FGD1

Summary: FGD1 is recruited to membrane ruffles.

Reason: The combined source joins mouse P52734 and its Ensembl model with UniProt ruffle mapping SL-0300. PMID:12913069 Figure 4 and its Results show tagged mouse Fgd1 redistribution to cortical ruffles in stimulated COS-7 cells. Retain the conserved, dynamic location as non-core; this is ortholog evidence, not a human endogenous ruffle assay.

Summary: The ortholog source supports dynamic ruffle localization.

Reason: The P52734 manual source traces to PMID:12913069. Its mouse Fgd1 construct colocalizes with cortactin and mAbp1 at membrane ruffles in Figure 4. The verified ortholog relationship supports transfer, with the engineered protein and primate host-cell boundaries retained.

Summary: FGD1 is a guanyl-nucleotide exchange factor acting on CDC42.

Reason: The literal positive IBD at PTN000292731 lies on the actual PTHR12673 path to human FGD1 leaf PTN002489341; the ungapped target MSA sequence exactly matches 961-residue P98174. Independent human DH–PH-fragment exchange measurements in PMID:8969170 support GDP release and GTP loading on CDC42. The broad ancestral GEF annotation does not imply that FGD1 activates every Rho-family substrate.

Summary: FGD1 promotes GDP–GTP exchange on Cdc42.

Reason: PMID:8969170 directly measures GDP dissociation and GTPγS loading using purified human FGD1 residues 330–710, containing the DH and first PH domains. The recombinant fragment stimulates membrane-derived, post-translationally modified Cdc42Hs from Sf9 cells; bacterially expressed Cdc42Hs is not stimulated in those assays. This establishes guanyl-nucleotide exchange factor activity, with the stated substrate and construct limits. It is not a natural splice-product comparison or proof that every FGD1 construct has the same activity.

Summary: The target Dbl homology domain supports GEF activity.

Reason: The genuine target InterPro record places IPR000219 at residues 373–561 and maps it to GO:0005085. This is the catalytic DH domain within the experimentally active human 330–710 DH–PH fragment in PMID:8969170. Domain mapping and direct exchange activity agree; CDC42 specificity comes from the target experiment rather than the domain name.

Summary: FGD1 catalyzes CDC42 nucleotide exchange in the curated event.

Reason: R-HSA-9013159 names the CDC42 exchange step. Catalyst 9013228 points to CDC42 GEF set 9013227, whose established hasMember list includes FGD1 entity 194935 (P98174 residues 1–961). This is a catalytic role, corroborated by the human-fragment exchange assay in PMID:8969170, not cargo or substrate membership.

Summary: More specific positive locations cover the inherited cytoplasmic claim.

Reason: The positive cytoplasm IBD at PTN000292731 is on the verified human target path. Cytosol is a strict part_of descendant of cytoplasm and is retained with actual human HPA evidence at row 11; the distinct Golgi localization is also retained. The broad inherited location adds no separate compartment claim here. The IBD itself is not rejected.

Summary: Cytosol and Golgi records retain the positive cytoplasmic coverage.

Reason: ARBA00026971 condition branch 1298 matches the three target FunFam identifiers, and the combined mouse/Ensembl/SL-0086 sources independently support cytoplasmic distribution. Retained cytosol and Golgi annotations supply the more informative locations; the saved strict cytosol part_of cytoplasm relation supports TOO_GENERAL. This is a granularity decision, not a failed mapping.

Summary: The mouse-derived broad location is covered by retained specific compartments.

Reason: PMID:12913069 Results accompanying Figure 4 explicitly report cytoplasmic and Golgi distribution of mouse Fgd1 before redistribution toward the cortex. The positive ortholog transfer is sound. Retained human cytosol and ortholog-supported Golgi locations provide the specific coverage, with cytosol verified as part_of cytoplasm.

Summary: Ortholog evidence supports Golgi-associated FGD1.

Reason: The actual Ensembl record joins ENSMUSP00000026296 to mouse P52734 by one-to-one orthology. Its manual Golgi annotation traces to PMID:12913069, whose Figure 4 Results report tagged mouse Fgd1 in the Golgi complex as well as cytoplasm. Retain this location as non-core with donor and construct limits; no Golgi-lumen topology or new trafficking-process annotation is inferred.

Summary: The mouse donor supports a Golgi-associated pool.

Reason: PMID:12913069 Figure 4 Results distinguish Golgi and cytoplasmic mouse Fgd1 from stimulus-recruited cortical pools. The manual ortholog transfer is consistent with this distribution. The inspected experiment uses GFP-tagged mouse Fgd1 in COS-7 cells and does not establish an exclusively Golgi-localized human protein.

Summary: Human FGD1 has a cytosolic pool.

Reason: The actual HPA FGD1 XML assigns enhanced cytosol and plasma-membrane localization. HPA000911 has positive A-431 and U2OS assignments; HPA076516 has positive A-431 and PODO/TERT256 assignments. The inspected U2OS and A-431 sample images show extranuclear cytoplasmic staining compatible with the cytosol assignment. These images do not quantify soluble versus membrane-associated fractions.

Summary: The actual Reactome entity is cytosolic FGD1.

Reason: R-HSA-205039 reaches catalyst 204987, generic GEF set 194849 and member 194935, explicitly P98174 residues 1–961 in cytosol. This supports the imported compartment, corroborated by HPA. Membership in the generic GEF set does not establish that FGD1 directly exchanges RAC1 or mediates every p75NTR reaction.

Summary: The target entity retains a cytosolic location in the generic GEF set.

Reason: R-HSA-419166 reaches catalyst 194957, GEF set 194849 and FGD1 member 194935 in cytosol. The imported claim concerns this location, not RhoA/B/C substrate specificity. The event summation itself distinguishes FGD1/CDC42 specificity from the Rho-selective example; human HPA localization corroborates the compartment.

Summary: The CDC42 exchange event uses cytosolic FGD1.

Reason: The explicit route 9013159 → catalyst 9013228 → set 9013227 → FGD1 entity 194935 places the canonical protein in cytosol. This is consistent with the independent HPA cytosolic pool and does not exclude recruitment to membrane-associated CDC42.

Summary: FGD1 associates with the cortical actin system through binding partners.

Reason: The source is the reviewed UniProt SL-0090 cytoskeleton vocabulary mapping, not an HPA assay. PMID:12913069 Figures 3–7 show mouse Fgd1 interaction with cortactin/mAbp1 and targeting to cortical actin structures; altered targeting changes the actin pattern. Retain the location as non-core while distinguishing partner-mediated association from direct FGD1–actin binding. The preserved UniProt SUBCELLULAR LOCATION comment explicitly lists Cytoplasm, cytoskeleton with ECO:0000250; this is the underlying by-similarity location statement, not a direct human actin-binding assay.

Summary: Human FGD1 is associated with the plasma membrane.

Reason: HPA assigns enhanced plasma-membrane localization from the inspected antibody/cell-line records, alongside cytosol. Actual U2OS HPA000911 and A-431 HPA076516 sample images were viewed; membrane-associated signal is interpreted with the curated assignments rather than as proof of membrane-spanning topology. The GO definition includes membrane-associated proteins. FGD1 is not asserted to be an integral membrane protein.

Summary: The retained actin-specific process covers this broader inherited organization term.

Reason: The positive PTN000292819 IBD is on the verified FGD1 target path. Human-fragment experiments in PMID:8969170 and the mouse targeting experiments in PMID:12913069 concern actin organization, retained at row 26 as GO:0030036. Official GO data identify that term as an is_a child of GO:0007010. No additional non-actin cytoskeletal process is established by this broad row.

Summary: The supported actin-specific process subsumes the ARBA output.

Reason: ARBA00026736 branch 103 requires three FunFam identifiers that all occur in the target UniProt record and outputs cytoskeleton organization. The mapping is genuine, but the retained GO:0030036 actin cytoskeleton organization is a verified is_a child and supplies the experimentally grounded scope. No additional microtubule-organizing activity is inferred from this rule.

Summary: The donor evidence specifically concerns the actin cytoskeleton.

Reason: Mouse P52734 manual evidence traces to PMID:12913069. Figure 7 and Table 1 show altered actin aggregates, cords and rings after mistargeting Fgd1; they do not establish general organization of all cytoskeletal systems. Retained human GO:0030036 covers the positive actin process and is a verified is_a child of GO:0007010.

Summary: FGD1 regulates Cdc42-mediated signal transduction through nucleotide exchange.

Reason: The human DH–PH fragment in PMID:8969170 stimulates nucleotide exchange on CDC42, with selective GTPase association and Cdc42-dependent actin and kinase responses in mouse fibroblasts. GO:0032489 preserves that demonstrated CDC42 regulatory specificity; the downstream kinase assays do not make FGD1 a kinase. The current ontology places GO:0032489 below regulation of small GTPase mediated signal transduction (GO:0051056). Replacing generic GO:0007165 is a correction to the supported regulatory role, not a claim that this regulation term is a strict is_a/part_of descendant of signal transduction.

Proposed replacements: regulation of Cdc42 protein signal transduction

Summary: FGD1-mediated signaling can alter cell shape.

Reason: The Ensembl transfer resolves to mouse P52734 and PMID:12913069. Figure 7 and Table 1 connect engineered Fgd1 mistargeting with abnormal cell morphology and actin organization in cultured cells. Retain this downstream response as non-core relative to nucleotide exchange, without turning a donor overexpression/mistargeting phenotype into a universal human-cell requirement.

Summary: The ortholog source supports a contextual cell-shape role.

Reason: PMID:12913069 compares full-length mouse Fgd1 with altered targeting constructs and quantifies morphology in Table 1. It supports cell-shape regulation through the actin system, with toxicity and engineered-expression limits stated in the paper. This is a positive downstream role rather than the core molecular activity.

Summary: Human FGD1 mutations are associated with developmental abnormalities; the source-specific organ-morphogenesis scope remains unresolved.

Reason: The verified PMID:7954831 abstract identifies a human translocation-disrupted FGD1 gene and cosegregating mutations in Aarskog–Scott syndrome. This supports a developmental association, but the original operative Methods and Results were not recovered after bounded publisher and repository attempts. The available evidence does not resolve the specific organ-morphogenesis assertion or distinguish the protein’s mechanistic contribution from genetic necessity. Preserve the TAS source and uncertainty without treating the disease emphasis or absent full text as evidence of curator error.

Summary: FGD1 can localize to lamellipodia.

Reason: The combined mouse P52734/Ensembl/SL-0291 source is supported by PMID:12913069 Figure 4 Results: tagged Fgd1 colocalizes with mAbp1 at the leading edge in lamellipodia. Retain this dynamic non-core location; recruitment does not establish that FGD1 is a lamellipodial structural filament or that the compartment was measured in human endogenous cells.

Summary: The donor experiment supports lamellipodial recruitment.

Reason: The mouse P52734 manual source is PMID:12913069. Its Figure 4 localization Results explicitly distinguish leading-edge lamellipodia from cytoplasmic and Golgi pools. Retain the ortholog-supported secondary location with the mouse construct and COS-7-cell context.

Summary: FGD1-dependent Cdc42 activation reorganizes filamentous actin in fibroblasts.

Reason: PMID:8969170 microinjects the human DH–PH fragment into serum-starved mouse Swiss 3T3 cells and visualizes actin with phalloidin. Peripheral microspikes and cell-shape changes are suppressed by coinjected dominant-negative Cdc42HsT17N. Retain this positive downstream cellular role as non-core relative to the resolved nucleotide-exchange mechanism. The experiment does not establish direct actin binding or filament-assembly catalysis by FGD1, and it does not compare natural splice products.

Summary: The FGD1 DH–PH fragment associates selectively with Cdc42Hs in the tested GTPase panel.

Reason: PMID:8969170 recovers Flag-tagged human FGD1 residues 330–710 from NIH 3T3 lysate with immobilized GST-Cdc42Hs, but not the other tested small GTPases. This is a positive substrate-recognition interaction, corroborated by purified nucleotide-exchange activity. Retain the specific small-GTPase-binding annotation as non-core alongside the more mechanistic exchange-factor activity. The binding experiment uses cell lysate rather than a purified binary-affinity measurement; no broader partner list or distinct natural isoform function is inferred.

Summary: FGD1 activates CDC42 by promoting guanine-nucleotide exchange.

Reason: The broader GO:0043087 definition concerns GTP-hydrolysis rate, but its strict descendant GO:0090630 is explicitly defined by replacement of GDP with GTP to activate a GTPase. That exchange-defined process matches the GDP-release and GTPγS-loading measurements in PMID:8969170. Refine the reviewed assertion to GO:0090630 without assigning GTP-hydrolysis catalysis or GAP activity to FGD1. Current typed ancestor and descendant responses independently verify the hierarchy. Original source term, evidence code and reference remain unchanged.

Proposed replacements: activation of GTPase activity

Summary: Conserved FGD1 signaling supports filopodial responses downstream of CDC42.

Reason: The literal filopodium IBD at PTN000292819 is on the verified human target path and includes experimental target evidence. PMID:8969170 reports peripheral actin microspikes after human DH–PH-fragment microinjection into mouse fibroblasts, suppressed by dominant-negative CDC42. Retain the inherited downstream role as non-core, consistently with the direct row, without assigning FGD1 structural filament assembly activity.

Summary: FGD1 activates the Cdc42 pathway that produces peripheral actin microspikes.

Reason: PMID:8969170 reports long protrusions and phalloidin-positive peripheral actin microspikes after microinjection of the human DH–PH fragment into mouse Swiss 3T3 cells. Coinjected dominant-negative Cdc42 reverses the response. Retain the imported filopodium-assembly annotation as a contextual downstream role, without claiming that FGD1 is a structural filament component or that the experiment establishes all stages of physiological filopodium formation. The actual observed microspike morphology and construct scope are retained.

Summary: The FYVE domain supports a structural metal-binding inference.

Reason: The actual target match places IPR000306 FYVE zinc finger at residues 722–791, and the official entry maps it to GO:0046872. Its conserved metal-coordinating fold supports the electronic annotation. Retain this supporting domain property as non-core; no target-specific metal affinity, catalytic metal function, or phosphoinositide specificity was measured in the inspected sources.

Summary: FGD1 regulates small-GTPase signaling by nucleotide exchange.

Reason: ARBA00027280 branch 4 matches target FunFam 1.20.900.10:FF:000013 and the Primates taxonomic condition, outputting GO:0051056. The independent human CDC42 exchange results in PMID:8969170 directly support this regulatory role. It is not GTP hydrolysis by FGD1 or a nonspecific requirement for every downstream response.

Summary: FGD1 directly regulates the CDC42 branch of the RHO GTPase cycle.

Reason: The actual pathway route is 9012999 → CDC42 cycle 9013148 → exchange event 9013159 → catalyst 9013228 → set 9013227 → FGD1 entity 194935. Thus FGD1 performs nucleotide exchange in the cycle rather than serving merely as cargo or a substrate. The broad pathway does not confer activity toward every RHO-family member.