Desmoglein-3 is a calcium-dependent desmosomal cadherin of stratified squamous epithelia, expressed throughout the basal and spinous layers of the epidermis and in oral, oesophageal and other mucosae. It is a single-pass type I membrane glycoprotein whose extracellular cadherin domains project from the cell surface and mediate adhesive trans-interactions between neighbouring keratinocytes, while its cytoplasmic tail couples the junction to the desmosomal plaque and the keratin intermediate filament network. Beyond the desmosomal pool, a detergent-soluble non-junctional pool at the cell surface acts as a signalling scaffold, regulating Src and E-cadherin at nascent adherens junctions, Rac1 and Cdc42 and cortical actin, p38MAPK-dependent keratinocyte migration, and membrane retention of phospho-YAP under mechanical strain. DSG3 is the autoantigen of pemphigus vulgaris, and loss of its adhesive function causes suprabasal acantholysis; loss in mice additionally releases telogen hairs from the follicle.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001533 cornified envelope | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: DSG3 is a living-layer desmosomal cadherin, not a documented constituent of the cornified envelope. Reason: The cornified envelope is the cross-linked protein scaffold of corneocytes, and its desmosomal residue, the corneodesmosome, is dominated by DSG1 and DSC1. DSG3 is expressed in the basal and spinous layers with only weak granular-layer expression, and no DSG3-specific localization experiment places it in the cornified envelope. The rule-based assignment follows family membership rather than observation. Supporting Evidence: file:human/DSG3/DSG3-uniprot.txt Expressed throughout the basal and spinous layer of the epidermis with weak expression in the granular layer |
| GO:0001533 cornified envelope | TAS Reactome:R-HSA-6814764 | MARK AS OVER ANNOTATED | Summary: The assignment comes from membership in the cornification pathway, not from a DSG3 localization experiment. Reason: Reactome places DSG3 in reactions of keratinocyte cornification, and the compartment label propagates from that pathway context. The same over-annotation argument applies as for the rule-based row. Supporting Evidence: file:human/DSG3/DSG3-uniprot.txt Expressed throughout the basal and spinous layer of the epidermis with weak expression in the granular layer |
| GO:0002159 desmosome assembly | IMP PMID:9701552 Desmoglein 3 anchors telogen hair in the follicle. | ACCEPT | Summary: Loss of DSG3 causes acantholysis and defective desmosomes in the hair follicle and epidermis. Reason: In DSG3 knockout mice, cells around the telogen club lose adhesion and electron microscopy shows half-desmosomes, a direct assembly defect. Desmosome assembly is a core role of the protein. Supporting Evidence: PMID:9701552 showed loss of cell adhesion (acantholysis) between the cells surrounding the telogen club and the basal layer of the outer root sheath epithelium file:human/DSG3/DSG3-uniprot.txt Required for adherens and desmosome junction assembly in response to mechanical force in keratinocytes |
| GO:0005509 calcium ion binding | IBA GO_REF:0000033 | ACCEPT | Summary: Calcium binding at the cadherin-domain interfaces is intrinsic to desmoglein adhesion. Reason: The PAINT node assertion applies to the cadherin ectodomain architecture that DSG3 retains, and UniProt records the canonical three-calcium interdomain sites. Calcium dependence of desmosomal adhesion is a defining property of the family. Supporting Evidence: file:human/DSG3/DSG3-uniprot.txt Three calcium ions are usually bound at the interface of each cadherin domain and rigidify the connections |
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: Cadherin-domain signatures support calcium binding. Reason: The cadherin and desmoglein InterPro signatures match the DSG3 ectodomain, and the calcium sites are a conserved structural feature of those domains. Supporting Evidence: file:human/DSG3/DSG3-uniprot.txt Three calcium ions are usually bound at the interface of each cadherin domain and rigidify the connections |
| GO:0005515 protein binding | IPI PMID:11790773 Protein binding and functional characterization of plakophil... | REMOVE | Summary: Bare protein binding for the PKP2 interaction carries no functional information. Reason: The interaction with plakophilin-2 is curated from this paper and is not disputed, but GO:0005515 says nothing about what DSG3 does. Plakophilins are plaque components rather than cadherins, so no informative molecular-function term follows from this row alone; the plaque role is captured by the desmosome and desmosome-assembly annotations. Supporting Evidence: file:human/DSG3/DSG3-uniprot.txt Interacts with PKP2 (PubMed:11790773) |
| GO:0005515 protein binding | IPI PMID:18343367 P120-catenin is a novel desmoglein 3 interacting partner: id... | MODIFY | Summary: The interactor is p120-catenin (CTNND1), a delta-catenin family armadillo protein, so an informative term is available. Reason: Co-immunoprecipitation and deletion mapping localise the p120-catenin binding site to the membrane-proximal intracellular anchor region of DSG3, and the interaction retains non-junctional DSG3 at the cell surface. Replace the generic term with delta-catenin binding. Proposed replacements: delta-catenin binding Supporting Evidence: PMID:18343367 Using co-immunoprecipitation, we show here that p120ctn associates to desmogleins (Dsg) 1 and 3. file:human/DSG3/DSG3-uniprot.txt Interacts with CTNND1; the interaction facilitates DSG3 localization and retention at cell-cell junctions |
| GO:0005515 protein binding | IPI PMID:19717567 Desmocollin 3-mediated binding is crucial for keratinocyte c... | MODIFY | Summary: The interactor DSC3 is a desmosomal cadherin, and the study measured cadherin trans-interactions directly. Reason: Single-molecule force spectroscopy and laser-tweezer trapping in this study measure binding between desmosomal cadherins at the keratinocyte surface, and UniProt curates DSG3 homodimer formation from the same work. Cadherin binding is the informative replacement for the generic term. Proposed replacements: cadherin binding Supporting Evidence: PMID:19717567 Desmocollin (Dsc) 1-3 and desmoglein (Dsg) 1-4, transmembrane proteins of the cadherin family, form the adhesive core of desmosomes. file:human/DSG3/DSG3-uniprot.txt Homodimer (PubMed:19717567) |
| GO:0005515 protein binding | IPI PMID:22294297 Non-junctional human desmoglein 3 acts as an upstream regula... | MODIFY | Summary: The interactor is E-cadherin (CDH1), so cadherin binding is the informative term. Reason: Non-junctional DSG3 associates with E-cadherin, and the association is required for E-cadherin recruitment to developing adherens junctions. Replace the generic term with cadherin binding. Proposed replacements: cadherin binding Supporting Evidence: PMID:22294297 it is the detergent-soluble, non-desmosomal Dsg3 that regulates the activity of Src and its association with E-cadherin in adherens junction formation file:human/DSG3/DSG3-uniprot.txt Interacts with CDH1; the interaction is required for CDH1 localization to developing adherens junctions |
| GO:0005515 protein binding | IPI PMID:22796473 Desmoglein 3 acting as an upstream regulator of Rho GTPases,... | MODIFY | Summary: The interactor is RAC1, a small GTPase, and the interaction is functionally characterised. Reason: DSG3 interacts with RAC1, and the interaction is required for DSG3 translocation to cell-cell junctions and for organisation of cortical actin. Small GTPase binding replaces the uninformative generic term. Proposed replacements: small GTPase binding Supporting Evidence: PMID:22796473 endogenous Dsg3 colocalises and interacts with actin, particularly the junctional actin in a Rac1-dependent manner file:human/DSG3/DSG3-uniprot.txt Interacts with RAC1; the interaction is required for DSG3 translocation to cell-cell junctions |
| GO:0005515 protein binding | IPI PMID:31835537 Evidence for the Desmosomal Cadherin Desmoglein-3 in Regulat... | REMOVE | Summary: Bare protein binding for the YAP1, YWHAG and PKP1 complex carries no functional information. Reason: The DSG3, PKP1, YAP1 and YWHAG complex is real and curated, but none of these partners is a cadherin, catenin or GTPase for which a specific binding term applies, and inventing a molecular function from complex membership is not warranted. The functional content of this work is retained in the protein-localization and junction-assembly annotations. Supporting Evidence: file:human/DSG3/DSG3-uniprot.txt Part of a complex that contains DSG3, PKP1, YAP1 and YWHAG; the complex is required for localization of DSG3 and YAP1 to the cell membrane in keratinocytes |
| GO:0005737 cytoplasm | IDA PMID:22796473 Desmoglein 3 acting as an upstream regulator of Rho GTPases,... | KEEP AS NON CORE | Summary: A cytoplasmic pool of DSG3 is observed, distinct from the junctional pool. Reason: DSG3 is a transmembrane protein whose tail and non-junctional pool are detected in the cytoplasmic compartment in these experiments, and UniProt records cytoplasm from this paper. Real but peripheral to the adhesive function at the membrane. Supporting Evidence: file:human/DSG3/DSG3-uniprot.txt Cytoplasm {ECO |
| GO:0005737 cytoplasm | IDA PMID:31835537 Evidence for the Desmosomal Cadherin Desmoglein-3 in Regulat... | KEEP AS NON CORE | Summary: Cytoplasmic DSG3 staining is also reported in the mechanotransduction study. Reason: Same assessment as the other cytoplasm row. The pool is documented and curated by UniProt, but the functionally decisive locations are the plasma membrane and the desmosome. Supporting Evidence: PMID:31835537 Dsg3 formed a complex with phospho-YAP and sequestered it to the plasma membrane |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Mapping of the curated UniProt cytoplasm location. Reason: The mapping faithfully reflects the curated subcellular-location line, which rests on the two experimental papers above. Non-core for the same reason. Supporting Evidence: file:human/DSG3/DSG3-uniprot.txt Cytoplasm {ECO |
| GO:0005829 cytosol | TAS Reactome:R-HSA-201631 | KEEP AS NON CORE | Summary: The cytosol assignment refers to the caspase-released cytoplasmic fragment of DSG3 during apoptosis. Reason: Reactome models caspase cleavage of desmoglein-3, after which the cytoplasmic fragment becomes a soluble cytosolic species. That is a genuine but condition-specific state of a cleavage product rather than the location of the intact protein, so the term is kept as strictly non-core. Supporting Evidence: Reactome:R-HSA-201631 Desmogleins are a major component of the desmosome are specifically cleaved after onset of apoptosis. |
| GO:0005886 plasma membrane | EXP PMID:19717567 Desmocollin 3-mediated binding is crucial for keratinocyte c... | ACCEPT | Summary: Desmosomal cadherins are measured at the keratinocyte cell surface in this study. Reason: Atomic force microscopy and laser-tweezer binding assays probe desmosomal cadherins presented on the plasma membrane of intact keratinocytes. The plasma membrane is the core location of DSG3, with the adhesive ectodomain extracellular. Supporting Evidence: PMID:19717567 pemphigus autoantibodies reduced binding of Dsc3-coated beads to the keratinocyte cell surface |
| GO:0005886 plasma membrane | IDA PMID:30949721 Plakophilin 1 but not plakophilin 3 regulates desmoglein clu... | ACCEPT | Summary: AFM measurements detect DSG3 availability and binding at the keratinocyte membrane. Reason: Membrane availability and binding frequency of DSG3 at cell borders were measured directly on living keratinocytes, which requires plasma-membrane localization of the protein. Supporting Evidence: PMID:30949721 both Pkp-deficient keratinocyte cell lines showed reduced membrane availability and binding frequency of Dsg1 and 3 at cell borders |
| GO:0005886 plasma membrane | IDA PMID:31835537 Evidence for the Desmosomal Cadherin Desmoglein-3 in Regulat... | ACCEPT | Summary: DSG3 is localized at the plasma membrane, where it sequesters phospho-YAP. Reason: The complex of DSG3 with PKP1, YAP1 and YWHAG is required for membrane localization of both DSG3 and YAP1, which is direct evidence for a plasma-membrane pool. Supporting Evidence: PMID:31835537 Dsg3 formed a complex with phospho-YAP and sequestered it to the plasma membrane |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Automated mapping agrees with the experimentally established location. Reason: The cadherin cytoplasmic-region signature and the curated cell-membrane location both point to the plasma membrane, which the experimental rows confirm. Supporting Evidence: file:human/DSG3/DSG3-uniprot.txt Single-pass type I membrane protein |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-201631 | ACCEPT | Summary: Reactome places intact DSG3 at the plasma membrane before caspase cleavage. Reason: The compartment assignment matches the experimentally established location of the protein. Supporting Evidence: file:human/DSG3/DSG3-uniprot.txt Single-pass type I membrane protein |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6809393 | ACCEPT | Summary: DSG3 is modelled as a plasma-membrane desmosome component that links to keratin filaments through the plaque. Reason: Consistent with the experimentally established plasma-membrane location. Supporting Evidence: file:human/DSG3/DSG3-uniprot.txt Single-pass type I membrane protein |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6810357 | ACCEPT | Summary: Plasma-membrane assignment within a keratinocyte cornification reaction. Reason: The location is correct for DSG3 even though the pathway context is differentiation-specific. Supporting Evidence: file:human/DSG3/DSG3-uniprot.txt Single-pass type I membrane protein |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6810937 | ACCEPT | Summary: Plasma-membrane assignment within a cornified-envelope reaction. Reason: The compartment is right for DSG3, which sits in the plasma membrane as part of desmosomes. Supporting Evidence: file:human/DSG3/DSG3-uniprot.txt Single-pass type I membrane protein |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6811539 | ACCEPT | Summary: Plasma-membrane assignment within a cornified-envelope reaction. Reason: Consistent with the experimentally established location of DSG3. Supporting Evidence: file:human/DSG3/DSG3-uniprot.txt Single-pass type I membrane protein |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6814298 | ACCEPT | Summary: Plasma-membrane assignment within a cornified-envelope reaction. Reason: Consistent with the experimentally established location of DSG3. Supporting Evidence: file:human/DSG3/DSG3-uniprot.txt Single-pass type I membrane protein |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6814387 | ACCEPT | Summary: Plasma-membrane assignment within a keratinocyte differentiation reaction. Reason: Consistent with the experimentally established location of DSG3. Supporting Evidence: file:human/DSG3/DSG3-uniprot.txt Single-pass type I membrane protein |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6814695 | ACCEPT | Summary: DSG3 is a plasma-membrane desmosome component in the PERP-binding reaction. Reason: Consistent with the experimentally established location of DSG3. Supporting Evidence: file:human/DSG3/DSG3-uniprot.txt Single-pass type I membrane protein |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6814734 | ACCEPT | Summary: Plasma-membrane assignment within a cornified-envelope reaction. Reason: Consistent with the experimentally established location of DSG3. Supporting Evidence: file:human/DSG3/DSG3-uniprot.txt Single-pass type I membrane protein |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6814764 | ACCEPT | Summary: Plasma-membrane assignment within the plasma-membrane resorption reaction. Reason: Consistent with the experimentally established location of DSG3. Supporting Evidence: file:human/DSG3/DSG3-uniprot.txt Single-pass type I membrane protein |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8942224 | ACCEPT | Summary: DSG3 is a plasma-membrane desmosome component in the filaggrin-binding reaction. Reason: Consistent with the experimentally established location of DSG3. Supporting Evidence: file:human/DSG3/DSG3-uniprot.txt Single-pass type I membrane protein |
| GO:0005911 cell-cell junction | IDA PMID:18343367 P120-catenin is a novel desmoglein 3 interacting partner: id... | ACCEPT | Summary: DSG3 is detected at cell-cell contacts, including a pool outside desmosomes. Reason: This study explicitly distinguishes DSG3 at the cell surface from the desmosomal pool, so the general cell-cell junction term is as precise as this evidence allows and should not be sharpened to desmosome. Supporting Evidence: PMID:18343367 p120ctn does not localize to desmosomes, but colocalizes with Dsg3 at the cell surface |
| GO:0005911 cell-cell junction | IDA PMID:19717567 Desmocollin 3-mediated binding is crucial for keratinocyte c... | ACCEPT | Summary: DSG3 is located at keratinocyte cell-cell contacts. Reason: Binding measurements at cell borders in intact keratinocyte monolayers support junctional localization without resolving desmosomal from non-desmosomal pools. Supporting Evidence: PMID:19717567 a loss of intercellular adhesion in cultured keratinocytes |
| GO:0005911 cell-cell junction | IEA GO_REF:0000117 | ACCEPT | Summary: Rule-based cell-cell junction assignment agrees with the experimental rows. Reason: The location is independently established by direct observation in keratinocytes, so the rule-based row adds no error. Supporting Evidence: PMID:18343367 colocalizes with Dsg3 at the cell surface |
| GO:0005923 bicellular tight junction | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: A tight-junction pool is curated from the actin-anchoring study. Reason: UniProt records a tight-junction location with experimental evidence, where DSG3 contributes to anchoring cortical actin. It is a secondary site relative to the desmosome, so it is kept as non-core rather than accepted as core. Supporting Evidence: file:human/DSG3/DSG3-uniprot.txt Cell junction, tight junction |
| GO:0007015 actin filament organization | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: DSG3 regulates cortical actin organisation through Rac1 and Cdc42. Reason: Human DSG3 experiments support the same conclusion as the ortholog transfer. Silencing DSG3 changes actin organisation, and overexpression raises Rac1 and Cdc42 activity. This is a signalling-dependent regulatory role rather than the core adhesive function. Supporting Evidence: PMID:22796473 inhibition of Dsg3 by RNAi results in profound changes in the organisation of actin cytoskeleton |
| GO:0007155 cell adhesion | IEA GO_REF:0000002 | TOO GENERAL | Summary: A parent of the specific adhesion terms already asserted for DSG3. Reason: Homophilic cell-cell adhesion and cell-cell adhesion are accepted in this review and entail this term. The claim is true but adds nothing. Supporting Evidence: PMID:19717567 form the adhesive core of desmosomes |
| GO:0007156 homophilic cell-cell adhesion | IEA GO_REF:0000002 | ACCEPT | Summary: DSG3 forms homodimers and mediates calcium-dependent homophilic adhesion. Reason: UniProt curates DSG3 homodimer formation from direct binding measurements, and homophilic trans-interaction between desmogleins on opposing keratinocytes is an adhesive mechanism of the desmosome. Supporting Evidence: file:human/DSG3/DSG3-uniprot.txt Homodimer (PubMed:19717567) PMID:19717567 form the adhesive core of desmosomes |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: Correct but less specific than the evidence allows. Reason: DSG3 is a single-pass type I protein of the plasma membrane, a term it already carries with experimental evidence. Use the specific descendant. Proposed replacements: plasma membrane Supporting Evidence: file:human/DSG3/DSG3-uniprot.txt Single-pass type I membrane protein |
| GO:0030054 cell junction | IDA PMID:22796473 Desmoglein 3 acting as an upstream regulator of Rho GTPases,... | MODIFY | Summary: The junctions observed are cell-cell contacts between keratinocytes. Reason: The study localises DSG3 and junctional actin at cell borders, so the more specific cell-cell junction term, which DSG3 already carries, is warranted. Proposed replacements: cell-cell junction Supporting Evidence: PMID:22796473 Assembly of the junctional actin at the cell borders is accompanied with enhanced levels of Dsg3 |
| GO:0030057 desmosome | IBA GO_REF:0000033 | ACCEPT | Summary: The desmosome is where DSG3 performs its adhesive function. Reason: The PAINT node covers the desmosomal cadherin clade, and DSG3 is a canonical member whose loss produces acantholysis and half-desmosomes. This is the core location. Supporting Evidence: PMID:19717567 form the adhesive core of desmosomes PMID:9701552 Electron microscopy revealed 'half-desmosomes' at the plasma membranes |
| GO:0030057 desmosome | IEA GO_REF:0000044 | ACCEPT | Summary: Mapping of the curated desmosome location. Reason: Agrees with the phylogenetic assertion and with the mouse knockout ultrastructure. Core location. Supporting Evidence: PMID:9701552 Electron microscopy revealed 'half-desmosomes' at the plasma membranes |
| GO:0030336 negative regulation of cell migration | IMP PMID:26763450 Desmoglein 3-Dependent Signaling Regulates Keratinocyte Migr... | KEEP AS NON CORE | Summary: Silencing or knockout of DSG3 accelerates keratinocyte migration. Reason: Loss of function in human keratinocytes and in mouse cells increases migration, and the effect is p38MAPK-dependent, so DSG3 restrains migration. This is a signalling consequence of the adhesive protein rather than its core function. Supporting Evidence: PMID:26763450 Human keratinocytes after silencing of Dsg3 as well as primary cells isolated from Dsg3 knockout animals exhibited accelerated migration |
| GO:0031647 regulation of protein stability | IMP PMID:22294297 Non-junctional human desmoglein 3 acts as an upstream regula... | KEEP AS NON CORE | Summary: DSG3 levels affect the abundance of desmosomal plaque proteins. Reason: Silencing DSG3 reduces desmosomal protein expression, and UniProt records a possible role in the stability of DSP, JUP, PKP1, PKP2 and PKP3. The mechanism is indirect, so this is retained as non-core. Supporting Evidence: PMID:22294297 Dsg3 silencing caused retardation of calcium-induced E-cadherin junction assembly and a reduction of desmosomal protein expression. file:human/DSG3/DSG3-uniprot.txt May play a role in the protein stability of the desmosome plaque components DSP, JUP, PKP1, PKP2 and PKP3 |
| GO:0034333 adherens junction assembly | IMP PMID:31835537 Evidence for the Desmosomal Cadherin Desmoglein-3 in Regulat... | KEEP AS NON CORE | Summary: DSG3 is required for strain-induced remodelling of E-cadherin junctions. Reason: Knockdown of DSG3 blocks strain-induced junctional remodelling of E-cadherin and myosin IIa, and separately DSG3 silencing delays calcium-induced E-cadherin junction assembly. A real role, but secondary to desmosomal adhesion. Supporting Evidence: PMID:31835537 The knockdown of Dsg3 by siRNA blocked strain-induced junctional remodeling of E-cadherin and Myosin IIa. file:human/DSG3/DSG3-uniprot.txt Required for adherens and desmosome junction assembly in response to mechanical force in keratinocytes |
| GO:0046983 protein dimerization activity | ISS GO_REF:0000024 | MODIFY | Summary: The dimer formed by DSG3 is a homodimer, which is directly curated for the human protein. Reason: UniProt records DSG3 homodimer formation from single-molecule measurements, so the more specific descendant term is supported and should replace the general one. Proposed replacements: protein homodimerization activity Supporting Evidence: file:human/DSG3/DSG3-uniprot.txt Homodimer (PubMed:19717567) |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: DSG3 was identified in a large-scale urinary exosome proteome. Reason: Membrane proteins of epithelia are routinely recovered in exosome preparations. The detection is credible but says nothing about DSG3 function, so it is retained as non-core. Supporting Evidence: PMID:19056867 the analysis identified 1132 proteins unambiguously |
| GO:0070160 tight junction | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A tight-junction pool is curated for human DSG3 as well as inferred from the ortholog. Reason: UniProt records a tight-junction location with experimental evidence from the actin-anchoring study, so the inferred term matches human data. Secondary to the desmosome. Supporting Evidence: file:human/DSG3/DSG3-uniprot.txt Cell junction, tight junction |
| GO:0070161 anchoring junction | EXP PMID:18343367 P120-catenin is a novel desmoglein 3 interacting partner: id... | MODIFY | Summary: The anchoring junction that DSG3 belongs to is the desmosome. Reason: Desmosome is a descendant of anchoring junction, is supported for DSG3 by ultrastructure and by curated localization, and is already carried by the gene. Use the specific term. Proposed replacements: desmosome Supporting Evidence: PMID:9701552 Electron microscopy revealed 'half-desmosomes' at the plasma membranes |
| GO:0070161 anchoring junction | IEA GO_REF:0000044 | MODIFY | Summary: The curated anchoring-junction location resolves to the desmosome for DSG3. Reason: UniProt separately records the desmosome location, which is the specific descendant supported by the experimental evidence. Proposed replacements: desmosome Supporting Evidence: PMID:19717567 form the adhesive core of desmosomes |
| GO:0098609 cell-cell adhesion | IBA GO_REF:0000033 | ACCEPT | Summary: Cell-cell adhesion is the core biological process of DSG3. Reason: The inherited cadherin-family assertion is directly supported for DSG3 by acantholysis in knockout mice, by pemphigus autoantibody-induced loss of keratinocyte cohesion, and by direct binding measurements. Supporting Evidence: PMID:9701552 showed loss of cell adhesion (acantholysis) between the cells surrounding the telogen club and the basal layer of the outer root sheath epithelium PMID:19717567 form the adhesive core of desmosomes |
| GO:0098609 cell-cell adhesion | ISS GO_REF:0000024 | ACCEPT | Summary: Transfer from mouse Dsg3 agrees with direct human evidence. Reason: The human protein has its own adhesion evidence, so the inferred row is consistent and core. Supporting Evidence: PMID:19717567 form the adhesive core of desmosomes |
| GO:0120192 tight junction assembly | IMP PMID:31835537 Evidence for the Desmosomal Cadherin Desmoglein-3 in Regulat... | KEEP AS NON CORE | Summary: DSG3 contributes to junction formation under mechanical strain, including tight junctions. Reason: Knockdown of DSG3 impairs strain-induced junctional remodelling, and the related actin study reports anchoring of actin at tight junctions. The role is real but downstream of DSG3 signalling rather than part of desmosomal adhesion. Supporting Evidence: PMID:31835537 The knockdown of Dsg3 by siRNA blocked strain-induced junctional remodeling of E-cadherin and Myosin IIa. file:human/DSG3/DSG3-uniprot.txt Positively regulates cellular contractility and cell junction formation via organization of cortical F- |
| GO:1903348 positive regulation of bicellular tight junction assembly | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of tight-junction assembly, consistent with the human actin-anchoring data. Reason: The inferred term matches the curated human statement that DSG3 promotes cell junction formation through cortical actin organisation and actin anchoring at tight junctions. Secondary to desmosomal adhesion. Supporting Evidence: file:human/DSG3/DSG3-uniprot.txt Positively regulates cellular contractility and cell junction formation via organization of cortical F- |
| GO:1903753 negative regulation of p38MAPK cascade | IMP PMID:26763450 Desmoglein 3-Dependent Signaling Regulates Keratinocyte Migr... | KEEP AS NON CORE | Summary: DSG3 associates with p38MAPK and suppresses its activity. Reason: p38MAPK activation is detectable in Dsg3-deficient mouse skin and at the wound edge where DSG3 is lost, and the migration phenotype is p38MAPK-dependent. Well supported, but peripheral to the adhesive core function. Supporting Evidence: PMID:26763450 Recently, we have shown that Dsg3 associates with p38 mitogen- activated protein kinase (p38MAPK) and suppresses its activity. PMID:26763450 In lesional and perilesional biopsies, p38MAPK activation was detectable compared with control animals. |
| GO:1904704 positive regulation of protein localization to adherens junction | IMP PMID:22294297 Non-junctional human desmoglein 3 acts as an upstream regula... | KEEP AS NON CORE | Summary: Non-junctional DSG3 promotes recruitment of E-cadherin and beta-catenin to developing adherens junctions. Reason: Modulating DSG3 levels alters Src activity and E-cadherin association, and silencing retards calcium-induced E-cadherin junction assembly. A genuine regulatory role of the non-desmosomal pool, kept as non-core. Supporting Evidence: PMID:22294297 Modulation of Dsg3 levels, either by Dsg3 silencing or over-expression, alters Src activity and its association with E-cadherin. file:human/DSG3/DSG3-uniprot.txt The cytoplasmic pool of DSG3 is required for the localization of CDH1 and CTNNB1 at developing adherens junctions |
| GO:1905477 positive regulation of protein localization to membrane | IMP PMID:31835537 Evidence for the Desmosomal Cadherin Desmoglein-3 in Regulat... | KEEP AS NON CORE | Summary: DSG3 retains phospho-YAP at the plasma membrane in strained keratinocytes. Reason: The DSG3, PKP1, YAP1 and YWHAG complex is required for membrane localization of YAP1, and DSG3 depletion releases YAP. A mechanotransduction role downstream of the adhesive function. Supporting Evidence: PMID:31835537 Dsg3 formed a complex with phospho-YAP and sequestered it to the plasma membrane file:human/DSG3/DSG3-uniprot.txt Required for YAP1 localization at the plasma membrane in keratinocytes in response to mechanical strain |
| GO:0098632 cell-cell adhesion mediator activity | IDA PMID:19717567 Desmocollin 3-mediated binding is crucial for keratinocyte c... | NEW | Summary: DSG3 has no molecular-function annotation for the adhesive activity itself, only the calcium binding that supports it and the adhesion processes it drives. Reason: Desmogleins and desmocollins form the adhesive core of the desmosome, and binding of desmosomal cadherins at the keratinocyte surface is measured directly by force spectroscopy and laser-tweezer trapping in this study, with UniProt curating DSG3 homodimer formation from the same work. DSG3 itself performs the adhesive binding, so this molecular function belongs on the gene rather than on a partner. Supporting Evidence: PMID:19717567 Desmocollin (Dsc) 1-3 and desmoglein (Dsg) 1-4, transmembrane proteins of the cadherin family, form the adhesive core of desmosomes. file:human/DSG3/DSG3-uniprot.txt Homodimer (PubMed:19717567) |
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Download this section (compressed HTML)Q: What fraction of surface DSG3 is non-desmosomal in normal epithelium, and is the signalling pool a distinct species or simply cadherin not yet incorporated into desmosomes?
Q: Is DSG3 genuinely a component of tight junctions, or does it act on tight junctions indirectly through cortical actin and Rac1?
Q: Does DSG3 contribute to the cornified envelope or corneodesmosome in any epithelium, given that its expression is confined largely to the basal and spinous layers?
Experiment: Separate detergent-soluble and insoluble DSG3 pools after acute, reversible disruption of desmosomes, and test whether Src activation and phospho-YAP membrane retention track the soluble pool while adhesion strength tracks the insoluble pool.
Hypothesis: The non-junctional surface pool of DSG3, not the desmosomal pool, carries the Src and YAP signalling functions.
Experiment: Single-molecule force spectroscopy with recombinant DSG3 and DSC3 ectodomains on living keratinocytes, in the presence and absence of calcium and of pemphigus vulgaris autoantibodies, measuring unbinding forces for each pairing.
Hypothesis: DSG3 trans-interacts homophilically as well as heterophilically with DSC3 at the keratinocyte surface.
Experiment: Immunogold electron microscopy and sequential-extraction immunoblotting of human epidermis, comparing DSG3 with DSG1 and DSC1 across the spinous, granular and cornified layers.
Hypothesis: DSG3 is absent from the cornified envelope despite its membership in the cornification pathway.
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