CDH2

Summary: Retain cell morphogenesis as a developmental consequence of cadherin-mediated tissue organization.

Reason: The PAINT assertion at PTN000616280 is compatible with the conserved role of classical cadherins in organizing cell contacts. Human disease and adhesion assays corroborate the biological importance of this architecture. Morphogenesis is retained outside the activity-centered adhesion core; neither a short donor list nor target self-evidence is treated as a defect.

Summary: Retain the pancreatic beta-cell developmental context of N-cadherin adhesion.

Reason: This is an ortholog transfer from mouse P15116, whose reviewed record describes contacts between pancreatic beta cells and neural crest stem cells. It is a specialized developmental context, not a direct human pancreatic differentiation assay or an independent molecular activity. Preserve the original transfer and its species scope.

Summary: Retain the pancreatic beta-cell developmental context of N-cadherin adhesion.

Reason: This is an ortholog transfer from mouse P15116, whose reviewed record describes contacts between pancreatic beta cells and neural crest stem cells. It is a specialized developmental context, not a direct human pancreatic differentiation assay or an independent molecular activity. Preserve the original transfer and its species scope.

Summary: The mouse donor annotation is confirmed, but the cited complete primary study and supplementary data do not establish cadherin-2 protein binding to RNA.

Reason: The human IEA transfers GO:0003723 from mouse Cdh2/P15116. Current MGI independently links that donor IDA to PMID:27783602 (J:241317), with an embryonic-fibroblast extension. The accessible primary Methods instead describe mouse embryonic stem cells and genetic perturbation followed by RNA abundance measurements. Publisher Supplementary Note S5 and Table S1 (Targeted Loci, row 28) measure Chd2 transcript changes after linc2025 promoter deletion; Table S3 supplies Chd2 hybrid-selection probes. These are measurements of RNA and do not demonstrate binding of RNA by Cdh2 protein. All three supplementary workbooks and the nine supplementary notes were checked, resolving the earlier missing-supplement limitation. Thus this exact electronic source chain exceeds what the cited experiments establish. The origin of MGI's assertion remains unresolved: no Chd2-to-Cdh2 naming error is claimed, and this decision does not rule out RNA binding under other conditions. Preserve all original human and donor fields.

Summary: Calcium binding is integral to the adhesive cadherin ectodomain.

Reason: Conserved extracellular cadherin domains contain calcium-binding interdomain sites. The primary structure-function study reports a calcium-complexed N-cadherin fragment, corroborating the mouse-derived and domain-based source assertions. Calcium-dependent adhesion and variant structural models are kept distinct from direct measurements of human mutant calcium affinity.

Summary: Calcium binding is integral to the adhesive cadherin ectodomain.

Reason: Conserved extracellular cadherin domains contain calcium-binding interdomain sites. The primary structure-function study reports a calcium-complexed N-cadherin fragment, corroborating the mouse-derived and domain-based source assertions. Calcium-dependent adhesion and variant structural models are kept distinct from direct measurements of human mutant calcium affinity.

Summary: Refine the N-cadherin–beta-catenin interaction to beta-catenin binding.

Reason: The inspected full primary Results and Figure 2 include N-cadherin cytoplasmic GST fusions tested with beta-catenin, despite the paper’s emphasis on VE-cadherin and PAR proteins. This target control supports the specific binding term. Construct species was not independently resolved from the inaccessible supplement; separate endogenous human-cell experiments corroborate the target activity.

Proposed replacements: beta-catenin binding

Summary: Refine the N-cadherin–plakoglobin interaction to gamma-catenin binding.

Reason: The full Results and Figure 2 assay gamma-catenin recovery with cadherin from U373 lysates. The authors used pan-cadherin antibodies and estimated that N-cadherin constitutes approximately 95% of cadherin in these cells. This supports the specific catenin association, with antibody specificity and complex-association limits preserved.

Proposed replacements: gamma-catenin binding

Summary: Refine the beta-catenin association to its specific binding term.

Reason: The full primary paper measures N-cadherin co-immunoprecipitation with beta-catenin in U373 cells and its reduction after pleiotrophin stimulation. The pan-cadherin reagent limitation is disclosed; the result is supported independently by endogenous N-cadherin binding in HEK293 cells.

Proposed replacements: beta-catenin binding

Summary: Beta-catenin binding is the supported specific activity for this preserved partner.

Reason: The original study used affinity purification/mass spectrometry to study the beta-catenin interaction network. Its abstract does not independently resolve the exact CDH2 edge, and no exact record was recovered in the inspected IntAct query. The preserved P35222 association is nevertheless independently established by direct target experiments in PMID:17679699 and PMID:17098867. Refine using that independent evidence without claiming that the original screen row was inspected. The specific partner follows the original GOA WITH/FROM record UniProtKB:P35222; it is not an independently inspected row from that screen.

Proposed replacements: beta-catenin binding

Summary: Human endogenous N-cadherin binds beta-catenin.

Reason: The inspected Figure 4B and Results test endogenous N-cadherin in HEK293 cells with epitope-tagged wild-type or mutant beta-catenin. Deletion of the beta-catenin armadillo domain disrupts association. These are human-cell binding experiments, distinct from the paper’s cultured hippocampal-neuron physiology.

Proposed replacements: beta-catenin binding

Summary: Refine the human-cell N-cadherin association to beta-catenin binding.

Reason: The inspected Figure 5E and Results measure beta-catenin association with N-cadherin in 293T cells after ephrin-A5 stimulation or EphA2 expression. The human-cell assay is separate from the mouse lens knockout experiments, and establishes the specific pair rather than a new CDH2 kinase activity.

Proposed replacements: beta-catenin binding

Summary: N-cadherin association with p120-catenin is supported.

Reason: The full RET study and exact IntAct EBI-5276971 record support the P19022–O60716 association. RET cleavage alters p120 recruitment and cadherin stabilization; this does not confer RET kinase or protease activity on CDH2. Retain the source interaction as non-core generic binding under the ClinGen project instruction.

Summary: Refine the RET-context cadherin association to beta-catenin binding.

Reason: The exact IntAct EBI-5276977 pair and inspected primary study support N-cadherin association with beta-catenin. The conserved junctional interaction is independently demonstrated in human HEK293 cells. This does not imply CDH2 is the RET signaling enzyme.

Proposed replacements: beta-catenin binding

Summary: The exact human CDH2–connexin43 interaction remains unresolved.

Reason: The accessible abstract describes connexin43 immunoprecipitation in mouse retinal pigment epithelium and functional assays in human ARPE-19 cells. It does not resolve which target constructs or species support the preserved P19022–P17302 pair; the full experimental record was not recovered. No exact matching IntAct record was found in the bounded query. This is source-specific uncertainty, not a conclusion that the curator used the wrong gene or that junctional association is impossible.

Summary: BioPlex supports association with p120-catenin.

Reason: Exact accession/PMID matching identifies the positive P19022–O60716 record EBI-54736260. It is an affinity-purification association, not an independently measured purified binary interface or an additional CDH2 signaling activity. Preserve generic binding as non-core.

Summary: Refine BioPlex beta-catenin association to beta-catenin binding.

Reason: The exact positive P19022–P35222 BioPlex record EBI-54583800 supports the association. Independent human-cell experiments establish the specific binding activity, so the generic term can be refined without treating affinity purification as proof of isolated binary binding.

Proposed replacements: beta-catenin binding

Summary: Use beta-catenin binding for this independently established target pair.

Reason: The source OpenCell endogenous-tagging screen provides relevant interaction context, but the exact target data row was not independently recovered from its supplementary network or the bounded IntAct query. Preserve that source limitation. The P19022–P35222 interaction itself is independently established in human-cell experiments, supporting this specific refinement without claiming target-level inspection of the screen. The specific partner follows the original GOA WITH/FROM record UniProtKB:P35222; it is not an independently inspected row from that screen.

Proposed replacements: beta-catenin binding

Summary: The FCER2 interaction awaits exact target-level assay verification.

Reason: The released source-data workbook explicitly identifies human CDH2 (P19022) and FCER2 (P06734) in Figure1_network row172, with a SAVEXIS screening score of 2.970475; Figure2_network row126 carries the same pair. Selected full Methods describe recombinant extracellular-domain screening and independent validation of the retained network. This exact target record supports the existing binding annotation as a non-core association under the project binding policy. A target-specific SPR trace and native-cell physiological role were not independently established; the numerical affinity field in the modelling sheet is not treated as a measured CDH2–FCER2 affinity.

Summary: Use beta-catenin binding for this independently established target pair.

Reason: The source human induced-neuron interaction study provides relevant interaction context, but the exact target data row was not independently recovered from its supplementary network or the bounded IntAct query. Preserve that source limitation. The P19022–P35222 interaction itself is independently established in human-cell experiments, supporting this specific refinement without claiming target-level inspection of the screen. The specific partner follows the original GOA WITH/FROM record UniProtKB:P35222; it is not an independently inspected row from that screen.

Proposed replacements: beta-catenin binding

Summary: Refine the plakoglobin association to gamma-catenin binding.

Reason: The authentic abstract describes plakoglobin deletion constructs transfected into human HT-1080 fibrosarcoma cells, with immunofluorescence and co-immunoprecipitation mapping the N-cadherin association. Gamma-catenin is plakoglobin; the term names the actual partner. Full methods were not independently recovered.

Proposed replacements: gamma-catenin binding

Summary: Refine the membrane-associated catenin-binding activity to the adherens junction.

Reason: The conserved cytoplasmic tail binds catenins at the intracellular face of an adherens junction. GO:0005737 excludes the plasma membrane, so those experiments support the junctional location more precisely than a separate cytoplasmic activity of intact N-cadherin. Refine to adherens junction, independently supported in human cells, while preserving the original PAINT node and is_active_in qualifier. The sibling IDA located_in annotation describes intracellular immunoreactivity and is not an activity assay; the distinction is location scope, not an evidence-code ranking.

Proposed replacements: adherens junction

Summary: Retain the experimentally curated intracellular localization outside the junctional core.

Reason: The radixin study examines human PC3 and MDA-MB-231 cells, but its accessible abstract does not resolve the exact N-cadherin cytoplasmic staining panel. Intracellular cadherin immunoreactivity is independently observed in U373 cells during altered junctional turnover. Preserve the original IDA location without equating intracellular staining with a separate soluble biochemical activity.

Summary: Refine the mature transmembrane CDH2 substrate location to the ER membrane.

Reason: The current Reactome reaction R-HSA-8952289 contains complex R-HSA-8952321 and substrate set R-HSA-8956956, whose CDH2 member R-HSA-8956761.1 explicitly represents human P19022 residues 160–906 in the ER lumen. That mature chain includes transmembrane residues 725–745 and cytoplasmic residues 746–906 in the preserved UniProt record; it is not a soluble propeptide or isolated ectodomain. GO:0005788 denotes the enclosed luminal volume, whereas GO:0005789 denotes the surrounding lipid bilayer. ER membrane is the more accurate location for this biosynthetic substrate, with its N-terminal domain exposed to the lumen. Preserve the TAS reaction provenance and do not assign FAM20C kinase activity to CDH2.

Proposed replacements: endoplasmic reticulum membrane

Summary: Plasma-membrane localization is central to N-cadherin adhesion.

Reason: The original DSC2-focused paper’s abstract does not expose its CDH2 staining controls; no wrong-paralog conclusion is drawn. Independent N-cadherin junctional staining and human-cell adhesion experiments support this location. Retain the original source and evidence code; extracellular trans adhesion is coupled to an intracellular catenin-binding tail.

Summary: Plasma-membrane localization is central to N-cadherin adhesion.

Reason: Independent N-cadherin junctional staining and human-cell adhesion experiments support this location. Retain the original source and evidence code; extracellular trans adhesion is coupled to an intracellular catenin-binding tail. The exact HPA target page independently reports supported plasma-membrane and cell-junction staining.

Summary: Plasma-membrane localization is central to N-cadherin adhesion.

Reason: The original radixin paper’s abstract does not expose its exact CDH2 staining panel. Independent N-cadherin junctional staining and human-cell adhesion experiments support this location. Retain the original source and evidence code; extracellular trans adhesion is coupled to an intracellular catenin-binding tail.

Summary: Plasma-membrane localization is central to N-cadherin adhesion.

Reason: Independent N-cadherin junctional staining and human-cell adhesion experiments support this location. Retain the original source and evidence code; extracellular trans adhesion is coupled to an intracellular catenin-binding tail.

Summary: Plasma-membrane localization is central to N-cadherin adhesion.

Reason: Independent N-cadherin junctional staining and human-cell adhesion experiments support this location. Retain the original source and evidence code; extracellular trans adhesion is coupled to an intracellular catenin-binding tail.

Summary: Plasma-membrane localization is central to N-cadherin adhesion.

Reason: The named Reactome event supplies pathway context, not an independent localization experiment or evidence that CDH2 performs the event catalyst’s reaction. Independent N-cadherin junctional staining and human-cell adhesion experiments support this location. Retain the original source and evidence code; extracellular trans adhesion is coupled to an intracellular catenin-binding tail.

Summary: Plasma-membrane localization is central to N-cadherin adhesion.

Reason: The named Reactome event supplies pathway context, not an independent localization experiment or evidence that CDH2 performs the event catalyst’s reaction. Independent N-cadherin junctional staining and human-cell adhesion experiments support this location. Retain the original source and evidence code; extracellular trans adhesion is coupled to an intracellular catenin-binding tail.

Summary: Plasma-membrane localization is central to N-cadherin adhesion.

Reason: The named Reactome event supplies pathway context, not an independent localization experiment or evidence that CDH2 performs the event catalyst’s reaction. Independent N-cadherin junctional staining and human-cell adhesion experiments support this location. Retain the original source and evidence code; extracellular trans adhesion is coupled to an intracellular catenin-binding tail.

Summary: Plasma-membrane localization is central to N-cadherin adhesion.

Reason: The named Reactome event supplies pathway context, not an independent localization experiment or evidence that CDH2 performs the event catalyst’s reaction. Independent N-cadherin junctional staining and human-cell adhesion experiments support this location. Retain the original source and evidence code; extracellular trans adhesion is coupled to an intracellular catenin-binding tail.

Summary: Plasma-membrane localization is central to N-cadherin adhesion.

Reason: The named Reactome event supplies pathway context, not an independent localization experiment or evidence that CDH2 performs the event catalyst’s reaction. Independent N-cadherin junctional staining and human-cell adhesion experiments support this location. Retain the original source and evidence code; extracellular trans adhesion is coupled to an intracellular catenin-binding tail.

Summary: The cell-junction location is part of the N-cadherin adhesion machinery.

Reason: Human leukemia-stroma adherens-junction staining and U373 cadherin/catenin localization independently support a functional junctional cadherin complex. This supports location and, for the PAINT activity assertion, the molecular work of intercellular adhesion.

Summary: The cell-junction location is part of the N-cadherin adhesion machinery.

Reason: Human leukemia-stroma adherens-junction staining and U373 cadherin/catenin localization independently support a functional junctional cadherin complex. This supports location and, for the PAINT activity assertion, the molecular work of intercellular adhesion.

Summary: The cell-junction location is part of the N-cadherin adhesion machinery.

Reason: Human leukemia-stroma adherens-junction staining and U373 cadherin/catenin localization independently support a functional junctional cadherin complex. This supports location and, for the PAINT activity assertion, the molecular work of intercellular adhesion.

Summary: The cell-junction location is part of the N-cadherin adhesion machinery.

Reason: Human leukemia-stroma adherens-junction staining and U373 cadherin/catenin localization independently support a functional junctional cadherin complex. This supports location and, for the PAINT activity assertion, the molecular work of intercellular adhesion.

Summary: The cell-junction location is part of the N-cadherin adhesion machinery.

Reason: The flotillin study includes N-cadherin experiments in mouse C2C12 cells and E-cadherin experiments in human MCF7 cells; these are not conflated. Human leukemia-stroma adherens-junction staining and U373 cadherin/catenin localization independently support a functional junctional cadherin complex. This supports location and, for the PAINT activity assertion, the molecular work of intercellular adhesion.

Summary: The cell-junction location is part of the N-cadherin adhesion machinery.

Reason: Human leukemia-stroma adherens-junction staining and U373 cadherin/catenin localization independently support a functional junctional cadherin complex. This supports location and, for the PAINT activity assertion, the molecular work of intercellular adhesion.

Summary: Retain fascia adherens as a specialized cardiac junctional location.

Reason: The mouse ortholog transfer is compatible with N-cadherin-containing cardiac adhering junctions and intercalated discs. This is a tissue-specific instance of junctional adhesion, not a separate molecular activity or a direct human assay.

Summary: The exact N-cadherin focal-adhesion proteomics result was not recovered.

Reason: The inspected primary methods isolate substrate-associated adhesion fractions from human HFF1 fibroblasts for mass spectrometry. The exact CDH2 peptide/protein record in the target supplementary data was not independently recovered. This does not refute the original HDA localization, but adherens-junction membership alone cannot establish focal-adhesion localization.

Summary: N-cadherin contributes physical adhesion architecture to junction assembly and organization.

Reason: The extracellular adhesion interface and intracellular catenin linkage supply components of the junction itself, rather than merely affecting an unrelated downstream phenotype. The PAINT or ortholog provenance is preserved and is independently coherent with human-cell junctional adhesion experiments.

Summary: N-cadherin contributes physical adhesion architecture to junction assembly and organization.

Reason: The extracellular adhesion interface and intracellular catenin linkage supply components of the junction itself, rather than merely affecting an unrelated downstream phenotype. The PAINT or ortholog provenance is preserved and is independently coherent with human-cell junctional adhesion experiments.

Summary: N-cadherin contributes physical adhesion architecture to junction assembly and organization.

Reason: The extracellular adhesion interface and intracellular catenin linkage supply components of the junction itself, rather than merely affecting an unrelated downstream phenotype. The PAINT or ortholog provenance is preserved and is independently coherent with human-cell junctional adhesion experiments.

Summary: N-cadherin directly mediates cell-cell adhesion.

Reason: N-cadherin directly supplies the adhesive interaction between neighboring cells. This is a core process executed by the protein’s ectodomain; the existing broad and specific source assertions are retained with their original evidence provenance.

Summary: N-cadherin directly mediates cell-cell adhesion.

Reason: N-cadherin directly supplies the adhesive interaction between neighboring cells. This is a core process executed by the protein’s ectodomain; the existing broad and specific source assertions are retained with their original evidence provenance. The early human gene-mapping paper provides historical identity, while later functional experiments independently establish adhesion.

Summary: N-cadherin directly mediates cell-cell adhesion.

Reason: N-cadherin directly supplies the adhesive interaction between neighboring cells. This is a core process executed by the protein’s ectodomain; the existing broad and specific source assertions are retained with their original evidence provenance.

Summary: Retain inherited synapse assembly as a specialized neuronal adhesion context.

Reason: N-cadherin contributes to synaptic organization and cooperates with neuroligin in vesicle accumulation. The PAINT node PTN002771722 is retained as a phylogenetic inference; rodent neuronal experiments are not relabeled as direct human synaptogenesis assays.

Summary: Beta-catenin binding couples N-cadherin to the junctional catenin machinery.

Reason: The cytoplasmic N-cadherin tail binds beta-catenin in the junctional complex. Human HEK293 association and human SH-SY5Y/293T experiments independently corroborate this conserved activity.

Summary: Beta-catenin binding couples N-cadherin to the junctional catenin machinery.

Reason: The cytoplasmic N-cadherin tail binds beta-catenin in the junctional complex. Human HEK293 association and human SH-SY5Y/293T experiments independently corroborate this conserved activity.

Summary: Beta-catenin binding couples N-cadherin to the junctional catenin machinery.

Reason: The cytoplasmic N-cadherin tail binds beta-catenin in the junctional complex. Human HEK293 association and human SH-SY5Y/293T experiments independently corroborate this conserved activity. The accessible original CoCoA abstract does not resolve its cadherin-specific support; this correct activity is retained using independent target evidence without alleging miscitation.

Summary: Cell-surface exposure is required for N-cadherin trans adhesion.

Reason: The extracellular cadherin domains engage the apposed cell while the protein remains membrane anchored. Human-cell junctional staining and direct aggregation studies support the source location, rather than implying a freely soluble secreted protein.

Summary: Cell-surface exposure is required for N-cadherin trans adhesion.

Reason: The extracellular cadherin domains engage the apposed cell while the protein remains membrane anchored. Human-cell junctional staining and direct aggregation studies support the source location, rather than implying a freely soluble secreted protein.

Summary: The exact glial-differentiation transfer remains unresolved.

Reason: The mouse source is linked to PMID:24952463. Its accessible abstract establishes neural stem-cell anchorage, quiescence and MMP24-dependent activation, but does not resolve the specific glial-differentiation experiment. The full primary paper was not recovered. Keep the original transfer pending the target differentiation evidence rather than equating quiescence with differentiation.

Summary: The exact glial-differentiation transfer remains unresolved.

Reason: The mouse source is linked to PMID:24952463. Its accessible abstract establishes neural stem-cell anchorage, quiescence and MMP24-dependent activation, but does not resolve the specific glial-differentiation experiment. The full primary paper was not recovered. Keep the original transfer pending the target differentiation evidence rather than equating quiescence with differentiation.

Summary: Retain neural crest cell development as an ortholog-supported adhesion context.

Reason: The mouse N-cadherin source describes contact-dependent behavior of neural crest stem cells with pancreatic beta cells. This supports a developmental role of the adhesion system with explicit species and tissue scope; it is not a newly asserted human neural-crest pathway.

Summary: Retain neural crest cell development as an ortholog-supported adhesion context.

Reason: The mouse N-cadherin source describes contact-dependent behavior of neural crest stem cells with pancreatic beta cells. This supports a developmental role of the adhesion system with explicit species and tissue scope; it is not a newly asserted human neural-crest pathway.

Summary: Retain the cardiac membrane/intercalated-disc context of N-cadherin adhesion.

Reason: Mouse cardiac junctional localization and the conserved cadherin/catenin architecture support this specialized location. The source PAINT or ortholog assertion is retained; the activity is junctional adhesion/catenin binding, not a cardiac ion-channel or kinase activity.

Summary: Retain the cardiac membrane/intercalated-disc context of N-cadherin adhesion.

Reason: Mouse cardiac junctional localization and the conserved cadherin/catenin architecture support this specialized location. The source PAINT or ortholog assertion is retained; the activity is junctional adhesion/catenin binding, not a cardiac ion-channel or kinase activity.

Summary: Retain the cardiac membrane/intercalated-disc context of N-cadherin adhesion.

Reason: Mouse cardiac junctional localization and the conserved cadherin/catenin architecture support this specialized location. The source PAINT or ortholog assertion is retained; the activity is junctional adhesion/catenin binding, not a cardiac ion-channel or kinase activity.

Summary: N-cadherin is a membrane-anchored adhesion protein.

Reason: The conserved single-pass transmembrane topology and direct cell-surface junctional experiments support the broad InterPro membrane mapping. It is a valid broader location for the core cell-cell adhesion system.

Summary: Retain the specialized polarized-membrane location with ortholog scope.

Reason: This Ensembl transfer from mouse P15116 describes a cell-context-dependent membrane subdomain. Such distributions are compatible with a dynamically organized cadherin adhesion system; they are not promoted to a universal human-cell polarity pattern or a new biochemical function. The original transfer remains intact.

Summary: Retain the specialized polarized-membrane location with ortholog scope.

Reason: This Ensembl transfer from mouse P15116 describes a cell-context-dependent membrane subdomain. Such distributions are compatible with a dynamically organized cadherin adhesion system; they are not promoted to a universal human-cell polarity pattern or a new biochemical function. The original transfer remains intact.

Summary: Retain the specialized polarized-membrane location with ortholog scope.

Reason: This Ensembl transfer from mouse P15116 describes a cell-context-dependent membrane subdomain. Such distributions are compatible with a dynamically organized cadherin adhesion system; they are not promoted to a universal human-cell polarity pattern or a new biochemical function. The original transfer remains intact.

Summary: N-cadherin directly mediates cell-cell adhesion.

Reason: N-cadherin directly supplies the adhesive interaction between neighboring cells. This is a core process executed by the protein’s ectodomain; the existing broad and specific source assertions are retained with their original evidence provenance.

Summary: N-cadherin is part of the junctional catenin complex.

Reason: The cytoplasmic tail associates with beta-catenin or plakoglobin and p120-catenin, with alpha-catenin linking downstream components. The original human HT-1080 co-immunoprecipitation study and independent human-cell experiments support complex membership. This does not require every component to contact CDH2 directly.

Summary: N-cadherin is part of the junctional catenin complex.

Reason: The cytoplasmic tail associates with beta-catenin or plakoglobin and p120-catenin, with alpha-catenin linking downstream components. The original human HT-1080 co-immunoprecipitation study and independent human-cell experiments support complex membership. This does not require every component to contact CDH2 directly.

Summary: Retain cell migration as a context of regulated cadherin adhesion.

Reason: The PAINT PTN008601603 inference is coherent with adhesion-dependent cell movement and with human radixin/cadherin and disease contexts. Migration is a broader cellular outcome of junction regulation and is retained outside the principal molecular-function core, without using donor count to challenge the phylogenetic judgment.

Summary: Retain enzyme association in the mouse-derived cadherin-turnover context.

Reason: The donor-linked MMP24 study establishes regulated N-cadherin shedding in a neural stem-cell niche. CDH2 is the adhesion substrate and binding partner, not the protease; no catalytic activity or protein-processing process is transferred to it. The exact binding geometry is not resolved by the abstract.

Summary: Retain protein-kinase association with source-species limits.

Reason: The donor-linked obscurin study reports phosphorylation of the N-cadherin cytoplasmic domain by the SK2 kinase domain. This supports association as a substrate, not kinase activity of CDH2. The abstract was inspected; full construct-specific methods and the later correction were not independently resolved.

Summary: Retain phosphatase binding without assigning phosphatase catalysis.

Reason: The primary donor-linked abstract explicitly includes N-cadherin among proteins recovered in RPTPrho GST-pulldown assays from brain. The strongest dephosphorylation substrate evidence concerns E-cadherin and p120; it is not transferred to CDH2. Preserve the ortholog-derived binding assertion with this scope.

Summary: Retain a peripheral protrusion context for cadherin function.

Reason: The PTN002771722 PAINT assertion is compatible with N-cadherin adhesion machinery at dynamic cell protrusions. The conserved inference is retained outside the principal mature-junction core. Exact human lamellipodial activity and historical ancestral reconstruction were not independently re-established, and localization is not promoted to actin-polymerization activity.

Summary: The exact human lamellipodium localization remains unresolved.

Reason: The source flotillin paper includes N-cadherin experiments in mouse C2C12 cells and E-cadherin experiments in human MCF7 cells. The exact human N-cadherin construct/localization evidence underlying this IDA was not independently recovered. Preserve the original assertion without assuming the human E-cadherin experiment assayed human CDH2.

Summary: Retain lamellipodial localization as an ortholog-derived peripheral context.

Reason: The mouse transfer is compatible with cadherin recruitment during cell-contact formation. Preserve its comparative scope outside the main junctional core; it does not independently establish a human lamellipodial actin-regulatory activity.

Summary: The cell-junction location is part of the N-cadherin adhesion machinery.

Reason: Human leukemia-stroma adherens-junction staining and U373 cadherin/catenin localization independently support a functional junctional cadherin complex. This supports location and, for the PAINT activity assertion, the molecular work of intercellular adhesion. The exact HPA target page independently reports supported plasma-membrane and cell-junction staining.

Summary: The cell-junction location is part of the N-cadherin adhesion machinery.

Reason: The DLG5 paper supplies a human-cell junctional context, not evidence that CDH2 executes Hippo kinase signaling. Human leukemia-stroma adherens-junction staining and U373 cadherin/catenin localization independently support a functional junctional cadherin complex. This supports location and, for the PAINT activity assertion, the molecular work of intercellular adhesion.

Summary: Retain the specialized cardiac adhering-junction/desmosomal context with limits.

Reason: The traced mouse UniProt source PMID:15479741 shows N-cadherin colocalization with desmoplakin and other junctional proteins in embryonic cardiac intercalated-disc contacts. This is the mixed cardiac adhering-junction context associated with the area composita, rather than a claim that N-cadherin belongs to the desmosomal-cadherin family. It does not make N-cadherin a desmosomal cadherin or establish universal localization at epithelial desmosomes.

Summary: Retain the specialized cardiac adhering-junction/desmosomal context with limits.

Reason: The traced mouse UniProt source PMID:15479741 shows N-cadherin colocalization with desmoplakin and other junctional proteins in embryonic cardiac intercalated-disc contacts. This is the mixed cardiac adhering-junction context associated with the area composita, rather than a claim that N-cadherin belongs to the desmosomal-cadherin family. It does not make N-cadherin a desmosomal cadherin or establish universal localization at epithelial desmosomes.

Summary: Retain neuronal projection localization as an adhesion-related context.

Reason: Mouse injury/regeneration evidence places the N-cadherin-containing complex at axonal growth fronts, while neuronal cadherin studies support membrane-associated function in projections. The source ortholog/PAINT scope is retained; no human axon-regeneration assay is inferred.

Summary: Retain neuronal projection localization as an adhesion-related context.

Reason: Mouse injury/regeneration evidence places the N-cadherin-containing complex at axonal growth fronts, while neuronal cadherin studies support membrane-associated function in projections. The source ortholog/PAINT scope is retained; no human axon-regeneration assay is inferred.

Summary: The precise human cortical-actin colocalization assay remains unresolved.

Reason: The source qualifier is colocalizes_with, not direct actin binding. The flotillin study supports cadherin/flotillin association with F-actin at cell contacts, but its N-cadherin versus E-cadherin species/construct contexts must be distinguished. Exact human CDH2 target provenance was not resolved; preserve the original IDA without converting it to actin binding.

Summary: The target extracellular-matrix proteomics assignment remains unresolved.

Reason: The authentic cache describes extraction and glycoproteomic enrichment of human atrial ECM, but its purported full-text field contains limited article material and the exact CDH2 peptide record was not recovered. An ectodomain or co-extracted membrane component is possible; neither proves constitutive ECM residency of full-length N-cadherin. Preserve the HDA assertion pending target data.

Summary: N-cadherin contributes physical adhesion architecture to junction assembly and organization.

Reason: The extracellular adhesion interface and intracellular catenin linkage supply components of the junction itself, rather than merely affecting an unrelated downstream phenotype. The PAINT or ortholog provenance is preserved and is independently coherent with human-cell junctional adhesion experiments.

Summary: Retain the stated cardiac mechanosensing context outside the principal core.

Reason: The inspected full paper explicitly identifies the intercellular N-cadherin/beta-catenin complex as a mechanosensor and measures its abundance under cardiac pressure overload. This supports retaining the original TAS statement about the cadherin complex in mechanical coupling outside the principal core. The perturbations target gelsolin/PI3K and do not isolate CDH2-dependent signal conversion; therefore this is not presented as a direct CDH2 assay or a standalone molecular-sensor function. Lack of such an IDA experiment does not alone negate this author-stated TAS context.

Summary: Retain the cardiac membrane/intercalated-disc context of N-cadherin adhesion.

Reason: Mouse cardiac junctional localization and the conserved cadherin/catenin architecture support this specialized location. The source PAINT or ortholog assertion is retained; the activity is junctional adhesion/catenin binding, not a cardiac ion-channel or kinase activity.

Summary: Homotypic cadherin association supports the core adhesive interface.

Reason: N-cadherin molecules on apposing cells mediate homotypic adhesion, with source ortholog binding evidence and independent cell-aggregation experiments. The broad identical-protein-binding assertion is retained; the core uses the more informative adhesion-mediator activity.

Summary: Retain neuronal projection localization as an adhesion-related context.

Reason: Mouse injury/regeneration evidence places the N-cadherin-containing complex at axonal growth fronts, while neuronal cadherin studies support membrane-associated function in projections. The source ortholog/PAINT scope is retained; no human axon-regeneration assay is inferred.

Summary: N-cadherin directly mediates cell-cell adhesion.

Reason: N-cadherin directly supplies the adhesive interaction between neighboring cells. This is a core process executed by the protein’s ectodomain; the existing broad and specific source assertions are retained with their original evidence provenance.

Summary: N-cadherin directly mediates cell-cell adhesion.

Reason: N-cadherin directly supplies the adhesive interaction between neighboring cells. This is a core process executed by the protein’s ectodomain; the existing broad and specific source assertions are retained with their original evidence provenance.

Summary: N-cadherin directly mediates cell-cell adhesion.

Reason: N-cadherin directly supplies the adhesive interaction between neighboring cells. This is a core process executed by the protein’s ectodomain; the existing broad and specific source assertions are retained with their original evidence provenance.

Summary: Retain membrane-raft association as a regulated junctional context.

Reason: The flotillin paper links cadherin stabilization and p120 association to GM1-containing membrane microdomains. The source mouse transfer is retained without relabeling the human E-cadherin experiments as human N-cadherin assays. This is a spatial/regulatory context rather than a separate core molecular activity.

Summary: Retain the inherited apical adhesion context with cell-type limits.

Reason: PTN002771722 supplies an inherited activity-location assertion compatible with apical cell contacts in polarized tissues. N-cadherin adhesion and catenin linkage can act in specialized membrane domains; this is not interpreted as a universal apical distribution or reconstructed from donor count alone.

Summary: Retain the synaptic membrane context of N-cadherin adhesion.

Reason: Cadherin-dependent synaptic organization and vesicle clustering support the neuronal context. The presynapse mapping is logical inference from the seeded process; it is not treated as a separate direct human localization experiment.

Summary: A direct N-cadherin–alpha-catenin interaction is not resolved.

Reason: The authentic abstract maps plakoglobin’s alpha-catenin-binding and N-cadherin-binding regions in human HT-1080 cells. This supports shared complex membership but does not settle direct binding of CDH2 to alpha-catenin. The original IPI and P35221 partner are retained pending the full assay context; an indirect complex association is not declared a wrong-gene annotation.

Summary: Gamma-catenin binding supports an alternative junctional catenin linkage.

Reason: Plakoglobin is gamma-catenin. Its association with N-cadherin is mapped by human HT-1080 co-immunoprecipitation in the source abstract and corroborated by U373 junctional-complex experiments. This is a specific binding contribution to the adhesion architecture.

Summary: CDH2 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: independent aggregation and mixed-cell assays show that N-cadherin binding supplies trans adhesion, and the conserved PAINT cadherin-binding assertion is preserved.

Summary: Retain the axon-extension context of the N-cadherin adhesion complex.

Reason: The mouse donor study links desmoplakin-dependent recruitment of N-cadherin to regenerating axonal growth fronts and neurite extension. Its accessible abstract foregrounds desmoplakin perturbation; the precise CDH2-specific extension assay was not independently exposed. Preserve the curated ortholog inference as contextual, without claiming a newly demonstrated human regeneration mechanism.

Summary: Retain the axon-extension context of the N-cadherin adhesion complex.

Reason: The mouse donor study links desmoplakin-dependent recruitment of N-cadherin to regenerating axonal growth fronts and neurite extension. Its accessible abstract foregrounds desmoplakin perturbation; the precise CDH2-specific extension assay was not independently exposed. Preserve the curated ortholog inference as contextual, without claiming a newly demonstrated human regeneration mechanism.

Summary: The cell-junction location is part of the N-cadherin adhesion machinery.

Reason: The DLG5 paper supplies a human-cell junctional context, not evidence that CDH2 executes Hippo kinase signaling. Human leukemia-stroma adherens-junction staining and U373 cadherin/catenin localization independently support a functional junctional cadherin complex. This supports location and, for the PAINT activity assertion, the molecular work of intercellular adhesion.

Summary: The cell-junction location is part of the N-cadherin adhesion machinery.

Reason: Human leukemia-stroma adherens-junction staining and U373 cadherin/catenin localization independently support a functional junctional cadherin complex. This supports location and, for the PAINT activity assertion, the molecular work of intercellular adhesion.

Summary: Retain presynaptic vesicle clustering as a specialized neuronal cadherin function.

Reason: The source mouse function is corroborated by Cdh2-mutant neuronal vesicle-clustering phenotypes and by N-cadherin/neuroligin cooperation. These are rodent neuronal experiments; the activity-centered core remains adhesion rather than a newly inferred vesicle-trafficking enzyme.

Summary: Retain presynaptic vesicle clustering as a specialized neuronal cadherin function.

Reason: The source mouse function is corroborated by Cdh2-mutant neuronal vesicle-clustering phenotypes and by N-cadherin/neuroligin cooperation. These are rodent neuronal experiments; the activity-centered core remains adhesion rather than a newly inferred vesicle-trafficking enzyme.

Summary: Retain neuroligin clustering as a specialized transsynaptic adhesion context.

Reason: The donor-linked study reports N-cadherin-dependent postsynaptic accumulation of neuroligin-1, coupled to presynaptic vesicle clustering. This supports the existing ortholog transfer; it does not imply that CDH2 is neuroligin or a catalytic trafficking factor.

Summary: Retain neural stem-cell niche maintenance through adhesive anchorage.

Reason: The donor-linked primary abstract describes N-cadherin-dependent attachment of adult murine neural stem cells to ependymocytes and regulated quiescence after MMP24 cleavage. This is a specific niche context of adhesion, with mouse scope preserved rather than promoted to a direct human stem-cell assay.

Summary: Retain neural stem-cell niche maintenance through adhesive anchorage.

Reason: The donor-linked primary abstract describes N-cadherin-dependent attachment of adult murine neural stem cells to ependymocytes and regulated quiescence after MMP24 cleavage. This is a specific niche context of adhesion, with mouse scope preserved rather than promoted to a direct human stem-cell assay.

Summary: N-cadherin directly mediates cell-cell adhesion.

Reason: N-cadherin directly supplies the adhesive interaction between neighboring cells. This is a core process executed by the protein’s ectodomain; the existing broad and specific source assertions are retained with their original evidence provenance.

Summary: N-cadherin directly mediates cell-cell adhesion.

Reason: The original study directly measures N-cadherin-dependent L-cell aggregation and mixed-cell trans adhesion. This supports participation in adhesion itself, beyond disease necessity; the construct-species limitation and calcium-present assay conditions are retained in the source assessment.

Summary: N-cadherin directly mediates cell-cell adhesion.

Reason: N-cadherin directly supplies the adhesive interaction between neighboring cells. This is a core process executed by the protein’s ectodomain; the existing broad and specific source assertions are retained with their original evidence provenance.

Summary: Retain the synaptic membrane context of N-cadherin adhesion.

Reason: Cadherin-dependent synaptic organization and vesicle clustering support the neuronal context. The presynapse mapping is logical inference from the seeded process; it is not treated as a separate direct human localization experiment.

Summary: Retain postsynaptic scaffold clustering as a neuronal regulatory context.

Reason: The source ortholog transfer belongs to the N-cadherin/neuroligin synaptic-organizing system. The accessible donor abstract establishes transsynaptic organization but not every PSD95-specific assay; the curated transfer is retained without claiming independent inspection of that exact readout or adding a separate human postsynaptic scaffold activity.

Summary: Retain regulation of protein localization in the axonal adhesion context.

Reason: The mouse donor study connects the desmoplakin/N-cadherin complex to recruitment of adhesion/cytoskeletal components at regenerating axonal fronts. Preserve the broad existing ortholog process, while keeping the desmoplakin perturbation distinct from a direct human CDH2 cargo-targeting activity.

Summary: Retain regulation of protein localization in the axonal adhesion context.

Reason: The mouse donor study connects the desmoplakin/N-cadherin complex to recruitment of adhesion/cytoskeletal components at regenerating axonal fronts. Preserve the broad existing ortholog process, while keeping the desmoplakin perturbation distinct from a direct human CDH2 cargo-targeting activity.

Summary: Retain positive regulation of synaptic vesicle clustering as a specialized adhesion output.

Reason: The donor study reports N-cadherin-dependent neuroligin organization and enhanced presynaptic vesicle accumulation. This contextual regulatory process is consistent with the adhesion machinery and is retained with comparative scope, not proposed anew as an independent human vesicle-trafficking role.