DISP1

Summary: DISP1 has a validated yeast two-hybrid association with LAPTM5.

Reason: The PMID:25416956 IntAct records EBI-10386352, EBI-10230189 and EBI-10548906 identify human DISP1 and LAPTM5 in array, pooling and validated two-hybrid assays (Table S2G). Sequence checksums match the current 1524-residue DISP1 and 262-residue LAPTM5 records. The original describes repeated pair testing and identity confirmation; independent assay validation was performed on sampled pairs, and is not asserted for this pair. LAPTM5 is a lysosomal multipass protein, without an established enzyme, receptor or cytoskeletal partner class that would justify a narrower binding term here. Retain the supported interaction as non-core under the explicit project policy. These heterologous assays do not establish an endogenous membrane complex, stoichiometry or a role in Hedgehog export.

Summary: DISP1 has a validated yeast two-hybrid association with WFS1.

Reason: PMID:32814053 Table S2 is represented by exact human DISP1–WFS1 IntAct records EBI-25899640, EBI-26054738 and EBI-26208885, spanning array, pooling and validated two-hybrid assays. Both sequence checksums match the current reviewed proteins. The actual original Methods describe reporter-based screening with bait-autoactivation controls; this pair has no demonstrated mammalian co-immunoprecipitation or physiological stoichiometry in the retrieved pair records. WFS1 regulates calcium homeostasis and ER stress, but that does not establish it as an enzyme, receptor or cytoskeletal protein for a specific partner-class replacement. Retain the positive pair as non-core rather than infer that DISP1 shares WFS1 physiological activities.

Summary: DISP1 performs the ligand-release step that supplies Hedgehog/Smoothened signaling.

Reason: The current PTHR45951 tree places human DISP1 (PTN002473772) below PTN002244706, whose GO:0007224 IBD is grounded in zebrafish disp1 and PMID:19948063. Mutant craniofacial defects and rescue by soluble ShhN support the ligand-release contribution; direct human DISP1/SHH release assays in PMID:34845226 establish the performed export step. Although the GO definition names signals generated after Smoothened activation, curated pathway usage includes ligand-side participants such as SHH. DISP1 supplies the ligand rather than merely being affected by the pathway, and this is central to its biological function. Accept the existing pathway assertion as core while retaining the distinction between ligand delivery in producing cells and downstream Smoothened transduction in responding cells. No additional regulation term is needed.

Summary: DISP1 directly participates in secretion of a lipid-modified protein ligand.

Reason: The ISS donor Q3TDN0 is mouse Disp1, with peptide-transport IDA/IMP evidence from PMID:12372301 and PMID:12421714. Their accessible abstracts support ligand release, while detailed donor experiments were not independently recovered here. More recent directly read human DISP1 experiments in PMID:34845226 establish binding and release of SHH to extracellular acceptors. Protein secretion specifies the performed cellular export step more precisely than the broad peptide-transport description; this refinement does not imply passage of the SHH protein through the lipid bilayer.

Proposed replacements: protein secretion

Summary: DISP1 performs ligand export at the plasma membrane.

Reason: The broad membrane IBA is biologically sound. The family tree places the human sequence beneath PTN002244707, whose IBD cites canine DISP1 and C. elegans CHE-14. Current dog isoform annotations do not reconstruct every historical experimental seed, but CHE-14 has experimental apical-membrane localization and the node placement is compatible with the conserved multipass architecture. Human cell-surface release assays and the resolved transmembrane protein in PMID:34845226 support the more informative plasma membrane location. This is a target-specific refinement, not rejection of the ancestral membrane assertion or a claim that DISP1 is restricted to this compartment.

Proposed replacements: plasma membrane

Summary: The electronic membrane assignment can be refined to the functional cell-surface compartment.

Reason: InterPro IPR004869 is the RND-like transporter transmembrane domain and explicitly maps to GO:0016020. Its current target match covers DISP1 residues 973–1123; the official human record additionally contains twelve transmembrane segments and the membrane location source SL-0162. These sources support membrane association. Direct human DISP1 binding and release experiments support plasma membrane as the more informative nonexclusive functional location. The broad family domain is not evidence for bacterial substrate specificity or a different transport chemistry.

Proposed replacements: plasma membrane

Summary: A basolateral location is supported in polarized epithelial donor experiments.

Reason: The ISS donor A0A8I3S3W7 is canine DISP1. Its current GO record traces basolateral membrane IDA to PMID:20023168. The actual original Methods use V5-tagged canine Disp1 in polarized MDCK cells, and the Results report basolateral accumulation with CTD-dependent targeting; this is not human DISP1 merely because some parallel experiments use human host cells. Retain the curator-supported polarized-cell context without claiming a direct human basolateral assay or universal basolateral restriction. The core location remains plasma membrane.

Summary: DISP1 directly performs the ligand-release step of protein secretion.

Reason: The canine donor A0A8I3S3W7 has an experimental secretion-regulation annotation from PMID:20023168. The original knockdown and dominant-negative assays show reduced SHH release and increased cellular retention. The later human binding and release experiments establish DISP1 as part of the transport machinery itself. Protein secretion better captures that directly performed step than the broad description of changing secretion rate. These GO terms are related by regulates, not an is_a parent-child path; the replacement is a mechanistic recasting, not a false claim of ontological narrowing. No separate NEW process is added.

Proposed replacements: protein secretion

Summary: The cited study nominates DISP1 as a candidate contributor to diaphragm development.

Reason: The full PMID:20799323 Methods and Results identify a mosaic de novo human A1471G variant in a congenital diaphragmatic hernia case and demonstrate wild-type mouse Disp1 expression in the pleuroperitoneal fold. They do not establish the variant effect with a DISP1 functional assay or test diaphragm development after a controlled DISP1 perturbation. The lineage-tracing experiment concerns Shh-expressing cells, not Disp1, and the authors explicitly leave the DISP1 mechanism and mutant diaphragm phenotype unresolved. Preserve the imported IMP assertion as undecided rather than conclude that the association is false or that a causal diaphragm function has been demonstrated. This decision is based on the accessed full original, not the title or an abstract-only inference.

Summary: DISP1 is a membrane-resident protein transporter rather than a cargo-travelling molecular carrier.

Reason: The electronic transfer traces to mouse Q3TDN0/ENSMUSP00000003035, whose GO:0140104 IDA is based on PMID:12372301. That source supports release activity, and is not rejected on the basis of its abstract. The current molecular-carrier comment specifically requires the carrier to move with cargo. In contrast, the human and mouse structural/functional studies support membrane-resident DISP1 binding lipid-modified SHH and delivering it to extracellular acceptors. GO:0140318 protein transporter activity captures this performed molecular role. Its broad definition does not require the bacterial LolCDE pathway or movement of the protein across a bilayer. No independent human sodium-transporter, lipid-carrier or ATPase activity is inferred.

Proposed replacements: protein transporter activity