FGD4

Summary: Transfer of the FGD1 ruffle location to FGD4 remains unresolved.

Reason: The donor is mouse Fgd1 P52734, not a mouse FGD4 ortholog. PMID:12913069 Figure 4 supports tagged Fgd1 recruitment to ruffles in COS-7 cells. FGD4 has a different N-terminal targeting architecture; its positive actin-rich microspike and cortical recruitment evidence does not identify a ruffle compartment. Retain uncertainty about this specific paralog localization transfer rather than infer absence from the lack of a matching target assay.

Summary: FGD4 retains the ancestral guanyl-nucleotide exchange function.

Reason: The actual PTHR12673 v19 path places Q96M96 leaf PTN002489344 below positive IBD node PTN000292731, and its 766-residue ungapped alignment exactly matches canonical FGD4. The target DH domain and established CDC42-GEF membership in Reactome agree with this inference. Human FGD1 fragment data in PMID:8969170 supply a separately bounded paralog biochemical source; they are not a purified human FGD4 assay. The curated human UniProt FUNCTION record independently assigns CDC42 nucleotide exchange, with ECO:0000269/PMID:15133042 and similarity evidence. That paper supplies human-cell evidence for frabin participation upstream of CDC42; its cellular signaling readout is not a purified human FGD4 exchange assay.

Summary: The target DH–PH architecture supports GEF activity.

Reason: The actual Q96M96 InterPro response places catalytic DH entry IPR000219 at residues 206–393 and FGD4 N-terminal PH entry IPR037742 at 423–516; both map to GO:0005085. The PH match is targeting/architecture evidence, not a claim that the isolated PH domain catalyzes exchange. The curated CDC42 event supplies concordant target-level function. The curated human UniProt FUNCTION record independently assigns CDC42 nucleotide exchange, with ECO:0000269/PMID:15133042 and similarity evidence. That paper supplies human-cell evidence for frabin participation upstream of CDC42; its cellular signaling readout is not a purified human FGD4 exchange assay.

Summary: The FGD1 paralog source supports conserved FGD4 exchange activity.

Reason: PMID:8969170 measures GDP release and GTP loading on CDC42 with human FGD1 residues 330–710. P98174 is human FGD1, not FGD4; transfer is supported by the intact target DH–PH architecture, actual shared ancestral GEF placement and FGD4-specific CDC42-GEF assignment. This does not transfer every FGD1 interaction or localization. The curated human UniProt FUNCTION record independently assigns CDC42 nucleotide exchange, with ECO:0000269/PMID:15133042 and similarity evidence. That paper supplies human-cell evidence for frabin participation upstream of CDC42; its cellular signaling readout is not a purified human FGD4 exchange assay.

Summary: FGD4 is an established catalyst member of the CDC42 exchange event.

Reason: Event 9013159 reaches catalyst 9013228, established CDC42-GEF set 9013227 and FGD4 entity 3000215 (Q96M96 residues 1–766). The summation explicitly lists FGD4 among GEFs reported to activate CDC42. This is a catalytic role, distinct from cargo or substrate membership; the event record is not itself a newly inspected purified-protein experiment. The curated human UniProt FUNCTION record independently assigns CDC42 nucleotide exchange, with ECO:0000269/PMID:15133042 and similarity evidence. That paper supplies human-cell evidence for frabin participation upstream of CDC42; its cellular signaling readout is not a purified human FGD4 exchange assay.

Summary: The inherited assertion places FGD4 activity in the cytoplasm.

Reason: The positive is_active_in cytoplasm IBD at PTN000292731 lies on the independently verified FGD4 target lineage. This supports the ancestral cellular setting of its GEF activity. The retained located_in cytosol records describe a physical compartment and corroborate cytoplasmic localization, but do not entail the distinct is_active_in relation. Retain the activity-location assertion rather than treating it as redundant with those rows.

Summary: The broad donor-derived location is covered by retained target cytosol.

Reason: The mouse Fgd1 source in PMID:12913069 supports a cytoplasmic pool, but is a paralog observation. Actual target Reactome entity 3000215 is assigned to cytosol in three retained rows. The verified cytosol part_of cytoplasm relation supplies the more specific positive coverage without requiring transfer of the donor’s Golgi or ruffle pattern.

Summary: The FGD1 Golgi localization has not been resolved for FGD4.

Reason: PMID:12913069 Figure 4 Results explicitly localize mouse Fgd1 to Golgi and cytoplasm. FGD4 is a distinct paralog with a different N-terminal targeting region. The inspected target studies support actin-rich protrusions or localized membrane recruitment, but do not establish its Golgi pool. Neither the shared catalytic fold nor absence of a target Golgi assay warrants a confident positive or negative localization judgment.

Summary: The actual target entity is placed in cytosol.

Reason: The source route is 205039 → catalyst 204987 → generic GEF set 194849 → FGD4 entity 3000215, explicitly Q96M96 residues 1–766 in cytosol. Retain that modeled compartment; the generic set does not establish FGD4-specific RAC activation or every upstream p75NTR step.

Summary: The generic GEF event preserves the target’s cytosolic compartment.

Reason: Event 419166 reaches catalyst 194957, GEF set 194849 and cytosolic FGD4 entity 3000215. The imported claim is location. It does not assert that FGD4 exchanges RhoA/B/C; the event summation itself distinguishes GEF substrate specificities.

Summary: The CDC42 exchange reaction uses cytosolic FGD4.

Reason: The complete target route 9013159 → 9013228 → 9013227 → 3000215 identifies canonical Q96M96 in cytosol. This compartment is compatible with recruitment to cortical or membrane-associated CDC42 and is not an exclusive localization claim.

Summary: FGD4 associates with actin-rich cytoskeletal structures.

Reason: The electronic source is UniProt subcellular vocabulary SL-0090, not an HPA assay. PMID:17564959 Results and Figures 5–6 show rat full-length Frabin-GFP colocalizing with F-actin in microspikes, with altered protrusion formation after engineered truncation. Retain the broad actin-associated neurite-tip/growth-cone pool as well as the named microspikes; that measured spatial scope is not exhausted by the more specific filopodium location in row 17. Colocalization is not a direct binding measurement or a human natural-isoform assay.

Summary: Actin-specific organization supplies the retained process scope.

Reason: Positive IBD node PTN000292819 lies on the verified FGD4 path. The target ortholog experiments concern actin-rich microspikes and cell shape, retained under GO:0030036 at row 16. Official GO data identify that term as an is_a child of cytoskeleton organization. No separate non-actin organizing activity is established by this broad row.

Summary: The supported actin process covers this broader paralog transfer.

Reason: Mouse Fgd1 PMID:12913069 Figure 7 and Table 1 concern actin patterns and cell morphology; FGD4-specific ortholog studies independently support actin-rich protrusions. Retained GO:0030036 is a verified is_a child of GO:0007010. Normal-looking microtubules in the inspected human patient fibroblasts are a context-specific observation, not a universal loss claim.

Summary: FGD4 can regulate cell shape through its actin-linked signaling role.

Reason: The original P52734 source is mouse Fgd1, but the transfer is corroborated by the FGD4 studies: PMID:17564972 Figure 3 shows frabin-dependent shape changes in rat Schwann cells, and PMID:17564959 compares rat full-length and engineered truncated Frabin. Retain this downstream response as non-core. The 17564972 construct species is not explicit in the inspected body.

Summary: Specific FGD4 lamellipodial localization remains unresolved.

Reason: Mouse Fgd1 colocalization at lamellipodia is explicit in PMID:12913069 Figure 4. The FGD4 study PMID:17564972 demonstrates induction of lamellipodia in rat Schwann cells, which does not by itself establish residence of FGD4 in that compartment. Reviewed UniProt notes poor lamellipodial detection, not universal absence. Preserve this paralog-transfer uncertainty without discarding the positive formation phenotype.

Summary: FGD4 signaling contributes to actin cytoskeleton organization.

Reason: Human FGD1 donor experiments in PMID:8969170 induce CDC42-dependent peripheral actin structures. Independently, PMID:17564959 shows that rat Frabin changes F-actin-rich microspike formation, and PMID:17564972 reports Schwann-cell protrusions and altered shape. Retain this conserved downstream role without attributing all cytoskeletal systems or direct filament-polymerizing activity to FGD4.

Summary: FGD4 can localize to filopodial actin-rich protrusions.

Reason: UniProt SL-0286 maps specifically to filopodium. PMID:17564959 Results and Figure 5 describe rat full-length Frabin-GFP colocalization with F-actin in microspikes and neurite tips, supporting conservative target-ortholog transfer. This is a dynamic location, not proof that every human splice product has identical targeting.

Summary: The CDC42 interaction is consistent with the conserved exchange mechanism.

Reason: The P98174 donor is human FGD1; PMID:8969170 establishes interaction with and nucleotide exchange on CDC42 using its DH–PH fragment. The actual FGD4 DH architecture and established CDC42-GEF event support the mechanistic transfer. Retain the binding claim as non-core alongside the more informative GEF activity, without treating it as broad affinity for every small GTPase.

Summary: FGD4 promotes exchange-defined activation of CDC42.

Reason: Official GO:0090630 defines activation through replacement of GDP by GTP and is a verified strict descendant of the imported GO:0043087. The actual human FGD1 donor assay in PMID:8969170 measures nucleotide exchange, and the target CDC42 catalyst role is explicit in Reactome:R-HSA-9013159. This supports the exchange-defined refinement despite the broader parent definition referring to hydrolysis. No GAP activity, acceleration of GTP hydrolysis or purified human FGD4 measurement is inferred.

Proposed replacements: activation of GTPase activity

Summary: Inherited signaling contributes to filopodium assembly.

Reason: The positive filopodium-assembly IBD at PTN000292819 is on the verified target path. Rat Frabin-GFP promotes F-actin-rich microspikes in PMID:17564959 Figures 5–6, and frabin expression promotes filopodia in rat Schwann cells in PMID:17564972 Figure 3. Retain this downstream phenotype as non-core relative to nucleotide exchange; no direct filament-assembly chemistry is implied.

Summary: Target-ortholog evidence corroborates the donor’s filopodial response.

Reason: The original donor is human FGD1, whose DH–PH fragment induces CDC42-dependent microspikes in PMID:8969170. Independent FGD4 studies in rat cells support filopodial/microspike formation. This is a conserved downstream contribution, with construct and host-cell boundaries, rather than a claim that the two GEF paralogs share every targeting interaction.

Summary: The FYVE zinc-finger fold supports structural metal binding.

Reason: The actual target IPR000306 match spans residues 551–620 and the official entry maps to GO:0046872. Reviewed UniProt independently specifies the FYVE domain and inferred zinc-coordinating residues. Retain this supporting domain property as non-core; neither a target metal-affinity measurement nor catalytic metal chemistry is established by the mapping.

Summary: FGD4 regulates small-GTPase signaling through nucleotide exchange.

Reason: Actual ARBA00027280 branch 4 requires FunFam 1.20.900.10:FF:000013 and Primates, both present in the official Q96M96 record. The rule outputs GO:0051056 and agrees with FGD4’s established CDC42-GEF role. The exact rule match is inference evidence, not an independent biochemical assay.

Summary: Specify the CDC42 regulatory process supported by the target catalytic route.

Reason: The explicit target route is 9012999 → CDC42 cycle 9013148 → exchange event 9013159 → catalyst 9013228 → established set 9013227 → FGD4 entity 3000215. This is regulatory catalytic participation rather than cargo or substrate presence, and it does not confer all other RHO-family activities. GO:0032489 regulation of Cdc42 protein signal transduction is a verified strict descendant of GO:0051056 and captures this target-specific route. Refining this existing assertion links the reviewed process to the core without adding a NEW annotation.

Proposed replacements: regulation of Cdc42 protein signal transduction