P-cadherin (cadherin-3) is a type I classical cadherin that mediates calcium-dependent homophilic cell-cell adhesion. Its extracellular cadherin domains recognize P-cadherin on adjoining cells, while its intracellular region associates with beta-catenin in adhesive junctions. It is expressed in epithelial compartments including basal cells and hair follicles. P-cadherin supports follicular keratinocyte proliferation, maintenance of the hair growth phase and follicular pigmentation through context-dependent signaling relationships. Biallelic CDH3 defects cause sparse hair with progressive macular dysfunction, and can also cause ectodermal dysplasia with limb abnormalities.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000902 cell morphogenesis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Adhesive contacts support cell organization and morphology. Reason: The PAINT assertion is compatible with conserved classical-cadherin adhesion and the target-dependent follicular structural phenotypes. Retain the broad morphogenetic process as non-core; adhesion and junction organization describe the defining molecular role more precisely. The ancestral node was not independently re-curated. |
| GO:0001895 retina homeostasis | IMP PMID:23143461 Homozygous deletion in CDH3 and hypotrichosis with juvenile ... | KEEP AS NON CORE | Summary: CDH3 contributes to maintenance of macular function. Reason: The full clinical report describes two siblings with a homozygous deletion of CDH3 exons 12β13 and progressive central retinal dysfunction with macular degeneration. This supports a tissue-maintenance phenotype, rather than assigning a retinal biochemical activity or phototransduction mechanism to the cadherin. Retain as a non-core tissue context. Supporting Evidence: file:human/CDH3/CDH3-manual-evidence.md Funduscopy in the proband revealed bilateral symmetrical macular degeneration |
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: Calcium binding stabilizes the adhesive ectodomain. Reason: The InterPro inference is independently supported by the human P-cadherin EC1β2 biophysical study, whose abstract reports calcium binding and calcium-dependent homophilic dimerization. Calcium coordination stabilizes the adhesive ectodomain and is integral to the represented core adhesion mechanism. Retain it as a core biochemical property without adding a redundant stand-alone core function. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | UNDECIDED | Summary: The specific cytoplasmic activity remains unresolved. Reason: The PAINT is_active_in assertion concerns activity in cytoplasm, which excludes the plasma membrane. A membrane-associated cytoplasmic tail and catenin interaction do not by themselves establish an independently active cytoplasmic pool. The full human biopsy study notes occasional weak cytoplasmic P-cadherin staining, but does not resolve that poolβs activity. Preserve the inherited assertion pending its exact functional context; established junctional function does not prove that a separate cytoplasmic role is absent. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN002771833 Β· PTN002771833 UNRESOLVED The source node is preserved from the genuine seed. Its specific inherited cytoplasmic activity was not resolved by target staining or membrane catenin association; no absence, loss or erroneous node placement is asserted. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: P-cadherin acts at the plasma membrane. Reason: The immunofluorescence-curated localization agrees with the single-pass membrane topology, cell-surface adhesion experiments and independent human tissue immunostaining. It is a core functional location. |
| GO:0005886 plasma membrane | IDA PMID:10460003 Cadherin and catenin expression in normal human bronchial ep... | ACCEPT | Summary: Human bronchial tissue expresses membrane P-cadherin. Reason: The original source examines P-cadherin in normal human bronchial epithelium and lung tumors; its abstract reports strong expression in basal epithelial cells. Retain the curated IDA membrane assignment, independently corroborated by full human breast-biopsy immunostaining and functional human-protein adhesion assays. The original full article was not accessed. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: The combined electronic membrane assignment is biologically consistent. Reason: The source combines mouse Cdh3 P10287/Ensembl orthology, cadherin-domain, ARBA and subcellular-location mappings. P10287 was verified as mouse Cdh3. Independent human target experiments establish membrane adhesion, supporting this location without pretending that each combined rule branch was reconstructed. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-419001 | ACCEPT | Summary: The Reactome adhesion event places CDH3 at the plasma membrane. Reason: R-HSA-419001 consumes the Classic Cadherin set R-HSA-418977, whose members include human CDH3 R-HSA-198241 at the plasma membrane. This target-linked event location agrees with human-protein adhesion assays. The event is a curated family model, not an independent CDH3 experiment. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-419002 | ACCEPT | Summary: The Reactome catenin-association event uses membrane CDH3. Reason: R-HSA-419002 consumes the same Classic Cadherin set containing human CDH3 R-HSA-198241 and forms a membrane cadherin:catenin complex. Native human P-cadherin/beta-catenin co-immunoprecipitation independently supports the target association. Retain the plasma-membrane location as core. |
| GO:0005912 adherens junction | IBA GO_REF:0000033 | ACCEPT | Summary: Adherens junctions are a functional site of P-cadherin. Reason: The inherited is_active_in assertion accords with the cadherin-catenin adhesive role and P-cadherin-dependent membrane beta-catenin organization in human hair follicles. No target-specific divergence contradicts the PAINT placement. |
| GO:0005912 adherens junction | IEA GO_REF:0000107 | ACCEPT | Summary: The mouse ortholog transfer agrees with human junctional evidence. Reason: The source ortholog P10287 is mouse Cdh3, not another cadherin. Human P-cadherin-mediated adhesion and catenin association independently support adherens-junction localization; retain the original electronic transfer and its source identifiers. |
| GO:0007043 cell-cell junction assembly | IBA GO_REF:0000033 | ACCEPT | Summary: P-cadherin supplies adhesive structure to cell-cell junction assembly. Reason: The inherited process is consistent with human P-cadherin establishing adhesive contacts and associating with the catenin machinery. CDH3 itself supplies the membrane adhesion component; this is structural participation rather than a claim inferred solely from downstream necessity. |
| GO:0007155 cell adhesion | IEA GO_REF:0000002 | ACCEPT | Summary: Cell adhesion is a direct core process. Reason: The cadherin-domain inference is corroborated by human P-cadherin cDNA conferring adhesive function on NIH3T3 cells. Retain the broad correct parent process; the core uses the more informative cadherin-mediated cell-cell adhesion term without duplicating all ancestors. |
| GO:0007155 cell adhesion | TAS PMID:2793940 Molecular cloning of a human Ca2+-dependent cell-cell adhesi... | ACCEPT | Summary: Human P-cadherin directly mediates cell adhesion. Reason: The accessible original abstract explicitly reports functional adhesion after transfection of human P-cadherin cDNA into mouse NIH3T3 cells. The human target protein and heterologous host are distinct. Retain this direct adhesion process, without transferring the mouse placental expression pattern to humans. Supporting Evidence: |
| GO:0007156 homophilic cell-cell adhesion | IEA GO_REF:0000002 | ACCEPT | Summary: Homophilic recognition underlies P-cadherin cell adhesion. Reason: The electronic assertion is supported by specific self-recognition of human P-cadherin EC1β2 in the purified-protein study, together with the original human-protein cell-adhesion assay. It is part of the defining adhesion mechanism. |
| GO:0008013 beta-catenin binding | IBA GO_REF:0000033 | ACCEPT | Summary: Beta-catenin association links P-cadherin to the junctional complex. Reason: Retain the specific PAINT molecular function. Full PMID18320359 Methods and Fig.3c report beta-catenin immunoprecipitation from a human breast-tumor sample followed by P-cadherin immunoblotting, with a negative IP control in Fig.3g. This corroborates the target association; it is not a purified binary-interface assay and does not transfer beta-catenin transcriptional activity to CDH3. |
| GO:0010838 positive regulation of keratinocyte proliferation | IMP PMID:22696062 P-cadherin regulates human hair growth and cycling via canon... | KEEP AS NON CORE | Summary: P-cadherin supports hair-matrix keratinocyte proliferation. Reason: In organ-cultured human scalp follicles, CDH3 siRNA reduces Ki67-positive hair-matrix keratinocytes compared with scrambled controls, including an anagen-only comparison. Retain this regulatory tissue outcome as non-core; CDH3 is not thereby assigned cell-cycle catalysis. Supporting Evidence: PMID:22696062 inhibited hair matrix keratinocyte proliferation |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: Membrane localization is an accurate broad core location. Reason: The electronic topology-based location is consistent with the human single-pass cadherin and direct membrane adhesion. Retain the correct parent localization; plasma membrane and adherens junction provide the precise core locations. |
| GO:0016339 calcium-dependent cell-cell adhesion | IBA GO_REF:0000033 | ACCEPT | Summary: Calcium-dependent cell-cell adhesion is a defining process. Reason: The PAINT inference agrees with functional human P-cadherin adhesion and the calcium-dependent assembly of the human ectodomain. The protein supplies the adhesive contacts itself, rather than acting solely through a downstream phenotype. |
| GO:0016342 catenin complex | IBA GO_REF:0000033 | ACCEPT | Summary: P-cadherin participates in a catenin-containing adhesive complex. Reason: The original part_of IBA is supported by native human P-cadherin recovery in beta-catenin immunoprecipitates and the target-containing Reactome cadherin:catenin model. These establish complex association without claiming a particular purified stoichiometry or an intrinsic catenin activity for CDH3. |
| GO:0016477 cell migration | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Cell migration is a broader context of cadherin-mediated organization. Reason: The PAINT assertion supplies positive evolutionary evidence for a cadherin contribution to cell migration through adhesive-contact organization. P-cadherin itself supplies adhesive contacts; process involvement does not require autonomous force generation or an intrinsic motor activity. Retain this broader process as non-core while the defining molecular role remains adhesion. The ancestral placement was not independently re-curated, and tumor-expression correlations are not presented as migration assays. Supporting Evidence: GO_REF:0000033 |
| GO:0022405 hair cycle process | IMP PMID:23143461 Homozygous deletion in CDH3 and hypotrichosis with juvenile ... | KEEP AS NON CORE | Summary: Hair-cycle involvement has independent human functional support. Reason: The original clinical report establishes congenital sparse hair in CDH3-deletion siblings, not a direct assay of cycle progression. Independent human follicle perturbation in PMID22696062 demonstrates premature catagen after CDH3 silencing. Retain the broad non-core process using this corroboration while preserving the original IMP source and distinguishing its clinical evidence from the cycling experiment. |
| GO:0030054 cell junction | IDA GO_REF:0000052 | ACCEPT | Summary: Cell junction is a core localization. Reason: The immunofluorescence annotation is consistent with cadherin-mediated contacts and catenin association. Retain this broad correct location; adherens junction is the more precise core site. |
| GO:0030054 cell junction | IEA GO_REF:0000117 | ACCEPT | Summary: The ARBA junction inference agrees with direct target biology. Reason: The electronic assignment is consistent with human P-cadherin adhesion and junctional catenin association. The specific ARBA rule chain was not independently reconstructed; independent target evidence supports its asserted location. |
| GO:0030512 negative regulation of transforming growth factor beta receptor signaling pathway | IMP PMID:22696062 P-cadherin regulates human hair growth and cycling via canon... | KEEP AS NON CORE | Summary: P-cadherin restrains a TGF-beta-associated catagen pathway. Reason: CDH3 knockdown increases TGF-beta2 in human follicles, and neutralization partly rescues the growth/cycle effect. Preserve the original acts_upstream_of_or_within_negative_effect qualifier and the contextual regulatory interpretation. This is not evidence that P-cadherin binds the TGF-beta receptor or catalyzes receptor signaling. Supporting Evidence: PMID:22696062 Neutralizing TGFΞ² antagonized the catagen-promoting effects |
| GO:0031424 keratinization | IMP PMID:22696062 P-cadherin regulates human hair growth and cycling via canon... | UNDECIDED | Summary: The exact keratinization step remains unresolved. Reason: The full study reports precortical keratin clumps and altered hair-keratin transcripts after CDH3 silencing, with no significant increase in precortical apoptosis. These are genuine structural phenotypes. They do not yet establish which step in formation of the keratinized layer CDH3 performs, as distinct from adhesion-dependent organization or transport of keratin filaments. Preserve the experimental assertion as unresolved rather than discard it from an incomplete abstract reading. Supporting Evidence: |
| GO:0034332 adherens junction organization | IBA GO_REF:0000033 | ACCEPT | Summary: P-cadherin organizes adherens junctions. Reason: The inherited process matches the proteinβs adhesive contribution and catenin engagement; CDH3 depletion perturbs membrane beta-catenin in human follicles. Retain junction organization as a direct structural role, without assigning beta-catenin-dependent transcription to the cadherin itself. |
| GO:0043568 positive regulation of insulin-like growth factor receptor signaling pathway | IMP PMID:22696062 P-cadherin regulates human hair growth and cycling via canon... | KEEP AS NON CORE | Summary: An upstream IGF signaling relationship is supported in follicles. Reason: The full source reports reduced IGF1 transcript after CDH3 silencing. Preserve the original acts_upstream_of_positive_effect qualifier: this supports an upstream ligand-expression relationship in the follicular model, not a direct assay of IGF receptor activity or CDH3 receptor/kinase function. Retain as a non-core regulatory context. Supporting Evidence: PMID:22696062 anagen-promoting growth factor, IGF-1 |
| GO:0044331 cell-cell adhesion mediated by cadherin | IBA GO_REF:0000033 | ACCEPT | Summary: P-cadherin is an adhesion mediator in cadherin-dependent cell contacts. Reason: The PAINT process is corroborated by the human cDNA cell-adhesion assay and human ectodomain self-recognition. P-cadherin supplies the adhesive contact, satisfying direct structural participation. |
| GO:0045296 cadherin binding | IBA GO_REF:0000033 | ACCEPT | Summary: CDH3 binds cadherins; the cadherin binding (GO:0045296) genus is correct as it stands, and the cell-cell adhesion context is carried by the core functions rather than by the precomposed GO:0098641. Reason: The genus GO:0045296 is the right term. An earlier pass proposed MODIFY to the precomposed GO:0098641; per projects/INVOLVED_IN_PRECOMPOSITION.md that adds only the cell-cell adhesion context, which is carried by the core functions. Evidence retained from the earlier reasoning: human P-cadherin confers cell adhesion in the cDNA experiment, and its EC1β2 region undergoes specific homophilic association; the original IBA assertion and its provenance are preserved. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN008601603 Β· PTN008601603 SUPPORTS TRANSFER The PAINT cadherin-binding assertion transfers at the right granularity; the earlier MODIFY to the precomposed GO:0098641 is reversed because the adhesion context belongs in the core functions. |
| GO:0048023 positive regulation of melanin biosynthetic process | IMP PMID:23334344 Topobiology of human pigmentation: P-cadherin selectively st... | KEEP AS NON CORE | Summary: P-cadherin supports follicular melanin synthesis regulation. Reason: The full source compares anagen-VI human follicles and separately studies follicular melanocytes: CDH3 silencing lowers melanin, tyrosinase readouts and MITF-related expression. Retain the positive regulatory process as non-core; tyrosinase, not CDH3, catalyzes melanin synthesis. In the Results on manuscript pages 10β11 (Figure 5j), lithium does not restore MITF transcript despite normalization of phospho-beta-catenin. The primary-source excerpt and assay context are preserved in CDH3-manual-evidence.md; exclusive Wnt mediation is not established. Supporting Evidence: PMID:23334344 reduced HF melanogenesis and tyrosinase activity file:human/CDH3/CDH3-manual-evidence.md MITF mRNA steady state-level was not reversed |
| GO:0048820 hair follicle maturation | IMP PMID:23334344 Topobiology of human pigmentation: P-cadherin selectively st... | UNDECIDED | Summary: Acquisition of follicular maturity is not resolved by the selected assays. Reason: The inspected source uses already mature anagen-VI follicles and assesses pigmentation and melanocyte signaling. GO:0048820 concerns attainment of a mature functional state; maintained pigment production in adult follicles does not by itself establish that developmental transition. Keep this specific experimental assertion unresolved, without denying the demonstrated pigmentary role or assuming the curator saw no additional evidence. Supporting Evidence: |
| GO:0051796 negative regulation of timing of catagen | IMP PMID:22696062 P-cadherin regulates human hair growth and cycling via canon... | KEEP AS NON CORE | Summary: P-cadherin delays entry into catagen in the human follicle model. Reason: CDH3 silencing accelerates catagen by quantitative follicle staging and inhibits hair-shaft growth. Retain the measured timing regulation as a non-core tissue outcome, with no claim that P-cadherin directly executes apoptotic regression. Supporting Evidence: PMID:22696062 prematurely induced HF regression (catagen) |
| GO:0090263 positive regulation of canonical Wnt signaling pathway | IMP PMID:22696062 P-cadherin regulates human hair growth and cycling via canon... | KEEP AS NON CORE | Summary: P-cadherin supports canonical Wnt output in the follicular context. Reason: CDH3 depletion changes membrane beta-catenin, GSK3beta/phospho-beta-catenin and AXIN2; lithium partly rescues the growth phenotype and restores AXIN2 expression. These findings support the existing positive regulatory process in human follicles. They do not make CDH3 a Wnt ligand or kinase, and the separate pigmentation study does not establish exclusive Wnt mediation. Supporting Evidence: PMID:22696062 partially reversed by inhibiting GSK3Ξ² file:human/CDH3/CDH3-manual-evidence.md |
| GO:0098609 cell-cell adhesion | IEA GO_REF:0000002 | ACCEPT | Summary: Cell-cell adhesion is directly executed by P-cadherin. Reason: The InterPro mapping is independently supported by human P-cadherin-mediated contacts. Retain the broad correct process while representing its cadherin-specific mechanism in the core. |
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Download this section (compressed HTML)Q: Which CDH3-dependent structural or signaling step contributes specifically to keratinization, beyond the observed keratin clumping and adhesion-dependent follicular organization?
Q: Does CDH3 participate in acquisition of follicular maturity, separately from maintaining pigment production in already mature anagen follicles?
Q: What functional cytoplasmic CDH3 pool underlies the PAINT is_active_in assertion, separately from the membrane-associated catenin-binding tail?
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