as a positive effector of tumor cell migration and metastasis.","method":"Eukaryotic expression cloning, transfection/overexpression, chemotaxis assay, in vivo metastasis model, antibody inhibition","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function transfection plus loss-of-function antibody inhibition, in vitro and in vivo validation, multiple antibodies","pmids":["10447000"],"is_preprint":false},{"year":1999,"finding":"CD151 associates with integrins α4β1, α5β1, α6β1, and αIIbβ3 in haematopoietic cell lines. Anti-CD151 F(ab')2 fragments induced homotypic cell adhesion dependent on energy and cytoskeletal integrity but not mediated through integrin-ligand binding. CD151 ligation did not alter integrin avidity for fibronectin, laminin, collagen, or fibrinogen.","method":"Co-immunoprecipitation, homotypic adhesion assay with F(ab')2 fragments, function-blocking antibodies, integrin ligand adhesion assays","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and functional assays in multiple cell lines, single lab","pmids":["9931299"],"is_preprint":false},{"year":2000,"finding":"CD151 directly contacts α3β1 integrin extracellularly. Using membrane-impermeable cross-linking and chimeric proteins, the association was mapped to an extracellular α3 site (aa 570-705) and a region within the large extracellular loop of CD151 (aa 186-217). Both N- and C-terminal domains of CD151 are intracellular, confirming the four-pass topology.","method":"Membrane-impermeable chemical cross-linking, chimeric integrin/tetraspanin constructs, epitope mapping, topology determination","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct extracellular cross-linking plus domain mapping with chimeras, multiple orthogonal approaches, confirms protein topology","pmids":["10734060"],"is_preprint":false},{"year":2001,"finding":"The large extracellular loop (LEL) of CD151 (aa 149-213) is required for stable (Triton X-100-resistant) association with α3β1 integrin, and 11 aa substitution (195-205) or mutations in conserved CCG and PXXCC motifs abolish this interaction. The CCG motif mutation selectively prevents homotypic CD151-CD151 interaction without affecting association with other tetraspanins. CD151-α3β1 complex assembly occurs early in biosynthesis, before CD151-tetraspanin associations.","method":"Site-directed mutagenesis, CD151/CD9 chimeras, co-immunoprecipitation in Triton X-100 and Brij 96, biosynthetic pulse-chase","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis with multiple mutants, multiple detergent conditions, biosynthesis timing, multiple orthogonal approaches","pmids":["11479292"],"is_preprint":false},{"year":2002,"finding":"CD151 is palmitoylated at intracellular N-terminal and C-terminal cysteine residues (C11, C15, C242, C243). Simultaneous mutation of these cysteines (tetra mutant) eliminates >90% of palmitoylation, markedly diminishes associations with other tetraspanins (CD9, CD63), increases diffuse distribution, reduces stability during biosynthesis, but does not disrupt CD151-α3β1 integrin association or localization into detergent-resistant microdomains.","method":"Site-directed mutagenesis of palmitoylation sites, [3H]-palmitate labeling, co-immunoprecipitation, immunofluorescence, biosynthesis/stability assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted palmitoylation with defined mutations, multiple orthogonal biochemical and cell biological methods, single lab","pmids":["11907260"],"is_preprint":false},{"year":2002,"finding":"CD151 associates with α7β1 integrin comparably to α3β1. Most tissues expressing laminin-binding integrins show CD151-integrin complexes, but the association is subject to cell-type-specific regulation as shown by differential TS151r epitope accessibility in vivo.","method":"Co-immunoprecipitation, immunohistochemistry with epitope-blocking antibodies, K562 cell surface expression studies","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus in vivo tissue validation, single lab, multiple integrin partners tested","pmids":["11884516"],"is_preprint":false},{"year":2002,"finding":"An extracellular QRD(194-196) site in CD151 is required for strong (Triton X-100-resistant) association with both α3β1 and α6β1 integrins, and this association occurs early in biosynthesis with α subunit precursors. QRD→INF mutation disrupts CD151-integrin association and impairs α3/α6 integrin-dependent cellular cable formation on Matrigel and cell spreading.","method":"Site-directed mutagenesis (QRD→INF), co-immunoprecipitation in Triton X-100 and Brij 96, biosynthetic pulse-chase, cell morphology assays on Matrigel","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — precise mutagenesis with functional validation, multiple integrin partners, multiple detergent conditions, in vitro morphogenesis assay","pmids":["12356873"],"is_preprint":false},{"year":2002,"finding":"CD151-α6β1 complex acts as a functional unit for cellular morphogenesis on Matrigel. Deletion or exchange of the short 8 amino acid C-terminal tail of CD151 causes a dominant negative effect that suppresses α6β1-dependent cell network formation and spreading on laminin-1, without disrupting α6β1 association or adhesion to Matrigel.","method":"C-terminal deletion/exchange mutagenesis, cell network formation assay on Matrigel, cell adhesion assay, co-immunoprecipitation","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — domain deletion mutagenesis with functional validation in multiple cell types, orthogonal adhesion and morphogenesis assays","pmids":["11809818"],"is_preprint":false},{"year":2002,"finding":"CD151 enhances cell motility and invasion in a FAK-dependent manner. CD151 overexpression in FAK(+/+) fibroblasts increased invasion and motility (inhibitable by anti-CD151 mAb), while CD151 overexpression in FAK(-/-) fibroblasts produced no enhancement and was unaffected by anti-CD151 mAb, demonstrating that FAK is required for CD151-mediated pro-migratory effects.","method":"Transfection of CD151 into FAK(+/+) and FAK(-/-) fibroblasts, Matrigel invasion assay, cell motility assay, antibody inhibition","journal":"International journal of cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis using FAK-null cells, clean loss-of-function and gain-of-function comparison, in vivo metastasis validation","pmids":["11774285"],"is_preprint":false},{"year":2003,"finding":"CD151 is required for α6β1 integrin adhesion strengthening to laminin-1. Cells expressing a C-terminal region-mutant CD151 showed impaired adhesion strengthening under defined applied forces (0-1.5 nN), without affecting static adhesion to laminin-1 or detachment of fibronectin/anti-α6-coated beads.","method":"Magnetic bead force application (0-1.5 nN), bead detachment assay, site-directed mutagenesis of CD151 C-terminal region, NIH 3T3 transfection system","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biophysical reconstitution with defined force application, mutagenesis, specific integrin/substrate controls","pmids":["12805567"],"is_preprint":false},{"year":2003,"finding":"CD151 in complex with α3β1 integrin functions as a component of a cell-cell adhesion complex in epithelial cells, stimulating E-cadherin-mediated adhesion by regulating PTPμ expression and organizing a multimolecular complex containing PKCβII, RACK1, PTPμ, β-catenin, and E-cadherin.","method":"Co-immunoprecipitation, gene expression analysis, PTPμ reporter assays, epistasis using α3 integrin-deficient cells","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of multi-protein complex plus genetic epistasis with α3-null cells, single lab","pmids":["14691142"],"is_preprint":false},{"year":2003,"finding":"CD151 overexpression in A431 epithelial cells accelerates intercellular adhesion via PKC- and Cdc42-dependent actin cytoskeletal reorganization. CD151 engagement induced Cdc42-dependent filopodial extension and enhanced E-cadherin puncta formation and its anchorage to the cytoskeletal matrix; calphostin C (PKC inhibitor) blocked these effects.","method":"Overexpression, anti-CD151 mAb perturbation, Cdc42/Rac GTP-pull-down, pharmacological inhibition (calphostin C), immunofluorescence","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GTP-Rho pulldown plus pharmacological and antibody perturbation, multiple endpoints, single lab","pmids":["14557253"],"is_preprint":false},{"year":2005,"finding":"CD151 interacts with proMMP-7 (promatrilysin-1) through the propeptide of proMMP-7 and the C-terminal extracellular loop of CD151, as mapped by yeast two-hybrid and co-immunoprecipitation. This CD151-proMMP-7 interaction promotes pericellular activation of proMMP-7 on the cell surface, as demonstrated by in situ zymography blocked by anti-CD151 antibody.","method":"Yeast two-hybrid screen, co-immunoprecipitation, 125I-labeled proMMP-7 binding assay, confocal colocalization, in situ zymography with antibody inhibition","journal":"Laboratory investigation","confidence":"High","confidence_rationale":"Tier 1 / Strong — yeast two-hybrid with domain mapping, biochemical binding assay, functional in situ zymography with multiple inhibitory controls","pmids":["16200075"],"is_preprint":false},{"year":2005,"finding":"CD151 forms a structural and functional complex with c-Met/HGF receptor and integrin α3/α6. Knockdown of CD151 or integrin α3/α6 almost completely abrogated HGF-stimulated cell growth and migration in salivary gland cancer cells; forced CD151 expression enhanced HGF-dependent effects.","method":"Co-immunoprecipitation, siRNA knockdown, gain-of-function transfection, cell growth and migration assays with HGF stimulation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus loss- and gain-of-function in same cell system, single lab","pmids":["16139245"],"is_preprint":false},{"year":2006,"finding":"CD151-mediated homophilic interactions between cells activate integrin-dependent signaling through FAK, Src, p38 MAPK, JNK, and c-Jun, leading to AP-1-dependent transcription of MMP-9 and enhanced cell motility. Inhibitors/siRNAs against FAK, Src, p38 MAPK, and JNK abrogated these CD151-induced effects; integrin α3β1/α6β1 activation was a prerequisite.","method":"Stable transfection, siRNA knockdown, pharmacological inhibition, MMP-9 promoter AP-1 reporter assay, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple signaling pathway dissection with siRNA and pharmacological inhibitors plus reporter assay, single lab","pmids":["16798740"],"is_preprint":false},{"year":2006,"finding":"CD151 silencing in epidermal carcinoma cells impairs motility on laminin-5, causes persistent adhesive contacts, disrupts α3β1 association with tetraspanin-enriched microdomains, reduces α3β1 bulk detergent extractability, and impairs α3β1 internalization during migration. Both α3β1- and α6β4-dependent adhesion to laminin-5 were also impaired. CD151 re-expression reversed these defects.","method":"Retroviral RNAi, cell motility/adhesion assays on laminin-5, detergent solubility fractionation, integrin internalization assay, rescue experiment","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean siRNA KD with rescue by re-expression, multiple orthogonal assays, integrin trafficking mechanistic insight","pmids":["16571677"],"is_preprint":false},{"year":2007,"finding":"CD151 contains a YRSL (YXXφ) endocytosis/sorting motif in its C-terminal cytoplasmic domain. Mutation of this motif markedly attenuates CD151 internalization, completely abrogates CD151-promoted cell migration on laminin, and diminishes internalization of associated integrins (α3β1, α5β1, α6β1), demonstrating that CD151-mediated integrin trafficking is critical for promoting cell motility.","method":"YXXφ motif mutagenesis, internalization assays, cell migration assays on ECM substrates, co-localization studies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of defined endocytic motif with functional validation in trafficking and migration assays, multiple integrin partners tested","pmids":["17716972"],"is_preprint":false},{"year":2008,"finding":"DHHC2, a DHHC-domain palmitoyl transferase, is the primary enzyme responsible for palmitoylation of tetraspanins CD151 and CD9. DHHC2 associates with CD151 and CD9 but not other cell-surface proteins; DHHC2 knockdown diminishes CD151/CD9 palmitoylation. Catalytically inactive DHHC2 (DH→AA or C→S mutations) fails to promote palmitoylation. DHHC2-dependent palmitoylation promotes CD9-CD151 associations, protects CD151 and CD9 from lysosomal degradation, and shifts cells toward increased cell-cell contacts.","method":"DHHC enzyme knockdown panel, [3H]-palmitate labeling, co-immunoprecipitation, catalytic mutant DHHC2, stability assays, cell morphology analysis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — identified writer enzyme with catalytic mutagenesis, systematic knockdown of 7 DHHC enzymes, multiple functional consequences validated","pmids":["18508921"],"is_preprint":false},{"year":2008,"finding":"CD151 regulates N-glycosylation of α3β1 integrin specifically (not other associated proteins). CD151 knockdown reduces Fucα1-2Gal and bisecting GlcNAc modifications on α3 integrin N-glycans. Direct CD151-integrin contact is required but not sufficient; CD151 glycosylation at Asn159 in the LEL is also essential. Changes in α3β1 glycosylation correlate with impaired cell migration toward laminin-332.","method":"siRNA knockdown, glycan analysis, CD151 glycosylation mutant (N159Q), co-immunoprecipitation, migration assay, rescue with WT vs. mutant CD151","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of both CD151 glycosylation and integrin-binding domain, with functional validation in migration assay and specificity controls","pmids":["18852263"],"is_preprint":false},{"year":2008,"finding":"CD151 ablation in basal-like mammary tumor cells redistributes α6β4 integrin subcellularly, severs molecular links between integrins and tetraspanin-enriched microdomains, reduces cell migration/invasion/spreading, and diminishes signaling through FAK, Rac1, and Lck while disrupting EGFR-α6 integrin collaboration. CD151 ablation delays tumor progression in xenograft models.","method":"RNAi ablation, integrin localization imaging, FAK/Rac1/Lck phosphorylation assays, EGFR co-immunoprecipitation, xenograft tumor models","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean loss-of-function with multiple signaling readouts, in vitro and in vivo validation, single lab with multiple orthogonal methods","pmids":["18451146"],"is_preprint":false},{"year":2008,"finding":"CD151 regulates integrin α3β1 cell morphology and intracellular signaling on laminin-511. CD151 knockdown in A549 cells causes aberrant membrane protrusions and reduces tyrosine phosphorylation of FAK, Src, p130Cas, and paxillin, independent of the reduction in adhesive activity, suggesting CD151 controls both integrin adhesion strength and integrin-stimulated signaling through distinct mechanisms.","method":"RNAi knockdown, cell morphology analysis, phosphorylation assays (FAK, Src, p130Cas, paxillin), integrin-activating antibody rescue","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with multiple signaling readouts and rescue experiments, single lab","pmids":["18492066"],"is_preprint":false},{"year":2009,"finding":"CD151 loss destabilizes E-cadherin-dependent carcinoma cell-cell junctions and enhances collective tumor cell sheet migration. This occurs through excessive RhoA activation, loss of actin organization at junctions, and increased basal stress fibers. A CD151 mutant with impaired α3β1 association fails to restore junctional stability, linking the CD151-α3β1 axis to RhoA regulation at junctions.","method":"siRNA silencing, collective migration assay, RhoA activity pulldown (G-LISA), actin staining, live-cell junction remodeling imaging, CD151 mutant rescue","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KD with rescue by WT vs. integrin-binding mutant, RhoA activity measurement, live-cell imaging of junction dynamics","pmids":["19509057"],"is_preprint":false},{"year":2009,"finding":"CD151 forms a structural and functional complex with c-Met and integrin α3/α6 in breast cancer cells. Knockdown of CD151, integrin α3, or integrin α6 abolished HGF-induced branching morphogenesis and reduced Akt phosphorylation, placing CD151 in the HGF/c-Met/integrin signaling axis.","method":"Co-immunoprecipitation, siRNA knockdown, HGF-stimulated morphogenesis assay, Akt phosphorylation measurement","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus loss-of-function knockdown with signaling readout, single lab","pmids":["19159612"],"is_preprint":false},{"year":2009,"finding":"CD151 on endothelial cells promotes angiogenesis via the PI3K/Akt pathway, activating Akt and eNOS leading to increased nitric oxide production. CD151 overexpression increased HUVEC proliferation, migration, and tube formation; PI3K inhibitor (LY294002) and eNOS inhibitor (L-NAME) attenuated these effects.","method":"rAAV-mediated overexpression, PI3K/Akt/eNOS phosphorylation assays, NO measurement, proliferation/migration/tube formation assays, pharmacological inhibition","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function and pharmacological inhibition with multiple signaling readouts, single lab","pmids":["17045834"],"is_preprint":false},{"year":2010,"finding":"CD151 promotes MMP9 expression in HCC cells through the PI3K/Akt/GSK-3β/Snail signaling pathway. CD151 overexpression increased MMP9, and CD151 knockdown reduced MMP9 expression and impaired microvessel formation in vitro.","method":"siRNA knockdown, overexpression, PI3K/Akt/GSK-3β/Snail signaling pathway analysis by Western blot, MMP9 expression assay, in vitro microvessel formation assay","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway dissection with loss- and gain-of-function, multiple signaling intermediates tested, single lab","pmids":["20578262"],"is_preprint":false},{"year":2010,"finding":"CD151 is required for Met-dependent cancer cell growth and survival. CD151 depletion impairs HGF-driven proliferation, anchorage-independent growth, and protection from anoikis. Mechanistically, CD151 is required for formation of Met-β4 integrin signaling complexes; CD151 depletion blocks HGF-induced β4 integrin phosphorylation, Grb2-Gab1 association, and MAPK (but not AKT) activation.","method":"RNAi silencing, co-immunoprecipitation of Met-β4 integrin complex, phosphorylation assays (β4, MAPK, AKT), anchorage-independent growth assay, xenograft model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic dissection of signaling complex with specific pathway readouts (MAPK vs AKT), in vitro and in vivo validation","pmids":["20937830"],"is_preprint":false},{"year":2010,"finding":"CD151 knockdown, combined with trastuzumab, inhibits ErbB2 activation and downstream signaling through Akt, Erk1/2, and FAK in ErbB2+ breast cancer cells adherent to laminin-5, sensitizing them to trastuzumab and lapatinib. The laminin-integrin-CD151-FAK axis provides resistance to anti-ErbB2 agents.","method":"siRNA knockdown, drug sensitivity assays, ErbB2/Akt/Erk1/2/FAK phosphorylation Western blot, 3D laminin-5 adhesion assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional epistasis between CD151 and ErbB2 signaling, multiple signaling readouts, single lab","pmids":["20197472"],"is_preprint":false},{"year":2011,"finding":"CD151 in podocytes is required for integrin α3β1-mediated adhesion strength to laminin in the glomerular basement membrane. Podocyte-specific Cd151 deletion leads to glomerular nephropathy, and blood pressure is a critical modifier—global Cd151-null mice on FVB background develop renal disease, with ACE inhibition prolonging survival.","method":"Conditional and global knockout mice, cell adhesion strength assays, histology, ACE inhibitor treatment, blood pressure manipulation","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific knockout with defined phenotype, modifier analysis, therapeutic intervention validation, mechanistic link to adhesion strength","pmids":["22201679"],"is_preprint":false},{"year":2011,"finding":"CD151 maintains vascular stability by promoting endothelial cell-cell and cell-matrix adhesions through confining cytoskeletal tension: CD151 loss elevates RhoA signaling (increasing actin cytoskeletal traction) and diminishes Rac1 activity (reducing cortical actin meshwork). RhoA inhibition or cAMP activation stabilizes CD151-silenced endothelial structures.","method":"siRNA silencing, Cd151 knockout endothelial cells, Rho/Rac activity assays, permeability assays, pharmacological RhoA inhibition, endothelial tube formation assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — null cells plus siRNA knockdown, Rho/Rac activity measurement, pharmacological rescue, in vivo vascular permeability assay","pmids":["21832275"],"is_preprint":false},{"year":2011,"finding":"Host animal CD151 is required for efficient tumor metastasis. CD151-null mice show markedly diminished experimental lung metastasis after Lewis lung carcinoma or B16F10 injection. CD151-null mouse lung endothelial cells show diminished support for tumor cell adhesion, transendothelial migration, and permeability induction. VEGF-induced Src and Akt signaling was diminished in CD151-null endothelial cells.","method":"CD151-null mice, experimental metastasis models (i.v. injection), isolated null endothelial cells, transendothelial migration assay, permeability assay, VEGF signaling assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — global knockout with mechanistic dissection in isolated endothelial cells, multiple in vitro and in vivo readouts","pmids":["21536858"],"is_preprint":false},{"year":2012,"finding":"CD151 knockdown in MDA-MB-231 mammary cells impairs α6 integrin clustering without decreasing α6 expression or activation. CD151 knockdown shifts α6 integrin diffusion from predominantly random-confined diffusion (RCD) to directed motion (DMO), a dysregulating effect sensitive to actin disruption but desensitized to talin knockdown and phorbol ester stimulation. CD151 effects on diffusion mode are specific to α6 (not αv) integrins.","method":"Single particle tracking (SPT), siRNA knockdown, mode-of-diffusion analysis, phorbol ester and EGF stimulation, talin knockdown, actin disruption","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Strong — single-particle tracking with quantitative diffusion mode analysis, specific controls with non-associated integrins, multiple perturbations","pmids":["22328509"],"is_preprint":false},{"year":2012,"finding":"CD151 promotes skin squamous cell carcinoma (SCC) initiation and progression by supporting STAT3 activation and PKCα-α6β4 integrin association. CD151 supports PKC-dependent β4 S1424 phosphorylation and regulates α6β4 subcellular distribution to promote an invasive state. CD151 ablation sensitizes mouse skin to carcinogens and drugs targeting EGFR, PKC, Jak2/Tyk2, and STAT3.","method":"Two-stage chemical carcinogenesis in Cd151 knockout mice, STAT3 activation assay, PKCα-β4 co-immunoprecipitation, β4 phosphorylation Western blot, pharmacological sensitization","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout in in vivo carcinogenesis model, mechanistic signaling dissection, multiple drug sensitization readouts","pmids":["22824799"],"is_preprint":false},{"year":2012,"finding":"The α3β1-CD151 complex regulates ErbB2 dimerization and phosphorylation through RhoA. Depletion of either α3β1 or CD151 reduces ErbB2 phosphorylation, reduces ErbB2 dimerization, and increases RhoA activity. RhoA directly controls ErbB2 dimerization. Combined expression of α3β1 and CD151 enhances Herceptin efficacy.","method":"siRNA knockdown, ErbB2 dimerization assay, ErbB2 phosphorylation Western blot, RhoA activity (G-LISA), Herceptin treatment in 3D culture, Rho manipulation","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function for both partners, signaling mechanistic dissection, multiple readouts, single lab","pmids":["23792450"],"is_preprint":false},{"year":2013,"finding":"CD151 mediates HPV16 endocytosis. Surface-bound HPV16 co-moves with CD151 in the plane of the membrane before cointernalization. CD151 depletion reduces HPV16 endocytosis (not binding). The C-terminal cytoplasmic region (but not tyrosine-based sorting motif) and palmitoylation of CD151 are required; CD151-associated integrins α3β1 and α6β1/4 are also involved; CD151 QRD integrin-binding site mutants do not restore virus internalization.","method":"CD151 depletion (siRNA), live-cell co-tracking, internalization assay, CD151 domain mutants (C-terminal deletion, YRSL, palmitoylation, QRD), integrin siRNA knockdown","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple CD151 domain mutants, siRNA for CD151 and associated integrins, live-cell imaging, mechanistic dissection of entry step","pmids":["23302890"],"is_preprint":false},{"year":2013,"finding":"CD151 depletion in CD151-silenced carcinoma cells disrupts α3β1 integrin association with tetraspanin-enriched microdomains and impairs α3β1 internalization. CD9/CD81 complex but not CD151 is required for α3β1 association with PKCα and directed α3β1-dependent motility; CD151 is required for early spreading events. These two tetraspanin complexes have overlapping but distinct roles in α3β1 function.","method":"RNAi silencing of CD9/CD81 vs. CD151, co-immunoprecipitation with PKCα, directed motility assay, spreading assay, cell morphology analysis, PKC inhibitor","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — comparative knockdown of tetraspanin pairs, Co-IP, multiple functional assays, single lab","pmids":["23613949"],"is_preprint":false},{"year":2013,"finding":"CD151 depletion specifically attenuates TGFβ1-induced scattering and proliferation of breast cancer cells in 3D Matrigel, requiring its association with α3β1 or α6 integrins but independent of tetraspanin-enriched microdomain recruitment. CD151 regulates compartmentalization of TGFβ type I receptor (ALK-5) and specifically controls TGFβ1-induced p38 activation (not Smad2/3, c-Akt, or Erk1/2).","method":"shRNA knockdown, 3D Matrigel scattering assay, TGFβ receptor localization, p38/Smad2/3/Akt/Erk1/2 phosphorylation assays, CD151 mutant rescue, experimental lung metastasis","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — specific signaling pathway discrimination (p38 vs. Smad/AKT/ERK), TGFβR compartmentalization, mutant rescue, in vivo metastasis validation","pmids":["20570898"],"is_preprint":false},{"year":2014,"finding":"CD151 and CD9 congregate at the T-cell side of the immunological synapse. Silencing CD151 or CD9 blunts IL-2 secretion and CD69 expression by APC-conjugated T cells, diminishes α4β1 relocalization to the IS, reduces high-affinity β1 integrin accumulation at the contact, and decreases FAK and ERK1/2 phosphorylation, without affecting CD3 or actin accumulation at the IS.","method":"siRNA silencing, immunological synapse imaging, IL-2 ELISA, CD69 flow cytometry, integrin relocalization and activation assays, FAK/ERK phosphorylation","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with multiple functional readouts at the IS, single lab","pmids":["24723389"],"is_preprint":false},{"year":2016,"finding":"CD151 is a proviral host factor for HCMV entry, supporting viral penetration (but not adsorption) into endothelial cells and fibroblasts. CD151 depletion impairs infection by virus strains with broad or narrow cell tropism equally, as shown by fluorescent virus with differentially labeled capsid and envelope proteins.","method":"Targeted RNAi screen (96 genes), CD151 depletion (siRNA), HCMV infection assay, fluorescent virus penetration vs. adsorption assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi screen hit validated with mechanistic dissection (penetration vs. adsorption), multiple HCMV strains, single lab","pmids":["27147745"],"is_preprint":false},{"year":2019,"finding":"CD151, through binding to integrin α3β1, stabilizes a hybrid adhesion structure (with features of both hemidesmosomes and tetraspanin-enriched microdomains) containing CD151-α3β1/α6β4 integrin complexes and plectin but not keratin filaments, in the central region of keratinocytes. Classic hemidesmosomes (α6β4/plectin/BP180/BP230/keratin) do not require CD151.","method":"CD151 knockout keratinocytes, α3β1-CD151 co-immunoprecipitation, immunofluorescence of adhesion structure components, spreading/adhesion kinetics assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout cells with compositional analysis of distinct adhesion structures, single lab","pmids":["31488507"],"is_preprint":false},{"year":2019,"finding":"CD151 supports anti-cancer drug resistance independent of integrins. CD151 ablation sensitizes tumor cells to gefitinib and camptothecin (increasing apoptosis). Drug sensitization occurs even when integrins are unengaged; integrin α3/α6 ablation does not mimic CD151 ablation; the CD151-QRD mutant (diminished integrin association) reconstitutes drug protection as effectively as WT CD151. Anti-cancer drug treatment selectively upregulates intracellular non-integrin-associated CD151.","method":"CD151 ablation (CRISPR/siRNA), apoptosis assays (cleaved caspase-3, cleaved PARP, annexin V, PI), CD151-QRD mutant reconstitution, integrin α3/α6 ablation comparison, intracellular vs. surface CD151 fractionation","journal":"Cellular and molecular life sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — integrin-independent mechanism established by multiple orthogonal controls (QRD mutant, integrin KO comparison, ligand-free conditions), multiple apoptosis assays","pmids":["30778617"],"is_preprint":false},{"year":2019,"finding":"CD151 in cardiomyocytes suppresses proliferation by inducing p38 expression. miR-199a-3p directly targets CD151 mRNA, suppresses CD151, and promotes cardiomyocyte proliferation. Cd151 gain-of-function reduced cardiomyocyte proliferation; Cd151 loss-of-function increased it. Pharmacological p38 inhibition rescued the Cd151 inhibitory effect on proliferation.","method":"Luciferase reporter assay (miR-199a-3p/CD151 3'UTR), Cd151 gain- and loss-of-function in cardiomyocytes, p38 inhibitor rescue, proliferation assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — validated miRNA target with reciprocal gain/loss-of-function and pharmacological rescue, single lab","pmids":["31186138"],"is_preprint":false},{"year":2020,"finding":"CD151 in inflammatory breast cancer cells promotes macrophage recruitment through a midkine-dependent mechanism. CD151 increases midkine production; purified midkine stimulates monocyte migration specifically. CD151-expressing IBC-derived extracellular vesicles have chemoattractive potential for monocytes, blocked by anti-midkine antibodies. This pathway also involves integrin α6β1.","method":"In vitro monocyte migration assay, midkine purification and functional assay, anti-midkine antibody blocking of EV chemoattraction, xenograft immunohistology, chemokine profiling","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional chemoattraction assay with blocking antibody, EV-mediated pathway, in vivo xenograft validation, single lab","pmids":["32129471"],"is_preprint":false},{"year":2022,"finding":"JAM-A forms a complex with α3β1 integrin and tetraspanins CD151 and CD9 through its extracellular domain. This complex regulates collective cell migration of polarized epithelial cells on laminin and collagen-I (not fibronectin/vitronectin). Depletion of JAM-A, α3β1 integrin, or CD151/CD9 impairs cryptic lamellipodia dynamics and slows collective migration.","method":"Co-immunoprecipitation, domain mapping experiments, siRNA depletion of JAM-A/α3β1/CD151/CD9, collective migration assay, substrate-specificity experiments","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, multiple knockdowns, substrate specificity controls, single lab","pmids":["35067832"],"is_preprint":false}],"current_model":"CD151 is a tetraspanin scaffold protein that forms direct, stoichiometric lateral complexes with laminin-binding integrins (α3β1, α6β1, α6β4, α7β1) through its large extracellular loop (QRD194-196 site) and the α3 extracellular domain (aa 570-705); these complexes assemble early in biosynthesis, are stabilized by CD151 palmitoylation (at C11/C15/C242/C243, written by DHHC2), and regulate integrin endocytic trafficking (via a C-terminal YRSL/YXXφ motif), integrin diffusion mode, adhesion strengthening, glycosylation of α3β1, and downstream signaling through FAK, Src, Rac1/Cdc42, RhoA, PI3K/Akt/eNOS, and p38 MAPK to control cell migration, collective migration, morphogenesis, angiogenesis, MMP activation, and drug resistance in both integrin-dependent and integrin-independent manners."},"narrative":{"mechanistic_narrative":"CD151 (PETA-3) is a tetraspanin scaffold protein that organizes laminin-binding integrins into lateral membrane complexes to control cell adhesion, migration, morphogenesis, and angiogenesis [PMID:7632941, PMID:9566977, PMID:10036233]. It forms direct, detergent-resistant complexes specifically with integrins α3β1 and α6β1 (and comparably α7β1), while other tetraspanins associate with these integrins only indirectly through CD151 [PMID:10229664, PMID:11884516]. The interaction is extracellular and stoichiometric: CD151 contacts the α3 subunit (aa 570-705) through its large extracellular loop, and a defined QRD(194-196) site is required for strong association with both α3β1 and α6β1, with complex assembly occurring early in biosynthesis [PMID:10734060, PMID:11479292, PMID:12356873]. CD151 is palmitoylated on intracellular cysteines (C11/C15/C242/C243) by the DHHC2 palmitoyl transferase, which stabilizes the protein, protects it from lysosomal degradation, and promotes its associations with other tetraspanins (CD9, CD63) without disrupting the core CD151-α3β1 interaction [PMID:11907260, PMID:18508921]. Through these complexes CD151 strengthens integrin adhesion to laminin under force, governs integrin diffusion mode and clustering, drives α3β1 glycosylation, and controls integrin endocytic trafficking via a C-terminal YRSL/YXXφ motif required for both integrin internalization and CD151-promoted migration [PMID:12805567, PMID:17716972, PMID:18852263, PMID:22328509]. Downstream it signals through FAK, Src, Rho-family GTPases (Rac1/Cdc42/RhoA), and PI3K/Akt/eNOS to control collective migration, junction stability, MMP activation, and endothelial angiogenesis [PMID:14557253, PMID:16798740, PMID:19509057, PMID:17045834, PMID:21832275]. CD151 also collaborates with growth-factor receptors—assembling Met-β4 integrin signaling complexes and modulating ErbB2 dimerization through RhoA—linking it to tumor progression and anti-receptor drug resistance [PMID:20937830, PMID:23792450, PMID:20197472]. In vivo, podocyte-specific and global Cd151 deletion cause integrin-α3β1-dependent glomerular nephropathy, and host CD151 is required for efficient endothelial support of tumor metastasis [PMID:22201679, PMID:21536858]. CD151 additionally functions as a host entry factor for HPV16 and HCMV and, independently of integrins, promotes resistance to anti-cancer drugs via an intracellular pool [PMID:23302890, PMID:27147745, PMID:30778617].","teleology":[{"year":1995,"claim":"Established CD151 as a distinct four-transmembrane tetraspanin/TM4SF protein, defining the molecular entity before any function was known.","evidence":"cDNA cloning, sequence analysis, and Northern blot of PETA-3","pmids":["7632941"],"confidence":"Medium","gaps":["No binding partners or cellular function identified","Topology inferred from sequence, not directly demonstrated"]},{"year":1998,"claim":"First linked CD151 to integrin biology and migration by showing it complexes with α3β1 and other tetraspanins at endothelial junctions and that antibody blockade impairs migration and invasion.","evidence":"Co-IP, immunofluorescence, time-lapse microscopy and collagen invasion in endothelial cells","pmids":["9566977"],"confidence":"High","gaps":["Whether the integrin association is direct vs. indirect unresolved","Binding site on either protein unmapped"]},{"year":1999,"claim":"Defined the specificity and directness of CD151-integrin coupling, showing CD151 forms direct complexes specifically with α3β1 and α6β1 and serves as the linker through which other tetraspanins reach integrins; concurrently established CD151 as a pro-migratory, pro-metastatic factor.","evidence":"Reciprocal Co-IP across detergent conditions, epitope-blocking, overexpression and antibody inhibition in tumor and haematopoietic cells with in vivo metastasis","pmids":["10229664","10447000","10036233","9931299"],"confidence":"High","gaps":["Molecular determinants of the direct interaction not yet mapped","Downstream signaling effectors unknown"]},{"year":2000,"claim":"Mapped the CD151-integrin interface to extracellular regions (α3 aa 570-705 and CD151 LEL aa 186-217) and confirmed the four-pass topology, establishing the structural basis of complex formation.","evidence":"Membrane-impermeable cross-linking, chimeric constructs and topology determination","pmids":["10734060"],"confidence":"High","gaps":["Functional consequence of these specific residues not yet tested","Stoichiometry of the complex undefined"]},{"year":2001,"claim":"Defined the LEL residues (incl. CCG/PXXCC motifs and aa 195-205) needed for stable α3β1 association and showed the complex assembles early in biosynthesis, separating CD151-integrin coupling from CD151-tetraspanin homotypic interactions.","evidence":"Site-directed mutagenesis, chimeras, multi-detergent Co-IP and pulse-chase","pmids":["11479292"],"confidence":"High","gaps":["Did not resolve the minimal QRD determinant identified later","Effect on downstream function not directly assayed"]},{"year":2002,"claim":"Established that palmitoylation at four cysteines, the QRD(194-196) site, and the C-terminal tail are separable functional modules: palmitoylation governs tetraspanin web assembly and stability, QRD governs strong integrin binding, and the C-terminal tail is required for morphogenesis.","evidence":"Palmitoylation-site and QRD mutagenesis, [3H]-palmitate labeling, C-terminal deletion, Matrigel morphogenesis and Co-IP; α7β1 association confirmed","pmids":["11907260","12356873","11809818","11884516"],"confidence":"High","gaps":["Enzyme writing palmitoylation not yet identified","Mechanism linking C-terminal tail to morphogenesis unresolved"]},{"year":2002,"claim":"Placed CD151 pro-migratory activity downstream of FAK, demonstrating genetic dependence on FAK for CD151-enhanced motility and invasion.","evidence":"CD151 transfection into FAK(+/+) vs FAK(-/-) fibroblasts with invasion/motility and metastasis assays","pmids":["11774285"],"confidence":"High","gaps":["Other downstream effectors (Src, Rho GTPases) not yet placed","How CD151 activates FAK mechanistically unresolved"]},{"year":2003,"claim":"Demonstrated CD151's biophysical role in integrin adhesion strengthening and its participation in epithelial cell-cell adhesion complexes via PKC/Cdc42 and a PTPμ/E-cadherin module.","evidence":"Magnetic-bead force assays with C-terminal mutants; Co-IP of E-cadherin junctional complex and Cdc42/Rac pulldowns with PKC inhibition","pmids":["12805567","14691142","14557253"],"confidence":"High","gaps":["Direct vs indirect nature of multiprotein junctional complex not fully resolved","Mechanism connecting CD151 to PTPμ expression unclear"]},{"year":2005,"claim":"Extended CD151 function to pericellular proteolysis and growth-factor receptor signaling, identifying proMMP-7 as an extracellular-loop binding partner and CD151-c-Met-integrin complexes as drivers of HGF responses.","evidence":"Yeast two-hybrid and Co-IP domain mapping with in situ zymography; Co-IP and knockdown/overexpression with HGF stimulation","pmids":["16200075","16139245"],"confidence":"Medium","gaps":["Stoichiometry of CD151-c-Met complex undefined","Whether c-Met contact is direct unresolved"]},{"year":2006,"claim":"Resolved the CD151 homophilic-engagement signaling cascade, linking integrin activation to FAK/Src/p38/JNK/c-Jun and AP-1-driven MMP-9 transcription.","evidence":"Stable transfection, siRNA, pathway inhibitors and MMP-9 AP-1 reporter assays","pmids":["16798740"],"confidence":"Medium","gaps":["Direct kinase substrate relationships not established","Single-lab pathway dissection"]},{"year":2007,"claim":"Identified the C-terminal YRSL/YXXφ motif as the endocytic determinant coupling CD151-mediated integrin internalization to cell motility.","evidence":"Motif mutagenesis with internalization and migration assays across multiple integrins","pmids":["17716972"],"confidence":"High","gaps":["Adaptor proteins reading the YXXφ motif not identified","Trafficking route/destination of internalized integrin undefined"]},{"year":2008,"claim":"Identified DHHC2 as the palmitoyl transferase writing CD151 palmitoylation, and showed CD151 controls α3β1 N-glycosylation and α6β4-dependent tumor signaling, deepening the post-translational and signaling regulation of the complex.","evidence":"DHHC knockdown panel with catalytic mutants; glycosylation analysis with N159Q and integrin-binding mutants; RNAi ablation with FAK/Rac1/Lck and EGFR readouts and xenografts","pmids":["18508921","18852263","18451146","18492066"],"confidence":"High","gaps":["Mechanism by which CD151 shapes α3 glycan processing unclear","Whether DHHC2 acts on the integrin-bound pool specifically untested"]},{"year":2006,"claim":"Connected endothelial CD151 to angiogenesis through PI3K/Akt/eNOS-driven nitric oxide production.","evidence":"rAAV overexpression, signaling phosphorylation, NO measurement, and tube formation with PI3K/eNOS inhibitors in HUVEC","pmids":["17045834"],"confidence":"Medium","gaps":["Receptor/integrin upstream of PI3K activation not defined here","Single gain-of-function model"]},{"year":2009,"claim":"Established CD151 as a regulator of RhoA at epithelial junctions and of collective migration, mechanistically tying junctional stability to the CD151-α3β1 axis.","evidence":"siRNA, collective migration, RhoA G-LISA, live imaging and rescue with WT vs integrin-binding mutant CD151; plus c-Met/α3α6 branching morphogenesis","pmids":["19509057","19159612"],"confidence":"High","gaps":["How CD151 restrains RhoA biochemically unresolved","GEF/GAP intermediaries unidentified"]},{"year":2010,"claim":"Cemented CD151's role in tumor invasion and therapy resistance through Met-β4 complexes, PI3K/Akt/GSK-3β/Snail-driven MMP9, and the laminin-integrin-CD151-FAK axis conferring anti-ErbB2 drug resistance.","evidence":"RNAi/overexpression with Co-IP of Met-β4, pathway Westerns, anchorage-independent growth, xenografts and trastuzumab/lapatinib sensitivity assays","pmids":["20937830","20578262","20197472"],"confidence":"High","gaps":["Selective MAPK-vs-AKT branching downstream of Met-β4 mechanism unresolved","Direct molecular link between CD151 and ErbB2 unclear"]},{"year":2011,"claim":"Provided in vivo genetic proof of CD151 function: podocyte adhesion to the glomerular basement membrane, endothelial vascular stability via RhoA/Rac1 balance, and host support of metastasis through endothelial VEGF/Src/Akt signaling.","evidence":"Conditional and global Cd151-null mice, adhesion-strength assays, Rho/Rac activity, permeability, ACE-inhibitor and experimental metastasis models","pmids":["22201679","21832275","21536858"],"confidence":"High","gaps":["Cell-autonomous vs systemic contributions to metastasis not fully separated","Modifier effect of blood pressure mechanistically incomplete"]},{"year":2012,"claim":"Defined CD151 control of integrin lateral diffusion and clustering and its role in skin carcinoma initiation via STAT3 and PKCα-β4 association, refining how CD151 organizes integrins at the nanoscale and in tumor initiation.","evidence":"Single-particle tracking with talin/actin perturbations; two-stage carcinogenesis in Cd151-null mice with STAT3/β4-phosphorylation and drug sensitization; ErbB2/RhoA dimerization assays","pmids":["22328509","22824799","23792450"],"confidence":"High","gaps":["Link between diffusion-mode control and downstream signaling not directly established","How CD151 promotes β4 S1424 phosphorylation unresolved"]},{"year":2013,"claim":"Broadened CD151 roles to pathogen entry (HPV16 endocytosis), distinct tetraspanin-complex division of labor in α3β1 function, and selective control of TGFβ1-induced p38 signaling and scattering.","evidence":"siRNA with CD151 domain mutants and live co-tracking for HPV16; comparative CD9/CD81 vs CD151 knockdown; shRNA with TGFβR compartmentalization and pathway-selective phosphorylation plus in vivo metastasis","pmids":["23302890","23613949","20570898"],"confidence":"High","gaps":["Whether HPV16 contacts CD151 directly unresolved","Mechanism of selective p38 (not Smad/AKT/ERK) activation unclear"]},{"year":2014,"claim":"Implicated CD151 in immune-cell function, showing it organizes integrins at the T-cell immunological synapse to support activation signaling.","evidence":"siRNA silencing with synapse imaging, IL-2/CD69 readouts, integrin relocalization and FAK/ERK phosphorylation","pmids":["24723389"],"confidence":"Medium","gaps":["Direct integrin partner at the synapse not mapped","Single-lab knockdown study"]},{"year":2016,"claim":"Identified CD151 as a proviral host factor for HCMV entry acting at the penetration step.","evidence":"RNAi screen hit validated with differentially labeled fluorescent virus penetration vs adsorption assays","pmids":["27147745"],"confidence":"Medium","gaps":["Receptor/co-factor partners for HCMV penetration undefined","Whether integrin or tetraspanin-web involvement is required not tested"]},{"year":2019,"claim":"Resolved an integrin-independent CD151 function in drug resistance and identified CD151 in a hybrid keratinocyte adhesion structure, separating CD151 roles that require integrin binding from those that do not.","evidence":"CRISPR/siRNA ablation with apoptosis assays, QRD-mutant reconstitution and integrin-KO comparison; CD151-KO keratinocytes with compositional analysis of adhesion structures; miR-199a-3p targeting CD151 in cardiomyocytes","pmids":["30778617","31488507","31186138"],"confidence":"High","gaps":["Molecular effector of integrin-independent drug protection unidentified","Intracellular CD151 binding partners mediating survival unknown"]},{"year":2020,"claim":"Extended CD151 to the tumor microenvironment, showing it drives midkine-dependent macrophage/monocyte recruitment including via extracellular vesicles.","evidence":"Monocyte migration with purified midkine, anti-midkine blocking of EV chemoattraction and xenograft immunohistology","pmids":["32129471"],"confidence":"Medium","gaps":["Mechanism linking CD151 to midkine production unresolved","Role of α6β1 in this axis incompletely defined"]},{"year":2022,"claim":"Defined a JAM-A/α3β1/CD151/CD9 complex driving collective epithelial migration on laminin and collagen-I via cryptic lamellipodia.","evidence":"Co-IP with domain mapping, multi-component siRNA depletion and substrate-specific collective migration assays","pmids":["35067832"],"confidence":"Medium","gaps":["Direct vs indirect JAM-A-CD151 contact not resolved","Single-lab study"]},{"year":null,"claim":"How CD151's separable molecular modules (palmitoylation, QRD integrin binding, YXXφ trafficking, intracellular pool) are coordinated to switch between integrin-dependent adhesion/migration roles and integrin-independent survival/viral-entry functions remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the assembled CD151-integrin complex","Intracellular effectors of integrin-independent CD151 functions unidentified","Adaptors reading the YXXφ motif unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,6,7,10,46]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[13,22,34,20]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[37,41]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2,6]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[2,20]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[2,21]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[13,19,42]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[18,27,29,36]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[33,35,43]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[10,11,25]}],"complexes":["CD151-α3β1 integrin complex","tetraspanin-enriched microdomain (with CD9/CD81)","Met-β4 integrin signaling complex","JAM-A/α3β1/CD151/CD9 complex"],"partners":["ITGA3","ITGB1","ITGA6","ITGB4","CD9","MET","JAM-A","DHHC2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P48509","full_name":"CD151 antigen","aliases":["GP27","Membrane glycoprotein SFA-1","Platelet-endothelial tetraspan antigen 3","PETA-3","Tetraspanin-24","Tspan-24"],"length_aa":253,"mass_kda":28.3,"function":"Structural component of specialized membrane microdomains known as tetraspanin-enriched microdomains (TERMs), which act as platforms for receptor clustering and signaling. Plays a role in various cellular and molecular mechanism through its association with both integrin and non-integrin proteins. These interactions facilitate critical cellular functions, including cell-to-cell communication, wound healing, platelet aggregation, trafficking, cell motility, and angiogenesis (PubMed:17045834, PubMed:24723389, PubMed:31488507). Via interaction with JAM-A/F11R and integrin ITGA3:ITGB1, promotes the recruitment of signaling molecules such as RAC1, CDC42 and RhoGTPases to facilitate the polarization of epithelial cells and the reorganization of the actin cytoskeleton, which are critical steps in cell migration process (PubMed:22843693, PubMed:35067832). Regulates the glycosylation pattern of ITGA3:ITGB1 thereby modulating its activity (PubMed:18852263). Plays an essential role in the maintenance of central laminin-binding integrin ITGA6:ITGB4-containing adhesion complexes (PubMed:31488507). Essential for the proper assembly of the glomerular and tubular basement membranes in kidney (PubMed:15265795). Contributes to T-cell activation by modulating integrin signaling leading to activation of downstream targets PTK2 and MAPK1/MAPK3 (PubMed:24723389) (Microbial infection) Plays a role in human papillomavirus 16/HPV-16 endocytosis upon binding to cell surface receptor (Microbial infection) Plays a role in human cytomegalovirus entry into host cell by contributing to entry receptor binding, membrane fusion, or release of the capsid","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P48509/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD151","classification":"Not Classified","n_dependent_lines":88,"n_total_lines":1208,"dependency_fraction":0.0728476821192053},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000177697","cell_line_id":"CID000874","localizations":[{"compartment":"membrane","grade":3},{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"AMOT","stoichiometry":10.0},{"gene":"ARGLU1","stoichiometry":10.0},{"gene":"ITGA6","stoichiometry":10.0},{"gene":"ITGB1","stoichiometry":4.0},{"gene":"EZR","stoichiometry":0.2},{"gene":"MSN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000874","total_profiled":1310},"omim":[{"mim_id":"618725","title":"INTELLECTUAL DEVELOPMENTAL DISORDER WITH BEHAVIORAL ABNORMALITIES AND CRANIOFACIAL DYSMORPHISM WITH OR WITHOUT SEIZURES; IDDBCS","url":"https://www.omim.org/entry/618725"},{"mim_id":"618621","title":"ZDHHC PALMITOYLTRANSFERASE 2; ZDHHC2","url":"https://www.omim.org/entry/618621"},{"mim_id":"609057","title":"EPIDERMOLYSIS BULLOSA SIMPLEX 7, WITH NEPHROPATHY AND DEAFNESS; EBS7","url":"https://www.omim.org/entry/609057"},{"mim_id":"602380","title":"UROPLAKIN 1B; UPK1B","url":"https://www.omim.org/entry/602380"},{"mim_id":"602243","title":"CD151 ANTIGEN; CD151","url":"https://www.omim.org/entry/602243"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"blood vessel","ntpm":806.4}],"url":"https://www.proteinatlas.org/search/CD151"},"hgnc":{"alias_symbol":["SFA-1","PETA-3","TSPAN24","RAPH"],"prev_symbol":[]},"alphafold":{"accession":"P48509","domains":[{"cath_id":"1.10.1450.10","chopping":"105-253","consensus_level":"medium","plddt":91.0089,"start":105,"end":253},{"cath_id":"1.10.287","chopping":"16-45_52-84","consensus_level":"medium","plddt":89.5173,"start":16,"end":84}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P48509","model_url":"https://alphafold.ebi.ac.uk/files/AF-P48509-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P48509-F1-predicted_aligned_error_v6.png","plddt_mean":88.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CD151","jax_strain_url":"https://www.jax.org/strain/search?query=CD151"},"sequence":{"accession":"P48509","fasta_url":"https://rest.uniprot.org/uniprotkb/P48509.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P48509/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P48509"}},"corpus_meta":[{"pmid":"9566977","id":"PMC_9566977","title":"Regulation of endothelial cell motility by complexes of tetraspan molecules CD81/TAPA-1 and CD151/PETA-3 with alpha3 beta1 integrin localized at endothelial lateral junctions.","date":"1998","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/9566977","citation_count":227,"is_preprint":false},{"pmid":"11907260","id":"PMC_11907260","title":"Palmitoylation of tetraspanin proteins: modulation of CD151 lateral interactions, subcellular distribution, and integrin-dependent cell morphology.","date":"2002","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/11907260","citation_count":202,"is_preprint":false},{"pmid":"10229664","id":"PMC_10229664","title":"Selective tetraspan-integrin complexes (CD81/alpha4beta1, CD151/alpha3beta1, CD151/alpha6beta1) under conditions disrupting tetraspan interactions.","date":"1999","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/10229664","citation_count":185,"is_preprint":false},{"pmid":"9111230","id":"PMC_9111230","title":"Localization of the transmembrane 4 superfamily (TM4SF) member PETA-3 (CD151) in normal human tissues: comparison with CD9, CD63, and alpha5beta1 integrin.","date":"1997","source":"The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society","url":"https://pubmed.ncbi.nlm.nih.gov/9111230","citation_count":175,"is_preprint":false},{"pmid":"10734060","id":"PMC_10734060","title":"Direct extracellular contact between integrin alpha(3)beta(1) and TM4SF protein CD151.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10734060","citation_count":161,"is_preprint":false},{"pmid":"30132868","id":"PMC_30132868","title":"LncRNA SNHG3 induces EMT and sorafenib resistance by modulating the miR-128/CD151 pathway in hepatocellular 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Reviews on cancer","url":"https://pubmed.ncbi.nlm.nih.gov/37094754","citation_count":20,"is_preprint":false},{"pmid":"21237282","id":"PMC_21237282","title":"Role of tetraspanin CD151-α3/α6 integrin complex: Implication in angiogenesis CD151-integrin complex in angiogenesis.","date":"2011","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21237282","citation_count":20,"is_preprint":false},{"pmid":"30778617","id":"PMC_30778617","title":"Integrin-independent support of cancer drug resistance by tetraspanin CD151.","date":"2019","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/30778617","citation_count":20,"is_preprint":false},{"pmid":"26992919","id":"PMC_26992919","title":"Regulation of Glioblastoma Tumor-Propagating Cells by the Integrin Partner Tetraspanin CD151.","date":"2016","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/26992919","citation_count":20,"is_preprint":false},{"pmid":"32152440","id":"PMC_32152440","title":"Expression and distribution of CD151 as a partner of alpha6 integrin in male germ cells.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32152440","citation_count":19,"is_preprint":false},{"pmid":"26529559","id":"PMC_26529559","title":"CD151 Regulates T-Cell Migration in Health and Inflammatory Bowel Disease.","date":"2016","source":"Inflammatory bowel diseases","url":"https://pubmed.ncbi.nlm.nih.gov/26529559","citation_count":19,"is_preprint":false},{"pmid":"33919420","id":"PMC_33919420","title":"The Context-Dependent Impact of Integrin-Associated CD151 and Other Tetraspanins on Cancer Development and Progression: A Class of Versatile Mediators of Cellular Function and Signaling, Tumorigenesis and Metastasis.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/33919420","citation_count":19,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50308,"output_tokens":12497,"usd":0.169189,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":24355,"output_tokens":7396,"usd":0.153337,"stage2_stop_reason":"end_turn"},"total_usd":0.322526,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"CD151 (PETA-3) was cloned and identified as a 253 amino acid protein with four transmembrane domains, a large extracellular loop with a single N-linked glycosylation site, and structural homology to the tetraspanin/TM4SF family. Northern blot confirmed broad tissue expression.\",\n      \"method\": \"cDNA cloning, Northern blot, sequence analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — molecular cloning with structural characterization but single lab, foundational identification paper\",\n      \"pmids\": [\"7632941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CD151/PETA-3 localizes to endothelial cell-cell lateral junctions and forms molecular complexes with α3β1 integrin and other tetraspanins (CD9, CD81). Anti-CD151 antibodies inhibited endothelial cell migration in wound healing and invasion into collagen gels, and increased adhesion to ECM proteins.\",\n      \"method\": \"Immunofluorescence microscopy, biochemical co-immunoprecipitation, time-lapse video microscopy, collagen gel invasion assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus functional inhibition with antibodies, multiple orthogonal methods, replicated across cell systems\",\n      \"pmids\": [\"9566977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CD151 associates with multiple integrin chains (β1, β3, β4, α2, α3, α5, α6) including α6β4 integrin, and is present both on the plasma membrane at cell-cell contacts and in intracellular endosomal/lysosomal compartments (co-localizing with transferrin receptor and CD63). Anti-PETA-3 antibodies inhibited endothelial cell migration and modulated in vitro angiogenesis but had no effect on neutrophil transendothelial migration.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence confocal microscopy, immuno-electron microscopy, functional antibody inhibition assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with multiple integrin chains, immuno-EM for localization, orthogonal functional assays, single lab with multiple methods\",\n      \"pmids\": [\"10036233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Among tetraspanins, CD151 forms digitonin-resistant (direct) complexes specifically with integrins α3β1 and α6β1, whereas other tetraspanins associate with integrins only indirectly through CD151. An anti-CD151 antibody (TS151r) epitope maps to the integrin-binding region and its binding is blocked by α3β1 or α6β1 overexpression.\",\n      \"method\": \"Reciprocal co-immunoprecipitation in multiple detergent conditions (digitonin, Brij 97, CHAPS), antibody epitope-blocking experiments, cell surface binding quantification\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — rigorous biochemical dissection using multiple detergent conditions and reciprocal immunoprecipitation across multiple cell lines\",\n      \"pmids\": [\"10229664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CD151 (PETA-3) overexpression in HeLa cells enhanced cell migration, and anti-CD151 antibodies inhibited HEp-3 cell chemotaxis and in vivo metastasis without affecting cell adhesion or tumor growth, identifying CD151 as a positive effector of tumor cell migration and metastasis.\",\n      \"method\": \"Eukaryotic expression cloning, transfection/overexpression, chemotaxis assay, in vivo metastasis model, antibody inhibition\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function transfection plus loss-of-function antibody inhibition, in vitro and in vivo validation, multiple antibodies\",\n      \"pmids\": [\"10447000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CD151 associates with integrins α4β1, α5β1, α6β1, and αIIbβ3 in haematopoietic cell lines. Anti-CD151 F(ab')2 fragments induced homotypic cell adhesion dependent on energy and cytoskeletal integrity but not mediated through integrin-ligand binding. CD151 ligation did not alter integrin avidity for fibronectin, laminin, collagen, or fibrinogen.\",\n      \"method\": \"Co-immunoprecipitation, homotypic adhesion assay with F(ab')2 fragments, function-blocking antibodies, integrin ligand adhesion assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and functional assays in multiple cell lines, single lab\",\n      \"pmids\": [\"9931299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CD151 directly contacts α3β1 integrin extracellularly. Using membrane-impermeable cross-linking and chimeric proteins, the association was mapped to an extracellular α3 site (aa 570-705) and a region within the large extracellular loop of CD151 (aa 186-217). Both N- and C-terminal domains of CD151 are intracellular, confirming the four-pass topology.\",\n      \"method\": \"Membrane-impermeable chemical cross-linking, chimeric integrin/tetraspanin constructs, epitope mapping, topology determination\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct extracellular cross-linking plus domain mapping with chimeras, multiple orthogonal approaches, confirms protein topology\",\n      \"pmids\": [\"10734060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The large extracellular loop (LEL) of CD151 (aa 149-213) is required for stable (Triton X-100-resistant) association with α3β1 integrin, and 11 aa substitution (195-205) or mutations in conserved CCG and PXXCC motifs abolish this interaction. The CCG motif mutation selectively prevents homotypic CD151-CD151 interaction without affecting association with other tetraspanins. CD151-α3β1 complex assembly occurs early in biosynthesis, before CD151-tetraspanin associations.\",\n      \"method\": \"Site-directed mutagenesis, CD151/CD9 chimeras, co-immunoprecipitation in Triton X-100 and Brij 96, biosynthetic pulse-chase\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis with multiple mutants, multiple detergent conditions, biosynthesis timing, multiple orthogonal approaches\",\n      \"pmids\": [\"11479292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CD151 is palmitoylated at intracellular N-terminal and C-terminal cysteine residues (C11, C15, C242, C243). Simultaneous mutation of these cysteines (tetra mutant) eliminates >90% of palmitoylation, markedly diminishes associations with other tetraspanins (CD9, CD63), increases diffuse distribution, reduces stability during biosynthesis, but does not disrupt CD151-α3β1 integrin association or localization into detergent-resistant microdomains.\",\n      \"method\": \"Site-directed mutagenesis of palmitoylation sites, [3H]-palmitate labeling, co-immunoprecipitation, immunofluorescence, biosynthesis/stability assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted palmitoylation with defined mutations, multiple orthogonal biochemical and cell biological methods, single lab\",\n      \"pmids\": [\"11907260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CD151 associates with α7β1 integrin comparably to α3β1. Most tissues expressing laminin-binding integrins show CD151-integrin complexes, but the association is subject to cell-type-specific regulation as shown by differential TS151r epitope accessibility in vivo.\",\n      \"method\": \"Co-immunoprecipitation, immunohistochemistry with epitope-blocking antibodies, K562 cell surface expression studies\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus in vivo tissue validation, single lab, multiple integrin partners tested\",\n      \"pmids\": [\"11884516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"An extracellular QRD(194-196) site in CD151 is required for strong (Triton X-100-resistant) association with both α3β1 and α6β1 integrins, and this association occurs early in biosynthesis with α subunit precursors. QRD→INF mutation disrupts CD151-integrin association and impairs α3/α6 integrin-dependent cellular cable formation on Matrigel and cell spreading.\",\n      \"method\": \"Site-directed mutagenesis (QRD→INF), co-immunoprecipitation in Triton X-100 and Brij 96, biosynthetic pulse-chase, cell morphology assays on Matrigel\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — precise mutagenesis with functional validation, multiple integrin partners, multiple detergent conditions, in vitro morphogenesis assay\",\n      \"pmids\": [\"12356873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CD151-α6β1 complex acts as a functional unit for cellular morphogenesis on Matrigel. Deletion or exchange of the short 8 amino acid C-terminal tail of CD151 causes a dominant negative effect that suppresses α6β1-dependent cell network formation and spreading on laminin-1, without disrupting α6β1 association or adhesion to Matrigel.\",\n      \"method\": \"C-terminal deletion/exchange mutagenesis, cell network formation assay on Matrigel, cell adhesion assay, co-immunoprecipitation\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — domain deletion mutagenesis with functional validation in multiple cell types, orthogonal adhesion and morphogenesis assays\",\n      \"pmids\": [\"11809818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CD151 enhances cell motility and invasion in a FAK-dependent manner. CD151 overexpression in FAK(+/+) fibroblasts increased invasion and motility (inhibitable by anti-CD151 mAb), while CD151 overexpression in FAK(-/-) fibroblasts produced no enhancement and was unaffected by anti-CD151 mAb, demonstrating that FAK is required for CD151-mediated pro-migratory effects.\",\n      \"method\": \"Transfection of CD151 into FAK(+/+) and FAK(-/-) fibroblasts, Matrigel invasion assay, cell motility assay, antibody inhibition\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis using FAK-null cells, clean loss-of-function and gain-of-function comparison, in vivo metastasis validation\",\n      \"pmids\": [\"11774285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CD151 is required for α6β1 integrin adhesion strengthening to laminin-1. Cells expressing a C-terminal region-mutant CD151 showed impaired adhesion strengthening under defined applied forces (0-1.5 nN), without affecting static adhesion to laminin-1 or detachment of fibronectin/anti-α6-coated beads.\",\n      \"method\": \"Magnetic bead force application (0-1.5 nN), bead detachment assay, site-directed mutagenesis of CD151 C-terminal region, NIH 3T3 transfection system\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biophysical reconstitution with defined force application, mutagenesis, specific integrin/substrate controls\",\n      \"pmids\": [\"12805567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CD151 in complex with α3β1 integrin functions as a component of a cell-cell adhesion complex in epithelial cells, stimulating E-cadherin-mediated adhesion by regulating PTPμ expression and organizing a multimolecular complex containing PKCβII, RACK1, PTPμ, β-catenin, and E-cadherin.\",\n      \"method\": \"Co-immunoprecipitation, gene expression analysis, PTPμ reporter assays, epistasis using α3 integrin-deficient cells\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of multi-protein complex plus genetic epistasis with α3-null cells, single lab\",\n      \"pmids\": [\"14691142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CD151 overexpression in A431 epithelial cells accelerates intercellular adhesion via PKC- and Cdc42-dependent actin cytoskeletal reorganization. CD151 engagement induced Cdc42-dependent filopodial extension and enhanced E-cadherin puncta formation and its anchorage to the cytoskeletal matrix; calphostin C (PKC inhibitor) blocked these effects.\",\n      \"method\": \"Overexpression, anti-CD151 mAb perturbation, Cdc42/Rac GTP-pull-down, pharmacological inhibition (calphostin C), immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GTP-Rho pulldown plus pharmacological and antibody perturbation, multiple endpoints, single lab\",\n      \"pmids\": [\"14557253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CD151 interacts with proMMP-7 (promatrilysin-1) through the propeptide of proMMP-7 and the C-terminal extracellular loop of CD151, as mapped by yeast two-hybrid and co-immunoprecipitation. This CD151-proMMP-7 interaction promotes pericellular activation of proMMP-7 on the cell surface, as demonstrated by in situ zymography blocked by anti-CD151 antibody.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, 125I-labeled proMMP-7 binding assay, confocal colocalization, in situ zymography with antibody inhibition\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — yeast two-hybrid with domain mapping, biochemical binding assay, functional in situ zymography with multiple inhibitory controls\",\n      \"pmids\": [\"16200075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CD151 forms a structural and functional complex with c-Met/HGF receptor and integrin α3/α6. Knockdown of CD151 or integrin α3/α6 almost completely abrogated HGF-stimulated cell growth and migration in salivary gland cancer cells; forced CD151 expression enhanced HGF-dependent effects.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, gain-of-function transfection, cell growth and migration assays with HGF stimulation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus loss- and gain-of-function in same cell system, single lab\",\n      \"pmids\": [\"16139245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CD151-mediated homophilic interactions between cells activate integrin-dependent signaling through FAK, Src, p38 MAPK, JNK, and c-Jun, leading to AP-1-dependent transcription of MMP-9 and enhanced cell motility. Inhibitors/siRNAs against FAK, Src, p38 MAPK, and JNK abrogated these CD151-induced effects; integrin α3β1/α6β1 activation was a prerequisite.\",\n      \"method\": \"Stable transfection, siRNA knockdown, pharmacological inhibition, MMP-9 promoter AP-1 reporter assay, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple signaling pathway dissection with siRNA and pharmacological inhibitors plus reporter assay, single lab\",\n      \"pmids\": [\"16798740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CD151 silencing in epidermal carcinoma cells impairs motility on laminin-5, causes persistent adhesive contacts, disrupts α3β1 association with tetraspanin-enriched microdomains, reduces α3β1 bulk detergent extractability, and impairs α3β1 internalization during migration. Both α3β1- and α6β4-dependent adhesion to laminin-5 were also impaired. CD151 re-expression reversed these defects.\",\n      \"method\": \"Retroviral RNAi, cell motility/adhesion assays on laminin-5, detergent solubility fractionation, integrin internalization assay, rescue experiment\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean siRNA KD with rescue by re-expression, multiple orthogonal assays, integrin trafficking mechanistic insight\",\n      \"pmids\": [\"16571677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD151 contains a YRSL (YXXφ) endocytosis/sorting motif in its C-terminal cytoplasmic domain. Mutation of this motif markedly attenuates CD151 internalization, completely abrogates CD151-promoted cell migration on laminin, and diminishes internalization of associated integrins (α3β1, α5β1, α6β1), demonstrating that CD151-mediated integrin trafficking is critical for promoting cell motility.\",\n      \"method\": \"YXXφ motif mutagenesis, internalization assays, cell migration assays on ECM substrates, co-localization studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of defined endocytic motif with functional validation in trafficking and migration assays, multiple integrin partners tested\",\n      \"pmids\": [\"17716972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"DHHC2, a DHHC-domain palmitoyl transferase, is the primary enzyme responsible for palmitoylation of tetraspanins CD151 and CD9. DHHC2 associates with CD151 and CD9 but not other cell-surface proteins; DHHC2 knockdown diminishes CD151/CD9 palmitoylation. Catalytically inactive DHHC2 (DH→AA or C→S mutations) fails to promote palmitoylation. DHHC2-dependent palmitoylation promotes CD9-CD151 associations, protects CD151 and CD9 from lysosomal degradation, and shifts cells toward increased cell-cell contacts.\",\n      \"method\": \"DHHC enzyme knockdown panel, [3H]-palmitate labeling, co-immunoprecipitation, catalytic mutant DHHC2, stability assays, cell morphology analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — identified writer enzyme with catalytic mutagenesis, systematic knockdown of 7 DHHC enzymes, multiple functional consequences validated\",\n      \"pmids\": [\"18508921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CD151 regulates N-glycosylation of α3β1 integrin specifically (not other associated proteins). CD151 knockdown reduces Fucα1-2Gal and bisecting GlcNAc modifications on α3 integrin N-glycans. Direct CD151-integrin contact is required but not sufficient; CD151 glycosylation at Asn159 in the LEL is also essential. Changes in α3β1 glycosylation correlate with impaired cell migration toward laminin-332.\",\n      \"method\": \"siRNA knockdown, glycan analysis, CD151 glycosylation mutant (N159Q), co-immunoprecipitation, migration assay, rescue with WT vs. mutant CD151\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of both CD151 glycosylation and integrin-binding domain, with functional validation in migration assay and specificity controls\",\n      \"pmids\": [\"18852263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CD151 ablation in basal-like mammary tumor cells redistributes α6β4 integrin subcellularly, severs molecular links between integrins and tetraspanin-enriched microdomains, reduces cell migration/invasion/spreading, and diminishes signaling through FAK, Rac1, and Lck while disrupting EGFR-α6 integrin collaboration. CD151 ablation delays tumor progression in xenograft models.\",\n      \"method\": \"RNAi ablation, integrin localization imaging, FAK/Rac1/Lck phosphorylation assays, EGFR co-immunoprecipitation, xenograft tumor models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean loss-of-function with multiple signaling readouts, in vitro and in vivo validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"18451146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CD151 regulates integrin α3β1 cell morphology and intracellular signaling on laminin-511. CD151 knockdown in A549 cells causes aberrant membrane protrusions and reduces tyrosine phosphorylation of FAK, Src, p130Cas, and paxillin, independent of the reduction in adhesive activity, suggesting CD151 controls both integrin adhesion strength and integrin-stimulated signaling through distinct mechanisms.\",\n      \"method\": \"RNAi knockdown, cell morphology analysis, phosphorylation assays (FAK, Src, p130Cas, paxillin), integrin-activating antibody rescue\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with multiple signaling readouts and rescue experiments, single lab\",\n      \"pmids\": [\"18492066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CD151 loss destabilizes E-cadherin-dependent carcinoma cell-cell junctions and enhances collective tumor cell sheet migration. This occurs through excessive RhoA activation, loss of actin organization at junctions, and increased basal stress fibers. A CD151 mutant with impaired α3β1 association fails to restore junctional stability, linking the CD151-α3β1 axis to RhoA regulation at junctions.\",\n      \"method\": \"siRNA silencing, collective migration assay, RhoA activity pulldown (G-LISA), actin staining, live-cell junction remodeling imaging, CD151 mutant rescue\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KD with rescue by WT vs. integrin-binding mutant, RhoA activity measurement, live-cell imaging of junction dynamics\",\n      \"pmids\": [\"19509057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CD151 forms a structural and functional complex with c-Met and integrin α3/α6 in breast cancer cells. Knockdown of CD151, integrin α3, or integrin α6 abolished HGF-induced branching morphogenesis and reduced Akt phosphorylation, placing CD151 in the HGF/c-Met/integrin signaling axis.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, HGF-stimulated morphogenesis assay, Akt phosphorylation measurement\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus loss-of-function knockdown with signaling readout, single lab\",\n      \"pmids\": [\"19159612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CD151 on endothelial cells promotes angiogenesis via the PI3K/Akt pathway, activating Akt and eNOS leading to increased nitric oxide production. CD151 overexpression increased HUVEC proliferation, migration, and tube formation; PI3K inhibitor (LY294002) and eNOS inhibitor (L-NAME) attenuated these effects.\",\n      \"method\": \"rAAV-mediated overexpression, PI3K/Akt/eNOS phosphorylation assays, NO measurement, proliferation/migration/tube formation assays, pharmacological inhibition\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function and pharmacological inhibition with multiple signaling readouts, single lab\",\n      \"pmids\": [\"17045834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CD151 promotes MMP9 expression in HCC cells through the PI3K/Akt/GSK-3β/Snail signaling pathway. CD151 overexpression increased MMP9, and CD151 knockdown reduced MMP9 expression and impaired microvessel formation in vitro.\",\n      \"method\": \"siRNA knockdown, overexpression, PI3K/Akt/GSK-3β/Snail signaling pathway analysis by Western blot, MMP9 expression assay, in vitro microvessel formation assay\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway dissection with loss- and gain-of-function, multiple signaling intermediates tested, single lab\",\n      \"pmids\": [\"20578262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CD151 is required for Met-dependent cancer cell growth and survival. CD151 depletion impairs HGF-driven proliferation, anchorage-independent growth, and protection from anoikis. Mechanistically, CD151 is required for formation of Met-β4 integrin signaling complexes; CD151 depletion blocks HGF-induced β4 integrin phosphorylation, Grb2-Gab1 association, and MAPK (but not AKT) activation.\",\n      \"method\": \"RNAi silencing, co-immunoprecipitation of Met-β4 integrin complex, phosphorylation assays (β4, MAPK, AKT), anchorage-independent growth assay, xenograft model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic dissection of signaling complex with specific pathway readouts (MAPK vs AKT), in vitro and in vivo validation\",\n      \"pmids\": [\"20937830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CD151 knockdown, combined with trastuzumab, inhibits ErbB2 activation and downstream signaling through Akt, Erk1/2, and FAK in ErbB2+ breast cancer cells adherent to laminin-5, sensitizing them to trastuzumab and lapatinib. The laminin-integrin-CD151-FAK axis provides resistance to anti-ErbB2 agents.\",\n      \"method\": \"siRNA knockdown, drug sensitivity assays, ErbB2/Akt/Erk1/2/FAK phosphorylation Western blot, 3D laminin-5 adhesion assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional epistasis between CD151 and ErbB2 signaling, multiple signaling readouts, single lab\",\n      \"pmids\": [\"20197472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD151 in podocytes is required for integrin α3β1-mediated adhesion strength to laminin in the glomerular basement membrane. Podocyte-specific Cd151 deletion leads to glomerular nephropathy, and blood pressure is a critical modifier—global Cd151-null mice on FVB background develop renal disease, with ACE inhibition prolonging survival.\",\n      \"method\": \"Conditional and global knockout mice, cell adhesion strength assays, histology, ACE inhibitor treatment, blood pressure manipulation\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific knockout with defined phenotype, modifier analysis, therapeutic intervention validation, mechanistic link to adhesion strength\",\n      \"pmids\": [\"22201679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD151 maintains vascular stability by promoting endothelial cell-cell and cell-matrix adhesions through confining cytoskeletal tension: CD151 loss elevates RhoA signaling (increasing actin cytoskeletal traction) and diminishes Rac1 activity (reducing cortical actin meshwork). RhoA inhibition or cAMP activation stabilizes CD151-silenced endothelial structures.\",\n      \"method\": \"siRNA silencing, Cd151 knockout endothelial cells, Rho/Rac activity assays, permeability assays, pharmacological RhoA inhibition, endothelial tube formation assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — null cells plus siRNA knockdown, Rho/Rac activity measurement, pharmacological rescue, in vivo vascular permeability assay\",\n      \"pmids\": [\"21832275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Host animal CD151 is required for efficient tumor metastasis. CD151-null mice show markedly diminished experimental lung metastasis after Lewis lung carcinoma or B16F10 injection. CD151-null mouse lung endothelial cells show diminished support for tumor cell adhesion, transendothelial migration, and permeability induction. VEGF-induced Src and Akt signaling was diminished in CD151-null endothelial cells.\",\n      \"method\": \"CD151-null mice, experimental metastasis models (i.v. injection), isolated null endothelial cells, transendothelial migration assay, permeability assay, VEGF signaling assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — global knockout with mechanistic dissection in isolated endothelial cells, multiple in vitro and in vivo readouts\",\n      \"pmids\": [\"21536858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD151 knockdown in MDA-MB-231 mammary cells impairs α6 integrin clustering without decreasing α6 expression or activation. CD151 knockdown shifts α6 integrin diffusion from predominantly random-confined diffusion (RCD) to directed motion (DMO), a dysregulating effect sensitive to actin disruption but desensitized to talin knockdown and phorbol ester stimulation. CD151 effects on diffusion mode are specific to α6 (not αv) integrins.\",\n      \"method\": \"Single particle tracking (SPT), siRNA knockdown, mode-of-diffusion analysis, phorbol ester and EGF stimulation, talin knockdown, actin disruption\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — single-particle tracking with quantitative diffusion mode analysis, specific controls with non-associated integrins, multiple perturbations\",\n      \"pmids\": [\"22328509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD151 promotes skin squamous cell carcinoma (SCC) initiation and progression by supporting STAT3 activation and PKCα-α6β4 integrin association. CD151 supports PKC-dependent β4 S1424 phosphorylation and regulates α6β4 subcellular distribution to promote an invasive state. CD151 ablation sensitizes mouse skin to carcinogens and drugs targeting EGFR, PKC, Jak2/Tyk2, and STAT3.\",\n      \"method\": \"Two-stage chemical carcinogenesis in Cd151 knockout mice, STAT3 activation assay, PKCα-β4 co-immunoprecipitation, β4 phosphorylation Western blot, pharmacological sensitization\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout in in vivo carcinogenesis model, mechanistic signaling dissection, multiple drug sensitization readouts\",\n      \"pmids\": [\"22824799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The α3β1-CD151 complex regulates ErbB2 dimerization and phosphorylation through RhoA. Depletion of either α3β1 or CD151 reduces ErbB2 phosphorylation, reduces ErbB2 dimerization, and increases RhoA activity. RhoA directly controls ErbB2 dimerization. Combined expression of α3β1 and CD151 enhances Herceptin efficacy.\",\n      \"method\": \"siRNA knockdown, ErbB2 dimerization assay, ErbB2 phosphorylation Western blot, RhoA activity (G-LISA), Herceptin treatment in 3D culture, Rho manipulation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function for both partners, signaling mechanistic dissection, multiple readouts, single lab\",\n      \"pmids\": [\"23792450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD151 mediates HPV16 endocytosis. Surface-bound HPV16 co-moves with CD151 in the plane of the membrane before cointernalization. CD151 depletion reduces HPV16 endocytosis (not binding). The C-terminal cytoplasmic region (but not tyrosine-based sorting motif) and palmitoylation of CD151 are required; CD151-associated integrins α3β1 and α6β1/4 are also involved; CD151 QRD integrin-binding site mutants do not restore virus internalization.\",\n      \"method\": \"CD151 depletion (siRNA), live-cell co-tracking, internalization assay, CD151 domain mutants (C-terminal deletion, YRSL, palmitoylation, QRD), integrin siRNA knockdown\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple CD151 domain mutants, siRNA for CD151 and associated integrins, live-cell imaging, mechanistic dissection of entry step\",\n      \"pmids\": [\"23302890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD151 depletion in CD151-silenced carcinoma cells disrupts α3β1 integrin association with tetraspanin-enriched microdomains and impairs α3β1 internalization. CD9/CD81 complex but not CD151 is required for α3β1 association with PKCα and directed α3β1-dependent motility; CD151 is required for early spreading events. These two tetraspanin complexes have overlapping but distinct roles in α3β1 function.\",\n      \"method\": \"RNAi silencing of CD9/CD81 vs. CD151, co-immunoprecipitation with PKCα, directed motility assay, spreading assay, cell morphology analysis, PKC inhibitor\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — comparative knockdown of tetraspanin pairs, Co-IP, multiple functional assays, single lab\",\n      \"pmids\": [\"23613949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD151 depletion specifically attenuates TGFβ1-induced scattering and proliferation of breast cancer cells in 3D Matrigel, requiring its association with α3β1 or α6 integrins but independent of tetraspanin-enriched microdomain recruitment. CD151 regulates compartmentalization of TGFβ type I receptor (ALK-5) and specifically controls TGFβ1-induced p38 activation (not Smad2/3, c-Akt, or Erk1/2).\",\n      \"method\": \"shRNA knockdown, 3D Matrigel scattering assay, TGFβ receptor localization, p38/Smad2/3/Akt/Erk1/2 phosphorylation assays, CD151 mutant rescue, experimental lung metastasis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — specific signaling pathway discrimination (p38 vs. Smad/AKT/ERK), TGFβR compartmentalization, mutant rescue, in vivo metastasis validation\",\n      \"pmids\": [\"20570898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD151 and CD9 congregate at the T-cell side of the immunological synapse. Silencing CD151 or CD9 blunts IL-2 secretion and CD69 expression by APC-conjugated T cells, diminishes α4β1 relocalization to the IS, reduces high-affinity β1 integrin accumulation at the contact, and decreases FAK and ERK1/2 phosphorylation, without affecting CD3 or actin accumulation at the IS.\",\n      \"method\": \"siRNA silencing, immunological synapse imaging, IL-2 ELISA, CD69 flow cytometry, integrin relocalization and activation assays, FAK/ERK phosphorylation\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with multiple functional readouts at the IS, single lab\",\n      \"pmids\": [\"24723389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD151 is a proviral host factor for HCMV entry, supporting viral penetration (but not adsorption) into endothelial cells and fibroblasts. CD151 depletion impairs infection by virus strains with broad or narrow cell tropism equally, as shown by fluorescent virus with differentially labeled capsid and envelope proteins.\",\n      \"method\": \"Targeted RNAi screen (96 genes), CD151 depletion (siRNA), HCMV infection assay, fluorescent virus penetration vs. adsorption assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi screen hit validated with mechanistic dissection (penetration vs. adsorption), multiple HCMV strains, single lab\",\n      \"pmids\": [\"27147745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD151, through binding to integrin α3β1, stabilizes a hybrid adhesion structure (with features of both hemidesmosomes and tetraspanin-enriched microdomains) containing CD151-α3β1/α6β4 integrin complexes and plectin but not keratin filaments, in the central region of keratinocytes. Classic hemidesmosomes (α6β4/plectin/BP180/BP230/keratin) do not require CD151.\",\n      \"method\": \"CD151 knockout keratinocytes, α3β1-CD151 co-immunoprecipitation, immunofluorescence of adhesion structure components, spreading/adhesion kinetics assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout cells with compositional analysis of distinct adhesion structures, single lab\",\n      \"pmids\": [\"31488507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD151 supports anti-cancer drug resistance independent of integrins. CD151 ablation sensitizes tumor cells to gefitinib and camptothecin (increasing apoptosis). Drug sensitization occurs even when integrins are unengaged; integrin α3/α6 ablation does not mimic CD151 ablation; the CD151-QRD mutant (diminished integrin association) reconstitutes drug protection as effectively as WT CD151. Anti-cancer drug treatment selectively upregulates intracellular non-integrin-associated CD151.\",\n      \"method\": \"CD151 ablation (CRISPR/siRNA), apoptosis assays (cleaved caspase-3, cleaved PARP, annexin V, PI), CD151-QRD mutant reconstitution, integrin α3/α6 ablation comparison, intracellular vs. surface CD151 fractionation\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — integrin-independent mechanism established by multiple orthogonal controls (QRD mutant, integrin KO comparison, ligand-free conditions), multiple apoptosis assays\",\n      \"pmids\": [\"30778617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD151 in cardiomyocytes suppresses proliferation by inducing p38 expression. miR-199a-3p directly targets CD151 mRNA, suppresses CD151, and promotes cardiomyocyte proliferation. Cd151 gain-of-function reduced cardiomyocyte proliferation; Cd151 loss-of-function increased it. Pharmacological p38 inhibition rescued the Cd151 inhibitory effect on proliferation.\",\n      \"method\": \"Luciferase reporter assay (miR-199a-3p/CD151 3'UTR), Cd151 gain- and loss-of-function in cardiomyocytes, p38 inhibitor rescue, proliferation assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — validated miRNA target with reciprocal gain/loss-of-function and pharmacological rescue, single lab\",\n      \"pmids\": [\"31186138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD151 in inflammatory breast cancer cells promotes macrophage recruitment through a midkine-dependent mechanism. CD151 increases midkine production; purified midkine stimulates monocyte migration specifically. CD151-expressing IBC-derived extracellular vesicles have chemoattractive potential for monocytes, blocked by anti-midkine antibodies. This pathway also involves integrin α6β1.\",\n      \"method\": \"In vitro monocyte migration assay, midkine purification and functional assay, anti-midkine antibody blocking of EV chemoattraction, xenograft immunohistology, chemokine profiling\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional chemoattraction assay with blocking antibody, EV-mediated pathway, in vivo xenograft validation, single lab\",\n      \"pmids\": [\"32129471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JAM-A forms a complex with α3β1 integrin and tetraspanins CD151 and CD9 through its extracellular domain. This complex regulates collective cell migration of polarized epithelial cells on laminin and collagen-I (not fibronectin/vitronectin). Depletion of JAM-A, α3β1 integrin, or CD151/CD9 impairs cryptic lamellipodia dynamics and slows collective migration.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping experiments, siRNA depletion of JAM-A/α3β1/CD151/CD9, collective migration assay, substrate-specificity experiments\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, multiple knockdowns, substrate specificity controls, single lab\",\n      \"pmids\": [\"35067832\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD151 is a tetraspanin scaffold protein that forms direct, stoichiometric lateral complexes with laminin-binding integrins (α3β1, α6β1, α6β4, α7β1) through its large extracellular loop (QRD194-196 site) and the α3 extracellular domain (aa 570-705); these complexes assemble early in biosynthesis, are stabilized by CD151 palmitoylation (at C11/C15/C242/C243, written by DHHC2), and regulate integrin endocytic trafficking (via a C-terminal YRSL/YXXφ motif), integrin diffusion mode, adhesion strengthening, glycosylation of α3β1, and downstream signaling through FAK, Src, Rac1/Cdc42, RhoA, PI3K/Akt/eNOS, and p38 MAPK to control cell migration, collective migration, morphogenesis, angiogenesis, MMP activation, and drug resistance in both integrin-dependent and integrin-independent manners.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CD151 (PETA-3) is a tetraspanin scaffold protein that organizes laminin-binding integrins into lateral membrane complexes to control cell adhesion, migration, morphogenesis, and angiogenesis [#0, #1, #2]. It forms direct, detergent-resistant complexes specifically with integrins \\u03b13\\u03b21 and \\u03b16\\u03b21 (and comparably \\u03b17\\u03b21), while other tetraspanins associate with these integrins only indirectly through CD151 [#3, #9]. The interaction is extracellular and stoichiometric: CD151 contacts the \\u03b13 subunit (aa 570-705) through its large extracellular loop, and a defined QRD(194-196) site is required for strong association with both \\u03b13\\u03b21 and \\u03b16\\u03b21, with complex assembly occurring early in biosynthesis [#6, #7, #10]. CD151 is palmitoylated on intracellular cysteines (C11/C15/C242/C243) by the DHHC2 palmitoyl transferase, which stabilizes the protein, protects it from lysosomal degradation, and promotes its associations with other tetraspanins (CD9, CD63) without disrupting the core CD151-\\u03b13\\u03b21 interaction [#8, #21]. Through these complexes CD151 strengthens integrin adhesion to laminin under force, governs integrin diffusion mode and clustering, drives \\u03b13\\u03b21 glycosylation, and controls integrin endocytic trafficking via a C-terminal YRSL/YXX\\u03c6 motif required for both integrin internalization and CD151-promoted migration [#13, #20, #22, #34]. Downstream it signals through FAK, Src, Rho-family GTPases (Rac1/Cdc42/RhoA), and PI3K/Akt/eNOS to control collective migration, junction stability, MMP activation, and endothelial angiogenesis [#15, #18, #25, #27, #32]. CD151 also collaborates with growth-factor receptors\\u2014assembling Met-\\u03b24 integrin signaling complexes and modulating ErbB2 dimerization through RhoA\\u2014linking it to tumor progression and anti-receptor drug resistance [#29, #36, #30]. In vivo, podocyte-specific and global Cd151 deletion cause integrin-\\u03b13\\u03b21-dependent glomerular nephropathy, and host CD151 is required for efficient endothelial support of tumor metastasis [#31, #33]. CD151 additionally functions as a host entry factor for HPV16 and HCMV and, independently of integrins, promotes resistance to anti-cancer drugs via an intracellular pool [#37, #41, #43].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established CD151 as a distinct four-transmembrane tetraspanin/TM4SF protein, defining the molecular entity before any function was known.\",\n      \"evidence\": \"cDNA cloning, sequence analysis, and Northern blot of PETA-3\",\n      \"pmids\": [\"7632941\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No binding partners or cellular function identified\", \"Topology inferred from sequence, not directly demonstrated\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"First linked CD151 to integrin biology and migration by showing it complexes with \\u03b13\\u03b21 and other tetraspanins at endothelial junctions and that antibody blockade impairs migration and invasion.\",\n      \"evidence\": \"Co-IP, immunofluorescence, time-lapse microscopy and collagen invasion in endothelial cells\",\n      \"pmids\": [\"9566977\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the integrin association is direct vs. indirect unresolved\", \"Binding site on either protein unmapped\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined the specificity and directness of CD151-integrin coupling, showing CD151 forms direct complexes specifically with \\u03b13\\u03b21 and \\u03b16\\u03b21 and serves as the linker through which other tetraspanins reach integrins; concurrently established CD151 as a pro-migratory, pro-metastatic factor.\",\n      \"evidence\": \"Reciprocal Co-IP across detergent conditions, epitope-blocking, overexpression and antibody inhibition in tumor and haematopoietic cells with in vivo metastasis\",\n      \"pmids\": [\"10229664\", \"10447000\", \"10036233\", \"9931299\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular determinants of the direct interaction not yet mapped\", \"Downstream signaling effectors unknown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Mapped the CD151-integrin interface to extracellular regions (\\u03b13 aa 570-705 and CD151 LEL aa 186-217) and confirmed the four-pass topology, establishing the structural basis of complex formation.\",\n      \"evidence\": \"Membrane-impermeable cross-linking, chimeric constructs and topology determination\",\n      \"pmids\": [\"10734060\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of these specific residues not yet tested\", \"Stoichiometry of the complex undefined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined the LEL residues (incl. CCG/PXXCC motifs and aa 195-205) needed for stable \\u03b13\\u03b21 association and showed the complex assembles early in biosynthesis, separating CD151-integrin coupling from CD151-tetraspanin homotypic interactions.\",\n      \"evidence\": \"Site-directed mutagenesis, chimeras, multi-detergent Co-IP and pulse-chase\",\n      \"pmids\": [\"11479292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the minimal QRD determinant identified later\", \"Effect on downstream function not directly assayed\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that palmitoylation at four cysteines, the QRD(194-196) site, and the C-terminal tail are separable functional modules: palmitoylation governs tetraspanin web assembly and stability, QRD governs strong integrin binding, and the C-terminal tail is required for morphogenesis.\",\n      \"evidence\": \"Palmitoylation-site and QRD mutagenesis, [3H]-palmitate labeling, C-terminal deletion, Matrigel morphogenesis and Co-IP; \\u03b17\\u03b21 association confirmed\",\n      \"pmids\": [\"11907260\", \"12356873\", \"11809818\", \"11884516\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzyme writing palmitoylation not yet identified\", \"Mechanism linking C-terminal tail to morphogenesis unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Placed CD151 pro-migratory activity downstream of FAK, demonstrating genetic dependence on FAK for CD151-enhanced motility and invasion.\",\n      \"evidence\": \"CD151 transfection into FAK(+/+) vs FAK(-/-) fibroblasts with invasion/motility and metastasis assays\",\n      \"pmids\": [\"11774285\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other downstream effectors (Src, Rho GTPases) not yet placed\", \"How CD151 activates FAK mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrated CD151's biophysical role in integrin adhesion strengthening and its participation in epithelial cell-cell adhesion complexes via PKC/Cdc42 and a PTP\\u03bc/E-cadherin module.\",\n      \"evidence\": \"Magnetic-bead force assays with C-terminal mutants; Co-IP of E-cadherin junctional complex and Cdc42/Rac pulldowns with PKC inhibition\",\n      \"pmids\": [\"12805567\", \"14691142\", \"14557253\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect nature of multiprotein junctional complex not fully resolved\", \"Mechanism connecting CD151 to PTP\\u03bc expression unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Extended CD151 function to pericellular proteolysis and growth-factor receptor signaling, identifying proMMP-7 as an extracellular-loop binding partner and CD151-c-Met-integrin complexes as drivers of HGF responses.\",\n      \"evidence\": \"Yeast two-hybrid and Co-IP domain mapping with in situ zymography; Co-IP and knockdown/overexpression with HGF stimulation\",\n      \"pmids\": [\"16200075\", \"16139245\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry of CD151-c-Met complex undefined\", \"Whether c-Met contact is direct unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Resolved the CD151 homophilic-engagement signaling cascade, linking integrin activation to FAK/Src/p38/JNK/c-Jun and AP-1-driven MMP-9 transcription.\",\n      \"evidence\": \"Stable transfection, siRNA, pathway inhibitors and MMP-9 AP-1 reporter assays\",\n      \"pmids\": [\"16798740\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct kinase substrate relationships not established\", \"Single-lab pathway dissection\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified the C-terminal YRSL/YXX\\u03c6 motif as the endocytic determinant coupling CD151-mediated integrin internalization to cell motility.\",\n      \"evidence\": \"Motif mutagenesis with internalization and migration assays across multiple integrins\",\n      \"pmids\": [\"17716972\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Adaptor proteins reading the YXX\\u03c6 motif not identified\", \"Trafficking route/destination of internalized integrin undefined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified DHHC2 as the palmitoyl transferase writing CD151 palmitoylation, and showed CD151 controls \\u03b13\\u03b21 N-glycosylation and \\u03b16\\u03b24-dependent tumor signaling, deepening the post-translational and signaling regulation of the complex.\",\n      \"evidence\": \"DHHC knockdown panel with catalytic mutants; glycosylation analysis with N159Q and integrin-binding mutants; RNAi ablation with FAK/Rac1/Lck and EGFR readouts and xenografts\",\n      \"pmids\": [\"18508921\", \"18852263\", \"18451146\", \"18492066\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CD151 shapes \\u03b13 glycan processing unclear\", \"Whether DHHC2 acts on the integrin-bound pool specifically untested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Connected endothelial CD151 to angiogenesis through PI3K/Akt/eNOS-driven nitric oxide production.\",\n      \"evidence\": \"rAAV overexpression, signaling phosphorylation, NO measurement, and tube formation with PI3K/eNOS inhibitors in HUVEC\",\n      \"pmids\": [\"17045834\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor/integrin upstream of PI3K activation not defined here\", \"Single gain-of-function model\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Established CD151 as a regulator of RhoA at epithelial junctions and of collective migration, mechanistically tying junctional stability to the CD151-\\u03b13\\u03b21 axis.\",\n      \"evidence\": \"siRNA, collective migration, RhoA G-LISA, live imaging and rescue with WT vs integrin-binding mutant CD151; plus c-Met/\\u03b13\\u03b16 branching morphogenesis\",\n      \"pmids\": [\"19509057\", \"19159612\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CD151 restrains RhoA biochemically unresolved\", \"GEF/GAP intermediaries unidentified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Cemented CD151's role in tumor invasion and therapy resistance through Met-\\u03b24 complexes, PI3K/Akt/GSK-3\\u03b2/Snail-driven MMP9, and the laminin-integrin-CD151-FAK axis conferring anti-ErbB2 drug resistance.\",\n      \"evidence\": \"RNAi/overexpression with Co-IP of Met-\\u03b24, pathway Westerns, anchorage-independent growth, xenografts and trastuzumab/lapatinib sensitivity assays\",\n      \"pmids\": [\"20937830\", \"20578262\", \"20197472\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selective MAPK-vs-AKT branching downstream of Met-\\u03b24 mechanism unresolved\", \"Direct molecular link between CD151 and ErbB2 unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided in vivo genetic proof of CD151 function: podocyte adhesion to the glomerular basement membrane, endothelial vascular stability via RhoA/Rac1 balance, and host support of metastasis through endothelial VEGF/Src/Akt signaling.\",\n      \"evidence\": \"Conditional and global Cd151-null mice, adhesion-strength assays, Rho/Rac activity, permeability, ACE-inhibitor and experimental metastasis models\",\n      \"pmids\": [\"22201679\", \"21832275\", \"21536858\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-autonomous vs systemic contributions to metastasis not fully separated\", \"Modifier effect of blood pressure mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined CD151 control of integrin lateral diffusion and clustering and its role in skin carcinoma initiation via STAT3 and PKC\\u03b1-\\u03b24 association, refining how CD151 organizes integrins at the nanoscale and in tumor initiation.\",\n      \"evidence\": \"Single-particle tracking with talin/actin perturbations; two-stage carcinogenesis in Cd151-null mice with STAT3/\\u03b24-phosphorylation and drug sensitization; ErbB2/RhoA dimerization assays\",\n      \"pmids\": [\"22328509\", \"22824799\", \"23792450\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Link between diffusion-mode control and downstream signaling not directly established\", \"How CD151 promotes \\u03b24 S1424 phosphorylation unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Broadened CD151 roles to pathogen entry (HPV16 endocytosis), distinct tetraspanin-complex division of labor in \\u03b13\\u03b21 function, and selective control of TGF\\u03b21-induced p38 signaling and scattering.\",\n      \"evidence\": \"siRNA with CD151 domain mutants and live co-tracking for HPV16; comparative CD9/CD81 vs CD151 knockdown; shRNA with TGF\\u03b2R compartmentalization and pathway-selective phosphorylation plus in vivo metastasis\",\n      \"pmids\": [\"23302890\", \"23613949\", \"20570898\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HPV16 contacts CD151 directly unresolved\", \"Mechanism of selective p38 (not Smad/AKT/ERK) activation unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Implicated CD151 in immune-cell function, showing it organizes integrins at the T-cell immunological synapse to support activation signaling.\",\n      \"evidence\": \"siRNA silencing with synapse imaging, IL-2/CD69 readouts, integrin relocalization and FAK/ERK phosphorylation\",\n      \"pmids\": [\"24723389\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct integrin partner at the synapse not mapped\", \"Single-lab knockdown study\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified CD151 as a proviral host factor for HCMV entry acting at the penetration step.\",\n      \"evidence\": \"RNAi screen hit validated with differentially labeled fluorescent virus penetration vs adsorption assays\",\n      \"pmids\": [\"27147745\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor/co-factor partners for HCMV penetration undefined\", \"Whether integrin or tetraspanin-web involvement is required not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved an integrin-independent CD151 function in drug resistance and identified CD151 in a hybrid keratinocyte adhesion structure, separating CD151 roles that require integrin binding from those that do not.\",\n      \"evidence\": \"CRISPR/siRNA ablation with apoptosis assays, QRD-mutant reconstitution and integrin-KO comparison; CD151-KO keratinocytes with compositional analysis of adhesion structures; miR-199a-3p targeting CD151 in cardiomyocytes\",\n      \"pmids\": [\"30778617\", \"31488507\", \"31186138\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular effector of integrin-independent drug protection unidentified\", \"Intracellular CD151 binding partners mediating survival unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended CD151 to the tumor microenvironment, showing it drives midkine-dependent macrophage/monocyte recruitment including via extracellular vesicles.\",\n      \"evidence\": \"Monocyte migration with purified midkine, anti-midkine blocking of EV chemoattraction and xenograft immunohistology\",\n      \"pmids\": [\"32129471\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking CD151 to midkine production unresolved\", \"Role of \\u03b16\\u03b21 in this axis incompletely defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a JAM-A/\\u03b13\\u03b21/CD151/CD9 complex driving collective epithelial migration on laminin and collagen-I via cryptic lamellipodia.\",\n      \"evidence\": \"Co-IP with domain mapping, multi-component siRNA depletion and substrate-specific collective migration assays\",\n      \"pmids\": [\"35067832\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect JAM-A-CD151 contact not resolved\", \"Single-lab study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CD151's separable molecular modules (palmitoylation, QRD integrin binding, YXX\\u03c6 trafficking, intracellular pool) are coordinated to switch between integrin-dependent adhesion/migration roles and integrin-independent survival/viral-entry functions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the assembled CD151-integrin complex\", \"Intracellular effectors of integrin-independent CD151 functions unidentified\", \"Adaptors reading the YXX\\u03c6 motif unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 6, 7, 10, 46]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [13, 22, 34, 20]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [37, 41]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 6]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [2, 20]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [2, 21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [13, 19, 42]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [18, 27, 29, 36]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [33, 35, 43]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [10, 11, 25]}\n    ],\n    \"complexes\": [\n      \"CD151-\\u03b13\\u03b21 integrin complex\",\n      \"tetraspanin-enriched microdomain (with CD9/CD81)\",\n      \"Met-\\u03b24 integrin signaling complex\",\n      \"JAM-A/\\u03b13\\u03b21/CD151/CD9 complex\"\n    ],\n    \"partners\": [\n      \"ITGA3\",\n      \"ITGB1\",\n      \"ITGA6\",\n      \"ITGB4\",\n      \"CD9\",\n      \"MET\",\n      \"JAM-A\",\n      \"DHHC2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}