FLT4

Summary: The human SAS carcinoma experiments in PMID:19779139 show reduced receptor and downstream phosphoprotein signals after engineered dominant-negative FLT4 expression.

Reason: The human SAS carcinoma experiments in PMID:19779139 show reduced receptor and downstream phosphoprotein signals after engineered dominant-negative FLT4 expression. Retain this positive regulation in the autocrine tumor context; the AKT, ERK and p38 measurements do not establish that FLT4 directly phosphorylates every downstream site.

Summary: The ARBA endothelial-proliferation assertion agrees with the VEGF-C-responsive growth and PCNA observations in primary human lymphatic endothelial cultures in PMID:11532940.

Reason: The ARBA endothelial-proliferation assertion agrees with the VEGF-C-responsive growth and PCNA observations in primary human lymphatic endothelial cultures in PMID:11532940. These growth assays used VEGF or VEGF-C; separate VEGFR3-selective VEGF-C156S experiments support receptor signaling, survival and migration, not a separately demonstrated C156S proliferation assay. Retain endothelial proliferation as a central receptor output without claiming that the PCNA experiment isolates FLT4 from VEGFR2. The rule is not independently re-derived, and membrane receptor function is not assigned to every soluble or alternative product.

Summary: PMID:11532940 documents VEGF-C-responsive growth and PCNA staining in isolated primary human lymphatic endothelial cultures; selective VEGF-C156S signaling and survival are separate assays.

Reason: PMID:11532940 documents VEGF-C-responsive growth and PCNA staining in isolated primary human lymphatic endothelial cultures. The growth experiment used VEGF or VEGF-C and does not itself isolate FLT4 from VEGFR2; separate VEGFR3-selective VEGF-C156S experiments establish signaling, survival and migration. Retain the curated endothelial-proliferation assertion within the receptor's central endothelial signaling role without claiming a C156S proliferation assay. The separate Ba/F3 receptor-ECD/EpoR chimera establishes ligand specificity, not native FLT4 intracellular signaling.

Summary: The original ARBA, mouse UniProt and mouse Ensembl sources are preserved.

Reason: The original ARBA, mouse UniProt and mouse Ensembl sources are preserved. Mouse experimental grounding is independently visible in QuickGO, and the human receptor has conserved vascular roles. Vasculature development is broader than the retained specific vascular processes; official lymphangiogenesis ancestry includes GO:0001944. No circularity is inferred from reciprocal electronic annotations.

Summary: Mouse P35917 has experimental vascular-development support from PMID:9794766; its original abstract explicitly reports null-embryo large-vessel/lumen defects after initial vasculogenesis.

Reason: Mouse P35917 has experimental vascular-development support from PMID:9794766; its original abstract explicitly reports null-embryo large-vessel/lumen defects after initial vasculogenesis. The assertion is sound but broad: retained lymph-vessel development and sprouting angiogenesis cover more informative vascular processes. Official GO ancestry includes vasculature development. This is specificity refinement, not donor rejection.

Summary: Preserve the mouse UniProt/Ensembl provenance.

Reason: Preserve the mouse UniProt/Ensembl provenance. The donor has experimental lymph-vessel-development annotations, including independently read ligand-depletion and genetic-interaction studies. This broader developmental role includes maintenance/patterning beyond vessel emergence and agrees with human FLT4 receptor biology; no natural-product-specific developmental assignment is established.

Summary: Mouse donor evidence includes actual neonatal VEGFR3-Fc blockade experiments in PMID:19903896 and Vegfr3 dosage interaction with Clp24 in PMID:20439428.

Reason: Mouse donor evidence includes actual neonatal VEGFR3-Fc blockade experiments in PMID:19903896 and Vegfr3 dosage interaction with Clp24 in PMID:20439428. They support lymph-vessel formation, maintenance and patterning, not merely a generic lethal phenotype. Human receptor signaling and primary lymphoedema data corroborate this central vascular role. Do not transfer ALK1/CLP24-specific mechanisms to FLT4.

Summary: The mouse UniProt and Ensembl transfer is consistent with the donor experimental lymphangiogenesis record and the human VEGF-C/D receptor program.

Reason: The mouse UniProt and Ensembl transfer is consistent with the donor experimental lymphangiogenesis record and the human VEGF-C/D receptor program. PMID:20697430 was read at original-abstract level, not full Methods. There is no target-specific loss argument against conservation; do not turn differing kinase-dependent and kinase-independent vascular contexts into a contradiction.

Summary: Lymphangiogenesis is a central FLT4 function, with this experiment testing tumor-cell contribution to host lymphatics.

Reason: Retain lymphangiogenesis as a central FLT4 function while preserving this experiment's scope. In PMID:19779139, dominant-negative FLT4 in human SAS tumor cells reduces VEGFC production and LYVE1-positive lymphatics in mouse xenografts. This tests tumor-cell autocrine/paracrine contribution, not direct knockout of host lymphatic endothelial FLT4, and does not establish reduced VEGFC as the sole causal route. Independent human endothelial signaling and mouse lymphatic-development evidence support the central function without upgrading this particular assay to a direct endothelial experiment.

Summary: Mouse P35917 lymphangiogenesis is experimentally grounded by PMID:20697430.

Reason: Mouse P35917 lymphangiogenesis is experimentally grounded by PMID:20697430. Its authentic abstract reports disrupted lymphatic growth after ligand-binding-domain or kinase alterations; full Results/Methods were inaccessible here. Human endothelial growth and selective-receptor migration assays and independently read mouse lymphatic-development experiments corroborate the function. Preserve the trusted ortholog assertion with this access limit.

Summary: Actual tree replay places the positive sprouting-angiogenesis IBD at PTN002814453 on the exact 1363-aa human target path.

Reason: Actual tree replay places the positive sprouting-angiogenesis IBD at PTN002814453 on the exact 1363-aa human target path. Human endothelial signaling/migration and mouse receptor-blockade evidence are biologically concordant. The receptor contributes an initiating signaling step to angiogenic behavior; donor number is not a weakness and no target-specific loss is established.

Summary: The mouse UniProt/Ensembl sprouting assignment is supported by an actual experimental donor annotation to PMID:18594512 and conserved endothelial responses.

Reason: The mouse UniProt/Ensembl sprouting assignment is supported by an actual experimental donor annotation to PMID:18594512 and conserved endothelial responses. The original paper is available here only as an authentic abstract, so no detailed conditional allele or antibody protocol is asserted. Retain the function without universalizing all receptor products.

Summary: Mouse P35917 sprouting-angiogenesis evidence includes PMID:18594512: the authentic abstract reports receptor blockade/genetic targeting effects on vascular sprouting and branching.

Reason: Mouse P35917 sprouting-angiogenesis evidence includes PMID:18594512: the authentic abstract reports receptor blockade/genetic targeting effects on vascular sprouting and branching. Full methods were not recovered. This trusted experimental donor role agrees with conserved human endothelial receptor signaling and migration; no claim is made that FLT4 supplies structural sprout material.

Summary: The InterPro kinase assignment is biologically correct for the membrane receptor products, but GO:0004672 is an official is_a ancestor of the independently retained VEGF receptor activity GO:0005021.

Reason: The InterPro kinase assignment is biologically correct for the membrane receptor products, but GO:0004672 is an official is_a ancestor of the independently retained VEGF receptor activity GO:0005021. Record redundancy, not absence of kinase activity.

Summary: PMID:7898938 describes human FLT4 isoforms and CSF1R-extracellular/FLT4-transmembrane-intracellular chimeras in Rat2 hosts.

Reason: PMID:7898938 describes human FLT4 isoforms and CSF1R-extracellular/FLT4-transmembrane-intracellular chimeras in Rat2 hosts. Its abstract does not give all original enzyme assays; independent human receptor phosphorylation evidence supports the kinase. GO:0004713 is entailed by retained GO:0005021, so breadth, not source invalidity, motivates TOO_GENERAL.

Summary: The UniProt/Rhea tyrosyl-protein phosphorylation reaction agrees with the receptor kinase.

Reason: The UniProt/Rhea tyrosyl-protein phosphorylation reaction agrees with the receptor kinase. GO:0004713 is an official is_a ancestor of retained GO:0005021; the broader catalytic row is redundant, not biologically contradicted.

Summary: The electronic transmembrane receptor tyrosine kinase annotation is correct for the long and short membrane products.

Reason: The electronic transmembrane receptor tyrosine kinase annotation is correct for the long and short membrane products. Official GO ancestry places retained VEGF receptor activity under GO:0004714. This is redundant catalytic breadth, not a claim that soluble P35916-3 has a kinase domain.

Summary: The human receptor kinase is supported, with PMID:7898938 studying natural short/long isoforms and engineered CSF1R-FLT4 chimeras rather than a VEGF-specific native-ligand test.

Reason: The human receptor kinase is supported, with PMID:7898938 studying natural short/long isoforms and engineered CSF1R-FLT4 chimeras rather than a VEGF-specific native-ligand test. GO:0004714 is entailed by independently supported GO:0005021; preserve the experimental source context while recording the general term as redundant.

Summary: PMID:8386825 describes human FLT4 cloning, a predicted 1298-aa receptor and COS7 expression.

Reason: PMID:8386825 describes human FLT4 cloning, a predicted 1298-aa receptor and COS7 expression. The accessible abstract alone does not detail a kinase assay, but subsequent receptor activation studies establish the function. GO:0004714 is an official ancestor of retained GO:0005021, so no biological refutation is implied.

Summary: ROOT actual tree/MSA/original-IBD replay places the exact 1363-aa human target under PTN002814453, with this positive GO:0005021 origin on its path.

Reason: ROOT actual tree/MSA/original-IBD replay places the exact 1363-aa human target under PTN002814453, with this positive GO:0005021 origin on its path. Human VEGF-C/D binding and activation experiments agree. Target self-evidence in WITH/FROM is legitimate descendant grounding, not circularity; no loss or divergence is established for the displayed membrane receptor.

Summary: PMID:23878260 directly tests VEGF-C binding to human receptor extracellular constructs, ligand-dependent solution dimerization and ligand-stimulated receptor phosphotyrosine in HEK293/PAE expression systems.

Reason: PMID:23878260 directly tests VEGF-C binding to human receptor extracellular constructs, ligand-dependent solution dimerization and ligand-stimulated receptor phosphotyrosine in HEK293/PAE expression systems. These complementary binding and activation assays establish VEGF receptor activity. C137A ligand/domain mutants are engineered experimental reagents, not natural receptor isoforms.

Summary: PMID:9012504 reports VEGF-C receptor binding and autophosphorylation; the accessible abstract specifies mouse ligand but does not settle receptor construct species.

Reason: PMID:9012504 reports VEGF-C receptor binding and autophosphorylation; the accessible abstract specifies mouse ligand but does not settle receptor construct species. Preserve the human IDA curation with that limit and corroboration from directly inspected human receptor experiments in PMID:23878260/9435229.

Summary: The electronic VEGF receptor assignment agrees with direct human VEGF-C/D receptor binding and activation in PMID:23878260 and PMID:9435229.

Reason: The electronic VEGF receptor assignment agrees with direct human VEGF-C/D receptor binding and activation in PMID:23878260 and PMID:9435229. Retain the original ARBA/donor provenance without assuming every natural isoform transmits a membrane signal; the membrane receptor products perform this activity.

Summary: Actual PMID:11532940 Methods/Results combine human VEGFR3 extracellular-domain binding/specificity assays with VEGFR3-selective VEGF-C156S responses in primary human endothelial cultures.

Reason: Actual PMID:11532940 Methods/Results combine human VEGFR3 extracellular-domain binding/specificity assays with VEGFR3-selective VEGF-C156S responses in primary human endothelial cultures. These establish ligand-responsive receptor activity. The separate Ba/F3 human receptor-ECD/mouse EpoR chimera tests extracellular specificity, not FLT4 intracellular kinase signaling; no natural splice product was isolated.

Summary: Actual PMID:19779139 demonstrates endogenous human FLT4 receptor phosphorylation and VEGF-C-responsive signaling in SAS oral carcinoma cells, with inhibition by an engineered cytoplasmic-domain-deleted dominant-negative receptor.

Reason: Actual PMID:19779139 demonstrates endogenous human FLT4 receptor phosphorylation and VEGF-C-responsive signaling in SAS oral carcinoma cells, with inhibition by an engineered cytoplasmic-domain-deleted dominant-negative receptor. Retain the defining receptor activity; the engineered inhibitor is not a natural soluble product, and tumor-context downstream phosphoproteins are not all direct FLT4 substrates.

Summary: The authentic PMID:10835628 abstract reports human disease-associated FLT4 proteins with inactive tyrosine kinase and impaired downstream gene activation.

Reason: The authentic PMID:10835628 abstract reports human disease-associated FLT4 proteins with inactive tyrosine kinase and impaired downstream gene activation. Full mutation/construct methods remain inaccessible, so do not invent them. The VEGF receptor activity itself is independently established by accessible human binding/activation assays in PMID:23878260 and PMID:9435229.

Summary: FLT4 associates with the signaling receptor KDR/VEGFR2 in curated human-cell co-immunoprecipitation experiments.

Reason: MODIFY to signaling receptor binding (GO:0005102). Two exact positive IntAct records from PMID:16530705 identify human FLT4-KDR co-immunoprecipitation. KDR/VEGFR2 is a signaling receptor, and this measured receptor association supports a more informative binding class than generic protein binding. The THP-1 host assignment comes from the curated records; complete pair-specific primary Methods were not recovered. Independent original PMID:20224550 experiments corroborate endogenous FLT4-KDR association in human endothelial cells, without supplying the missing protocol for this source. The refinement does not assign FLT4 an agonist role, a purified binary interface, a particular natural splice product, or the paper's downstream invasion phenotypes.

Proposed replacements: signaling receptor binding

Summary: VEGFC induces association of endogenous FLT4 and KDR/VEGFR2 in primary human endothelial cells.

Reason: MODIFY to signaling receptor binding (GO:0005102). Original PMID:20224550 Results and Methods demonstrate VEGFC-induced reciprocal VEGFR2/VEGFR3 co-immunoprecipitation in primary human saphenous-vein endothelial cells, with proximity-ligation evidence in intact cells. This is direct experimental evidence of a receptor-containing complex, supporting the receptor-binding class rather than a subtype inferred solely from the partner name. VEGFA produces proximity-ligation signal but not the same co-immunoprecipitation result, and the mouse embryoid-body sprouting experiments are separate. The authors describe receptor heterodimers; this replacement captures the measured receptor association without adding an exact stoichiometry, an isolated binary interface, an agonist role for FLT4, or a natural-product assignment.

Proposed replacements: signaling receptor binding

Summary: FLT4 associates with KDR/VEGFR2 in the receptor-dimerization study.

Reason: MODIFY to signaling receptor binding (GO:0005102). The verified PMID:21130043 abstract describes inhibition of VEGFR3/VEGFR2 heterodimer formation by a receptor-dimerization-blocking antibody. The exact positive human FLT4-KDR IntAct record reports anti-bait co-immunoprecipitation in an endothelial-cell context. This source-specific physical association supports the receptor-binding class. Full primary Methods were not independently recovered, so the curated assay and host remain explicitly attributed to IntAct. The replacement does not imply purified binary affinity, an exact interface or stoichiometry, FLT4 ligand agonism, or uniform binding by all natural products.

Proposed replacements: signaling receptor binding

Summary: Human FLT4 extracellular constructs bind processed VEGFC in curated solid-phase assays.

Reason: The same human FLT4-VEGFC interaction is more specifically represented by GO:0038085 vascular endothelial growth factor binding. Two exact positive IntAct records for PMID:21130043 document solid-phase interaction assays with human VEGFR3 extracellular constructs and a processed VEGFC construct. MODIFY the generic protein-binding assertion to this established ligand-class term, which is also the replacement for three existing growth-factor-binding contexts. Construct ranges and tags describe experimental reagents, not additional natural products. The full source Methods were not independently recovered; retain the curated assay provenance without inventing whole-cell affinity, all-product equivalence or behavior of unprocessed ligand.

Proposed replacements: vascular endothelial growth factor binding

Summary: Tagged FLT4 associates with HSP90AB1 in cellular LUMIER and immunoprecipitation assays.

Reason: MODIFY to Hsp90 protein binding (GO:0051879). Two exact positive PMID:22939624 IntAct records identify human FLT4-HSP90AB1 association in LUMIER and anti-tag co-immunoprecipitation assays in HEK293T cells. Original Results and Methods describe C-terminally tagged kinase baits, N-terminal Renilla-tagged HSP90beta, bait-abundance normalization, and lysis conditions that stabilize chaperone-client complexes. The measured association with HSP90AB1 supports this specific binding class; the term does not require the binding protein to be an HSP90 cochaperone. No purified binary interaction, FLT4-specific strong/weak-client class, target-specific inhibitor response, HSP90 regulation, or assignment across all natural FLT4 products is inferred.

Proposed replacements: Hsp90 protein binding

Summary: Human FLT4 extracellular domains bind engineered mature VEGFC in structural and thermodynamic assays.

Reason: Actual PMID:23878260 structural and thermodynamic experiments establish human VEGFR3 extracellular-domain binding to VEGFC. The more informative GO:0038085 vascular endothelial growth factor binding therefore applies to this same source interaction and replaces generic protein binding, consistently with the three existing growth-factor-binding refinements. The structure uses mature engineered VEGFC C137A and soluble receptor domains; ITC tests ECD truncations. These binding assays are distinct from receptor activation in human or porcine host cells and do not establish an exact natural splice-product identity, universal affinity or a new biological process.

Proposed replacements: vascular endothelial growth factor binding

Summary: The original PMID:27991863 abstract explicitly reports a CLEC14A–VEGFR3 complex in endothelial cells, supporting retention of the curated CLEC14A association as non-core.

Reason: The original PMID:27991863 abstract explicitly reports a CLEC14A–VEGFR3 complex in endothelial cells, supporting retention of the curated CLEC14A association as non-core. Complete pair-specific Results and Methods could not be consistently retrieved: one official PMC response supplied the abstract and early body, while subsequent access returned a browser challenge; the BioC response was HTML, not article XML. Consequently no particular human construct, direct binary interface, or assay-specific rescue is claimed. The mouse CLEC14A knockout phenotypes are not reinterpreted as FLT4 knockout experiments.

Summary: Original PMID:32822567 Results explicitly identify VEGFR3 as a CEACAM4 binding partner.

Reason: Original PMID:32822567 Results explicitly identify VEGFR3 as a CEACAM4 binding partner. The study screens multimerized extracellular constructs using a pooled ELISA-based platform and resolves positive pairs; its Methods describe mammalian-cell production of the bait and prey proteins. Retain this extracellular interaction as non-core. The general validation of a subset by surface plasmon resonance and cell binding is not silently assigned to this pair, whose exact supplementary construct boundaries and independent validation were not replayed. No physiological signaling, immune-response core function, or natural soluble-product identity follows from the screening result.

Summary: HSP90AB1 is recovered with tagged FLT4 by affinity purification in the receptor-interactome study.

Reason: MODIFY to Hsp90 protein binding (GO:0051879). The exact positive PMID:35384245 IntAct record identifies human HSP90AB1 with C-terminal MAC-tagged FLT4 by affinity purification in HEK293 Flp-In T-REx cells. Its spoke expansion records association within an isolated complex rather than a purified binary pair. Original Methods distinguish AP-MS from BioID and kinase-substrate assays and describe pervanadate treatment before harvesting. Thus the source supports the HSP90-binding class at the measured co-complex level, without relabeling this record as proximity-only evidence or inferring that HSP90AB1 is a FLT4 phosphorylation substrate. FLT4-specific ligand-stimulation validation, isolated binding affinity, native tissue stoichiometry, and natural-product generalization are not established.

Proposed replacements: Hsp90 protein binding

Summary: ATP binding is required for the receptor tyrosine kinase reaction and agrees with the official UniProt kinase-domain/ATP-binding features and Rhea reaction.

Reason: ATP binding is required for the receptor tyrosine kinase reaction and agrees with the official UniProt kinase-domain/ATP-binding features and Rhea reaction. This supports the membrane kinase products, without assigning ATP-dependent catalysis to the splice product lacking the mapped kinase domain.

Summary: UniProt SL-0243 denotes the secreted product context.

Reason: UniProt SL-0243 denotes the secreted product context. Actual PMID:18593464 demonstrates secretion and VEGF-D binding of a human 765-aa recombinant splice product. That construct is not proven identical to current 830-aa P35916-3. Retain an extracellular pool without assigning secretion to both membrane products or transferring a mapped decoy mechanism to every product.

Summary: The experimental nuclear assertion cites PMID:16452200, whose full Results/Methods could not be recovered after bounded publisher access.

Reason: The experimental nuclear assertion cites PMID:16452200, whose full Results/Methods could not be recovered after bounded publisher access. The authentic abstract does not resolve a nuclear receptor pool. Preserve this original experimental context as UNDECIDED, without claiming misattribution or absence of nuclear FLT4.

Summary: The UniProt nuclear-location mapping traces to PMID:16452200.

Reason: The UniProt nuclear-location mapping traces to PMID:16452200. The authentic abstract establishes FAK/FLT4 association and survival effects but does not establish nuclear localization; bounded original-publisher access failed. Preserve the mapping while leaving nucleus unresolved. Neither membrane-receptor architecture nor current cell-line localization is grounds to declare the experimental curator wrong.

Summary: The curated cytoplasmic localization remains supported, although this source-specific assay was not recovered.

Reason: Preserve the curator-supported PMID:16452200 cytoplasmic localization, independently corroborated by the human lymphatic-endothelial internalization experiments in PMID:20445537. The original source-specific localization Methods remain unavailable. A separate HPA cytosol observation cannot resolve or replace the broader internalized receptor pool; no source-specific subcompartment, nuclear localization or isoform identity is inferred.

Summary: Human endothelial receptor internalization supports a cytoplasmic pool that is not resolved as free cytosol.

Reason: Selected original PMID:20445537 Figure 3a and antibody-feeding Methods distinguish surface and internalized VEGFR3 in human lymphatic endothelial cells. This supports the existing broad cytoplasmic pool, which differs from an unproven free-cytosolic receptor. The HPA cytosol observation does not subsume this assay. Retain the peripheral localization without assigning an unmeasured early, late or other endosomal compartment.

Summary: The mapped cytoplasmic receptor pool is retained separately from the HPA cytosol observation.

Reason: The UniProt cytoplasm mapping remains a supported intracellular localization context. Internalized receptor in human endothelial cells in PMID:20445537 is not shown to be the same pool as HPA cytosolic staining. Although cytosol is part_of cytoplasm, that narrower independent observation does not replace this membrane-receptor trafficking context. No endosomal subcompartment or free soluble-cytosolic receptor identity is assigned.

Summary: The official HPA XML currently retains supported cytosolic ICC/IF localization with antibody HPA074389 in HEK293, MCF-7 and U2OS cells.

Reason: The official HPA XML currently retains supported cytosolic ICC/IF localization with antibody HPA074389 in HEK293, MCF-7 and U2OS cells. Retain this observed cellular pool as non-core. No isoform-specific identity, isolated soluble-receptor mechanism or independent image/antibody validation was performed here; the central signaling location remains the plasma membrane.

Summary: Actual PMID:20445537 Fig3a explicitly measures human LEC surface VEGFR3, with separate mouse knockout/biotinylation experiments.

Reason: Actual PMID:20445537 Fig3a explicitly measures human LEC surface VEGFR3, with separate mouse knockout/biotinylation experiments. The antibody-feeding protocol distinguishes surface from internalized receptor. Retain the core plasma-membrane location; do not transfer all mouse pathway measurements to human cells or every natural product.

Summary: Actual tree replay places the positive plasma-membrane IBD at PTN001230349 on the human target path.

Reason: Actual tree replay places the positive plasma-membrane IBD at PTN001230349 on the human target path. Human receptor surface localization and ligand-responsive signaling agree; the API taxonomic_range is Metazoa-Choanoflagellida, with no species field asserted. This concerns the signaling membrane products, not a claim that the soluble product is membrane-anchored.

Summary: Current official HPA XML records supported plasma-membrane ICC/IF localization in HEK293 and U2OS with HPA074389.

Reason: Current official HPA XML records supported plasma-membrane ICC/IF localization in HEK293 and U2OS with HPA074389. This agrees with independent human endothelial surface-receptor experiments and the core membrane-receptor role. The HPA record is corroboration, not a new isoform-specific localization assignment or an independently validated antibody experiment.

Summary: The authentic PMID:7898938 abstract explicitly describes a highly glycosylated cell-surface FLT4 kinase and separately details CSF1R/FLT4 chimeras in Rat2 hosts.

Reason: The authentic PMID:7898938 abstract explicitly describes a highly glycosylated cell-surface FLT4 kinase and separately details CSF1R/FLT4 chimeras in Rat2 hosts. Full original localization methods remain inaccessible, but independently inspected human endothelial surface assays corroborate the core location. No product-wide functional equivalence is implied.

Summary: UniProt SL-0039 correctly maps the membrane receptor products to the plasma membrane.

Reason: UniProt SL-0039 correctly maps the membrane receptor products to the plasma membrane. Independent human endothelial antibody-feeding/surface assays and receptor activation support this core location. Preserve the original electronic record without asserting that the secreted natural product shares a transmembrane topology.

Summary: PMID:8386825 describes human FLT4 cloning and COS7 expression in its authentic abstract; its detailed original localization methods were inaccessible.

Reason: PMID:8386825 describes human FLT4 cloning and COS7 expression in its authentic abstract; its detailed original localization methods were inaccessible. The membrane-receptor sequence and independently inspected human cell-surface measurements establish plasma membrane as a core location. Preserve the original TAS source without fabricating its assay details.

Summary: Actual Reactome R-HSA-194308 represents VEGF-C/D binding and receptor dimerization; its input explicitly includes human FLT4 [plasma membrane] and its output a membrane ligand-receptor complex.

Reason: Actual Reactome R-HSA-194308 represents VEGF-C/D binding and receptor dimerization; its input explicitly includes human FLT4 [plasma membrane] and its output a membrane ligand-receptor complex. This agrees with direct human receptor evidence. No additional partner enzymatic activity is assigned from pathway membership.

Summary: Actual Reactome R-NUL-9604519 is a mixed-species black-box transcription event: mouse NICD4 stimulates a human FLT4 promoter, and the explicit protein output is human FLT4 [plasma membrane].

Reason: Actual Reactome R-NUL-9604519 is a mixed-species black-box transcription event: mouse NICD4 stimulates a human FLT4 promoter, and the explicit protein output is human FLT4 [plasma membrane]. Retain that protein location. The nucleoplasmic input is FLT4 DNA, not evidence that the receptor protein is nuclear or performs Notch transcription.

Summary: InterPro receptor-kinase mapping agrees with FLT4 domain architecture and human activation assays.

Reason: InterPro receptor-kinase mapping agrees with FLT4 domain architecture and human activation assays. GO:0007169 is an official ancestor of retained VEGF receptor signaling GO:0048010 and VEGF signaling GO:0038084. The annotation is correct but unnecessarily broad; this is not a claim that receptor tyrosine kinase signaling is absent.

Summary: The authentic PMID:10835628 abstract reports human disease-associated FLT4 alleles with inactive kinase and impaired downstream activation; full mutation methods were unavailable.

Reason: The authentic PMID:10835628 abstract reports human disease-associated FLT4 alleles with inactive kinase and impaired downstream activation; full mutation methods were unavailable. Independently inspected human receptor assays establish VEGF signaling. GO:0007169 is an official ancestor of retained receptor-specific pathway terms, motivating TOO_GENERAL rather than a biological rejection.

Summary: Broader proliferation remains supported in non-endothelial contexts beyond the endothelial core response.

Reason: The positive proliferation IBD at PTN008404985 is sound and lies on the exact human target path. Endothelial proliferation GO:0001938 is a descendant of GO:0008284, but does not exhaust the independently supported SAS carcinoma and fibroblast transformation/growth contexts in PMID:19779139 and PMID:7675451. Retain the broader proliferation claim as non-core because that granularity is warranted across these existing contexts. The endothelial child does not replace them; neither donor count nor legitimate target self-donation argues against the IBA.

Summary: PMID:19779139 directly measures growth of human SAS carcinoma clones and xenografts after dominant-negative FLT4 expression.

Reason: PMID:19779139 directly measures growth of human SAS carcinoma clones and xenografts after dominant-negative FLT4 expression. Retain positive cell-population proliferation as this tumor-context response. The endothelial-specific core annotation does not replace the carcinoma result, and engineered receptor inhibition is not a natural isoform phenotype.

Summary: The authentic PMID:7675451 abstract describes long-form human FLT4-dependent fibroblast anchorage-independent growth/tumor formation and loss after Y1337F mutation.

Reason: The authentic PMID:7675451 abstract describes long-form human FLT4-dependent fibroblast anchorage-independent growth/tumor formation and loss after Y1337F mutation. Full protocols remain unavailable. Retain this context-specific transforming/proliferative role, supported by independent receptor growth assays; do not transfer the long-tail effect to the short or soluble natural product.

Summary: Actual PMID:19779139 separates human tumor-cell from mouse host VEGF transcripts and measures secreted human VEGF proteins.

Reason: Actual PMID:19779139 separates human tumor-cell from mouse host VEGF transcripts and measures secreted human VEGF proteins. Dominant-negative FLT4 suppresses an autocrine feedback program, particularly VEGF-C. Retain positive VEGF production as a carcinoma-context signaling output; FLT4 is not the enzyme that synthesizes VEGF.

Summary: The ARBA endothelial-migration assignment agrees with PMID:11532940 primary human lymphatic-endothelial Boyden-chamber responses to VEGFR3-selective VEGF-C156S and inhibition by soluble VEGFR3.

Reason: The ARBA endothelial-migration assignment agrees with PMID:11532940 primary human lymphatic-endothelial Boyden-chamber responses to VEGFR3-selective VEGF-C156S and inhibition by soluble VEGFR3. This is a central receptor-guided cellular response, not an unsupported generic binding-to-motility inference. The rule itself was not independently regenerated.

Summary: Actual PMID:11532940 shows primary human endothelial migration toward VEGF-C156S and blockade by soluble VEGFR3, separating VEGFR3 from VEGFR2 ligand responses.

Reason: Actual PMID:11532940 shows primary human endothelial migration toward VEGF-C156S and blockade by soluble VEGFR3, separating VEGFR3 from VEGFR2 ligand responses. The receptor initiates a directional signaling response relevant to vascular growth. Do not claim purified intracellular motility machinery or an isolated natural-product assay.

Summary: The cell-migration IBD at PTN008404985 lies on the exact human target path.

Reason: The cell-migration IBD at PTN008404985 lies on the exact human target path. Direct human endothelial migration toward selective ligand supports receptor participation as the signal-detecting/initiating component of migration. The term is not formally an ancestor of positive regulation of migration, and the reliable existing assertion is not rejected using the stricter NEW-annotation bar.

Summary: The human receptor is a tyrosine kinase that phosphorylates protein tyrosyl residues.

Reason: The human receptor is a tyrosine kinase that phosphorylates protein tyrosyl residues. Original PMID:7898938 uses isoforms/chimeric receptor systems, with complete assays unavailable here; directly inspected human receptor phosphotyrosine measurements in PMID:23878260/9435229 corroborate protein phosphorylation. This term describes chemistry, not direct phosphorylation of every downstream AKT/ERK/JNK readout.

Summary: The positive growth-factor-binding IBD at PTN004704336 is on the exact human target path; its API taxonomic_range is Euteleostomi, without a species field.

Reason: The positive growth-factor-binding IBD at PTN004704336 is on the exact human target path; its API taxonomic_range is Euteleostomi, without a species field. No challenge to ancestral placement is warranted. For this target, actual VEGF-C/D binding supports the more informative GO:0038085 vascular endothelial growth factor binding, an official is_a child-descendant of GO:0019838. This is target-specific refinement of a sound inherited assertion.

Proposed replacements: vascular endothelial growth factor binding

Summary: Growth-factor binding is sound but can be specified as GO:0038085 vascular endothelial growth factor binding.

Reason: Growth-factor binding is sound but can be specified as GO:0038085 vascular endothelial growth factor binding. Direct human VEGF-C binding/structural studies and VEGF-D receptor capture establish the ligand class. Preserve the original electronic context; do not invent binding to unrelated growth factors.

Proposed replacements: vascular endothelial growth factor binding

Summary: PMID:9435229 demonstrates capture of human VEGF-D by a soluble human VEGFR3 extracellular Ig fusion, with receptor-specific comparators, and activation of human VEGFR3 in NIH3T3 hosts.

Reason: PMID:9435229 demonstrates capture of human VEGF-D by a soluble human VEGFR3 extracellular Ig fusion, with receptor-specific comparators, and activation of human VEGFR3 in NIH3T3 hosts. The actual O43915 VEGF-D partner makes GO:0038085 vascular endothelial growth factor binding a supported refinement. The engineered truncated ligand and fusion receptor are not asserted to be natural full-length products.

Proposed replacements: vascular endothelial growth factor binding

Summary: PMID:20826270 shows co-immunoprecipitation of full-length human VEGFR3-V5 with FLAG-PTPN14 in HEK293 cells, enhanced by VEGF-C and absent for the V5-EB1 control.

Reason: PMID:20826270 shows co-immunoprecipitation of full-length human VEGFR3-V5 with FLAG-PTPN14 in HEK293 cells, enhanced by VEGF-C and absent for the V5-EB1 control. Q15678 is independently verified as PTPN14. Retain the phosphatase-containing association without claiming isolated binary binding, direct dephosphorylation or that this partner interaction defines the receptor core activity.

Summary: The positive cell-migration IBD at PTN002814453 is on the human target path; target self-evidence is legitimate descendant grounding.

Reason: The positive cell-migration IBD at PTN002814453 is on the human target path; target self-evidence is legitimate descendant grounding. Human endothelial migration is directly supported. Retained GO:0010595 is an official is_a descendant of GO:0030335, so this broader positive-regulation row is redundant for the established receptor function.

Summary: Inspection of the original PMID:9435229 human VEGF-D stimulation of human VEGFR3 in NIH3T3 hosts.

Reason: Inspection of the original PMID:9435229 human VEGF-D stimulation of human VEGFR3 in NIH3T3 hosts. This establishes receptor-mediated ligand response. Retained VEGF signaling GO:0038084 has GO:0035924 in its official is_a/part_of ancestry, so the general cellular-response row is redundant; the mouse host does not change the human receptor identity.

Summary: The VEGFC response in SAS cells is already represented by the retained receptor-signaling annotation.

Reason: PMID:19779139 measures VEGFC-responsive receptor and downstream phosphorylation in human SAS cells. The retained same-source GO:0048010 receptor-signaling annotation already records this tumor context, and retained ligand-initiated GO:0038084 has GO:0035924 in its official is_a/part_of ancestry. The general cellular response therefore adds no separate biological operation here. Preserve the original source and tumor/autocrine limits; this does not generalize all tumor outputs or identify downstream proteins as direct FLT4 substrates.

Summary: Actual PMID:23878260 human receptor-ECD binding/dimerization and receptor phosphotyrosine assays establish ligand-initiated VEGF signaling.

Reason: Actual PMID:23878260 human receptor-ECD binding/dimerization and receptor phosphotyrosine assays establish ligand-initiated VEGF signaling. FLT4 executes the receptor step. The engineered domain-interface and ligand mutations delineate the assay; they are not natural splice products, and activation measurements are not direct evidence for every downstream substrate.

Summary: PMID:23878260 shows ligand-dependent dimerization of soluble human receptor ECD by solution measurements, a D5 homotypic interface in structures, and impaired cellular receptor activation after interface mutation.

Reason: PMID:23878260 shows ligand-dependent dimerization of soluble human receptor ECD by solution measurements, a D5 homotypic interface in structures, and impaired cellular receptor activation after interface mutation. Homodimerization contributes directly to receptor activation; this does not establish ligand-free constitutive dimerization or identical behavior of all natural products.

Summary: Actual PMID:11532940 uses primary human endothelial survival assays, including nucleosome/annexin readouts, with receptor-selective VEGF-C156S.

Reason: Actual PMID:11532940 uses primary human endothelial survival assays, including nucleosome/annexin readouts, with receptor-selective VEGF-C156S. Retain the anti-apoptotic response as a supported downstream survival role. Its signaling context does not make FLT4 an apoptosis-executing enzyme or justify assigning the response to all natural products.

Summary: Actual target-path replay supports the receptor-complex IBD at PTN001230349.

Reason: Actual target-path replay supports the receptor-complex IBD at PTN001230349. Actual human VEGF-C/receptor dimerization and activation experiments agree with the official signaling-receptor-complex definition. No loss/divergence is established, and the claim is not that every natural product forms the same ligand-independent complex.

Summary: PMID:23382219 actual body reports human receptor-tail peptide arrays; its detailed cellular validation concerns InsR/TrkA, not a demonstrated native FLT4-SNX complex.

Reason: PMID:23382219 actual body reports human receptor-tail peptide arrays; its detailed cellular validation concerns InsR/TrkA, not a demonstrated native FLT4-SNX complex. The broad signaling-receptor-complex term is nevertheless clearly supported by actual human FLT4 ligand-induced dimerization in PMID:23878260 and the on-target IBD. Retain the term with this source-specific limitation, without inventing a trafficking mechanism.

Summary: MAPK regulation includes a tumor-associated p38 response beyond the separately retained endothelial ERK branch.

Reason: The positive MAPK IBD at PTN002814453 lies on the exact human target path and is sound. ERK1/2 regulation GO:0070374 is a descendant of GO:0043410, but does not cover the independently supported p38-associated tumor response in PMID:19779139. Retain broader MAPK regulation as non-core while the endothelial ERK branch remains specifically represented. These pathway effects do not establish direct FLT4 phosphorylation of MAPKs.

Summary: Actual PMID:19779139 measures ERK and p38 changes in the human SAS tumor model after dominant-negative receptor expression.

Reason: Actual PMID:19779139 measures ERK and p38 changes in the human SAS tumor model after dominant-negative receptor expression. Retain this broader tumor MAPK response, including context beyond the endothelial ERK core. No direct FLT4 phosphorylation of MAPKs is claimed, and the engineered receptor fragment is not a natural product.

Summary: Actual PMID:16076871 tests EGFR-ECD/FLT4-TM-intracellular chimeras in HUVECs stimulated with EGF.

Reason: Actual PMID:16076871 tests EGFR-ECD/FLT4-TM-intracellular chimeras in HUVECs stimulated with EGF. Y1063/CRK/MKK4 experiments and JNK assays support this receptor-tail-dependent JNK branch. Retain the existing regulatory assertion with the engineered context explicit; FLT4 is not shown to directly phosphorylate JNK, and no natural isoform-wide conclusion follows.

Summary: PMID:23878260 measures VEGF-C-induced receptor phosphotyrosine after receptor immunoprecipitation in HEK293/PAE expression systems, normalized to receptor abundance.

Reason: PMID:23878260 measures VEGF-C-induced receptor phosphotyrosine after receptor immunoprecipitation in HEK293/PAE expression systems, normalized to receptor abundance. Domain-interface mutation impairs this activation. Retain autophosphorylation with this cellular assay scope, not an invented isolated catalytic-rate measurement.

Summary: PMID:7675451 reports a potential autophosphorylation/docking site in the long human receptor tail and loss of transforming activity after Y1337F mutation; its full methods remain unavailable.

Reason: PMID:7675451 reports a potential autophosphorylation/docking site in the long human receptor tail and loss of transforming activity after Y1337F mutation; its full methods remain unavailable. Receptor autophosphorylation is independently supported by PMID:23878260/9435229. Do not turn the potential site into a uniquely proven catalytic site or transfer long-product numbering to short/soluble products.

Summary: PMID:9435229 measures phosphotyrosine on immunoprecipitated human VEGFR3 after recombinant human VEGF-D stimulation in NIH3T3 hosts, including the mature processed receptor band.

Reason: PMID:9435229 measures phosphotyrosine on immunoprecipitated human VEGFR3 after recombinant human VEGF-D stimulation in NIH3T3 hosts, including the mature processed receptor band. This supports ligand-induced receptor autophosphorylation, with engineered ligand truncation and host-cell boundaries explicit.

Summary: ROOT exact target/tree/MSA/original-IBD replay confirms the positive GO:0048010 origin at PTN002814453 on the human target path.

Reason: ROOT exact target/tree/MSA/original-IBD replay confirms the positive GO:0048010 origin at PTN002814453 on the human target path. Ligand binding and kinase activation make FLT4 an executing receptor component of VEGF receptor signaling, not merely a necessary downstream substrate. Human experiments support the inherited pathway role.

Summary: PMID:9012504 reports recombinant mouse VEGF-C binding and receptor autophosphorylation; its complete receptor construct/species methods remain inaccessible.

Reason: PMID:9012504 reports recombinant mouse VEGF-C binding and receptor autophosphorylation; its complete receptor construct/species methods remain inaccessible. Retain the curated human receptor-signaling assertion, independently corroborated by actual human receptor activation assays in PMID:23878260 and PMID:9435229. Do not convert the ligand species into a claim about the receptor species.

Summary: Actual PMID:11532940 shows receptor-selective VEGF-C156S stimulation in human endothelial cultures and downstream Akt/MAPK pathway responses, with ligand specificity independently tested.

Reason: Actual PMID:11532940 shows receptor-selective VEGF-C156S stimulation in human endothelial cultures and downstream Akt/MAPK pathway responses, with ligand specificity independently tested. FLT4 itself transduces this receptor signal. Distinguish these endogenous endothelial experiments from the EpoR signaling domains of the separate Ba/F3 chimera; no direct FLT4 catalysis on Akt/ERK is inferred.

Summary: Actual PMID:19779139 shows human SAS-cell endogenous FLT4 phosphorylation and VEGF-C-induced signaling, suppressed by a dominant-negative receptor lacking the cytoplasmic domain.

Reason: Actual PMID:19779139 shows human SAS-cell endogenous FLT4 phosphorylation and VEGF-C-induced signaling, suppressed by a dominant-negative receptor lacking the cytoplasmic domain. This supports direct receptor participation in the pathway. It does not make the tumor implantation study an endothelial-specific knockout or prove direct receptor catalysis on all downstream signaling readouts.

Summary: Preserve the original mouse UniProt/Ensembl transfer.

Reason: Preserve the original mouse UniProt/Ensembl transfer. The donor blood-vessel morphogenesis assertion has explicit null-embryo experimental support in PMID:9794766, although only the original abstract is accessible here. The role is biologically compatible with conserved receptor vascular function; do not invent precise human embryonic assays or a universal kinase-dependent mechanism.

Summary: Mouse P35917 has experimental PMID:9794766 grounding: its authentic abstract describes abnormal large-vessel organization/lumens and embryonic cardiovascular failure despite initial vasculogenesis/angiogenesis.

Reason: Mouse P35917 has experimental PMID:9794766 grounding: its authentic abstract describes abnormal large-vessel organization/lumens and embryonic cardiovascular failure despite initial vasculogenesis/angiogenesis. Retain the conserved early blood-vessel morphogenesis role as a developmental context. Complete original Methods were not recovered, and this is distinct from the later lymphatic receptor program.

Summary: The mouse UniProt/Ensembl remodeling transfer is experimentally grounded at the donor and compatible with FLT4 vascular signaling.

Reason: The mouse UniProt/Ensembl remodeling transfer is experimentally grounded at the donor and compatible with FLT4 vascular signaling. Keep it as an early developmental regulatory context. Evidence here includes authentic PMID:9794766 abstract and donor records, not reconstructed full Results; avoid a detailed kinase-independent mechanism beyond what was actually read.

Summary: The mouse donor carries PMID:9794766 experimental regulation-of-remodeling support, with the authentic abstract reporting failed large-vessel organization after initial vascular formation.

Reason: The mouse donor carries PMID:9794766 experimental regulation-of-remodeling support, with the authentic abstract reporting failed large-vessel organization after initial vascular formation. Retain this existing embryonic remodeling role with original full-method access limitations. Later ligand/kinase mutant phenotypes need not refute null-receptor effects, and no isolated structural-remodeling action is claimed.

Summary: The ARBA ERK-cascade assignment agrees with actual PMID:11532940 selective VEGFR3 stimulation in primary human lymphatic endothelial cultures and complementary engineered receptor-tail experiments in PMID:16076871.

Reason: The ARBA ERK-cascade assignment agrees with actual PMID:11532940 selective VEGFR3 stimulation in primary human lymphatic endothelial cultures and complementary engineered receptor-tail experiments in PMID:16076871. ERK is a central downstream signaling branch. The evidence supports positive regulation through a cascade, not direct tyrosine phosphorylation of ERK by FLT4.

Summary: Actual PMID:11532940 measures ERK1/2 activation following VEGFR3-selective ligand in primary human lymphatic endothelial cells and dissects pathway inhibitor sensitivity.

Reason: Actual PMID:11532940 measures ERK1/2 activation following VEGFR3-selective ligand in primary human lymphatic endothelial cells and dissects pathway inhibitor sensitivity. This supports a central receptor signaling branch. Keep the regulatory wording and do not convert pathway readouts into a claim of direct FLT4-to-ERK catalysis.