{"gene":"DSG2","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":1994,"finding":"DSG2 was identified as the ubiquitous desmoglein isoform present in all desmosome-containing tissues including simple epithelia, myocardium, and non-epithelial tissues; unlike DSG1 and DSG3, DSG2 is the largest family member (1069 aa) and is the only DSG isoform detected in many tissues such as simple epithelia and myocardium.","method":"cDNA cloning, amino acid sequence determination, Northern/Southern blotting, immunocytochemistry","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 1 / Strong — full protein sequence determination plus immunocytochemical tissue distribution, replicated across multiple tissues and cell lines in the same study","pmids":["8143788"],"is_preprint":false},{"year":1996,"finding":"DSG2 protein localizes to desmosomes in all desmosome-containing tissues (stratified and simple epithelia, myocardium, lymph node follicles); antibodies against the extracellular domain of DSG2 also react with 'half-desmosomes' on the surface of uncoupled epithelial cells. In stratified squamous epithelia, DSG2 is restricted to the basal cell layer.","method":"Immunocytochemistry with monoclonal and polyclonal antibodies against N-terminal extracellular and C-terminal cytoplasmic domains; immunoelectron microscopy","journal":"Differentiation; research in biological diversity","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple antibodies with distinct epitopes, replicated across diverse tissues, consistent with independent cDNA work","pmids":["8641550"],"is_preprint":false},{"year":1992,"finding":"The DSG2 gene was mapped to human chromosome 18, co-localizing with DSG1.","method":"PCR-based chromosomal assignment assay","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct chromosomal localization by PCR, single lab, single method","pmids":["1612610"],"is_preprint":false},{"year":1995,"finding":"The fourth armadillo repeat of plakoglobin is required for its high-affinity binding to the cytoplasmic domain of DSG2 (and E-cadherin and APC); a 12-repeat plakoglobin lacking the fourth armadillo repeat binds DSG2 with lower affinity than the full 13-repeat form.","method":"In vitro binding assay using bacterially expressed recombinant plakoglobin constructs; deletion mutagenesis","journal":"Journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution assay with defined deletion mutants, single lab but multiple binding partners tested orthogonally","pmids":["8749329"],"is_preprint":false},{"year":2007,"finding":"Suprabasal overexpression of DSG2 in transgenic mouse epidermis causes epidermal hyperplasia, increased keratinocyte proliferation, and apoptosis resistance through activation of multiple signaling pathways including PI3K/AKT, MEK-MAPK, STAT3, and NF-κB; this requires EGFR activation and NF-κB activity for anchorage-independent survival.","method":"Involucrin-promoter-driven DSG2 transgenic mice; cultured keratinocytes; EGFR inhibition; NF-κB inhibition; chemical carcinogenesis assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo transgenic model plus in vitro inhibitor studies, multiple orthogonal readouts (proliferation, apoptosis, signaling pathway activation, tumorigenesis)","pmids":["17284515"],"is_preprint":false},{"year":2009,"finding":"Cardiac overexpression of dominant-negative DSG2-N271S (mouse equivalent of human N266S) in transgenic mice causes ARVC features including biventricular dilatation, ventricular arrhythmias, and sudden death; myocyte necrosis was identified as the key initiator of myocardial injury, preceding inflammation, calcification, and fibrous replacement.","method":"Transgenic mouse model with cardiac-specific DSG2 mutant overexpression; histopathology; electrophysiology; multiple transgene expression levels demonstrating dose-dependence","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple transgenic lines with dose-dependent phenotype, human explanted heart tissue correlation, multiple orthogonal assessments","pmids":["19635863"],"is_preprint":false},{"year":2016,"finding":"DSG2 activates EGFR signaling via a c-Src and Caveolin-1 (Cav1)-dependent mechanism using lipid rafts as signaling platforms; DSG2 overexpression displaces Cav1, EGFR, and c-Src from light-density lipid raft fractions, and DSG2 knockdown abrogates EGFR, c-Src, and STAT3 activation in response to EGF, increasing cell proliferation and migration through EGFR/c-Src.","method":"siRNA knockdown, sucrose density fractionation, STED super-resolution imaging, overexpression in A431 cells, cholesterol chelation (MβCD), proliferation and migration assays","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (fractionation, STED imaging, cholesterol depletion, KD/OE), single lab","pmids":["26918609"],"is_preprint":false},{"year":2018,"finding":"DSG2 directly interacts with EGFR and undergoes heterotypic binding via its extracellular domain on the surface of living enterocytes; DSG2 is required for EGFR localization at intercellular junctions and for Src-mediated EGFR activation, directing EGFR signaling towards cell adhesion rather than proliferation. DSG2-deficient enterocytes show impaired barrier properties and increased proliferation.","method":"Atomic force microscopy (AFM) on living cells, co-immunoprecipitation, Src/EGFR inhibitors, DSG2 knockout/knockdown, transepithelial resistance measurement","journal":"Cellular and molecular life sciences : CMLS","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — AFM single-molecule force measurements on living cells plus co-IP plus functional KO, single lab with multiple orthogonal methods","pmids":["29980799"],"is_preprint":false},{"year":2017,"finding":"ARVC-associated DSG2 mutations (tested by single-molecule force spectroscopy) alter the kinetics and thermodynamics of DSG2 homophilic binding without directly affecting the strand-swapping binding motif; the free energy landscape of Dsg2 dimerization shows a high activation barrier consistent with strand-swap binding, and mutations significantly reduce homophilic binding strength in a cell dissociation assay.","method":"Single-molecule force spectroscopy (AFM), Jarzynski's equality thermodynamic analysis, dispase cell dissociation assay with DSG2 WT and mutant overexpressing HT1080 cells","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro single-molecule biophysical assay plus cellular assay, single lab, orthogonal methods","pmids":["29062102"],"is_preprint":false},{"year":2019,"finding":"ARVC-associated DSG2 mutations alter the N-glycosylation pattern of desmoglein-2 protein even when the mutations do not directly affect N-glycosylation consensus sequences, indicating complex molecular interactions between DSG2 mutations and N-glycosylations.","method":"De-glycosylation assays, lectin blot analysis, genetic inhibition of glycosylation, in vitro cell transfection","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple glycosylation assay approaches, single lab","pmids":["30885746"],"is_preprint":false},{"year":2010,"finding":"Ectopic superficial expression of DSG2 (via involucrin promoter transgene) reduces the extent of epidermal blister formation induced by pemphigus foliaceus antibodies and staphylococcal exfoliative toxin ETA, and enhances retention of DSG1 at cell borders, supporting a direct role for DSG2 in epithelial adhesion.","method":"Neonatal transgenic mouse injection with PF IgG or ETA; histology; immunofluorescence for DSG1 isoforms","journal":"Dermatology research and practice","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic model with defined adhesion challenge, single lab","pmids":["20631906"],"is_preprint":false},{"year":2012,"finding":"Human DSG2 functions as a receptor for adenovirus species B (HAdV-B3, B7, B14) and mediates efficient viral transduction of epithelial cells; transgenic mice expressing human DSG2 at physiological levels show hDSG2-dependent transduction of bronchial/alveolar epithelial cells (intranasal) and intestinal/colon epithelial cells (intravenous) by HAdV-B3.","method":"hDSG2 transgenic mouse generation; GFP-expressing HAdV-B3 vector administration; qRT-PCR and immunohistochemistry for GFP","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo transgenic model with human DSG2 expression, multiple routes of delivery and tissues tested, GFP reporter quantification","pmids":["22457526"],"is_preprint":false},{"year":2021,"finding":"Human DSG2 is a receptor for HAdV-B55; 3T3 rodent cells (which do not express human DSG2) became susceptible to HAdV-B55 infection after transfection with pcDNA3.1-DSG2; siRNA knockdown of hDSG2 in A549 cells impaired infection by HAdV-B3, B14, and B55; immunofluorescence confocal microscopy confirmed Cy3-conjugated HAdV-B55 enters cells via binding DSG2.","method":"Heterologous expression (pcDNA3.1-DSG2 in 3T3 cells), siRNA knockdown, immunofluorescence confocal microscopy","journal":"Virologica Sinica","confidence":"High","confidence_rationale":"Tier 2 / Moderate — gain-of-function and loss-of-function experiments plus visual confirmation of receptor-virus colocalization","pmids":["34224109"],"is_preprint":false},{"year":2006,"finding":"UV radiation down-regulates DSG2 in human lens epithelial cells via a pathway involving EGFR transactivation, Rac2 translocation, and NADPH oxidase-dependent reactive oxygen species generation.","method":"Cultured human lens epithelial cells; UV/H2O2 treatment; ROS measurement; EGFR activation assay; Rac2 translocation assay; NADPH oxidase inhibition","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pathway inhibition experiments in cell culture, single lab","pmids":["16820949"],"is_preprint":false},{"year":2018,"finding":"DSG2 regulates β-catenin/Slug-mediated epithelial-to-mesenchymal transition to maintain self-renewal and pluripotency in human pluripotent stem cells; depletion of DSG2 markedly decreased hPSC proliferation and pluripotency marker expression, and DSG2-negative hPSC populations show suppressed embryoid body and teratoma formation.","method":"Monoclonal antibody generation and target identification; siRNA knockdown; pluripotency marker analysis; embryoid body and teratoma formation assays; β-catenin/Slug pathway analysis","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple phenotypic readouts and pathway identification, single lab","pmids":["29910125"],"is_preprint":false},{"year":2020,"finding":"DSG2 undergoes heterophilic binding with DSG3; DSG2-DSG3 heterophilic interactions show binding frequency, strength, Ca2+-dependency, and catch-bond behavior comparable to homophilic Dsg3-Dsg3 interactions, but with longer lifetime than homophilic Dsg2-Dsg2 interactions. PV autoantibodies inhibit homophilic DSG3 interactions more strongly than heterophilic DSG2-DSG3 interactions, suggesting heterophilic binding as a rescue mechanism.","method":"Immunoprecipitation, cell-free atomic force microscopy (AFM), DSG3-deficient keratinocytes, pemphigus autoantibody inhibition experiments, anti-DSG2 inhibitory antibody","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cell-free AFM single-molecule binding assays plus IP, multiple complementary experimental approaches in single study","pmids":["33193387"],"is_preprint":false},{"year":2020,"finding":"DSG2 knockdown in anaplastic thyroid cancer cells increases cell migration and invasion through the c-Met/Src/Rac1 signaling axis without altering EMT-related molecule expression; specific c-Met inhibition blocks the motility increase caused by DSG2 depletion, placing DSG2 upstream of c-Met-dependent motility control.","method":"shRNA DSG2 knockdown, migration/invasion assays in vitro, in vivo distant metastasis models, c-Met/Src/Rac1 pathway analysis, c-Met inhibitor treatment","journal":"Endocrine-related cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function plus pathway inhibitor rescue experiments in vitro and in vivo, single lab","pmids":["33022637"],"is_preprint":false},{"year":2018,"finding":"DSG2 overexpression in basal keratinocytes (K5 promoter transgenic mice) accelerates full-thickness wound closure, increases wound-adjacent keratinocyte proliferation, and induces increased secretion and proteolytic processing of urokinase-type plasminogen activator receptor (uPAR); uPAR upregulation correlates with increased laminin-332 in transgenic skin upon wounding.","method":"K5-promoter DSG2 transgenic mice, wound healing assay, antibody profiler secretome array, immunohistochemistry for uPAR and laminin-332","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic wound model plus secretome profiling, single lab","pmids":["29753032"],"is_preprint":false},{"year":2015,"finding":"DSG2 regulates cystatin A (CSTA) expression; siRNA/shRNA knockdown of DSG2 reduces CSTA expression, while siRNA knockdown of CSTA leads to cytoplasmic mislocalization of DSG2, perturbed cytokeratin 14 staining, and reduced desmoplakin levels under mechanical stretching. Combined knockdown of DSG2 and CSTA has synergistic loss of cell adhesion in dispase assays.","method":"siRNA and shRNA knockdown, microarray and qPCR, immunoblotting, immunohistochemistry, dispase-based cell adhesion assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional KD experiments with multiple readouts, single lab","pmids":["25785582"],"is_preprint":false},{"year":2022,"finding":"In Dsg2-deficient (CS-Dsg2-/-) cardiac-specific knockout mice, cardiac lipid accumulation and heart failure result from impaired mTOR-4EBP1-PPARα-dependent fatty acid β-oxidation; rapamycin worsened the phenotype, while mTOR and 4EBP1 overexpression rescued FA β-oxidation. Fenofibrate or AAV9-Pparα treatment restored cardiac function.","method":"Cardiac-specific Dsg2 knockout mice, rapamycin treatment, AAV9-mTOR/4EBP1 overexpression, fenofibrate/AAV9-Pparα treatment, lipid staining, echocardiography","journal":"Acta pharmaceutica Sinica. B","confidence":"High","confidence_rationale":"Tier 2 / Moderate — cardiac-specific KO with pharmacological and genetic rescue experiments, multiple orthogonal interventions in one study","pmids":["36815030"],"is_preprint":false},{"year":2022,"finding":"Loss of DSG2 in cardiac-specific knockout mice leads to increased cardiac fibrosis via PPARα deficiency and hyperactivation of STAT3 and SMAD3; Stat3 siRNA reduced fibrotic markers; PPARα activation by fenofibrate or AAV9-Pparα reduced cardiac fibrosis and decreased phosphorylation of STAT3, SMAD3, and AKT.","method":"CS-Dsg2-/- mice, Masson staining, Western blot, Stat3 siRNA in HL-1 cells, fenofibrate treatment, AAV9-Pparα administration","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with pharmacological/genetic rescue, multiple downstream markers, single lab","pmids":["36291052"],"is_preprint":false},{"year":2024,"finding":"DSG2-F531C (F536C in mice) mutant protein undergoes misfolding, is recognized by BiP in the endoplasmic reticulum, triggering ER stress and activation of PERK-ATF4 signaling; increased ATF4 promotes TGF-β1 expression in cardiomyocytes, which activates cardiac fibroblasts via paracrine signaling leading to cardiac fibrosis. PERK-ATF4 pathway inhibition attenuated fibrosis in Dsg2 F536C/F536C knock-in mice.","method":"Dsg2 F536C knock-in mice (CRISPR), neonatal and adult mouse ventricular myocytes, transcriptomic analysis, mass spectrometry, BiP co-immunoprecipitation, PERK-ATF4 inhibitor treatment","journal":"BMC medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — knock-in mouse model plus mechanistic rescue experiments with defined inhibitors, multiple orthogonal approaches in single study","pmids":["39227800"],"is_preprint":false},{"year":2024,"finding":"PRKD2 (serine/threonine-protein kinase D2) phosphorylates DSG2 at threonine 730 (T730); this phosphorylation promotes esophageal squamous cell carcinoma cell migration and invasion by activating EGFR, Src, AKT, and ERK signaling pathways.","method":"Interactome/co-IP analysis plus mass spectrometry identification of PRKD2 as DSG2 kinase; T730A/D phosphomutant functional assays; ESCC cell migration/invasion assays; Western blot for downstream signaling","journal":"The Journal of pathology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct kinase-substrate identification by mass spectrometry plus functional phosphomutant validation, single lab with multiple orthogonal methods","pmids":["38411280"],"is_preprint":false},{"year":2022,"finding":"TROP2 interacts with DSG2 in gastric cancer cells (identified by co-immunoprecipitation and mass spectrometry); TROP2 overexpression decreases DSG2 levels and desmosome adhesion, promoting cell invasion and migration through EGFR/AKT and DSG2/plakoglobin/β-catenin pathways.","method":"Co-immunoprecipitation with mass spectrometry, TROP2 overexpression/knockdown, cell adhesion assays, electron microscopy of desmosomes, Western blotting of EGFR/AKT and DSG2/PG/β-catenin pathway components","journal":"Current cancer drug targets","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP identification plus functional OE/KD experiments, single lab","pmids":["35392784"],"is_preprint":false},{"year":2024,"finding":"DSG2 ectodomain organization (measured by fluorescence polarization microscopy) increases gradually over 8 hours during desmosome assembly, coinciding with increasing adhesive strength; a similar increase in ectodomain order occurs in desmosomes assembling at the leading edge of migratory cells during wound healing, indicating that cadherin ectodomain organization is a hallmark of desmosome maturity.","method":"Fluorescence polarization microscopy of Dsg2 ectodomain, scratch wound assay, time-course imaging of assembly","journal":"Cell adhesion & migration","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative biophysical imaging method directly reporting ectodomain organization during assembly, single lab","pmids":["38566311"],"is_preprint":false},{"year":2021,"finding":"A DSG2 nonsense mutation (p.S363X) located in the extracellular domain results in absence of the truncated DSG2 protein at the plasma membrane, as demonstrated by in vitro cell transfection experiments; this supports the pathogenic mechanism of loss of membrane-targeted DSG2 in arrhythmogenic cardiomyopathy.","method":"In vitro cell transfection, immunofluorescence of plasma membrane localization","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single transfection experiment showing loss of membrane targeting, single lab, single method","pmids":["34202524"],"is_preprint":false},{"year":2025,"finding":"DSG2 is a dominant counter receptor of Siglec-9 in melanoma cells; the DSG2-Siglec-9 interaction is primarily dependent on sialic acid-bearing N-glycans on DSG2; blocking this trans interaction significantly enhances macrophage phagocytosis of melanoma cells.","method":"Proximity labeling combined with CRISPR knockout screening; co-immunoprecipitation; sialic acid manipulation; phagocytosis assays","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — CRISPR screen plus proximity labeling plus functional phagocytosis assays with sialic acid dependency, single lab with multiple orthogonal methods","pmids":["39813162"],"is_preprint":false},{"year":2024,"finding":"Loss of DSG2 in cardiomyocytes leads to reduced contractility; iPSC-CMs carrying a heterozygous truncating DSG2 variant (p.Arg119Ter) showed reduced contractility in microforce testing; immunohistochemical analysis showed reduced desmoglein-2 AND desmoplakin expression, with widened and fragmented desmosomes and widened intercalated disc gaps by electron microscopy.","method":"iPSC-CM microforce contractility assay, immunohistochemistry, transmission electron microscopy, endomyocardial biopsy analysis","journal":"Human genome variation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct contractility measurement in patient-derived iPSC-CMs plus ultrastructural analysis, single lab","pmids":["39706847"],"is_preprint":false},{"year":2025,"finding":"DSG2 promotes pancreatic cancer stem cell stemness via an IL-8/CXCR2 axis that activates Wnt/β-catenin signaling; DSG2 knockdown suppressed IL-4 and GM-CSF expression and reduced tumour-associated macrophage niche support. The IL-8/CXCR2-DSG2 interaction promotes gemcitabine resistance.","method":"DSG2 knockdown (shRNA), cytokine expression analysis, Wnt/β-catenin pathway analysis, macrophage co-culture, gemcitabine resistance assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple pathway and functional readouts, single lab","pmids":["40615400"],"is_preprint":false},{"year":2025,"finding":"In Dsg2-mutant knock-in mice, loss of DSG2 function leads to Z-disc structural defects and increased myosin detachment rate; Ca2+-activated force was reduced in permeabilized left ventricular cardiac muscle bundles but preserved in isolated permeabilized cardiomyocytes, demonstrating that DSG2 is required for force transmission between as well as within sarcomeres.","method":"Homozygous Dsg2 mutant knock-in mice; permeabilized cardiac muscle bundle and isolated cardiomyocyte mechanical assays; electron microscopy of Z-discs","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct mechanical assays in KI mouse model with comparison of tissue vs isolated cell level, preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"Pathogenic autoantibodies from ACM patients bind to DSG2 in hiPSC-CMs, cleave DSG2, and reduce DSG2 interaction at the molecular level; these antibodies activate GSK-3β (upstream of p38MAPK), leading to phosphorylation and junctional loss of β-catenin, causing loss of cardiomyocyte cohesion. GSK-3β inhibition rescued antibody-induced loss of cohesion.","method":"hiPSC-CM cohesion assays, Western blotting for DSG2 cleavage, GSK-3β/p38MAPK/β-catenin pathway analysis, GSK-3β inhibitor rescue experiments","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional autoantibody mechanism defined with pathway rescue in hiPSC-CMs, preprint","pmids":[],"is_preprint":true},{"year":2025,"finding":"P-cadherin (Pcad) facilitates desmosome assembly by forming heterophilic trans strand-swap dimers with DSG2 on opposing cells; the interaction requires flexibility of the hinge on the swapped β-strands (terminating in conserved Trp residues); strand-swap deficient Pcad fails to rescue desmosome assembly in cells lacking classical cadherins, while strand-swap competent Pcad rescues assembly.","method":"Single-molecule AFM, super-resolution and confocal imaging, mutagenesis of strand-swap residues, atomistic simulations, cell-based desmosome assembly rescue assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — single-molecule AFM plus mutagenesis plus functional rescue, preprint not yet peer-reviewed but multiple rigorous methods","pmids":[],"is_preprint":true},{"year":2025,"finding":"The DSG2 interactome in primary neonatal cardiomyocytes (identified by proximity labeling and quantitative mass spectrometry) includes over 300 proteins; connexin 43 and plakin family cytolinker proteins are unique to DSG2 (vs N-cadherin); plakoglobin (JUP) and plakophilin-2 (PKP2) are the most abundant shared proteins between DSG2 and N-cadherin interactomes. PKP2 membrane recruitment in cardiomyocytes is tension-dependent.","method":"Proximity labeling (BioID or similar) combined with quantitative mass spectrometry in primary neonatal cardiomyocytes","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity labeling MS interactome in primary cardiac cells with comparative analysis, preprint","pmids":[],"is_preprint":true},{"year":2024,"finding":"DSG2 interacts with c-MYC (demonstrated by co-immunoprecipitation) in cervical cancer cells; DSG2 overexpression combined with c-MYC inhibition significantly decreases ADAM17 expression, cell proliferation, and migration compared to DSG2 overexpression alone, indicating DSG2 regulates ADAM17 expression through c-MYC interaction.","method":"Co-immunoprecipitation, c-MYC inhibitor treatment, ADAM17 qPCR and Western blot, cell proliferation and migration assays","journal":"Cancer management and research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP interaction identification plus inhibitor experiment, single lab","pmids":["38948682"],"is_preprint":false},{"year":2025,"finding":"DSG2 knockdown in lung adenocarcinoma cells enhances gemcitabine-induced apoptosis by downregulating the NFκB/STAT3/PTX3 signaling axis; adding recombinant PTX3 protein to DSG2 knockdown cells restores STAT3 activation and reduces gemcitabine efficacy, demonstrating DSG2 mediates gemcitabine resistance through PTX3.","method":"DSG2 siRNA knockdown, gemcitabine treatment, apoptosis assays, NFκB/STAT3/PTX3 pathway Western blot, recombinant PTX3 rescue experiment","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function plus protein rescue experiment defining the PTX3-mediated mechanism, single lab","pmids":["40316058"],"is_preprint":false},{"year":2025,"finding":"Oxymatrine (OMT) directly binds to DSG2 (confirmed by CETSA, DARTS, and microscale thermophoresis), stabilizing DSG2 and inhibiting caspase-8-dependent DSG2 cleavage; DSG2 knockdown diminishes the therapeutic effects of OMT in intestinal epithelial cells, demonstrating that OMT's barrier-protective effects require DSG2.","method":"CETSA, DARTS, microscale thermophoresis binding assays; caspase-8 activity assay; lentiviral Dsg2 knockdown; intestinal epithelial barrier function assays","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — three independent direct binding assays plus functional knockdown validation, single lab","pmids":["41076918"],"is_preprint":false},{"year":2025,"finding":"In Dsg2 knock-in mice with the F531C mutation, DSG2 deficiency leads to nuclear accumulation of β-catenin and PPAR-γ, promoting triacylglycerol biosynthesis, oxidative stress, cardiomyocyte death, and calcium-handling abnormalities; epicardial epithelial-to-mesenchymal transition and paracrine fibroblast activation via IL-6 and PDGF-BB contribute to fibrotic remodeling. PPAR-γ antagonist GW9662 treatment attenuated these features.","method":"CRISPR/Cas9 knock-in mice (Dsg2 F531C), transcriptomic profiling, in vitro cardiomyocyte/fibroblast assays, ex vivo optical mapping, GW9662 treatment, immunostaining","journal":"Circulation. Genomic and precision medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — knock-in model with multi-level mechanistic analysis and pharmacological rescue, multiple orthogonal methods, single lab","pmids":["41980193"],"is_preprint":false}],"current_model":"DSG2 is a transmembrane desmosomal cadherin that forms the adhesive core of desmosomes via homophilic strand-swap dimerization and heterophilic interactions with DSG3 and P-cadherin; its cytoplasmic tail binds plakoglobin (JUP) through the fourth armadillo repeat, linking to the desmosomal plaque; beyond structural adhesion, DSG2 acts as a signaling hub that activates EGFR via c-Src/Cav1-dependent lipid raft remodeling, regulates Wnt/β-catenin and downstream oncogenic pathways (AKT, MAPK, STAT3, NF-κB), and is phosphorylated by PRKD2 at Thr730 to further amplify EGFR/Src/AKT/ERK signaling; loss-of-function mutations in cardiac DSG2 disrupt desmosome integrity, impair force transmission between sarcomeres, trigger ER stress and PERK-ATF4-TGF-β1-driven fibrosis, and impair mTOR-PPARα-dependent fatty acid oxidation, causing arrhythmogenic cardiomyopathy; DSG2 also serves as a functional receptor for group B human adenoviruses and as a sialylated 'don't eat me' signal via Siglec-9 interaction on cancer cells."},"narrative":{"mechanistic_narrative":"DSG2 is the ubiquitously expressed desmosomal cadherin that forms the adhesive core of desmosomes in simple and stratified epithelia, myocardium, and other desmosome-bearing tissues [PMID:8143788, PMID:8641550]. Its extracellular domains mediate Ca2+-dependent homophilic strand-swap dimerization, whose free-energy landscape reflects a high activation barrier characteristic of strand-swap binding [PMID:29062102], and it also engages in heterophilic trans interactions with DSG3 and with P-cadherin, the latter providing strand-swap dimers that facilitate desmosome assembly [PMID:33193387]. Progressive ordering of the DSG2 ectodomain accompanies the maturation and strengthening of assembling desmosomes [PMID:38566311]. The cytoplasmic tail couples to the desmosomal plaque through high-affinity binding to plakoglobin (JUP) via the fourth armadillo repeat [PMID:8749329], and in cardiomyocytes DSG2 associates with plakophilin-2, connexin 43, and plakin cytolinkers in a tension-dependent interactome. Beyond adhesion, DSG2 functions as a signaling hub: it activates EGFR through a c-Src– and caveolin-1–dependent lipid-raft mechanism, driving STAT3, PI3K/AKT, MEK-MAPK, and NF-κB signaling that promotes proliferation, apoptosis resistance, and tumorigenesis [PMID:26918609, PMID:17284515], with EGFR engagement occurring through direct heterotypic surface binding that can also direct EGFR toward junctional adhesion rather than proliferation [PMID:29980799]; phosphorylation of DSG2 at Thr730 by PRKD2 further amplifies EGFR/Src/AKT/ERK signaling to promote carcinoma invasion [PMID:38411280]. In the heart, loss-of-function and missense DSG2 mutations disrupt desmosome integrity and force transmission within and between sarcomeres [PMID:39706847], causing arrhythmogenic/dilated cardiomyopathy with myocyte necrosis as the initiating injury [PMID:19635863]; misfolded mutant DSG2 is recognized by BiP and triggers PERK-ATF4–driven TGF-β1 fibrosis [PMID:39227800], while DSG2 deficiency impairs mTOR-4EBP1-PPARα–dependent fatty acid β-oxidation and drives STAT3/SMAD3- and PPARγ/β-catenin-mediated lipid accumulation and fibrosis [PMID:36815030, PMID:36291052, PMID:41980193]. DSG2 additionally serves as a cell-surface receptor for species B human adenoviruses (HAdV-B3/B7/B14/B55) [PMID:22457526, PMID:34224109] and, through sialylated N-glycans, as a counter-receptor for Siglec-9 that suppresses macrophage phagocytosis of tumor cells [PMID:39813162].","teleology":[{"year":1994,"claim":"Establishing DSG2 as the ubiquitous desmoglein isoform defined which tissues depend on it for desmosomal adhesion, distinguishing it from the restricted DSG1/DSG3.","evidence":"cDNA cloning, sequence determination, and immunocytochemistry across multiple tissues","pmids":["8143788","8641550"],"confidence":"High","gaps":["Does not address adhesive binding mechanism or signaling roles","Tissue distribution alone does not establish function"]},{"year":1995,"claim":"Mapping the plakoglobin-binding determinant resolved how the DSG2 cytoplasmic tail couples to the desmosomal plaque.","evidence":"In vitro binding assays with recombinant plakoglobin deletion mutants","pmids":["8749329"],"confidence":"High","gaps":["Affinity quantification incomplete","Does not address plakophilin or desmoplakin linkage in vivo"]},{"year":2009,"claim":"A dominant-negative cardiac DSG2 mutant model showed that DSG2 dysfunction causes arrhythmogenic cardiomyopathy and identified myocyte necrosis as the initiating lesion.","evidence":"Cardiac-specific DSG2 mutant transgenic mice with dose-dependent phenotyping and human tissue correlation","pmids":["19635863"],"confidence":"High","gaps":["Molecular trigger of necrosis not defined","Link between adhesion loss and electrical instability unresolved"]},{"year":2016,"claim":"Connecting DSG2 to EGFR through lipid-raft remodeling reframed DSG2 as a signaling platform rather than a purely structural adhesion molecule.","evidence":"siRNA knockdown/overexpression, sucrose fractionation, STED imaging, and cholesterol depletion in A431 cells","pmids":["26918609","17284515","29980799"],"confidence":"High","gaps":["Stoichiometry of DSG2-EGFR-Cav1-Src complex unresolved","How adhesion vs proliferation signaling outputs are selected remains incomplete"]},{"year":2017,"claim":"Single-molecule force spectroscopy showed ARVC mutations weaken DSG2 homophilic binding kinetically without disrupting the strand-swap motif, linking biophysical adhesion defects to disease.","evidence":"AFM single-molecule force spectroscopy and dispase dissociation assays with WT/mutant DSG2","pmids":["29062102"],"confidence":"High","gaps":["How altered binding kinetics translate to tissue-level failure not shown","Heterophilic binding contributions not tested here"]},{"year":2020,"claim":"Demonstrating heterophilic DSG2-DSG3 catch-bond binding revealed a partner-mixing mechanism that can buffer adhesion loss, with relevance to pemphigus.","evidence":"Cell-free AFM single-molecule binding and IP with autoantibody inhibition","pmids":["33193387","33387800"],"confidence":"High","gaps":["In vivo significance of heterophilic rescue not established","Quantitative contribution to tissue cohesion unclear"]},{"year":2012,"claim":"Identifying DSG2 as a species B adenovirus receptor explained tropism of HAdV-B and established a non-adhesive surface function.","evidence":"Human DSG2 transgenic mice and GFP-reporter HAdV-B transduction; later gain/loss-of-function in cell lines for HAdV-B55","pmids":["22457526","34224109"],"confidence":"High","gaps":["Receptor-binding interface on DSG2 not mapped","Whether viral binding perturbs desmosomal adhesion not addressed"]},{"year":2022,"claim":"Cardiac-specific DSG2 knockouts uncovered metabolic and fibrotic mechanisms—impaired mTOR-PPARα fatty acid oxidation and STAT3/SMAD3-driven fibrosis—linking adhesion loss to heart failure.","evidence":"CS-Dsg2-/- mice with rapamycin, mTOR/4EBP1 overexpression, fenofibrate, and AAV9-Pparα rescue","pmids":["36815030","36291052"],"confidence":"High","gaps":["How loss of a junctional protein controls metabolic transcription unresolved","Causal ordering of metabolic vs structural defects unclear"]},{"year":2024,"claim":"Knock-in models defined a proteostatic disease mechanism: misfolded DSG2 mutant engages BiP and triggers PERK-ATF4-TGF-β1 fibrosis, and PRKD2 phosphorylation at Thr730 was identified as a signaling-amplifying modification.","evidence":"Dsg2 F536C knock-in mice with BiP co-IP and PERK-ATF4 inhibition; PRKD2 kinase-substrate identification by MS and phosphomutant assays","pmids":["39227800","38411280"],"confidence":"High","gaps":["Generality of ER-stress mechanism across DSG2 mutations not established","Physiological substrates and regulation of T730 phosphorylation incompletely defined"]},{"year":2025,"claim":"DSG2 was established as a sialic-acid-dependent Siglec-9 counter-receptor functioning as a 'don't eat me' signal, and P-cadherin was shown to nucleate desmosome assembly via strand-swap dimers with DSG2.","evidence":"Proximity labeling/CRISPR screen and phagocytosis assays for Siglec-9; single-molecule AFM, mutagenesis, and rescue assays for P-cadherin (preprint)","pmids":["39813162"],"confidence":"High","gaps":["Structural basis of Siglec-9 glycan recognition not defined","P-cadherin findings remain preprint and require peer review"]},{"year":null,"claim":"How the dual structural and signaling functions of DSG2 are integrated and selectively engaged across epithelial homeostasis, cancer, cardiac mechanotransduction, and immune evasion remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of the DSG2 adhesive-signaling complex","Mechanism coupling junctional adhesion state to transcriptional/metabolic output undefined","Whether signaling roles are conserved across tissues unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[8,15,31,24]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[11,12]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[6,7,22]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,25,7]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[21]}],"pathway":[{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,1,24]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,7,22]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,21,19,36]},{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[29,27]}],"complexes":["desmosome","intercalated disc"],"partners":["JUP","EGFR","DSG3","PKP2","PRKD2","CDH3","TROP2","SIGLEC9"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14126","full_name":"Desmoglein-2","aliases":["Cadherin family member 5","HDGC"],"length_aa":1118,"mass_kda":122.3,"function":"A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion (PubMed:17559062, PubMed:38395410). Involved in the interaction of plaque proteins and intermediate filaments mediating cell-cell adhesion. Required for proliferation and viability of embryonic stem cells in the blastocyst, thereby crucial for progression of post-implantation embryonic development (By similarity). Maintains pluripotency by regulating epithelial to mesenchymal transition/mesenchymal to epithelial transition (EMT/MET) via interacting with and sequestering CTNNB1 to sites of cell-cell contact, thereby reducing translocation of CTNNB1 to the nucleus and subsequent transcription of CTNNB1/TCF-target genes (PubMed:29910125). Promotes pluripotency and the multi-lineage differentiation potential of hematopoietic stem cells (PubMed:27338829). Plays a role in endothelial cell sprouting and elongation via mediating the junctional-association of cortical actin fibers and CDH5 (PubMed:27338829). Promotes cardiomyocyte cell homeostasis and desmosome junction formation at intercalated disks, as a result plays a role in the maintenance of cardiac conduction and heart chamber integrity (By similarity). Positively regulates pancreatic islet development and maintenance of endothelial cell barrier integrity in the pancreas, therefore involved in the controlled release of insulin from islet cells into the circulation in response to glucose (By similarity). Plays a role in limiting inflammatory infiltration and the apoptotic response to injury in kidney tubular epithelial cells, potentially via its role in maintaining cell-cell adhesion and the epithelial barrier (PubMed:38395410). Acts as a positive modulator of CSK and EGFR activation via sequestering them away from lipid rafts, this is independent of its role in desmosome cell junctions (PubMed:26918609). Also disrupts the localization of CAV1 to lipid rafts resulting in its distribution throughout the cytoplasm (PubMed:26918609)","subcellular_location":"Cell membrane; Cell junction, desmosome; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q14126/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DSG2","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DDOST","stoichiometry":0.2},{"gene":"KRTCAP2","stoichiometry":0.2},{"gene":"OST4","stoichiometry":0.2},{"gene":"RPN1","stoichiometry":0.2},{"gene":"RPN2","stoichiometry":0.2},{"gene":"STT3B","stoichiometry":0.2},{"gene":"VAMP3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/DSG2","total_profiled":1310},"omim":[{"mim_id":"615821","title":"CARDIOMYOPATHY, DILATED, WITH WOOLLY HAIR, KERATODERMA, AND TOOTH AGENESIS; DCWHKTA","url":"https://www.omim.org/entry/615821"},{"mim_id":"612877","title":"CARDIOMYOPATHY, DILATED, 1BB; CMD1BB","url":"https://www.omim.org/entry/612877"},{"mim_id":"610476","title":"ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 11; ARVD11","url":"https://www.omim.org/entry/610476"},{"mim_id":"610193","title":"ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 10; ARVD10","url":"https://www.omim.org/entry/610193"},{"mim_id":"607892","title":"DESMOGLEIN 4; DSG4","url":"https://www.omim.org/entry/607892"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cell Junctions","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":99.0},{"tissue":"parathyroid gland","ntpm":148.5}],"url":"https://www.proteinatlas.org/search/DSG2"},"hgnc":{"alias_symbol":["CDHF5"],"prev_symbol":[]},"alphafold":{"accession":"Q14126","domains":[{"cath_id":"2.60.40.60","chopping":"57-151","consensus_level":"high","plddt":92.0917,"start":57,"end":151},{"cath_id":"2.60.40.60","chopping":"159-264","consensus_level":"medium","plddt":95.1269,"start":159,"end":264},{"cath_id":"2.60.40.60","chopping":"272-381","consensus_level":"medium","plddt":94.8678,"start":272,"end":381},{"cath_id":"2.60.40.60","chopping":"387-491","consensus_level":"high","plddt":93.827,"start":387,"end":491},{"cath_id":"2.60.40.60","chopping":"499-597","consensus_level":"high","plddt":90.161,"start":499,"end":597}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14126","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14126-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14126-F1-predicted_aligned_error_v6.png","plddt_mean":64.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DSG2","jax_strain_url":"https://www.jax.org/strain/search?query=DSG2"},"sequence":{"accession":"Q14126","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14126.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14126/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14126"}},"corpus_meta":[{"pmid":"8143788","id":"PMC_8143788","title":"Identification of the ubiquitous human desmoglein, Dsg2, and the expression catalogue of the desmoglein subfamily of desmosomal cadherins.","date":"1994","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/8143788","citation_count":216,"is_preprint":false},{"pmid":"16773573","id":"PMC_16773573","title":"DSG2 mutations contribute to arrhythmogenic right ventricular dysplasia/cardiomyopathy.","date":"2006","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16773573","citation_count":188,"is_preprint":false},{"pmid":"19635863","id":"PMC_19635863","title":"Myocyte necrosis underlies progressive myocardial dystrophy in mouse dsg2-related arrhythmogenic right ventricular cardiomyopathy.","date":"2009","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/19635863","citation_count":168,"is_preprint":false},{"pmid":"17284515","id":"PMC_17284515","title":"Suprabasal Dsg2 expression in transgenic mouse skin confers a hyperproliferative and apoptosis-resistant phenotype to keratinocytes.","date":"2007","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/17284515","citation_count":102,"is_preprint":false},{"pmid":"19458482","id":"PMC_19458482","title":"Increased expression of Dsg2 in malignant skin carcinomas: A tissue-microarray based study.","date":"2009","source":"Cell adhesion & migration","url":"https://pubmed.ncbi.nlm.nih.gov/19458482","citation_count":89,"is_preprint":false},{"pmid":"8641550","id":"PMC_8641550","title":"Immunological identification and characterization of the desmosomal cadherin Dsg2 in coupled and uncoupled epithelial cells and in human tissues.","date":"1996","source":"Differentiation; 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unlike DSG1 and DSG3, DSG2 is the largest family member (1069 aa) and is the only DSG isoform detected in many tissues such as simple epithelia and myocardium.\",\n      \"method\": \"cDNA cloning, amino acid sequence determination, Northern/Southern blotting, immunocytochemistry\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — full protein sequence determination plus immunocytochemical tissue distribution, replicated across multiple tissues and cell lines in the same study\",\n      \"pmids\": [\"8143788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"DSG2 protein localizes to desmosomes in all desmosome-containing tissues (stratified and simple epithelia, myocardium, lymph node follicles); antibodies against the extracellular domain of DSG2 also react with 'half-desmosomes' on the surface of uncoupled epithelial cells. In stratified squamous epithelia, DSG2 is restricted to the basal cell layer.\",\n      \"method\": \"Immunocytochemistry with monoclonal and polyclonal antibodies against N-terminal extracellular and C-terminal cytoplasmic domains; immunoelectron microscopy\",\n      \"journal\": \"Differentiation; research in biological diversity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple antibodies with distinct epitopes, replicated across diverse tissues, consistent with independent cDNA work\",\n      \"pmids\": [\"8641550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The DSG2 gene was mapped to human chromosome 18, co-localizing with DSG1.\",\n      \"method\": \"PCR-based chromosomal assignment assay\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct chromosomal localization by PCR, single lab, single method\",\n      \"pmids\": [\"1612610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The fourth armadillo repeat of plakoglobin is required for its high-affinity binding to the cytoplasmic domain of DSG2 (and E-cadherin and APC); a 12-repeat plakoglobin lacking the fourth armadillo repeat binds DSG2 with lower affinity than the full 13-repeat form.\",\n      \"method\": \"In vitro binding assay using bacterially expressed recombinant plakoglobin constructs; deletion mutagenesis\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution assay with defined deletion mutants, single lab but multiple binding partners tested orthogonally\",\n      \"pmids\": [\"8749329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Suprabasal overexpression of DSG2 in transgenic mouse epidermis causes epidermal hyperplasia, increased keratinocyte proliferation, and apoptosis resistance through activation of multiple signaling pathways including PI3K/AKT, MEK-MAPK, STAT3, and NF-κB; this requires EGFR activation and NF-κB activity for anchorage-independent survival.\",\n      \"method\": \"Involucrin-promoter-driven DSG2 transgenic mice; cultured keratinocytes; EGFR inhibition; NF-κB inhibition; chemical carcinogenesis assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo transgenic model plus in vitro inhibitor studies, multiple orthogonal readouts (proliferation, apoptosis, signaling pathway activation, tumorigenesis)\",\n      \"pmids\": [\"17284515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Cardiac overexpression of dominant-negative DSG2-N271S (mouse equivalent of human N266S) in transgenic mice causes ARVC features including biventricular dilatation, ventricular arrhythmias, and sudden death; myocyte necrosis was identified as the key initiator of myocardial injury, preceding inflammation, calcification, and fibrous replacement.\",\n      \"method\": \"Transgenic mouse model with cardiac-specific DSG2 mutant overexpression; histopathology; electrophysiology; multiple transgene expression levels demonstrating dose-dependence\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple transgenic lines with dose-dependent phenotype, human explanted heart tissue correlation, multiple orthogonal assessments\",\n      \"pmids\": [\"19635863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DSG2 activates EGFR signaling via a c-Src and Caveolin-1 (Cav1)-dependent mechanism using lipid rafts as signaling platforms; DSG2 overexpression displaces Cav1, EGFR, and c-Src from light-density lipid raft fractions, and DSG2 knockdown abrogates EGFR, c-Src, and STAT3 activation in response to EGF, increasing cell proliferation and migration through EGFR/c-Src.\",\n      \"method\": \"siRNA knockdown, sucrose density fractionation, STED super-resolution imaging, overexpression in A431 cells, cholesterol chelation (MβCD), proliferation and migration assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (fractionation, STED imaging, cholesterol depletion, KD/OE), single lab\",\n      \"pmids\": [\"26918609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DSG2 directly interacts with EGFR and undergoes heterotypic binding via its extracellular domain on the surface of living enterocytes; DSG2 is required for EGFR localization at intercellular junctions and for Src-mediated EGFR activation, directing EGFR signaling towards cell adhesion rather than proliferation. DSG2-deficient enterocytes show impaired barrier properties and increased proliferation.\",\n      \"method\": \"Atomic force microscopy (AFM) on living cells, co-immunoprecipitation, Src/EGFR inhibitors, DSG2 knockout/knockdown, transepithelial resistance measurement\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — AFM single-molecule force measurements on living cells plus co-IP plus functional KO, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29980799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ARVC-associated DSG2 mutations (tested by single-molecule force spectroscopy) alter the kinetics and thermodynamics of DSG2 homophilic binding without directly affecting the strand-swapping binding motif; the free energy landscape of Dsg2 dimerization shows a high activation barrier consistent with strand-swap binding, and mutations significantly reduce homophilic binding strength in a cell dissociation assay.\",\n      \"method\": \"Single-molecule force spectroscopy (AFM), Jarzynski's equality thermodynamic analysis, dispase cell dissociation assay with DSG2 WT and mutant overexpressing HT1080 cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro single-molecule biophysical assay plus cellular assay, single lab, orthogonal methods\",\n      \"pmids\": [\"29062102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ARVC-associated DSG2 mutations alter the N-glycosylation pattern of desmoglein-2 protein even when the mutations do not directly affect N-glycosylation consensus sequences, indicating complex molecular interactions between DSG2 mutations and N-glycosylations.\",\n      \"method\": \"De-glycosylation assays, lectin blot analysis, genetic inhibition of glycosylation, in vitro cell transfection\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple glycosylation assay approaches, single lab\",\n      \"pmids\": [\"30885746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Ectopic superficial expression of DSG2 (via involucrin promoter transgene) reduces the extent of epidermal blister formation induced by pemphigus foliaceus antibodies and staphylococcal exfoliative toxin ETA, and enhances retention of DSG1 at cell borders, supporting a direct role for DSG2 in epithelial adhesion.\",\n      \"method\": \"Neonatal transgenic mouse injection with PF IgG or ETA; histology; immunofluorescence for DSG1 isoforms\",\n      \"journal\": \"Dermatology research and practice\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic model with defined adhesion challenge, single lab\",\n      \"pmids\": [\"20631906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Human DSG2 functions as a receptor for adenovirus species B (HAdV-B3, B7, B14) and mediates efficient viral transduction of epithelial cells; transgenic mice expressing human DSG2 at physiological levels show hDSG2-dependent transduction of bronchial/alveolar epithelial cells (intranasal) and intestinal/colon epithelial cells (intravenous) by HAdV-B3.\",\n      \"method\": \"hDSG2 transgenic mouse generation; GFP-expressing HAdV-B3 vector administration; qRT-PCR and immunohistochemistry for GFP\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo transgenic model with human DSG2 expression, multiple routes of delivery and tissues tested, GFP reporter quantification\",\n      \"pmids\": [\"22457526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Human DSG2 is a receptor for HAdV-B55; 3T3 rodent cells (which do not express human DSG2) became susceptible to HAdV-B55 infection after transfection with pcDNA3.1-DSG2; siRNA knockdown of hDSG2 in A549 cells impaired infection by HAdV-B3, B14, and B55; immunofluorescence confocal microscopy confirmed Cy3-conjugated HAdV-B55 enters cells via binding DSG2.\",\n      \"method\": \"Heterologous expression (pcDNA3.1-DSG2 in 3T3 cells), siRNA knockdown, immunofluorescence confocal microscopy\",\n      \"journal\": \"Virologica Sinica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function and loss-of-function experiments plus visual confirmation of receptor-virus colocalization\",\n      \"pmids\": [\"34224109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"UV radiation down-regulates DSG2 in human lens epithelial cells via a pathway involving EGFR transactivation, Rac2 translocation, and NADPH oxidase-dependent reactive oxygen species generation.\",\n      \"method\": \"Cultured human lens epithelial cells; UV/H2O2 treatment; ROS measurement; EGFR activation assay; Rac2 translocation assay; NADPH oxidase inhibition\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pathway inhibition experiments in cell culture, single lab\",\n      \"pmids\": [\"16820949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DSG2 regulates β-catenin/Slug-mediated epithelial-to-mesenchymal transition to maintain self-renewal and pluripotency in human pluripotent stem cells; depletion of DSG2 markedly decreased hPSC proliferation and pluripotency marker expression, and DSG2-negative hPSC populations show suppressed embryoid body and teratoma formation.\",\n      \"method\": \"Monoclonal antibody generation and target identification; siRNA knockdown; pluripotency marker analysis; embryoid body and teratoma formation assays; β-catenin/Slug pathway analysis\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple phenotypic readouts and pathway identification, single lab\",\n      \"pmids\": [\"29910125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DSG2 undergoes heterophilic binding with DSG3; DSG2-DSG3 heterophilic interactions show binding frequency, strength, Ca2+-dependency, and catch-bond behavior comparable to homophilic Dsg3-Dsg3 interactions, but with longer lifetime than homophilic Dsg2-Dsg2 interactions. PV autoantibodies inhibit homophilic DSG3 interactions more strongly than heterophilic DSG2-DSG3 interactions, suggesting heterophilic binding as a rescue mechanism.\",\n      \"method\": \"Immunoprecipitation, cell-free atomic force microscopy (AFM), DSG3-deficient keratinocytes, pemphigus autoantibody inhibition experiments, anti-DSG2 inhibitory antibody\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cell-free AFM single-molecule binding assays plus IP, multiple complementary experimental approaches in single study\",\n      \"pmids\": [\"33193387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DSG2 knockdown in anaplastic thyroid cancer cells increases cell migration and invasion through the c-Met/Src/Rac1 signaling axis without altering EMT-related molecule expression; specific c-Met inhibition blocks the motility increase caused by DSG2 depletion, placing DSG2 upstream of c-Met-dependent motility control.\",\n      \"method\": \"shRNA DSG2 knockdown, migration/invasion assays in vitro, in vivo distant metastasis models, c-Met/Src/Rac1 pathway analysis, c-Met inhibitor treatment\",\n      \"journal\": \"Endocrine-related cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function plus pathway inhibitor rescue experiments in vitro and in vivo, single lab\",\n      \"pmids\": [\"33022637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DSG2 overexpression in basal keratinocytes (K5 promoter transgenic mice) accelerates full-thickness wound closure, increases wound-adjacent keratinocyte proliferation, and induces increased secretion and proteolytic processing of urokinase-type plasminogen activator receptor (uPAR); uPAR upregulation correlates with increased laminin-332 in transgenic skin upon wounding.\",\n      \"method\": \"K5-promoter DSG2 transgenic mice, wound healing assay, antibody profiler secretome array, immunohistochemistry for uPAR and laminin-332\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic wound model plus secretome profiling, single lab\",\n      \"pmids\": [\"29753032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DSG2 regulates cystatin A (CSTA) expression; siRNA/shRNA knockdown of DSG2 reduces CSTA expression, while siRNA knockdown of CSTA leads to cytoplasmic mislocalization of DSG2, perturbed cytokeratin 14 staining, and reduced desmoplakin levels under mechanical stretching. Combined knockdown of DSG2 and CSTA has synergistic loss of cell adhesion in dispase assays.\",\n      \"method\": \"siRNA and shRNA knockdown, microarray and qPCR, immunoblotting, immunohistochemistry, dispase-based cell adhesion assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional KD experiments with multiple readouts, single lab\",\n      \"pmids\": [\"25785582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In Dsg2-deficient (CS-Dsg2-/-) cardiac-specific knockout mice, cardiac lipid accumulation and heart failure result from impaired mTOR-4EBP1-PPARα-dependent fatty acid β-oxidation; rapamycin worsened the phenotype, while mTOR and 4EBP1 overexpression rescued FA β-oxidation. Fenofibrate or AAV9-Pparα treatment restored cardiac function.\",\n      \"method\": \"Cardiac-specific Dsg2 knockout mice, rapamycin treatment, AAV9-mTOR/4EBP1 overexpression, fenofibrate/AAV9-Pparα treatment, lipid staining, echocardiography\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cardiac-specific KO with pharmacological and genetic rescue experiments, multiple orthogonal interventions in one study\",\n      \"pmids\": [\"36815030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Loss of DSG2 in cardiac-specific knockout mice leads to increased cardiac fibrosis via PPARα deficiency and hyperactivation of STAT3 and SMAD3; Stat3 siRNA reduced fibrotic markers; PPARα activation by fenofibrate or AAV9-Pparα reduced cardiac fibrosis and decreased phosphorylation of STAT3, SMAD3, and AKT.\",\n      \"method\": \"CS-Dsg2-/- mice, Masson staining, Western blot, Stat3 siRNA in HL-1 cells, fenofibrate treatment, AAV9-Pparα administration\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with pharmacological/genetic rescue, multiple downstream markers, single lab\",\n      \"pmids\": [\"36291052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DSG2-F531C (F536C in mice) mutant protein undergoes misfolding, is recognized by BiP in the endoplasmic reticulum, triggering ER stress and activation of PERK-ATF4 signaling; increased ATF4 promotes TGF-β1 expression in cardiomyocytes, which activates cardiac fibroblasts via paracrine signaling leading to cardiac fibrosis. PERK-ATF4 pathway inhibition attenuated fibrosis in Dsg2 F536C/F536C knock-in mice.\",\n      \"method\": \"Dsg2 F536C knock-in mice (CRISPR), neonatal and adult mouse ventricular myocytes, transcriptomic analysis, mass spectrometry, BiP co-immunoprecipitation, PERK-ATF4 inhibitor treatment\",\n      \"journal\": \"BMC medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — knock-in mouse model plus mechanistic rescue experiments with defined inhibitors, multiple orthogonal approaches in single study\",\n      \"pmids\": [\"39227800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRKD2 (serine/threonine-protein kinase D2) phosphorylates DSG2 at threonine 730 (T730); this phosphorylation promotes esophageal squamous cell carcinoma cell migration and invasion by activating EGFR, Src, AKT, and ERK signaling pathways.\",\n      \"method\": \"Interactome/co-IP analysis plus mass spectrometry identification of PRKD2 as DSG2 kinase; T730A/D phosphomutant functional assays; ESCC cell migration/invasion assays; Western blot for downstream signaling\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct kinase-substrate identification by mass spectrometry plus functional phosphomutant validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"38411280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TROP2 interacts with DSG2 in gastric cancer cells (identified by co-immunoprecipitation and mass spectrometry); TROP2 overexpression decreases DSG2 levels and desmosome adhesion, promoting cell invasion and migration through EGFR/AKT and DSG2/plakoglobin/β-catenin pathways.\",\n      \"method\": \"Co-immunoprecipitation with mass spectrometry, TROP2 overexpression/knockdown, cell adhesion assays, electron microscopy of desmosomes, Western blotting of EGFR/AKT and DSG2/PG/β-catenin pathway components\",\n      \"journal\": \"Current cancer drug targets\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP identification plus functional OE/KD experiments, single lab\",\n      \"pmids\": [\"35392784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DSG2 ectodomain organization (measured by fluorescence polarization microscopy) increases gradually over 8 hours during desmosome assembly, coinciding with increasing adhesive strength; a similar increase in ectodomain order occurs in desmosomes assembling at the leading edge of migratory cells during wound healing, indicating that cadherin ectodomain organization is a hallmark of desmosome maturity.\",\n      \"method\": \"Fluorescence polarization microscopy of Dsg2 ectodomain, scratch wound assay, time-course imaging of assembly\",\n      \"journal\": \"Cell adhesion & migration\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative biophysical imaging method directly reporting ectodomain organization during assembly, single lab\",\n      \"pmids\": [\"38566311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A DSG2 nonsense mutation (p.S363X) located in the extracellular domain results in absence of the truncated DSG2 protein at the plasma membrane, as demonstrated by in vitro cell transfection experiments; this supports the pathogenic mechanism of loss of membrane-targeted DSG2 in arrhythmogenic cardiomyopathy.\",\n      \"method\": \"In vitro cell transfection, immunofluorescence of plasma membrane localization\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single transfection experiment showing loss of membrane targeting, single lab, single method\",\n      \"pmids\": [\"34202524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DSG2 is a dominant counter receptor of Siglec-9 in melanoma cells; the DSG2-Siglec-9 interaction is primarily dependent on sialic acid-bearing N-glycans on DSG2; blocking this trans interaction significantly enhances macrophage phagocytosis of melanoma cells.\",\n      \"method\": \"Proximity labeling combined with CRISPR knockout screening; co-immunoprecipitation; sialic acid manipulation; phagocytosis assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen plus proximity labeling plus functional phagocytosis assays with sialic acid dependency, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39813162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of DSG2 in cardiomyocytes leads to reduced contractility; iPSC-CMs carrying a heterozygous truncating DSG2 variant (p.Arg119Ter) showed reduced contractility in microforce testing; immunohistochemical analysis showed reduced desmoglein-2 AND desmoplakin expression, with widened and fragmented desmosomes and widened intercalated disc gaps by electron microscopy.\",\n      \"method\": \"iPSC-CM microforce contractility assay, immunohistochemistry, transmission electron microscopy, endomyocardial biopsy analysis\",\n      \"journal\": \"Human genome variation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct contractility measurement in patient-derived iPSC-CMs plus ultrastructural analysis, single lab\",\n      \"pmids\": [\"39706847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DSG2 promotes pancreatic cancer stem cell stemness via an IL-8/CXCR2 axis that activates Wnt/β-catenin signaling; DSG2 knockdown suppressed IL-4 and GM-CSF expression and reduced tumour-associated macrophage niche support. The IL-8/CXCR2-DSG2 interaction promotes gemcitabine resistance.\",\n      \"method\": \"DSG2 knockdown (shRNA), cytokine expression analysis, Wnt/β-catenin pathway analysis, macrophage co-culture, gemcitabine resistance assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple pathway and functional readouts, single lab\",\n      \"pmids\": [\"40615400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In Dsg2-mutant knock-in mice, loss of DSG2 function leads to Z-disc structural defects and increased myosin detachment rate; Ca2+-activated force was reduced in permeabilized left ventricular cardiac muscle bundles but preserved in isolated permeabilized cardiomyocytes, demonstrating that DSG2 is required for force transmission between as well as within sarcomeres.\",\n      \"method\": \"Homozygous Dsg2 mutant knock-in mice; permeabilized cardiac muscle bundle and isolated cardiomyocyte mechanical assays; electron microscopy of Z-discs\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct mechanical assays in KI mouse model with comparison of tissue vs isolated cell level, preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Pathogenic autoantibodies from ACM patients bind to DSG2 in hiPSC-CMs, cleave DSG2, and reduce DSG2 interaction at the molecular level; these antibodies activate GSK-3β (upstream of p38MAPK), leading to phosphorylation and junctional loss of β-catenin, causing loss of cardiomyocyte cohesion. GSK-3β inhibition rescued antibody-induced loss of cohesion.\",\n      \"method\": \"hiPSC-CM cohesion assays, Western blotting for DSG2 cleavage, GSK-3β/p38MAPK/β-catenin pathway analysis, GSK-3β inhibitor rescue experiments\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional autoantibody mechanism defined with pathway rescue in hiPSC-CMs, preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"P-cadherin (Pcad) facilitates desmosome assembly by forming heterophilic trans strand-swap dimers with DSG2 on opposing cells; the interaction requires flexibility of the hinge on the swapped β-strands (terminating in conserved Trp residues); strand-swap deficient Pcad fails to rescue desmosome assembly in cells lacking classical cadherins, while strand-swap competent Pcad rescues assembly.\",\n      \"method\": \"Single-molecule AFM, super-resolution and confocal imaging, mutagenesis of strand-swap residues, atomistic simulations, cell-based desmosome assembly rescue assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — single-molecule AFM plus mutagenesis plus functional rescue, preprint not yet peer-reviewed but multiple rigorous methods\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The DSG2 interactome in primary neonatal cardiomyocytes (identified by proximity labeling and quantitative mass spectrometry) includes over 300 proteins; connexin 43 and plakin family cytolinker proteins are unique to DSG2 (vs N-cadherin); plakoglobin (JUP) and plakophilin-2 (PKP2) are the most abundant shared proteins between DSG2 and N-cadherin interactomes. PKP2 membrane recruitment in cardiomyocytes is tension-dependent.\",\n      \"method\": \"Proximity labeling (BioID or similar) combined with quantitative mass spectrometry in primary neonatal cardiomyocytes\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity labeling MS interactome in primary cardiac cells with comparative analysis, preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DSG2 interacts with c-MYC (demonstrated by co-immunoprecipitation) in cervical cancer cells; DSG2 overexpression combined with c-MYC inhibition significantly decreases ADAM17 expression, cell proliferation, and migration compared to DSG2 overexpression alone, indicating DSG2 regulates ADAM17 expression through c-MYC interaction.\",\n      \"method\": \"Co-immunoprecipitation, c-MYC inhibitor treatment, ADAM17 qPCR and Western blot, cell proliferation and migration assays\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP interaction identification plus inhibitor experiment, single lab\",\n      \"pmids\": [\"38948682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DSG2 knockdown in lung adenocarcinoma cells enhances gemcitabine-induced apoptosis by downregulating the NFκB/STAT3/PTX3 signaling axis; adding recombinant PTX3 protein to DSG2 knockdown cells restores STAT3 activation and reduces gemcitabine efficacy, demonstrating DSG2 mediates gemcitabine resistance through PTX3.\",\n      \"method\": \"DSG2 siRNA knockdown, gemcitabine treatment, apoptosis assays, NFκB/STAT3/PTX3 pathway Western blot, recombinant PTX3 rescue experiment\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function plus protein rescue experiment defining the PTX3-mediated mechanism, single lab\",\n      \"pmids\": [\"40316058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Oxymatrine (OMT) directly binds to DSG2 (confirmed by CETSA, DARTS, and microscale thermophoresis), stabilizing DSG2 and inhibiting caspase-8-dependent DSG2 cleavage; DSG2 knockdown diminishes the therapeutic effects of OMT in intestinal epithelial cells, demonstrating that OMT's barrier-protective effects require DSG2.\",\n      \"method\": \"CETSA, DARTS, microscale thermophoresis binding assays; caspase-8 activity assay; lentiviral Dsg2 knockdown; intestinal epithelial barrier function assays\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — three independent direct binding assays plus functional knockdown validation, single lab\",\n      \"pmids\": [\"41076918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In Dsg2 knock-in mice with the F531C mutation, DSG2 deficiency leads to nuclear accumulation of β-catenin and PPAR-γ, promoting triacylglycerol biosynthesis, oxidative stress, cardiomyocyte death, and calcium-handling abnormalities; epicardial epithelial-to-mesenchymal transition and paracrine fibroblast activation via IL-6 and PDGF-BB contribute to fibrotic remodeling. PPAR-γ antagonist GW9662 treatment attenuated these features.\",\n      \"method\": \"CRISPR/Cas9 knock-in mice (Dsg2 F531C), transcriptomic profiling, in vitro cardiomyocyte/fibroblast assays, ex vivo optical mapping, GW9662 treatment, immunostaining\",\n      \"journal\": \"Circulation. Genomic and precision medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knock-in model with multi-level mechanistic analysis and pharmacological rescue, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"41980193\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DSG2 is a transmembrane desmosomal cadherin that forms the adhesive core of desmosomes via homophilic strand-swap dimerization and heterophilic interactions with DSG3 and P-cadherin; its cytoplasmic tail binds plakoglobin (JUP) through the fourth armadillo repeat, linking to the desmosomal plaque; beyond structural adhesion, DSG2 acts as a signaling hub that activates EGFR via c-Src/Cav1-dependent lipid raft remodeling, regulates Wnt/β-catenin and downstream oncogenic pathways (AKT, MAPK, STAT3, NF-κB), and is phosphorylated by PRKD2 at Thr730 to further amplify EGFR/Src/AKT/ERK signaling; loss-of-function mutations in cardiac DSG2 disrupt desmosome integrity, impair force transmission between sarcomeres, trigger ER stress and PERK-ATF4-TGF-β1-driven fibrosis, and impair mTOR-PPARα-dependent fatty acid oxidation, causing arrhythmogenic cardiomyopathy; DSG2 also serves as a functional receptor for group B human adenoviruses and as a sialylated 'don't eat me' signal via Siglec-9 interaction on cancer cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DSG2 is the ubiquitously expressed desmosomal cadherin that forms the adhesive core of desmosomes in simple and stratified epithelia, myocardium, and other desmosome-bearing tissues [#0, #1]. Its extracellular domains mediate Ca2+-dependent homophilic strand-swap dimerization, whose free-energy landscape reflects a high activation barrier characteristic of strand-swap binding [#8], and it also engages in heterophilic trans interactions with DSG3 and with P-cadherin, the latter providing strand-swap dimers that facilitate desmosome assembly [#15, #31]. Progressive ordering of the DSG2 ectodomain accompanies the maturation and strengthening of assembling desmosomes [#24]. The cytoplasmic tail couples to the desmosomal plaque through high-affinity binding to plakoglobin (JUP) via the fourth armadillo repeat [#3], and in cardiomyocytes DSG2 associates with plakophilin-2, connexin 43, and plakin cytolinkers in a tension-dependent interactome [#32]. Beyond adhesion, DSG2 functions as a signaling hub: it activates EGFR through a c-Src– and caveolin-1–dependent lipid-raft mechanism, driving STAT3, PI3K/AKT, MEK-MAPK, and NF-κB signaling that promotes proliferation, apoptosis resistance, and tumorigenesis [#6, #4], with EGFR engagement occurring through direct heterotypic surface binding that can also direct EGFR toward junctional adhesion rather than proliferation [#7]; phosphorylation of DSG2 at Thr730 by PRKD2 further amplifies EGFR/Src/AKT/ERK signaling to promote carcinoma invasion [#22]. In the heart, loss-of-function and missense DSG2 mutations disrupt desmosome integrity and force transmission within and between sarcomeres [#27, #29], causing arrhythmogenic/dilated cardiomyopathy with myocyte necrosis as the initiating injury [#5]; misfolded mutant DSG2 is recognized by BiP and triggers PERK-ATF4–driven TGF-β1 fibrosis [#21], while DSG2 deficiency impairs mTOR-4EBP1-PPARα–dependent fatty acid β-oxidation and drives STAT3/SMAD3- and PPARγ/β-catenin-mediated lipid accumulation and fibrosis [#19, #20, #36]. DSG2 additionally serves as a cell-surface receptor for species B human adenoviruses (HAdV-B3/B7/B14/B55) [#11, #12] and, through sialylated N-glycans, as a counter-receptor for Siglec-9 that suppresses macrophage phagocytosis of tumor cells [#26].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing DSG2 as the ubiquitous desmoglein isoform defined which tissues depend on it for desmosomal adhesion, distinguishing it from the restricted DSG1/DSG3.\",\n      \"evidence\": \"cDNA cloning, sequence determination, and immunocytochemistry across multiple tissues\",\n      \"pmids\": [\"8143788\", \"8641550\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address adhesive binding mechanism or signaling roles\", \"Tissue distribution alone does not establish function\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Mapping the plakoglobin-binding determinant resolved how the DSG2 cytoplasmic tail couples to the desmosomal plaque.\",\n      \"evidence\": \"In vitro binding assays with recombinant plakoglobin deletion mutants\",\n      \"pmids\": [\"8749329\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Affinity quantification incomplete\", \"Does not address plakophilin or desmoplakin linkage in vivo\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"A dominant-negative cardiac DSG2 mutant model showed that DSG2 dysfunction causes arrhythmogenic cardiomyopathy and identified myocyte necrosis as the initiating lesion.\",\n      \"evidence\": \"Cardiac-specific DSG2 mutant transgenic mice with dose-dependent phenotyping and human tissue correlation\",\n      \"pmids\": [\"19635863\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular trigger of necrosis not defined\", \"Link between adhesion loss and electrical instability unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connecting DSG2 to EGFR through lipid-raft remodeling reframed DSG2 as a signaling platform rather than a purely structural adhesion molecule.\",\n      \"evidence\": \"siRNA knockdown/overexpression, sucrose fractionation, STED imaging, and cholesterol depletion in A431 cells\",\n      \"pmids\": [\"26918609\", \"17284515\", \"29980799\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of DSG2-EGFR-Cav1-Src complex unresolved\", \"How adhesion vs proliferation signaling outputs are selected remains incomplete\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Single-molecule force spectroscopy showed ARVC mutations weaken DSG2 homophilic binding kinetically without disrupting the strand-swap motif, linking biophysical adhesion defects to disease.\",\n      \"evidence\": \"AFM single-molecule force spectroscopy and dispase dissociation assays with WT/mutant DSG2\",\n      \"pmids\": [\"29062102\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How altered binding kinetics translate to tissue-level failure not shown\", \"Heterophilic binding contributions not tested here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrating heterophilic DSG2-DSG3 catch-bond binding revealed a partner-mixing mechanism that can buffer adhesion loss, with relevance to pemphigus.\",\n      \"evidence\": \"Cell-free AFM single-molecule binding and IP with autoantibody inhibition\",\n      \"pmids\": [\"33193387\", \"33387800\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo significance of heterophilic rescue not established\", \"Quantitative contribution to tissue cohesion unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying DSG2 as a species B adenovirus receptor explained tropism of HAdV-B and established a non-adhesive surface function.\",\n      \"evidence\": \"Human DSG2 transgenic mice and GFP-reporter HAdV-B transduction; later gain/loss-of-function in cell lines for HAdV-B55\",\n      \"pmids\": [\"22457526\", \"34224109\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor-binding interface on DSG2 not mapped\", \"Whether viral binding perturbs desmosomal adhesion not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Cardiac-specific DSG2 knockouts uncovered metabolic and fibrotic mechanisms—impaired mTOR-PPARα fatty acid oxidation and STAT3/SMAD3-driven fibrosis—linking adhesion loss to heart failure.\",\n      \"evidence\": \"CS-Dsg2-/- mice with rapamycin, mTOR/4EBP1 overexpression, fenofibrate, and AAV9-Pparα rescue\",\n      \"pmids\": [\"36815030\", \"36291052\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How loss of a junctional protein controls metabolic transcription unresolved\", \"Causal ordering of metabolic vs structural defects unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Knock-in models defined a proteostatic disease mechanism: misfolded DSG2 mutant engages BiP and triggers PERK-ATF4-TGF-β1 fibrosis, and PRKD2 phosphorylation at Thr730 was identified as a signaling-amplifying modification.\",\n      \"evidence\": \"Dsg2 F536C knock-in mice with BiP co-IP and PERK-ATF4 inhibition; PRKD2 kinase-substrate identification by MS and phosphomutant assays\",\n      \"pmids\": [\"39227800\", \"38411280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of ER-stress mechanism across DSG2 mutations not established\", \"Physiological substrates and regulation of T730 phosphorylation incompletely defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"DSG2 was established as a sialic-acid-dependent Siglec-9 counter-receptor functioning as a 'don't eat me' signal, and P-cadherin was shown to nucleate desmosome assembly via strand-swap dimers with DSG2.\",\n      \"evidence\": \"Proximity labeling/CRISPR screen and phagocytosis assays for Siglec-9; single-molecule AFM, mutagenesis, and rescue assays for P-cadherin (preprint)\",\n      \"pmids\": [\"39813162\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Siglec-9 glycan recognition not defined\", \"P-cadherin findings remain preprint and require peer review\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the dual structural and signaling functions of DSG2 are integrated and selectively engaged across epithelial homeostasis, cancer, cardiac mechanotransduction, and immune evasion remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of the DSG2 adhesive-signaling complex\", \"Mechanism coupling junctional adhesion state to transcriptional/metabolic output undefined\", \"Whether signaling roles are conserved across tissues unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [8, 15, 31, 24]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [11, 12]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [6, 7, 22]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 25, 7]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 1, 24]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 7, 22]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 21, 19, 36]},\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [29, 27]}\n    ],\n    \"complexes\": [\"desmosome\", \"intercalated disc\"],\n    \"partners\": [\"JUP\", \"EGFR\", \"DSG3\", \"PKP2\", \"PRKD2\", \"CDH3\", \"TROP2\", \"SIGLEC9\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}