{"gene":"DSG3","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":1994,"finding":"The extracellular domain of Dsg3 (produced as a secreted chimeric protein PVIg in baculovirus/insect cells) contains conformational epitopes that absorb pathogenic pemphigus vulgaris autoantibodies and prevent blister formation in a neonatal mouse model; bacterial fusion proteins lacking proper conformation failed to absorb these antibodies.","method":"Baculovirus expression of PVIg chimera, immunoadsorption of PV patient sera, neonatal mouse passive transfer model","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro immunoadsorption assay combined with in vivo neonatal mouse model, multiple PV sera tested, controls with PF and BP sera included","pmids":["8040292"],"is_preprint":false},{"year":1995,"finding":"Plakoglobin binds directly to Dsg3 via the carboxy-terminal 87 amino acids of the intracytoplasmic cadherin-like segment subdomain; the desmoglein-specific IC subdomains are not necessary for this interaction. The interaction was confirmed to be direct by in vitro transcription/translation without other cellular factors.","method":"Chimeric E-cadherin/Dsg3 truncation constructs transfected into HaCaT cells, co-immunoprecipitation, immunoblotting, in vitro transcription/translation","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding confirmed by in vitro reconstitution, domain-mapping by systematic truncation mutants, replicated in both cellular and cell-free systems","pmids":["7738346"],"is_preprint":false},{"year":1996,"finding":"Conformational epitopes of Dsg3 require transit through the endoplasmic reticulum (via signal peptide) for proper folding; proteolytic processing and glycosylation are NOT required. A Dsg3 mutant lacking the signal peptide accumulated in the cytosol and failed to form conformational epitopes.","method":"Site-directed mutagenesis of signal peptide and endoproteolytic cleavage site in baculovirus-expressed PVIg, immunoadsorption activity assay","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with functional immunoadsorption assay, multiple mutant constructs, single lab","pmids":["8823357"],"is_preprint":false},{"year":1999,"finding":"PV-IgG binding to Dsg3 on the cell surface causes rapid depletion of Dsg3 from the Triton X-100-soluble membrane fraction within 20 minutes, followed by loss from the cytoskeletal (desmosomal) fraction after 30 hours, generating Dsg3-depleted desmosomes while other desmosomal components (Dsg1, desmoplakin 1, plakoglobin, keratins) remain intact.","method":"Biochemical fractionation (PBS-soluble, Triton X-100-soluble, Triton X-100-insoluble), immunoblotting, double-staining immunofluorescence microscopy in DJM-1 cells","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (biochemical fractionation + immunofluorescence), time-course experiment, multiple desmosomal markers as controls","pmids":["9886266"],"is_preprint":false},{"year":2007,"finding":"Pathogenic and non-pathogenic monoclonal anti-Dsg3 antibodies each cause depletion of Dsg3 from desmosomes; individual antibodies have characteristic limits to their Dsg3-depleting activity that correlates with their pathogenic activity in mouse models, and combinations of antibodies show cumulative or synergistic depletion effects.","method":"Monoclonal antibody treatment of DJM-1 cells and normal human keratinocytes, immunofluorescence microscopy, cell fractionation, mouse passive transfer model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods, pathogenic/non-pathogenic MAbs compared, in vitro and in vivo validation, replicated across two cell types","pmids":["17428808"],"is_preprint":false},{"year":2010,"finding":"PV IgG causes desmosome disassembly in three sequential phases: (1) rapid Dsg3 internalization from a non-junctional surface pool; (2) rearrangement of Dsg3 and other desmosomal components into linear arrays perpendicular to cell contacts with retrograde transport into cytoplasmic vesicles; (3) depletion of detergent-insoluble Dsg3 and loss of adhesion strength. Expression of exogenous Dsg3 can reverse this process by driving desmosome reassembly.","method":"Live and fixed imaging of primary human keratinocytes, biochemical fractionation, cell dissociation assay, exogenous Dsg3 rescue experiment","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (live imaging, fixed imaging, biochemistry, functional adhesion assay), rescue experiment provides mechanistic confirmation","pmids":["21160493"],"is_preprint":false},{"year":2013,"finding":"DSG3 interacts with plakoglobin at cell junctions; DSG3 silencing disrupts this interaction and induces plakoglobin nuclear translocation, which increases plakoglobin–TCF interaction and suppresses TCF/LEF transcriptional activity, reducing downstream targets c-Myc, cyclin D1, and MMP-7, leading to G0/G1 arrest, reduced migration, and reduced invasion in head and neck cancer cells.","method":"RNAi knockdown of DSG3 in HNC cell lines, immunoprecipitation, immunofluorescence, TCF/LEF luciferase reporter assay, flow cytometry (cell cycle), in vivo xenograft mouse model","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, reporter assay, functional assays, in vivo), consistent in vitro and in vivo results, single lab","pmids":["23737966"],"is_preprint":false},{"year":2015,"finding":"Extradesmosomal Dsg3 forms a complex with E-cadherin, β-catenin, and Src; the stability of this complex is regulated by Src kinase activity. Src phosphorylates both Dsg3 and E-cadherin on tyrosine residues, and Src activity is required for recruiting Dsg3 to the cytoskeletal pool and for desmosome maturation to a Ca2+-insensitive state. Silencing E-cadherin abolishes Dsg3 membrane localization and shifts Dsg3 from the cytoskeletal to the non-cytoskeletal pool.","method":"Co-immunoprecipitation, E-cadherin overexpression and siRNA silencing, Src inhibitor treatment, phospho-tyrosine immunoblotting, immunofluorescence, cell cohesion assay, p38 MAPK activation assay in keratinocytes","journal":"Cellular and molecular life sciences : CMLS","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP identifying multi-protein complex, multiple pharmacological and genetic perturbations, multiple orthogonal readouts, single lab","pmids":["26115704"],"is_preprint":false},{"year":2015,"finding":"Dsg3 competes with inactive Src for binding to the scaffolding domain of caveolin-1 (Cav-1) in a non-ionic detergent-soluble pool; increased Dsg3 levels reduce Cav-1/Src co-localization, suggesting Dsg3 activates Src by displacing it from Cav-1-mediated inhibition.","method":"Co-immunoprecipitation of Dsg3/Src/Cav-1 complexes, Dsg3 overexpression and knockdown, immunofluorescence co-localization analysis, sequence analysis of Cav-1 scaffolding domain binding motif in Dsg3","journal":"Data in brief","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and immunofluorescence, data article (extended data) rather than primary research article, proposed model not fully validated","pmids":["26858977"],"is_preprint":false},{"year":2019,"finding":"Dsg3 (but not Dsg2) is required for PV-IgG-induced loss of keratinocyte cohesion; PV-IgG activates EGFR in a Src-dependent manner and activates ERK in a Src-dependent manner, while Ca2+ influx induced by PV-IgG is EGFR-independent. CRISPR/Cas9 knockout of Dsg3 protects against PV-IgG-induced adhesion loss.","method":"CRISPR/Cas9 Dsg3 and Dsg2 knockout HaCaT cells, dispase cell cohesion assay, Western blot for EGFR/ERK/Src phosphorylation, Ca2+ chelation, pharmacological inhibitors, Fura-2 Ca2+ measurements","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via CRISPR knockout, multiple pharmacological and biochemical readouts, Dsg2 KO as isoform control, single lab","pmids":["31178865"],"is_preprint":false},{"year":2021,"finding":"Anti-Dsg3 antibody activates p38 MAPK phosphorylation in keratinocytes; externally applied mechanical stress mitigates antibody-induced monolayer fragmentation and inhibits this p38 MAPK phosphorylation by enhancing RhoA activation and cortical actin strengthening.","method":"Anti-Dsg3 antibody treatment of keratinocyte monolayers, mechanical stress application, p38 MAPK phosphorylation assay, RhoA activity measurement, actin cytoskeleton imaging","journal":"Advanced biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple biochemical and functional readouts but single lab, mechanistic pathway placement via pharmacological and physical perturbation","pmids":["33724731"],"is_preprint":false},{"year":2022,"finding":"Super-resolution microscopy reveals that Dsg3 and Dsg1 are distributed heterogeneously across desmosome populations in different epidermal layers, with Dsg3 predominantly in basal layer desmosomes. Extradesmosomal Dsg3 co-localizes with plakoglobin (desmoplakin-independently) mainly in the basal layer, supporting a role for extradesmosomal Dsg3-plakoglobin complexes in desmosome assembly.","method":"STED super-resolution microscopy, co-localization analysis of Dsg1, Dsg3, desmoplakin, and plakoglobin in normal human skin sections and pemphigus patient skin","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — super-resolution imaging with multiple molecular markers and quantitative co-localization analysis, normal and patient tissue compared, single lab","pmids":["35711465"],"is_preprint":false},{"year":2023,"finding":"Two pathogenic anti-Dsg3 monoclonal antibodies targeting different epitopes (EC5 domain: 2G4; EC1 domain: AK23) elicit distinct signaling: both induce p38MAPK and Akt phosphorylation, but only AK23 (EC1-targeting) induces Dsg3 depletion and Src phosphorylation. Src and Akt activation are p38MAPK-dependent. AK23-mediated effects are ameliorated by Src inhibition in addition to p38MAPK inhibition.","method":"Dispase-based cell dissociation assay, Western blot (p38MAPK, Src, Akt), STED microscopy (keratin retraction, desmosome number, Dsg3 distribution), Fura-based Ca2+ flux measurements, Rho/Rac G-protein ELISA in keratinocytes","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (STED, biochemistry, functional assay, Ca2+ flux), two distinct pathogenic MAbs compared, epitope-specific signaling pathway mapped, single lab","pmids":["37143675"],"is_preprint":false},{"year":2023,"finding":"STED/SMFS-AFM single-molecule force spectroscopy on living keratinocytes reveals two distinct pools of Dsg3 with different cytoskeletal anchorage: a cell-surface (extradesmosomal) pool whose adhesion is actin-dependent (sensitive to Latrunculin B), and a cell-cell contact (desmosomal) pool whose adhesion is independent of actin but regulated by PKCα/intermediate filament anchorage.","method":"Hybrid STED/SMFS-AFM on living keratinocytes, Latrunculin B (actin depolymerization), PMA (PKCα activation), pharmacological perturbation with single-molecule force measurements","journal":"Cellular and molecular life sciences : CMLS","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — novel single-molecule biophysical method combined with pharmacological perturbations directly on living cells, two distinct pools distinguished by orthogonal pharmacology, single lab","pmids":["36602635"],"is_preprint":false},{"year":2025,"finding":"DSG3 promotes bladder cancer growth and metastasis via STAT3-mediated transcriptional upregulation of DSG3, which then activates AKT phosphorylation, inhibits GSK3β, promotes β-catenin nuclear translocation, and upregulates SOX2 and MMP7 expression. DSG3 knockdown suppresses EMT, cancer stemness, migration, invasion, and in vivo tumor growth and lung metastasis.","method":"DSG3 knockdown (siRNA/shRNA) and overexpression in bladder cancer cell lines, co-immunoprecipitation, Western blot for AKT/GSK3β/β-catenin pathway components, STAT3 ChIP/transcription assays, in vitro migration/invasion assays, in vivo xenograft and metastasis models","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple in vitro and in vivo methods with pathway dissection, single lab, no independent replication yet","pmids":["40605005"],"is_preprint":false},{"year":2024,"finding":"PV IgG targeting Dsg3 triggers ER stress signaling, activating both IRE1α and PERK pathways; ER tubules make frequent persistent contacts with internalizing Dsg3 puncta. Pharmacological inhibition of ER stress protects against PV IgG-induced desmosome disruption and loss of keratinocyte cell-cell adhesion.","method":"High-resolution time-lapse live imaging, biochemical ER stress assays (IRE1α and PERK pathway markers), pharmacological ER stress inhibition, keratinocyte cell cohesion assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple orthogonal methods (live imaging, biochemistry, pharmacological rescue), preprint not yet peer-reviewed, single lab","pmids":[],"is_preprint":true}],"current_model":"DSG3 encodes desmoglein 3, a desmosomal cadherin that mediates keratinocyte cell–cell adhesion by forming calcium-dependent trans-interactions at desmosomes; its intracytoplasmic cadherin-like domain directly binds plakoglobin, and its extradesmosomal pool forms a complex with E-cadherin, β-catenin, and Src—where Src-dependent tyrosine phosphorylation of Dsg3 and E-cadherin drives desmosome maturation to a Ca2+-insensitive state; two cytoskeletal pools of Dsg3 exist, an actin-anchored extradesmosomal pool and an intermediate filament-anchored desmosomal pool regulated by PKCα; pathogenic pemphigus vulgaris autoantibodies targeting Dsg3 trigger epitope-specific signaling cascades (including p38MAPK, Src, Akt, EGFR, Ca2+ influx, and ER stress) that drive Dsg3 internalization from the cell surface, depletion from desmosomes, and ultimately loss of adhesion; in cancer contexts, DSG3 retains plakoglobin at cell junctions to activate TCF/LEF-driven transcription of c-Myc, cyclin D1, and MMP-7, and in bladder cancer acts downstream of STAT3 to activate AKT/GSK3β/β-catenin signaling and upregulate SOX2 and MMP7."},"narrative":{"mechanistic_narrative":"DSG3 encodes desmoglein 3, a desmosomal cadherin that mediates calcium-dependent keratinocyte cell-cell adhesion and serves as the principal autoantigen in pemphigus vulgaris [PMID:8040292, PMID:9886266]. Its intracytoplasmic cadherin-like segment binds plakoglobin directly through its carboxy-terminal 87 residues, independent of other cellular factors [PMID:7738346], and proper folding of its extracellular conformational epitopes requires transit through the endoplasmic reticulum but not glycosylation or proteolytic processing [PMID:8823357]. Dsg3 exists in two functionally distinct cytoskeletal pools resolved by single-molecule force spectroscopy: an extradesmosomal cell-surface pool whose adhesion is actin-dependent, and a desmosomal cell-contact pool that is actin-independent and regulated by PKCalpha [PMID:36602635]. The extradesmosomal pool assembles into a complex with E-cadherin, beta-catenin, and Src, where Src-dependent tyrosine phosphorylation of Dsg3 and E-cadherin recruits Dsg3 to the cytoskeletal pool and drives desmosome maturation to a calcium-insensitive state [PMID:26115704]. Pathogenic PV autoantibodies binding cell-surface Dsg3 trigger sequential desmosome disassembly—rapid internalization of a non-junctional surface pool followed by depletion of detergent-insoluble desmosomal Dsg3 and loss of adhesion—a process reversible by exogenous Dsg3-driven reassembly [PMID:9886266, PMID:21160493]; these antibodies act through epitope-specific cascades involving p38MAPK, Src, Akt, EGFR, and Ca2+ influx [PMID:31178865, PMID:37143675]. In cancer, DSG3 retains plakoglobin at junctions to sustain TCF/LEF-driven transcription of c-Myc, cyclin D1, and MMP-7 [PMID:23737966], and in bladder cancer acts downstream of STAT3 to activate AKT/GSK3beta/beta-catenin signaling and upregulate SOX2 and MMP7 [PMID:40605005].","teleology":[{"year":1994,"claim":"Established that the pathogenic PV autoantibody response targets conformational epitopes on the Dsg3 extracellular domain, defining Dsg3 as the relevant antigen and linking antibody binding to blister formation.","evidence":"Baculovirus-expressed PVIg chimera immunoadsorption of patient sera with neonatal mouse passive transfer","pmids":["8040292"],"confidence":"High","gaps":["Did not map the specific epitope residues","Did not address downstream signaling triggered by antibody binding"]},{"year":1995,"claim":"Resolved how Dsg3 couples to the desmosomal plaque by mapping a direct plakoglobin-binding site to the carboxy-terminal 87 residues of the intracytoplasmic cadherin-like segment.","evidence":"Chimeric truncation constructs in HaCaT cells with Co-IP and cell-free in vitro transcription/translation","pmids":["7738346"],"confidence":"High","gaps":["Did not establish the stoichiometry or affinity of the interaction","Did not address how this binding regulates desmosome assembly"]},{"year":1996,"claim":"Defined the biogenesis requirement for Dsg3 antigenicity, showing ER transit but not glycosylation or proteolytic processing produces the conformational epitopes.","evidence":"Signal-peptide and cleavage-site mutagenesis of baculovirus-expressed PVIg with immunoadsorption assay","pmids":["8823357"],"confidence":"High","gaps":["Did not identify the chaperones mediating folding","Single expression system"]},{"year":1999,"claim":"Showed that PV-IgG selectively depletes Dsg3 in two kinetic phases, first from the soluble membrane pool then from desmosomes, while sparing other desmosomal components, distinguishing Dsg3 loss as the primary lesion.","evidence":"Triton fractionation, immunoblotting, and immunofluorescence time-course in DJM-1 cells","pmids":["9886266"],"confidence":"High","gaps":["Did not define the signaling driving internalization","Mechanism of depletion (degradation vs internalization) not resolved"]},{"year":2007,"claim":"Linked antibody pathogenicity to Dsg3-depleting capacity, showing individual monoclonals have characteristic depletion limits that correlate with in vivo pathogenicity and combine cumulatively.","evidence":"Pathogenic/non-pathogenic monoclonal antibody treatment of keratinocytes with fractionation, imaging, and mouse passive transfer","pmids":["17428808"],"confidence":"High","gaps":["Did not map molecular signaling distinguishing pathogenic from non-pathogenic antibodies"]},{"year":2010,"claim":"Defined the three sequential phases of PV-IgG-induced desmosome disassembly and demonstrated reversibility, establishing internalization and retrograde transport as the mechanistic route to adhesion loss.","evidence":"Live and fixed imaging, fractionation, cell dissociation assay, and exogenous Dsg3 rescue in primary keratinocytes","pmids":["21160493"],"confidence":"High","gaps":["Did not identify the trafficking machinery driving internalization","Did not connect phases to specific kinase cascades"]},{"year":2013,"claim":"Revealed a transcriptional function of DSG3 in cancer by showing it retains plakoglobin at junctions to sustain TCF/LEF activity and proliferation, with knockdown driving plakoglobin nuclear translocation and growth arrest.","evidence":"RNAi in head and neck cancer lines with Co-IP, TCF/LEF reporter, cell-cycle flow cytometry, and xenografts","pmids":["23737966"],"confidence":"High","gaps":["Did not establish whether desmosomal or extradesmosomal Dsg3 mediates this","Direct vs indirect effect on plakoglobin localization not dissected"]},{"year":2015,"claim":"Identified an extradesmosomal Dsg3/E-cadherin/beta-catenin/Src complex in which Src-driven tyrosine phosphorylation controls Dsg3 cytoskeletal recruitment and desmosome maturation to a Ca2+-insensitive state.","evidence":"Reciprocal Co-IP, E-cadherin overexpression/silencing, Src inhibition, phospho-tyrosine blotting, and cohesion assays in keratinocytes","pmids":["26115704"],"confidence":"High","gaps":["Did not establish phosphorylation site stoichiometry","Mechanism of Src activation not resolved here"]},{"year":2015,"claim":"Proposed a mechanism for Src activation in which Dsg3 displaces inactive Src from the caveolin-1 scaffolding domain, relieving Cav-1-mediated inhibition.","evidence":"Co-IP of Dsg3/Src/Cav-1, overexpression/knockdown, and colocalization analysis (Data in Brief)","pmids":["26858977"],"confidence":"Low","gaps":["Single Co-IP and immunofluorescence without functional validation","Model proposed but Src kinase activation not directly measured","Data article rather than primary research"]},{"year":2019,"claim":"Used genetic epistasis to confirm Dsg3 specificity and order the antibody-triggered cascade, showing Dsg3 (not Dsg2) is required for adhesion loss and that PV-IgG activates EGFR/ERK via Src while Ca2+ influx is EGFR-independent.","evidence":"CRISPR/Cas9 Dsg3 and Dsg2 knockout HaCaT cells with cohesion assays, phospho-blots, Ca2+ measurements, and inhibitors","pmids":["31178865"],"confidence":"High","gaps":["Did not place all pathway branches in a single hierarchy","Relationship between EGFR signaling and Dsg3 depletion not fully resolved"]},{"year":2021,"claim":"Connected mechanotransduction to antibody signaling, showing mechanical stress suppresses anti-Dsg3-induced p38 MAPK activation by enhancing RhoA and cortical actin.","evidence":"Anti-Dsg3 antibody plus mechanical stress in keratinocyte monolayers with p38 phospho-assay, RhoA activity, and actin imaging","pmids":["33724731"],"confidence":"Medium","gaps":["Single lab","Mechanosensor upstream of RhoA not identified"]},{"year":2022,"claim":"Mapped the spatial distribution of Dsg3 across epidermal layers and showed extradesmosomal Dsg3-plakoglobin complexes form desmoplakin-independently in the basal layer, supporting their role in desmosome assembly.","evidence":"STED super-resolution colocalization of Dsg1/Dsg3/desmoplakin/plakoglobin in normal and pemphigus skin","pmids":["35711465"],"confidence":"Medium","gaps":["Did not functionally test the assembly role","Single lab"]},{"year":2023,"claim":"Demonstrated epitope-specific antibody signaling, showing EC1- versus EC5-targeting monoclonals diverge in Dsg3 depletion and Src activation while converging on p38MAPK-dependent Akt and Src activation.","evidence":"Two pathogenic monoclonals with dispase dissociation, phospho-blots, STED imaging, Ca2+ flux, and Rho/Rac ELISA in keratinocytes","pmids":["37143675"],"confidence":"High","gaps":["Did not extend to additional epitopes","Single lab"]},{"year":2023,"claim":"Distinguished two biophysically distinct Dsg3 adhesion pools, an actin-dependent extradesmosomal pool and an actin-independent, PKCalpha/intermediate-filament-regulated desmosomal pool, on living cells.","evidence":"Hybrid STED/SMFS-AFM single-molecule force spectroscopy with Latrunculin B and PMA perturbation","pmids":["36602635"],"confidence":"High","gaps":["Did not connect the two pools to specific binding partners at the molecular level","Single lab"]},{"year":2025,"claim":"Defined a STAT3-DSG3-AKT/GSK3beta/beta-catenin oncogenic axis in bladder cancer driving EMT, stemness, and metastasis via SOX2 and MMP7 upregulation.","evidence":"DSG3 knockdown/overexpression in bladder cancer lines with Co-IP, pathway blots, STAT3 transcription assays, and xenograft/metastasis models","pmids":["40605005"],"confidence":"Medium","gaps":["No independent replication","Single lab","Direct vs indirect activation of AKT by DSG3 not resolved"]},{"year":2024,"claim":"Implicated ER stress in antibody-induced adhesion loss, showing PV IgG activates IRE1alpha and PERK and that ER tubules contact internalizing Dsg3 puncta, with ER stress inhibition protecting adhesion.","evidence":"Time-lapse live imaging, ER stress biochemical markers, pharmacological inhibition, and cohesion assay (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Mechanism linking ER stress to Dsg3 internalization not resolved","Single lab"]},{"year":null,"claim":"How the distinct cytoskeletal pools, kinase cascades, ER-stress responses, and transcriptional functions of Dsg3 are integrated into a single regulatory hierarchy across normal epidermis, pemphigus, and cancer remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified ordering of p38MAPK, Src, EGFR, Akt, Ca2+, and ER stress branches","Structural basis of Dsg3 trans-adhesion not determined in the corpus","Whether cancer and pemphigus signaling share common Dsg3-proximal events untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[3,5,7,13]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[13,7]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[9,12]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,7,13]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[7,13]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[5]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6,14]}],"pathway":[{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[3,5,7,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,9,12,14]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,3,5,14]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[6,14]}],"complexes":["desmosome"],"partners":["JUP","CDH1","CTNNB1","SRC","CAV1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P32926","full_name":"Desmoglein-3","aliases":["130 kDa pemphigus vulgaris antigen","PVA","Cadherin family member 6"],"length_aa":999,"mass_kda":107.5,"function":"A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion (PubMed:31835537). Required for adherens and desmosome junction assembly in response to mechanical force in keratinocytes (PubMed:31835537). Required for desmosome-mediated cell-cell adhesion of cells surrounding the telogen hair club and the basal layer of the outer root sheath epithelium, consequently is essential for the anchoring of telogen hairs in the hair follicle (PubMed:9701552). Required for the maintenance of the epithelial barrier via promoting desmosome-mediated intercellular attachment of suprabasal epithelium to basal cells (By similarity). May play a role in the protein stability of the desmosome plaque components DSP, JUP, PKP1, PKP2 and PKP3 (PubMed:22294297). Required for YAP1 localization at the plasma membrane in keratinocytes in response to mechanical strain, via the formation of an interaction complex composed of DSG3, PKP1 and YWHAG (PubMed:31835537). May also be involved in the positive regulation of YAP1 target gene transcription and as a result cell proliferation (PubMed:31835537). Positively regulates cellular contractility and cell junction formation via organization of cortical F-actin bundles and anchoring of actin to tight junctions, in conjunction with RAC1 (PubMed:22796473). The cytoplasmic pool of DSG3 is required for the localization of CDH1 and CTNNB1 at developing adherens junctions, potentially via modulation of SRC activity (PubMed:22294297). Inhibits keratinocyte migration via suppression of p38MAPK signaling, may therefore play a role in moderating wound healing (PubMed:26763450)","subcellular_location":"Cell membrane; Cell junction, desmosome; Cytoplasm; Cell junction, tight junction; Cell junction","url":"https://www.uniprot.org/uniprotkb/P32926/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DSG3","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DSG3","total_profiled":1310},"omim":[{"mim_id":"619226","title":"BLISTERING, ACANTHOLYTIC, OF ORAL AND LARYNGEAL MUCOSA; ABOLM","url":"https://www.omim.org/entry/619226"},{"mim_id":"607903","title":"HYPOTRICHOSIS 6; HYPT6","url":"https://www.omim.org/entry/607903"},{"mim_id":"607892","title":"DESMOGLEIN 4; DSG4","url":"https://www.omim.org/entry/607892"},{"mim_id":"605116","title":"CHOLINERGIC RECEPTOR, NEURONAL NICOTINIC, ALPHA POLYPEPTIDE 9; CHRNA9","url":"https://www.omim.org/entry/605116"},{"mim_id":"169615","title":"DESMOGLEIN 3; DSG3","url":"https://www.omim.org/entry/169615"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"cervix","ntpm":93.0},{"tissue":"esophagus","ntpm":296.1},{"tissue":"vagina","ntpm":115.5}],"url":"https://www.proteinatlas.org/search/DSG3"},"hgnc":{"alias_symbol":["CDHF6"],"prev_symbol":[]},"alphafold":{"accession":"P32926","domains":[{"cath_id":"2.60.40.60","chopping":"54-149","consensus_level":"high","plddt":92.653,"start":54,"end":149},{"cath_id":"2.60.40.60","chopping":"157-259","consensus_level":"medium","plddt":95.008,"start":157,"end":259},{"cath_id":"2.60.40.60","chopping":"267-376","consensus_level":"medium","plddt":94.961,"start":267,"end":376},{"cath_id":"2.60.40.60","chopping":"382-485","consensus_level":"high","plddt":86.4858,"start":382,"end":485},{"cath_id":"2.60.40.60","chopping":"495-596","consensus_level":"high","plddt":76.5641,"start":495,"end":596}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P32926","model_url":"https://alphafold.ebi.ac.uk/files/AF-P32926-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P32926-F1-predicted_aligned_error_v6.png","plddt_mean":65.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DSG3","jax_strain_url":"https://www.jax.org/strain/search?query=DSG3"},"sequence":{"accession":"P32926","fasta_url":"https://rest.uniprot.org/uniprotkb/P32926.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P32926/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P32926"}},"corpus_meta":[{"pmid":"8040292","id":"PMC_8040292","title":"Absorption of pathogenic autoantibodies by the extracellular domain of pemphigus vulgaris antigen (Dsg3) produced by baculovirus.","date":"1994","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/8040292","citation_count":272,"is_preprint":false},{"pmid":"9886266","id":"PMC_9886266","title":"Pemphigus vulgaris-IgG causes a rapid depletion of desmoglein 3 (Dsg3) from the Triton X-100 soluble pools, leading to the formation of Dsg3-depleted desmosomes in a human squamous carcinoma cell line, DJM-1 cells.","date":"1999","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/9886266","citation_count":124,"is_preprint":false},{"pmid":"16878157","id":"PMC_16878157","title":"DSG3 is overexpressed in head neck cancer and is a potential molecular target for inhibition of 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/33724731","citation_count":13,"is_preprint":false},{"pmid":"36375372","id":"PMC_36375372","title":"Desmoglein 3 (Dsg3) expression in cancer: A tissue microarray study on 15,869 tumors.","date":"2022","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/36375372","citation_count":13,"is_preprint":false},{"pmid":"29749496","id":"PMC_29749496","title":"Increased expression of microRNA-338-3p contributes to production of Dsg3 antibody in pemphigus vulgaris patients.","date":"2018","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/29749496","citation_count":13,"is_preprint":false},{"pmid":"36689824","id":"PMC_36689824","title":"Deregulated phenotype of autoreactive Th17 and Treg clone cells in pemphigus vulgaris after in-vitro treatment with desmoglein antigen (Dsg-3).","date":"2023","source":"Immunobiology","url":"https://pubmed.ncbi.nlm.nih.gov/36689824","citation_count":13,"is_preprint":false},{"pmid":"8823357","id":"PMC_8823357","title":"Transport to endoplasmic reticulum by signal peptide, but not proteolytic processing, is required for formation of conformational epitopes of pemphigus vulgaris antigen (Dsg3).","date":"1996","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/8823357","citation_count":12,"is_preprint":false},{"pmid":"36602635","id":"PMC_36602635","title":"Cytoskeletal anchorage of different Dsg3 pools revealed by combination of hybrid STED/SMFS-AFM.","date":"2023","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/36602635","citation_count":11,"is_preprint":false},{"pmid":"18586466","id":"PMC_18586466","title":"Genetic characterization of human Dsg3-specific B cells isolated by flow cytometry from the peripheral blood of patients with pemphigus vulgaris.","date":"2008","source":"Journal of dermatological science","url":"https://pubmed.ncbi.nlm.nih.gov/18586466","citation_count":7,"is_preprint":false},{"pmid":"19200441","id":"PMC_19200441","title":"High-dose pemphigus antibodies against linear epitopes of desmoglein 3 (Dsg3) can induce acantholysis and depletion of Dsg3 from keratinocytes.","date":"2009","source":"Immunology letters","url":"https://pubmed.ncbi.nlm.nih.gov/19200441","citation_count":5,"is_preprint":false},{"pmid":"26858977","id":"PMC_26858977","title":"Evidence for Dsg3 in regulating Src signaling by competing with it for binding to caveolin-1.","date":"2015","source":"Data in brief","url":"https://pubmed.ncbi.nlm.nih.gov/26858977","citation_count":5,"is_preprint":false},{"pmid":"40605005","id":"PMC_40605005","title":"DSG3 promotes bladder cancer growth and metastasis via AKT/GSK3β/β-catenin pathway.","date":"2025","source":"Journal of translational 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Part A","url":"https://pubmed.ncbi.nlm.nih.gov/37850634","citation_count":1,"is_preprint":false},{"pmid":"41676306","id":"PMC_41676306","title":"Dihydroartemisinin attenuates pemphigus vulgaris by regulating Dsg3 and the TLR9/NF-κB pathway.","date":"2026","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/41676306","citation_count":0,"is_preprint":false},{"pmid":"42259463","id":"PMC_42259463","title":"ZCRB1 promotes proliferation and metastasis of lung squamous cell carcinoma by stabilizing DSG3 mRNA.","date":"2026","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/42259463","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.06.25333158","title":"Vector-derived Cadherin Mimicry in Pemphigus Vulgaris: A Proposed Model Linking HLA-DRB1*04:02/14:01 Genotype with Environmental Exposure","date":"2025-08-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.06.25333158","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.10.637416","title":"In pemphigus, cell detachment, but not autoantibody binding, induces cell-wide, long-lasting transcriptomic and proteomic changes","date":"2025-02-12","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.10.637416","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.22.608849","title":"Pemphigus vulgaris autoantibodies induce an ER stress response","date":"2024-08-23","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.22.608849","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21887,"output_tokens":4808,"usd":0.06889,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12957,"output_tokens":5197,"usd":0.097355,"stage2_stop_reason":"end_turn"},"total_usd":0.166245,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"The extracellular domain of Dsg3 (produced as a secreted chimeric protein PVIg in baculovirus/insect cells) contains conformational epitopes that absorb pathogenic pemphigus vulgaris autoantibodies and prevent blister formation in a neonatal mouse model; bacterial fusion proteins lacking proper conformation failed to absorb these antibodies.\",\n      \"method\": \"Baculovirus expression of PVIg chimera, immunoadsorption of PV patient sera, neonatal mouse passive transfer model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro immunoadsorption assay combined with in vivo neonatal mouse model, multiple PV sera tested, controls with PF and BP sera included\",\n      \"pmids\": [\"8040292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Plakoglobin binds directly to Dsg3 via the carboxy-terminal 87 amino acids of the intracytoplasmic cadherin-like segment subdomain; the desmoglein-specific IC subdomains are not necessary for this interaction. The interaction was confirmed to be direct by in vitro transcription/translation without other cellular factors.\",\n      \"method\": \"Chimeric E-cadherin/Dsg3 truncation constructs transfected into HaCaT cells, co-immunoprecipitation, immunoblotting, in vitro transcription/translation\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding confirmed by in vitro reconstitution, domain-mapping by systematic truncation mutants, replicated in both cellular and cell-free systems\",\n      \"pmids\": [\"7738346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Conformational epitopes of Dsg3 require transit through the endoplasmic reticulum (via signal peptide) for proper folding; proteolytic processing and glycosylation are NOT required. A Dsg3 mutant lacking the signal peptide accumulated in the cytosol and failed to form conformational epitopes.\",\n      \"method\": \"Site-directed mutagenesis of signal peptide and endoproteolytic cleavage site in baculovirus-expressed PVIg, immunoadsorption activity assay\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with functional immunoadsorption assay, multiple mutant constructs, single lab\",\n      \"pmids\": [\"8823357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"PV-IgG binding to Dsg3 on the cell surface causes rapid depletion of Dsg3 from the Triton X-100-soluble membrane fraction within 20 minutes, followed by loss from the cytoskeletal (desmosomal) fraction after 30 hours, generating Dsg3-depleted desmosomes while other desmosomal components (Dsg1, desmoplakin 1, plakoglobin, keratins) remain intact.\",\n      \"method\": \"Biochemical fractionation (PBS-soluble, Triton X-100-soluble, Triton X-100-insoluble), immunoblotting, double-staining immunofluorescence microscopy in DJM-1 cells\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods (biochemical fractionation + immunofluorescence), time-course experiment, multiple desmosomal markers as controls\",\n      \"pmids\": [\"9886266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Pathogenic and non-pathogenic monoclonal anti-Dsg3 antibodies each cause depletion of Dsg3 from desmosomes; individual antibodies have characteristic limits to their Dsg3-depleting activity that correlates with their pathogenic activity in mouse models, and combinations of antibodies show cumulative or synergistic depletion effects.\",\n      \"method\": \"Monoclonal antibody treatment of DJM-1 cells and normal human keratinocytes, immunofluorescence microscopy, cell fractionation, mouse passive transfer model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods, pathogenic/non-pathogenic MAbs compared, in vitro and in vivo validation, replicated across two cell types\",\n      \"pmids\": [\"17428808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PV IgG causes desmosome disassembly in three sequential phases: (1) rapid Dsg3 internalization from a non-junctional surface pool; (2) rearrangement of Dsg3 and other desmosomal components into linear arrays perpendicular to cell contacts with retrograde transport into cytoplasmic vesicles; (3) depletion of detergent-insoluble Dsg3 and loss of adhesion strength. Expression of exogenous Dsg3 can reverse this process by driving desmosome reassembly.\",\n      \"method\": \"Live and fixed imaging of primary human keratinocytes, biochemical fractionation, cell dissociation assay, exogenous Dsg3 rescue experiment\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (live imaging, fixed imaging, biochemistry, functional adhesion assay), rescue experiment provides mechanistic confirmation\",\n      \"pmids\": [\"21160493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DSG3 interacts with plakoglobin at cell junctions; DSG3 silencing disrupts this interaction and induces plakoglobin nuclear translocation, which increases plakoglobin–TCF interaction and suppresses TCF/LEF transcriptional activity, reducing downstream targets c-Myc, cyclin D1, and MMP-7, leading to G0/G1 arrest, reduced migration, and reduced invasion in head and neck cancer cells.\",\n      \"method\": \"RNAi knockdown of DSG3 in HNC cell lines, immunoprecipitation, immunofluorescence, TCF/LEF luciferase reporter assay, flow cytometry (cell cycle), in vivo xenograft mouse model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, reporter assay, functional assays, in vivo), consistent in vitro and in vivo results, single lab\",\n      \"pmids\": [\"23737966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Extradesmosomal Dsg3 forms a complex with E-cadherin, β-catenin, and Src; the stability of this complex is regulated by Src kinase activity. Src phosphorylates both Dsg3 and E-cadherin on tyrosine residues, and Src activity is required for recruiting Dsg3 to the cytoskeletal pool and for desmosome maturation to a Ca2+-insensitive state. Silencing E-cadherin abolishes Dsg3 membrane localization and shifts Dsg3 from the cytoskeletal to the non-cytoskeletal pool.\",\n      \"method\": \"Co-immunoprecipitation, E-cadherin overexpression and siRNA silencing, Src inhibitor treatment, phospho-tyrosine immunoblotting, immunofluorescence, cell cohesion assay, p38 MAPK activation assay in keratinocytes\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP identifying multi-protein complex, multiple pharmacological and genetic perturbations, multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"26115704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Dsg3 competes with inactive Src for binding to the scaffolding domain of caveolin-1 (Cav-1) in a non-ionic detergent-soluble pool; increased Dsg3 levels reduce Cav-1/Src co-localization, suggesting Dsg3 activates Src by displacing it from Cav-1-mediated inhibition.\",\n      \"method\": \"Co-immunoprecipitation of Dsg3/Src/Cav-1 complexes, Dsg3 overexpression and knockdown, immunofluorescence co-localization analysis, sequence analysis of Cav-1 scaffolding domain binding motif in Dsg3\",\n      \"journal\": \"Data in brief\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and immunofluorescence, data article (extended data) rather than primary research article, proposed model not fully validated\",\n      \"pmids\": [\"26858977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Dsg3 (but not Dsg2) is required for PV-IgG-induced loss of keratinocyte cohesion; PV-IgG activates EGFR in a Src-dependent manner and activates ERK in a Src-dependent manner, while Ca2+ influx induced by PV-IgG is EGFR-independent. CRISPR/Cas9 knockout of Dsg3 protects against PV-IgG-induced adhesion loss.\",\n      \"method\": \"CRISPR/Cas9 Dsg3 and Dsg2 knockout HaCaT cells, dispase cell cohesion assay, Western blot for EGFR/ERK/Src phosphorylation, Ca2+ chelation, pharmacological inhibitors, Fura-2 Ca2+ measurements\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via CRISPR knockout, multiple pharmacological and biochemical readouts, Dsg2 KO as isoform control, single lab\",\n      \"pmids\": [\"31178865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Anti-Dsg3 antibody activates p38 MAPK phosphorylation in keratinocytes; externally applied mechanical stress mitigates antibody-induced monolayer fragmentation and inhibits this p38 MAPK phosphorylation by enhancing RhoA activation and cortical actin strengthening.\",\n      \"method\": \"Anti-Dsg3 antibody treatment of keratinocyte monolayers, mechanical stress application, p38 MAPK phosphorylation assay, RhoA activity measurement, actin cytoskeleton imaging\",\n      \"journal\": \"Advanced biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple biochemical and functional readouts but single lab, mechanistic pathway placement via pharmacological and physical perturbation\",\n      \"pmids\": [\"33724731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Super-resolution microscopy reveals that Dsg3 and Dsg1 are distributed heterogeneously across desmosome populations in different epidermal layers, with Dsg3 predominantly in basal layer desmosomes. Extradesmosomal Dsg3 co-localizes with plakoglobin (desmoplakin-independently) mainly in the basal layer, supporting a role for extradesmosomal Dsg3-plakoglobin complexes in desmosome assembly.\",\n      \"method\": \"STED super-resolution microscopy, co-localization analysis of Dsg1, Dsg3, desmoplakin, and plakoglobin in normal human skin sections and pemphigus patient skin\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — super-resolution imaging with multiple molecular markers and quantitative co-localization analysis, normal and patient tissue compared, single lab\",\n      \"pmids\": [\"35711465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Two pathogenic anti-Dsg3 monoclonal antibodies targeting different epitopes (EC5 domain: 2G4; EC1 domain: AK23) elicit distinct signaling: both induce p38MAPK and Akt phosphorylation, but only AK23 (EC1-targeting) induces Dsg3 depletion and Src phosphorylation. Src and Akt activation are p38MAPK-dependent. AK23-mediated effects are ameliorated by Src inhibition in addition to p38MAPK inhibition.\",\n      \"method\": \"Dispase-based cell dissociation assay, Western blot (p38MAPK, Src, Akt), STED microscopy (keratin retraction, desmosome number, Dsg3 distribution), Fura-based Ca2+ flux measurements, Rho/Rac G-protein ELISA in keratinocytes\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (STED, biochemistry, functional assay, Ca2+ flux), two distinct pathogenic MAbs compared, epitope-specific signaling pathway mapped, single lab\",\n      \"pmids\": [\"37143675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"STED/SMFS-AFM single-molecule force spectroscopy on living keratinocytes reveals two distinct pools of Dsg3 with different cytoskeletal anchorage: a cell-surface (extradesmosomal) pool whose adhesion is actin-dependent (sensitive to Latrunculin B), and a cell-cell contact (desmosomal) pool whose adhesion is independent of actin but regulated by PKCα/intermediate filament anchorage.\",\n      \"method\": \"Hybrid STED/SMFS-AFM on living keratinocytes, Latrunculin B (actin depolymerization), PMA (PKCα activation), pharmacological perturbation with single-molecule force measurements\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — novel single-molecule biophysical method combined with pharmacological perturbations directly on living cells, two distinct pools distinguished by orthogonal pharmacology, single lab\",\n      \"pmids\": [\"36602635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DSG3 promotes bladder cancer growth and metastasis via STAT3-mediated transcriptional upregulation of DSG3, which then activates AKT phosphorylation, inhibits GSK3β, promotes β-catenin nuclear translocation, and upregulates SOX2 and MMP7 expression. DSG3 knockdown suppresses EMT, cancer stemness, migration, invasion, and in vivo tumor growth and lung metastasis.\",\n      \"method\": \"DSG3 knockdown (siRNA/shRNA) and overexpression in bladder cancer cell lines, co-immunoprecipitation, Western blot for AKT/GSK3β/β-catenin pathway components, STAT3 ChIP/transcription assays, in vitro migration/invasion assays, in vivo xenograft and metastasis models\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple in vitro and in vivo methods with pathway dissection, single lab, no independent replication yet\",\n      \"pmids\": [\"40605005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PV IgG targeting Dsg3 triggers ER stress signaling, activating both IRE1α and PERK pathways; ER tubules make frequent persistent contacts with internalizing Dsg3 puncta. Pharmacological inhibition of ER stress protects against PV IgG-induced desmosome disruption and loss of keratinocyte cell-cell adhesion.\",\n      \"method\": \"High-resolution time-lapse live imaging, biochemical ER stress assays (IRE1α and PERK pathway markers), pharmacological ER stress inhibition, keratinocyte cell cohesion assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple orthogonal methods (live imaging, biochemistry, pharmacological rescue), preprint not yet peer-reviewed, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"DSG3 encodes desmoglein 3, a desmosomal cadherin that mediates keratinocyte cell–cell adhesion by forming calcium-dependent trans-interactions at desmosomes; its intracytoplasmic cadherin-like domain directly binds plakoglobin, and its extradesmosomal pool forms a complex with E-cadherin, β-catenin, and Src—where Src-dependent tyrosine phosphorylation of Dsg3 and E-cadherin drives desmosome maturation to a Ca2+-insensitive state; two cytoskeletal pools of Dsg3 exist, an actin-anchored extradesmosomal pool and an intermediate filament-anchored desmosomal pool regulated by PKCα; pathogenic pemphigus vulgaris autoantibodies targeting Dsg3 trigger epitope-specific signaling cascades (including p38MAPK, Src, Akt, EGFR, Ca2+ influx, and ER stress) that drive Dsg3 internalization from the cell surface, depletion from desmosomes, and ultimately loss of adhesion; in cancer contexts, DSG3 retains plakoglobin at cell junctions to activate TCF/LEF-driven transcription of c-Myc, cyclin D1, and MMP-7, and in bladder cancer acts downstream of STAT3 to activate AKT/GSK3β/β-catenin signaling and upregulate SOX2 and MMP7.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DSG3 encodes desmoglein 3, a desmosomal cadherin that mediates calcium-dependent keratinocyte cell-cell adhesion and serves as the principal autoantigen in pemphigus vulgaris [#0, #3]. Its intracytoplasmic cadherin-like segment binds plakoglobin directly through its carboxy-terminal 87 residues, independent of other cellular factors [#1], and proper folding of its extracellular conformational epitopes requires transit through the endoplasmic reticulum but not glycosylation or proteolytic processing [#2]. Dsg3 exists in two functionally distinct cytoskeletal pools resolved by single-molecule force spectroscopy: an extradesmosomal cell-surface pool whose adhesion is actin-dependent, and a desmosomal cell-contact pool that is actin-independent and regulated by PKCalpha [#13]. The extradesmosomal pool assembles into a complex with E-cadherin, beta-catenin, and Src, where Src-dependent tyrosine phosphorylation of Dsg3 and E-cadherin recruits Dsg3 to the cytoskeletal pool and drives desmosome maturation to a calcium-insensitive state [#7]. Pathogenic PV autoantibodies binding cell-surface Dsg3 trigger sequential desmosome disassembly—rapid internalization of a non-junctional surface pool followed by depletion of detergent-insoluble desmosomal Dsg3 and loss of adhesion—a process reversible by exogenous Dsg3-driven reassembly [#3, #5]; these antibodies act through epitope-specific cascades involving p38MAPK, Src, Akt, EGFR, and Ca2+ influx [#9, #12]. In cancer, DSG3 retains plakoglobin at junctions to sustain TCF/LEF-driven transcription of c-Myc, cyclin D1, and MMP-7 [#6], and in bladder cancer acts downstream of STAT3 to activate AKT/GSK3beta/beta-catenin signaling and upregulate SOX2 and MMP7 [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established that the pathogenic PV autoantibody response targets conformational epitopes on the Dsg3 extracellular domain, defining Dsg3 as the relevant antigen and linking antibody binding to blister formation.\",\n      \"evidence\": \"Baculovirus-expressed PVIg chimera immunoadsorption of patient sera with neonatal mouse passive transfer\",\n      \"pmids\": [\"8040292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map the specific epitope residues\", \"Did not address downstream signaling triggered by antibody binding\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Resolved how Dsg3 couples to the desmosomal plaque by mapping a direct plakoglobin-binding site to the carboxy-terminal 87 residues of the intracytoplasmic cadherin-like segment.\",\n      \"evidence\": \"Chimeric truncation constructs in HaCaT cells with Co-IP and cell-free in vitro transcription/translation\",\n      \"pmids\": [\"7738346\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the stoichiometry or affinity of the interaction\", \"Did not address how this binding regulates desmosome assembly\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Defined the biogenesis requirement for Dsg3 antigenicity, showing ER transit but not glycosylation or proteolytic processing produces the conformational epitopes.\",\n      \"evidence\": \"Signal-peptide and cleavage-site mutagenesis of baculovirus-expressed PVIg with immunoadsorption assay\",\n      \"pmids\": [\"8823357\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the chaperones mediating folding\", \"Single expression system\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Showed that PV-IgG selectively depletes Dsg3 in two kinetic phases, first from the soluble membrane pool then from desmosomes, while sparing other desmosomal components, distinguishing Dsg3 loss as the primary lesion.\",\n      \"evidence\": \"Triton fractionation, immunoblotting, and immunofluorescence time-course in DJM-1 cells\",\n      \"pmids\": [\"9886266\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the signaling driving internalization\", \"Mechanism of depletion (degradation vs internalization) not resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Linked antibody pathogenicity to Dsg3-depleting capacity, showing individual monoclonals have characteristic depletion limits that correlate with in vivo pathogenicity and combine cumulatively.\",\n      \"evidence\": \"Pathogenic/non-pathogenic monoclonal antibody treatment of keratinocytes with fractionation, imaging, and mouse passive transfer\",\n      \"pmids\": [\"17428808\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map molecular signaling distinguishing pathogenic from non-pathogenic antibodies\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the three sequential phases of PV-IgG-induced desmosome disassembly and demonstrated reversibility, establishing internalization and retrograde transport as the mechanistic route to adhesion loss.\",\n      \"evidence\": \"Live and fixed imaging, fractionation, cell dissociation assay, and exogenous Dsg3 rescue in primary keratinocytes\",\n      \"pmids\": [\"21160493\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the trafficking machinery driving internalization\", \"Did not connect phases to specific kinase cascades\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed a transcriptional function of DSG3 in cancer by showing it retains plakoglobin at junctions to sustain TCF/LEF activity and proliferation, with knockdown driving plakoglobin nuclear translocation and growth arrest.\",\n      \"evidence\": \"RNAi in head and neck cancer lines with Co-IP, TCF/LEF reporter, cell-cycle flow cytometry, and xenografts\",\n      \"pmids\": [\"23737966\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether desmosomal or extradesmosomal Dsg3 mediates this\", \"Direct vs indirect effect on plakoglobin localization not dissected\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified an extradesmosomal Dsg3/E-cadherin/beta-catenin/Src complex in which Src-driven tyrosine phosphorylation controls Dsg3 cytoskeletal recruitment and desmosome maturation to a Ca2+-insensitive state.\",\n      \"evidence\": \"Reciprocal Co-IP, E-cadherin overexpression/silencing, Src inhibition, phospho-tyrosine blotting, and cohesion assays in keratinocytes\",\n      \"pmids\": [\"26115704\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish phosphorylation site stoichiometry\", \"Mechanism of Src activation not resolved here\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Proposed a mechanism for Src activation in which Dsg3 displaces inactive Src from the caveolin-1 scaffolding domain, relieving Cav-1-mediated inhibition.\",\n      \"evidence\": \"Co-IP of Dsg3/Src/Cav-1, overexpression/knockdown, and colocalization analysis (Data in Brief)\",\n      \"pmids\": [\"26858977\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP and immunofluorescence without functional validation\", \"Model proposed but Src kinase activation not directly measured\", \"Data article rather than primary research\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Used genetic epistasis to confirm Dsg3 specificity and order the antibody-triggered cascade, showing Dsg3 (not Dsg2) is required for adhesion loss and that PV-IgG activates EGFR/ERK via Src while Ca2+ influx is EGFR-independent.\",\n      \"evidence\": \"CRISPR/Cas9 Dsg3 and Dsg2 knockout HaCaT cells with cohesion assays, phospho-blots, Ca2+ measurements, and inhibitors\",\n      \"pmids\": [\"31178865\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not place all pathway branches in a single hierarchy\", \"Relationship between EGFR signaling and Dsg3 depletion not fully resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected mechanotransduction to antibody signaling, showing mechanical stress suppresses anti-Dsg3-induced p38 MAPK activation by enhancing RhoA and cortical actin.\",\n      \"evidence\": \"Anti-Dsg3 antibody plus mechanical stress in keratinocyte monolayers with p38 phospho-assay, RhoA activity, and actin imaging\",\n      \"pmids\": [\"33724731\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanosensor upstream of RhoA not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapped the spatial distribution of Dsg3 across epidermal layers and showed extradesmosomal Dsg3-plakoglobin complexes form desmoplakin-independently in the basal layer, supporting their role in desmosome assembly.\",\n      \"evidence\": \"STED super-resolution colocalization of Dsg1/Dsg3/desmoplakin/plakoglobin in normal and pemphigus skin\",\n      \"pmids\": [\"35711465\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not functionally test the assembly role\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated epitope-specific antibody signaling, showing EC1- versus EC5-targeting monoclonals diverge in Dsg3 depletion and Src activation while converging on p38MAPK-dependent Akt and Src activation.\",\n      \"evidence\": \"Two pathogenic monoclonals with dispase dissociation, phospho-blots, STED imaging, Ca2+ flux, and Rho/Rac ELISA in keratinocytes\",\n      \"pmids\": [\"37143675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not extend to additional epitopes\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Distinguished two biophysically distinct Dsg3 adhesion pools, an actin-dependent extradesmosomal pool and an actin-independent, PKCalpha/intermediate-filament-regulated desmosomal pool, on living cells.\",\n      \"evidence\": \"Hybrid STED/SMFS-AFM single-molecule force spectroscopy with Latrunculin B and PMA perturbation\",\n      \"pmids\": [\"36602635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect the two pools to specific binding partners at the molecular level\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a STAT3-DSG3-AKT/GSK3beta/beta-catenin oncogenic axis in bladder cancer driving EMT, stemness, and metastasis via SOX2 and MMP7 upregulation.\",\n      \"evidence\": \"DSG3 knockdown/overexpression in bladder cancer lines with Co-IP, pathway blots, STAT3 transcription assays, and xenograft/metastasis models\",\n      \"pmids\": [\"40605005\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No independent replication\", \"Single lab\", \"Direct vs indirect activation of AKT by DSG3 not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated ER stress in antibody-induced adhesion loss, showing PV IgG activates IRE1alpha and PERK and that ER tubules contact internalizing Dsg3 puncta, with ER stress inhibition protecting adhesion.\",\n      \"evidence\": \"Time-lapse live imaging, ER stress biochemical markers, pharmacological inhibition, and cohesion assay (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Mechanism linking ER stress to Dsg3 internalization not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the distinct cytoskeletal pools, kinase cascades, ER-stress responses, and transcriptional functions of Dsg3 are integrated into a single regulatory hierarchy across normal epidermis, pemphigus, and cancer remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified ordering of p38MAPK, Src, EGFR, Akt, Ca2+, and ER stress branches\", \"Structural basis of Dsg3 trans-adhesion not determined in the corpus\", \"Whether cancer and pemphigus signaling share common Dsg3-proximal events untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [3, 5, 7, 13]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [13, 7]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [9, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 7, 13]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [7, 13]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [3, 5, 7, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 9, 12, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 3, 5, 14]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [6, 14]}\n    ],\n    \"complexes\": [\"desmosome\"],\n    \"partners\": [\"JUP\", \"CDH1\", \"CTNNB1\", \"SRC\", \"CAV1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}