EDAR

Summary: Conserved transmembrane receptor activity is more precisely cytokine receptor activity.

Reason: The literal GO:0004888 IBD at PANTHER:PTN004336494 is ancestral to the exact 448-residue human EDAR leaf PTN002486226 in PTHR12120. The target itself and EDA2R are legitimate experimental descendants, not circular support. Independent EDA-A1 binding and EDAR signal-transmission evidence support the narrower GO:0004896. GO:0005031 requires tumor necrosis factor itself; TNFR-superfamily membership does not establish that ligand specificity.

Proposed replacements: cytokine receptor activity

Summary: EDA-A1 recognition supports the cytokine-receptor subclass.

Reason: The verified abstract of PMID:11039935 directly distinguishes EDA-A1 binding EDAR from EDA-A2 binding EDA2R. The full original remains unavailable in this review; no organ-culture or construct details are reconstructed. Independent selected original evidence from PMID:11035039 establishes EDAR ligand recognition and signal transmission. These support GO:0004896 without denying the imported positive IDA or assigning untested equivalence to the two natural products.

Proposed replacements: cytokine receptor activity

Summary: The historical receptor inference is corroborated by later ligand and signaling experiments.

Reason: PMID:10431241 identified human EDAR sequence and disease variants and proposed a receptor relationship; its Discussion explicitly left the EDAR–EDA ligand hypothesis for future testing. The NAS identity is retained. Later independent EDA-A1 binding and EDAR signaling in PMID:11039935 and PMID:11035039 support a gene-level refinement to cytokine receptor activity. The 1999 paper is not relabeled as a measured ligand assay.

Proposed replacements: cytokine receptor activity

Summary: EDAR binds the EDA-A1 cytokine through its extracellular region.

Reason: The selected original Methods, Results and captions of PMID:11035039 support binding of soluble EDAR-Fc and secreted Myc-EDA-A1 with control reagents. The assay used conditioned media, not a homogeneous purified pair. The literal IntAct EDA–EDAR record and reference-sequence checks corroborate participant identity, while original construct coordinates and deposited feature annotations remain source-specific. EDA-A1 is an independently established cytokine; GO:0019955 captures the demonstrated ligand class without inferring a new downstream activity.

Proposed replacements: cytokine binding

Summary: The independently reported EDA-A1–EDAR interaction warrants cytokine binding.

Reason: PMID:11039935 explicitly reports selective binding of EDA-A1 to EDAR in its authentic abstract. The inaccessible full text limits assay and construct resolution but does not negate the positive curated IPI. Independent original evidence in PMID:11035039 and the controlled extracellular-domain screen in PMID:32822567 corroborate this pair. The narrower binding class follows EDA-A1 cytokine identity; the source accession is unchanged.

Proposed replacements: cytokine binding

Summary: The retracted study cannot supply reliable independent evidence for this source-specific binding assertion.

Reason: PMID:42308199 retracts PMID:27144394 after unresolved image concerns affecting its results and conclusions. The complete notice specifically identifies duplicated-looking lanes and discontinuity in Fig. 1C, the receptor-binding panel used for the EDA-A1–EDAR comparison. This removal rejects that retracted experimental support, not the biological interaction: independent positive EDA–EDAR rows remain and are refined using PMID:11035039, PMID:11039935 and PMID:32822567. The original PMID, partner Q92838-1 and every imported source field remain unchanged; the retracted reference is explicitly flagged as invalid.

Summary: The extracellular-domain screen detects EDAR binding to the signaling receptor LILRB1.

Reason: PMID:32822567 Data S4 reports EDAR–LILRB1 in both bait/prey orientations, each with three measurements against a control; the two reported mean fold-over-background values are approximately 7.65 and 9.82. Data S1 identifies human EDAR residues 27–187 and LILRB1 residues 24–461; their library parent sequences match current official reference sequences. The control-normalized, bidirectional triplicate retest establishes a reproducible physical-binding observation within this avidity-enhanced extracellular-domain assay. LILRB1 is independently established as an inhibitory signaling receptor, so this positive pair supports GO:0005102 signaling receptor binding. Receptor agonism and an orthogonal SPR experiment are not requirements of that binding class. No EDAR entry was found in Data S5 SPR statistics; affinity and native physiological contact therefore remain unresolved. This evidence does not establish LILRB1 activation by EDAR, transfer its immune function, or identify a native signaling complex. The controlled screen is distinct from the specifically questioned binding panel in the retracted PMID:27144394.

Proposed replacements: signaling receptor binding

Summary: The same extracellular-domain screen independently confirms binding to the EDA cytokine.

Reason: PMID:32822567 Data S4 contains the EDA–EDAR pair in both orientations with triplicate measurements and mean fold-over-background values of approximately 2.93 and 12.61. Data S1 specifies EDAR residues 27–187 and EDA residues 63–391, with library parent sequences identical to the current reference sequences. The controlled positive assay and independently established EDA-A1 cytokine class support GO:0019955. The fusion-based screen does not establish natural processing of its EDA reagent, signaling potency or SPR validation for this pair.

Proposed replacements: cytokine binding

Summary: Conserved plasma-membrane localization is appropriate for EDAR signaling.

Reason: The GO:0005886 IBD at PANTHER:PTN000950406 lies on the verified EDAR target path. The literal donor set includes mouse Edar and human EDA2R, whose current records retain experimental plasma-membrane evidence. This inherited compartment agrees with EDAR extracellular ligand recognition and the target-specific plasma-membrane entity in Reactome. No inference depends on donor count or replacing EDAR with its paralog.

Summary: Mouse-to-human transfer of plasma-membrane localization is supported.

Reason: The declared mouse Edar donor Q9R187 retains a current MGI IDA plasma-membrane annotation to PMID:12629675. Its authentic abstract describes Edar protein localization during mouse salivary-gland development; the detailed original remains unavailable. That limitation does not establish a donor error. Independent human receptor evidence and target-resolved Reactome placement support the conserved cell-surface compartment.

Summary: The ligand-binding reaction places EDAR itself at the plasma membrane.

Reason: The saved Reactome R-HSA-5669012 reaction joins to entity 5669001, explicitly UniProt Q9UNE0 residues 27–448 in GO:0005886. The same target occurs in the EDA:EDAR product complex. This is an exact target-entity and compartment join, not a transfer from another reaction participant or an assay of every splice product.

Summary: Adaptor recruitment retains EDAR in the plasma-membrane receptor complex.

Reason: Reactome R-HSA-5675656 contains EDA:EDAR and its EDARADD-bound product. Both component paths reach EDAR entity 5669001, Q9UNE0 residues 27–448 in the plasma membrane. EDARADD has a separate cytosolic entity; its compartment is not assigned to EDAR. The imported modeled location is coherent with cell-surface receptor signaling.

Summary: The broader epidermis-development mapping is refined to EDAR participation in hair follicle placode formation.

Reason: The current ARBA00084990 rule contains a condition set matching EDAR FunFam 1.10.533.10:FF:000006 plus Chordata and emits GO:0008544. This broader developmental mapping is biologically supported, but GO:0060789 hair follicle placode formation gives the demonstrated process more precisely. In the mouse experiments of PMID:19619491, Edar-null/downless embryos retain early Wnt prepatterns but have poorly resolved placode boundaries and fail to maintain focal Wnt activity by E15.5. EDAR signaling participates in refining and maintaining developing primary hair placodes; constitutive EDAR signaling does not initiate them independently of Wnt. Human EDAR-associated ectodermal dysplasia in PMID:10431241 corroborates the conserved appendage role, without constituting a direct human placode assay. The current typed ontology places GO:0060789 beneath the imported epidermis-development term. No redundant hair-follicle-development or ectodermal-placode ancestor, and no unestablished dentin-specific step, is added. The hair-placode refinement describes the process resolved in these mouse experiments; it does not exhaustively encode EDAR roles in teeth and sweat glands.

Proposed replacements: hair follicle placode formation

Summary: The EDAR developmental statement is refined to hair follicle placode formation using independent mechanistic corroboration.

Reason: The Introduction of PMID:12270937 explicitly discusses human EDAR-associated ectodermal dysplasia and downless mice, citing prior EDAR work. Its new signaling experiments predominantly concern XEDAR/EDA2R, a distinct receptor; the imported TAS remains assessed at that background-statement scope. Independent mouse Methods and Results in PMID:19619491 show that EDAR signaling refines placode boundaries and maintains focal Wnt activity during primary hair placode formation, while early Wnt prepatterns can form without EDAR and constitutive EDAR cannot bypass Wnt. Together with human EDAR disease genetics in PMID:10431241, this supports refinement to GO:0060789. It does not transfer XEDAR experiments to EDAR or claim that placode formation was directly measured in humans. The original source and TAS evidence remain unchanged. The hair-placode refinement describes the process resolved in these mouse experiments; it does not exhaustively encode EDAR roles in teeth and sweat glands.

Proposed replacements: hair follicle placode formation

Summary: The general membrane mapping can be resolved to the cell surface.

Reason: The UniProt SL-0162 mapping supports a membrane protein but does not by itself specify which membrane. Independent extracellular-ligand signaling evidence and exact EDAR plasma-membrane placement in Reactome justify GO:0005886 as a more informative target-level location. The mapping source remains unchanged, and no additional soluble or intracellular pool is denied.

Proposed replacements: plasma membrane

Summary: Later target evidence resolves the historical membrane prediction to plasma membrane.

Reason: PMID:10431241 inferred a type-I membrane receptor from the human sequence; it did not measure plasma-membrane localization. Subsequent ligand/signaling work and the Q9UNE0-specific Reactome location support GO:0005886 for the gene-level assertion. The NAS and original reference are preserved, with independent evidence explicitly distinguished from the historical prediction.

Proposed replacements: plasma membrane

Summary: Cytokine-mediated signaling is an inherited and directly corroborated EDAR role.

Reason: The literal GO:0019221 IBD at PANTHER:PTN004336494 is on the verified human EDAR path. Mouse Edar and human EDA2R provide related experimental grounding, and human EDAR itself is a legitimate descendant source. Independent EDA-A1 recognition and downstream signaling directly corroborate the conserved process. Self-inclusion is not circular, and distinct EDA ligand specificities do not invalidate their shared cytokine-signaling ancestry.

Summary: EDA-A1-triggered EDAR signaling fits the cytokine-mediated pathway.

Reason: The verified PMID:11039935 abstract establishes selective EDA-A1–EDAR recognition and cytokine-receptor function. Full original methods were not recovered, so their assay details remain unresolved. Independent selected original PMID:11035039 demonstrates EDAR-dependent NF-kappaB signaling and supports the clearly correct process. Retain the positive IDA with these explicit access boundaries.

Summary: The combined automated sources support the established cytokine-signaling process.

Reason: ARBA00028236 has a condition set matching the EDAR FunFam and emits GO:0019221. The stated mouse Edar donor Q9R187 retains an MGI IMP cytokine-signaling annotation to PMID:19619491. Its preserved repository cache contains the Introduction and Discussion but omits detailed Results and Methods; no unseen experimental details are reconstructed. Direct human EDAR receptor and signaling evidence independently supports retention.

Summary: The combined receptor mapping is correct but can specify the cytokine ligand class.

Reason: ARBA00027254 matches the EDAR FunFam and emits signaling receptor activity; InterPro IPR047526 includes the EDAR/EDA2R/TNFRSF19 family and carries the same broad mapping. The mouse donor is consistent with receptor function. Direct human EDA-A1 recognition and signal transmission justify GO:0004896. This target-specific refinement does not transfer TNF ligand specificity or all activities of other family members.

Proposed replacements: cytokine receptor activity

Summary: EDAR promotes canonical NF-kappaB signaling.

Reason: The current IPR047526 mapping includes GO:0043123, and independent EDAR-specific reporter and EMSA evidence in PMID:11035039 corroborates the positive signaling role. EDA-A1 recognition and adaptor-dependent signal transmission provide a performed mechanism. The association of EDAR with TRAF/NIK proteins does not establish direct binding to each or resolve the entire endogenous signaling complex.

Summary: Apical localization is a positive polarized-epithelial context.

Reason: The exact mouse Edar donor Q9R187 retains an MGI IDA to GO:0045177 from PMID:12629675. The abstract describes localization at lumen and acinus formation in mouse salivary glands; full microscopy methods and images were not recovered. Preserve this curator-grounded ortholog transfer as a context-specific location rather than calling it false or requiring apical localization in every EDAR-expressing cell. The integrated receptor core uses the broader independently supported plasma membrane; this does not exclude an apical pool.

Summary: EDAR can promote JNK signaling, with context distinct from its developmental NF-kappaB core.

Reason: IPR047526 currently maps to GO:0046330. The authentic PMID:11035039 abstract positively reports EDAR-dependent JNK activation and effects of death-domain and disease-associated mutants, providing target-specific corroboration beyond a shared-family mapping. Retain this signaling output as non-core while endogenous ligand, expression and tissue conditions remain less resolved than the central NF-kappaB mechanism. No XEDAR-specific assay is silently reassigned to EDAR.