Rho GTPase-activating protein 6 (ARHGAP6) is an X-linked (Xp22.3) member of the RhoGAP superfamily: a largely disordered 974-residue protein built around a single Rho-GAP domain (residues 401-602) whose catalytic arginine finger is R433, carrying SH3-binding proline-rich motifs and terminating in a class I PDZ-binding motif (...LPETLV) that recruits a wide range of PDZ scaffolds. It has at least two genetically separable activities. Through its GAP domain it accelerates GTP hydrolysis on RhoA, and cells expressing it lose actin stress fibres and focal adhesions and retract from the growth surface; this arm requires R433. Independently of GAP catalysis, an N-terminal region co-localises with filamentous actin and recruits F-actin into thin, branching, filopodium-like processes, so the protein also behaves as a cytoskeletal component rather than purely as a switch regulator. A further GAP-independent activity is biochemical activation of phospholipase C-delta1: ARHGAP6 binds PLC-delta1 and raises its maximal rate and its calcium responsiveness by occluding inhibitory phospholipid binding sites, and raises cellular PLC output several fold when overexpressed; raised ARHGAP6 has separately been found alongside raised PLC activity, IP3 and DAG in mononuclear cells from hypertensive subjects. A PLC-dependent, GAP-independent ARHGAP6 effect lowers cell-surface expression of the HERG/KCNH2 potassium channel. Targeted disruption of the rhoGAP domain alone leaves mice phenotypically normal, consistent with the non-catalytic arms carrying much of the protein's biology. The gene lies in the Xp22.3 critical region for microphthalmia with linear skin defects and is deleted in affected individuals, though its contribution to that phenotype is unresolved. Expression is highest in kidney, heart and skeletal muscle, and the gene is subject to X inactivation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005096 GTPase activator activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic propagation of RhoA-GAP activity onto a protein that has its own experimental grounding for it. Reason: ARHGAP6 is a bona fide RhoA-directed GAP. The catalytic arginine finger is present and verified: a domain alignment to the structurally resolved anchor ARHGAP1 R282 (PDB 1TX4 chain A Arg85) and UniProt's own SITE feature independently place it at R433, and R433G is the mutation the literature uses to abolish GAP activity. Residue retention alone would not settle it, because in this family the residue and the annotation record come apart. The strong case is ARHGAP11B, which retains the arginine and carries two curated experimental NOT|enables GO:0005096 rows. The converse cases are weaker and are cited as facts about the annotation record rather than about activity: ARHGAP36 and OCRL substitute the arginine and still carry positive GO:0005096 rows, but those are an IBA and a FlyBase-assigned IDA that other literature disputes, so what they establish is that a positive GAP annotation can sit on a residue-dead protein, not that such proteins are active. Either way the decisive support here is functional: cells expressing wild-type ARHGAP6 lose stress fibres and the R433G mutant does not. The IBD node is seeded by mouse Arhgap6 (MGI:MGI:1196332), which carries its own IDA for this term from the same primary paper, so the propagation is both phylogenetically sound and experimentally anchored. Core. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:1196332 · Arhgap6 (Mus musculus) SUPPORTS TRANSFER Carries enables GO:0005096 by IDA from PMID:10699171 and PMID:25211221. The latter is titled for Arhgap28; the curator read the full text, which our cache does not have, so it is recorded as supporting rather than challenged. PANTHER:PTN000973894 · PTN000973894 SUPPORTS TRANSFER Ancestral node at which PAINT placed the GAP activity. Supporting Evidence: PMID:10699171 These results suggest that ARHGAP6 has two independent functions: one as a GAP with specificity for RhoA and the other as a cytoskeletal protein that promotes actin remodeling. PMID:10699171 Mutation of a conserved arginine residue in the rhoGAP domain prevents the loss of stress fibers but has little effect on process outgrowth. |
| GO:0005096 GTPase activator activity | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer of the mouse ortholog's experimental GAP activity. Reason: Ortholog transfer from mouse Arhgap6 (O54834), which carries enables GO:0005096 by IDA. Mouse and human share the Rho-GAP domain and the arginine finger (mouse R435, human R433, both confirmed against UniProt SITE features and by alignment to the 1TX4-resolved anchor), so there is no architectural reason the activity would not transfer. Redundant with the IBA and the Reactome rows but not wrong. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:O54834 · Arhgap6 (Mus musculus) SUPPORTS TRANSFER Experimental (IDA) for this term on the source record. Supporting Evidence: file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS.md | Arhgap6 (mouse) | O54834 (sv3) | 403-604 | R435 | R435 | yes | RETAINED | |
| GO:0005096 GTPase activator activity | TAS Reactome:R-HSA-8981637 | ACCEPT | Summary: Reactome's RHOA-GAP event, and the better-grounded of its two GAP assertions for this protein. Reason: R-HSA-8981637 places ARHGAP6 in the tier of GAPs shown to bind RHOA and stimulate its GTPase activity, citing Prakash et al. 2000 (PMID:10699171) and Muller et al. 2020 (PMID:32203420), the latter a family-wide substrate-specificity screen. Two independent lines for the same claim; this is the row that carries the RhoA GAP activity properly. Supporting Evidence: PMID:10699171 Transfected mammalian cells expressing ARHGAP6 lose their actin stress fibers, retract from the growth surface and extend thin, branching processes resembling filopodia. PMID:32203420 Through a family-wide characterization of substrate specificities, interactomes and localization, we reveal at the systems level how RhoGEFs and RhoGAPs contextualize and spatiotemporally control Rho signalling. |
| GO:0005096 GTPase activator activity | TAS Reactome:R-HSA-9018806 | ACCEPT | Summary: Same term, but reached through a RAC3-GAP claim that rests on a co-immunoprecipitation. Reason: The assertion is true and is kept: GO:0005096 is substrate-agnostic and ARHGAP6 enables it for RhoA. What is unsupported is the route. R-HSA-9018806 is 'RAC3 GAPs stimulate RAC3 GTPase activity', and Reactome puts ARHGAP6 in its top tier - binds RAC3 and stimulates its GTPase activity - on a single citation, Li et al. 2016 (PMID:26628301), whose only Rac3 experiment is a co-immunoprecipitation; GTPase activity is never measured. Reactome's own RHOA event cites Muller et al. 2020, which places ARHGAP6 among the RhoA-directed GAPs. Unsupported is not contradicted, so the row is not downgraded; the defect is recorded here and in propagation_review instead. GO cannot express the distinction on this term: GO:0005096 has zero descendants on both OLS4 and api.geneontology.org, and QuickGO's single child GO:1902773 is a cellular component reached by capable_of, so there is no substrate-specific GAP term to move to. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK Sources checked: Reactome:R-HSA-9018806 · RAC3 GAPs stimulate RAC3 GTPase activity SOURCE WEAK OR INFERRED Assigns ARHGAP6 RAC3-directed GAP activity on the strength of PMID:26628301, which shows binding only. Supporting Evidence: PMID:26628301 Co-immunoprecipitation assay was performed to validate the interaction between Arhgap6 and Rac3 (Ras-related C3 botulinum toxin substrate 3). |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Direct binding of ARHGAP6's C-terminal class I motif to a PDZ domain of MPDZ; replace the generic term with PDZ domain binding. Reason: Generic protein binding is uninformative as a molecular function, but here the cited paper does support a more specific one, so this is a MODIFY rather than a REMOVE. PMID:36115835 is a holdup screen of a recombinant PDZome library against a library of C-terminal PDZ-binding motif peptides, and IntAct records this pair as a direct interaction detected by holdup assay (MI:2437). MPDZ carries 13 PDZ domains, and ARHGAP6 terminates in ...LPETLV, a canonical class I PDZ-binding motif. What was measured is therefore binding between ARHGAP6's C-terminal motif and a PDZ domain, which GO:0030165 states exactly. Nothing beyond that is asserted - no adaptor, scaffolding, localisation or signalling role - because interaction evidence alone would not support one. Note that the cached full text of PMID:36115835 never names ARHGAP6: the pair is in the supplementary peptide library, so the per-pair evidence above is read from IntAct's curated record of that paper rather than from its prose. Finally, this stays peripheral evidence: GO:0030165 is deliberately not promoted to a core function, and core_functions does not contain it. MODIFY has no field for that, which is the one thing KEEP_AS_NON_CORE did convey, so it is stated here instead. Proposed replacements: PDZ domain binding Supporting Evidence: file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-pdz-interactome.md Distinct partners parsed from the GOA file: **22** (from 22 binding rows). Carrying at least one PDZ domain: **22**. file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-binding-evidence.md | MPDZ | O75970 | holdup assay (MI:2437) | direct interaction | |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Direct binding of ARHGAP6's C-terminal class I motif to a PDZ domain of DLG4; replace the generic term with PDZ domain binding. Reason: Generic protein binding is uninformative as a molecular function, but here the cited paper does support a more specific one, so this is a MODIFY rather than a REMOVE. PMID:36115835 is a holdup screen of a recombinant PDZome library against a library of C-terminal PDZ-binding motif peptides, and IntAct records this pair as a direct interaction detected by holdup assay (MI:2437). DLG4 carries 3 PDZ domains, and ARHGAP6 terminates in ...LPETLV, a canonical class I PDZ-binding motif. What was measured is therefore binding between ARHGAP6's C-terminal motif and a PDZ domain, which GO:0030165 states exactly. Nothing beyond that is asserted - no adaptor, scaffolding, localisation or signalling role - because interaction evidence alone would not support one. Note that the cached full text of PMID:36115835 never names ARHGAP6: the pair is in the supplementary peptide library, so the per-pair evidence above is read from IntAct's curated record of that paper rather than from its prose. Finally, this stays peripheral evidence: GO:0030165 is deliberately not promoted to a core function, and core_functions does not contain it. MODIFY has no field for that, which is the one thing KEEP_AS_NON_CORE did convey, so it is stated here instead. Proposed replacements: PDZ domain binding Supporting Evidence: file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-pdz-interactome.md Distinct partners parsed from the GOA file: **22** (from 22 binding rows). Carrying at least one PDZ domain: **22**. file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-binding-evidence.md | DLG4 | P78352 | holdup assay (MI:2437) | direct interaction | |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Direct binding of ARHGAP6's C-terminal class I motif to a PDZ domain of APBA1; replace the generic term with PDZ domain binding. Reason: Generic protein binding is uninformative as a molecular function, but here the cited paper does support a more specific one, so this is a MODIFY rather than a REMOVE. PMID:36115835 is a holdup screen of a recombinant PDZome library against a library of C-terminal PDZ-binding motif peptides, and IntAct records this pair as a direct interaction detected by holdup assay (MI:2437). APBA1 carries 2 PDZ domains, and ARHGAP6 terminates in ...LPETLV, a canonical class I PDZ-binding motif. What was measured is therefore binding between ARHGAP6's C-terminal motif and a PDZ domain, which GO:0030165 states exactly. Nothing beyond that is asserted - no adaptor, scaffolding, localisation or signalling role - because interaction evidence alone would not support one. Note that the cached full text of PMID:36115835 never names ARHGAP6: the pair is in the supplementary peptide library, so the per-pair evidence above is read from IntAct's curated record of that paper rather than from its prose. Finally, this stays peripheral evidence: GO:0030165 is deliberately not promoted to a core function, and core_functions does not contain it. MODIFY has no field for that, which is the one thing KEEP_AS_NON_CORE did convey, so it is stated here instead. Proposed replacements: PDZ domain binding Supporting Evidence: file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-pdz-interactome.md Distinct partners parsed from the GOA file: **22** (from 22 binding rows). Carrying at least one PDZ domain: **22**. file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-binding-evidence.md | APBA1 | Q02410 | holdup assay (MI:2437) | direct interaction | |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Direct binding of ARHGAP6's C-terminal class I motif to a PDZ domain of TJP1; replace the generic term with PDZ domain binding. Reason: Generic protein binding is uninformative as a molecular function, but here the cited paper does support a more specific one, so this is a MODIFY rather than a REMOVE. PMID:36115835 is a holdup screen of a recombinant PDZome library against a library of C-terminal PDZ-binding motif peptides, and IntAct records this pair as a direct interaction detected by holdup assay (MI:2437). TJP1 carries 3 PDZ domains, and ARHGAP6 terminates in ...LPETLV, a canonical class I PDZ-binding motif. What was measured is therefore binding between ARHGAP6's C-terminal motif and a PDZ domain, which GO:0030165 states exactly. Nothing beyond that is asserted - no adaptor, scaffolding, localisation or signalling role - because interaction evidence alone would not support one. Note that the cached full text of PMID:36115835 never names ARHGAP6: the pair is in the supplementary peptide library, so the per-pair evidence above is read from IntAct's curated record of that paper rather than from its prose. Finally, this stays peripheral evidence: GO:0030165 is deliberately not promoted to a core function, and core_functions does not contain it. MODIFY has no field for that, which is the one thing KEEP_AS_NON_CORE did convey, so it is stated here instead. Proposed replacements: PDZ domain binding Supporting Evidence: file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-pdz-interactome.md Distinct partners parsed from the GOA file: **22** (from 22 binding rows). Carrying at least one PDZ domain: **22**. file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-binding-evidence.md | TJP1 | Q07157 | holdup assay (MI:2437) | direct interaction | |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Direct binding of ARHGAP6's C-terminal class I motif to a PDZ domain of DLG1; replace the generic term with PDZ domain binding. Reason: Generic protein binding is uninformative as a molecular function, but here the cited paper does support a more specific one, so this is a MODIFY rather than a REMOVE. PMID:36115835 is a holdup screen of a recombinant PDZome library against a library of C-terminal PDZ-binding motif peptides, and IntAct records this pair as a direct interaction detected by holdup assay (MI:2437). DLG1 carries 3 PDZ domains, and ARHGAP6 terminates in ...LPETLV, a canonical class I PDZ-binding motif. What was measured is therefore binding between ARHGAP6's C-terminal motif and a PDZ domain, which GO:0030165 states exactly. Nothing beyond that is asserted - no adaptor, scaffolding, localisation or signalling role - because interaction evidence alone would not support one. Note that the cached full text of PMID:36115835 never names ARHGAP6: the pair is in the supplementary peptide library, so the per-pair evidence above is read from IntAct's curated record of that paper rather than from its prose. Finally, this stays peripheral evidence: GO:0030165 is deliberately not promoted to a core function, and core_functions does not contain it. MODIFY has no field for that, which is the one thing KEEP_AS_NON_CORE did convey, so it is stated here instead. Proposed replacements: PDZ domain binding Supporting Evidence: file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-pdz-interactome.md Distinct partners parsed from the GOA file: **22** (from 22 binding rows). Carrying at least one PDZ domain: **22**. file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-binding-evidence.md | DLG1 | Q12959 | holdup assay (MI:2437) | direct interaction | |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Direct binding of ARHGAP6's C-terminal class I motif to a PDZ domain of IL16; replace the generic term with PDZ domain binding. Reason: Generic protein binding is uninformative as a molecular function, but here the cited paper does support a more specific one, so this is a MODIFY rather than a REMOVE. PMID:36115835 is a holdup screen of a recombinant PDZome library against a library of C-terminal PDZ-binding motif peptides, and IntAct records this pair as a direct interaction detected by holdup assay (MI:2437). IL16 carries 4 PDZ domains, and ARHGAP6 terminates in ...LPETLV, a canonical class I PDZ-binding motif. What was measured is therefore binding between ARHGAP6's C-terminal motif and a PDZ domain, which GO:0030165 states exactly. Nothing beyond that is asserted - no adaptor, scaffolding, localisation or signalling role - because interaction evidence alone would not support one. Note that the cached full text of PMID:36115835 never names ARHGAP6: the pair is in the supplementary peptide library, so the per-pair evidence above is read from IntAct's curated record of that paper rather than from its prose. Finally, this stays peripheral evidence: GO:0030165 is deliberately not promoted to a core function, and core_functions does not contain it. MODIFY has no field for that, which is the one thing KEEP_AS_NON_CORE did convey, so it is stated here instead. Proposed replacements: PDZ domain binding Supporting Evidence: file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-pdz-interactome.md Distinct partners parsed from the GOA file: **22** (from 22 binding rows). Carrying at least one PDZ domain: **22**. file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-binding-evidence.md | IL16 | Q14005 | holdup assay (MI:2437) | direct interaction | |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Direct binding of ARHGAP6's C-terminal class I motif to a PDZ domain of SCRIB; replace the generic term with PDZ domain binding. Reason: Generic protein binding is uninformative as a molecular function, but here the cited paper does support a more specific one, so this is a MODIFY rather than a REMOVE. PMID:36115835 is a holdup screen of a recombinant PDZome library against a library of C-terminal PDZ-binding motif peptides, and IntAct records this pair as a direct interaction detected by holdup assay (MI:2437). SCRIB carries 4 PDZ domains, and ARHGAP6 terminates in ...LPETLV, a canonical class I PDZ-binding motif. What was measured is therefore binding between ARHGAP6's C-terminal motif and a PDZ domain, which GO:0030165 states exactly. Nothing beyond that is asserted - no adaptor, scaffolding, localisation or signalling role - because interaction evidence alone would not support one. Note that the cached full text of PMID:36115835 never names ARHGAP6: the pair is in the supplementary peptide library, so the per-pair evidence above is read from IntAct's curated record of that paper rather than from its prose. Finally, this stays peripheral evidence: GO:0030165 is deliberately not promoted to a core function, and core_functions does not contain it. MODIFY has no field for that, which is the one thing KEEP_AS_NON_CORE did convey, so it is stated here instead. Proposed replacements: PDZ domain binding Supporting Evidence: file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-pdz-interactome.md Distinct partners parsed from the GOA file: **22** (from 22 binding rows). Carrying at least one PDZ domain: **22**. file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-binding-evidence.md | SCRIB | Q14160 | holdup assay (MI:2437) | direct interaction | |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Direct binding of ARHGAP6's C-terminal class I motif to a PDZ domain of DLG2; replace the generic term with PDZ domain binding. Reason: Generic protein binding is uninformative as a molecular function, but here the cited paper does support a more specific one, so this is a MODIFY rather than a REMOVE. PMID:36115835 is a holdup screen of a recombinant PDZome library against a library of C-terminal PDZ-binding motif peptides, and IntAct records this pair as a direct interaction detected by holdup assay (MI:2437). DLG2 carries 3 PDZ domains, and ARHGAP6 terminates in ...LPETLV, a canonical class I PDZ-binding motif. What was measured is therefore binding between ARHGAP6's C-terminal motif and a PDZ domain, which GO:0030165 states exactly. Nothing beyond that is asserted - no adaptor, scaffolding, localisation or signalling role - because interaction evidence alone would not support one. Note that the cached full text of PMID:36115835 never names ARHGAP6: the pair is in the supplementary peptide library, so the per-pair evidence above is read from IntAct's curated record of that paper rather than from its prose. Finally, this stays peripheral evidence: GO:0030165 is deliberately not promoted to a core function, and core_functions does not contain it. MODIFY has no field for that, which is the one thing KEEP_AS_NON_CORE did convey, so it is stated here instead. Proposed replacements: PDZ domain binding Supporting Evidence: file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-pdz-interactome.md Distinct partners parsed from the GOA file: **22** (from 22 binding rows). Carrying at least one PDZ domain: **22**. file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-binding-evidence.md | DLG2 | Q15700 | holdup assay (MI:2437) | direct interaction | |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Direct binding of ARHGAP6's C-terminal class I motif to a PDZ domain of PDZK1; replace the generic term with PDZ domain binding. Reason: Generic protein binding is uninformative as a molecular function, but here the cited paper does support a more specific one, so this is a MODIFY rather than a REMOVE. PMID:36115835 is a holdup screen of a recombinant PDZome library against a library of C-terminal PDZ-binding motif peptides, and IntAct records this pair as a direct interaction detected by holdup assay (MI:2437). PDZK1 carries 4 PDZ domains, and ARHGAP6 terminates in ...LPETLV, a canonical class I PDZ-binding motif. What was measured is therefore binding between ARHGAP6's C-terminal motif and a PDZ domain, which GO:0030165 states exactly. Nothing beyond that is asserted - no adaptor, scaffolding, localisation or signalling role - because interaction evidence alone would not support one. Note that the cached full text of PMID:36115835 never names ARHGAP6: the pair is in the supplementary peptide library, so the per-pair evidence above is read from IntAct's curated record of that paper rather than from its prose. Finally, this stays peripheral evidence: GO:0030165 is deliberately not promoted to a core function, and core_functions does not contain it. MODIFY has no field for that, which is the one thing KEEP_AS_NON_CORE did convey, so it is stated here instead. Proposed replacements: PDZ domain binding Supporting Evidence: file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-pdz-interactome.md Distinct partners parsed from the GOA file: **22** (from 22 binding rows). Carrying at least one PDZ domain: **22**. file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-binding-evidence.md | PDZK1 | Q5T2W1 | holdup assay (MI:2437) | direct interaction | |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Direct binding of ARHGAP6's C-terminal class I motif to a PDZ domain of FRMPD2; replace the generic term with PDZ domain binding. Reason: Generic protein binding is uninformative as a molecular function, but here the cited paper does support a more specific one, so this is a MODIFY rather than a REMOVE. PMID:36115835 is a holdup screen of a recombinant PDZome library against a library of C-terminal PDZ-binding motif peptides, and IntAct records this pair as a direct interaction detected by holdup assay (MI:2437). FRMPD2 carries 3 PDZ domains, and ARHGAP6 terminates in ...LPETLV, a canonical class I PDZ-binding motif. What was measured is therefore binding between ARHGAP6's C-terminal motif and a PDZ domain, which GO:0030165 states exactly. Nothing beyond that is asserted - no adaptor, scaffolding, localisation or signalling role - because interaction evidence alone would not support one. Note that the cached full text of PMID:36115835 never names ARHGAP6: the pair is in the supplementary peptide library, so the per-pair evidence above is read from IntAct's curated record of that paper rather than from its prose. Finally, this stays peripheral evidence: GO:0030165 is deliberately not promoted to a core function, and core_functions does not contain it. MODIFY has no field for that, which is the one thing KEEP_AS_NON_CORE did convey, so it is stated here instead. Proposed replacements: PDZ domain binding Supporting Evidence: file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-pdz-interactome.md Distinct partners parsed from the GOA file: **22** (from 22 binding rows). Carrying at least one PDZ domain: **22**. file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-binding-evidence.md | FRMPD2 | Q68DX3 | holdup assay (MI:2437) | direct interaction | |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Direct binding of ARHGAP6's C-terminal class I motif to a PDZ domain of MAST2; replace the generic term with PDZ domain binding. Reason: Generic protein binding is uninformative as a molecular function, but here the cited paper does support a more specific one, so this is a MODIFY rather than a REMOVE. PMID:36115835 is a holdup screen of a recombinant PDZome library against a library of C-terminal PDZ-binding motif peptides, and IntAct records this pair as a direct interaction (also typed physical association) detected by fps (MI:0053) and holdup assay (MI:2437). Two orthogonal direct measurements are recorded for this pair, which corroborates the same determinant rather than adding a second claim. MAST2 carries 1 PDZ domain, and ARHGAP6 terminates in ...LPETLV, a canonical class I PDZ-binding motif. What was measured is therefore binding between ARHGAP6's C-terminal motif and a PDZ domain, which GO:0030165 states exactly. Nothing beyond that is asserted - no adaptor, scaffolding, localisation or signalling role - because interaction evidence alone would not support one. Note that the cached full text of PMID:36115835 never names ARHGAP6: the pair is in the supplementary peptide library, so the per-pair evidence above is read from IntAct's curated record of that paper rather than from its prose. Finally, this stays peripheral evidence: GO:0030165 is deliberately not promoted to a core function, and core_functions does not contain it. MODIFY has no field for that, which is the one thing KEEP_AS_NON_CORE did convey, so it is stated here instead. Proposed replacements: PDZ domain binding Supporting Evidence: file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-pdz-interactome.md Distinct partners parsed from the GOA file: **22** (from 22 binding rows). Carrying at least one PDZ domain: **22**. file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-binding-evidence.md | MAST2 | Q6P0Q8 | fps (MI:0053), holdup assay (MI:2437) | direct interaction, physical association | |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Direct binding of ARHGAP6's C-terminal class I motif to a PDZ domain of MAGI2; replace the generic term with PDZ domain binding. Reason: Generic protein binding is uninformative as a molecular function, but here the cited paper does support a more specific one, so this is a MODIFY rather than a REMOVE. PMID:36115835 is a holdup screen of a recombinant PDZome library against a library of C-terminal PDZ-binding motif peptides, and IntAct records this pair as a direct interaction detected by holdup assay (MI:2437). MAGI2 carries 6 PDZ domains, and ARHGAP6 terminates in ...LPETLV, a canonical class I PDZ-binding motif. What was measured is therefore binding between ARHGAP6's C-terminal motif and a PDZ domain, which GO:0030165 states exactly. Nothing beyond that is asserted - no adaptor, scaffolding, localisation or signalling role - because interaction evidence alone would not support one. Note that the cached full text of PMID:36115835 never names ARHGAP6: the pair is in the supplementary peptide library, so the per-pair evidence above is read from IntAct's curated record of that paper rather than from its prose. Finally, this stays peripheral evidence: GO:0030165 is deliberately not promoted to a core function, and core_functions does not contain it. MODIFY has no field for that, which is the one thing KEEP_AS_NON_CORE did convey, so it is stated here instead. Proposed replacements: PDZ domain binding Supporting Evidence: file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-pdz-interactome.md Distinct partners parsed from the GOA file: **22** (from 22 binding rows). Carrying at least one PDZ domain: **22**. file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-binding-evidence.md | MAGI2 | Q86UL8 | holdup assay (MI:2437) | direct interaction | |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Direct binding of ARHGAP6's C-terminal class I motif to a PDZ domain of NHERF4; replace the generic term with PDZ domain binding. Reason: Generic protein binding is uninformative as a molecular function, but here the cited paper does support a more specific one, so this is a MODIFY rather than a REMOVE. PMID:36115835 is a holdup screen of a recombinant PDZome library against a library of C-terminal PDZ-binding motif peptides, and IntAct records this pair as a direct interaction detected by holdup assay (MI:2437). NHERF4 carries 4 PDZ domains, and ARHGAP6 terminates in ...LPETLV, a canonical class I PDZ-binding motif. What was measured is therefore binding between ARHGAP6's C-terminal motif and a PDZ domain, which GO:0030165 states exactly. Nothing beyond that is asserted - no adaptor, scaffolding, localisation or signalling role - because interaction evidence alone would not support one. Note that the cached full text of PMID:36115835 never names ARHGAP6: the pair is in the supplementary peptide library, so the per-pair evidence above is read from IntAct's curated record of that paper rather than from its prose. Finally, this stays peripheral evidence: GO:0030165 is deliberately not promoted to a core function, and core_functions does not contain it. MODIFY has no field for that, which is the one thing KEEP_AS_NON_CORE did convey, so it is stated here instead. Proposed replacements: PDZ domain binding Supporting Evidence: file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-pdz-interactome.md Distinct partners parsed from the GOA file: **22** (from 22 binding rows). Carrying at least one PDZ domain: **22**. file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-binding-evidence.md | NHERF4 | Q86UT5 | holdup assay (MI:2437) | direct interaction | |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Direct binding of ARHGAP6's C-terminal class I motif to a PDZ domain of LNX2; replace the generic term with PDZ domain binding. Reason: Generic protein binding is uninformative as a molecular function, but here the cited paper does support a more specific one, so this is a MODIFY rather than a REMOVE. PMID:36115835 is a holdup screen of a recombinant PDZome library against a library of C-terminal PDZ-binding motif peptides, and IntAct records this pair as a direct interaction detected by holdup assay (MI:2437). LNX2 carries 4 PDZ domains, and ARHGAP6 terminates in ...LPETLV, a canonical class I PDZ-binding motif. What was measured is therefore binding between ARHGAP6's C-terminal motif and a PDZ domain, which GO:0030165 states exactly. Nothing beyond that is asserted - no adaptor, scaffolding, localisation or signalling role - because interaction evidence alone would not support one. Note that the cached full text of PMID:36115835 never names ARHGAP6: the pair is in the supplementary peptide library, so the per-pair evidence above is read from IntAct's curated record of that paper rather than from its prose. Finally, this stays peripheral evidence: GO:0030165 is deliberately not promoted to a core function, and core_functions does not contain it. MODIFY has no field for that, which is the one thing KEEP_AS_NON_CORE did convey, so it is stated here instead. Proposed replacements: PDZ domain binding Supporting Evidence: file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-pdz-interactome.md Distinct partners parsed from the GOA file: **22** (from 22 binding rows). Carrying at least one PDZ domain: **22**. file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-binding-evidence.md | LNX2 | Q8N448 | holdup assay (MI:2437) | direct interaction | |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Direct binding of ARHGAP6's C-terminal class I motif to a PDZ domain of PATJ; replace the generic term with PDZ domain binding. Reason: Generic protein binding is uninformative as a molecular function, but here the cited paper does support a more specific one, so this is a MODIFY rather than a REMOVE. PMID:36115835 is a holdup screen of a recombinant PDZome library against a library of C-terminal PDZ-binding motif peptides, and IntAct records this pair as a direct interaction detected by holdup assay (MI:2437). PATJ carries 10 PDZ domains, and ARHGAP6 terminates in ...LPETLV, a canonical class I PDZ-binding motif. What was measured is therefore binding between ARHGAP6's C-terminal motif and a PDZ domain, which GO:0030165 states exactly. Nothing beyond that is asserted - no adaptor, scaffolding, localisation or signalling role - because interaction evidence alone would not support one. Note that the cached full text of PMID:36115835 never names ARHGAP6: the pair is in the supplementary peptide library, so the per-pair evidence above is read from IntAct's curated record of that paper rather than from its prose. Finally, this stays peripheral evidence: GO:0030165 is deliberately not promoted to a core function, and core_functions does not contain it. MODIFY has no field for that, which is the one thing KEEP_AS_NON_CORE did convey, so it is stated here instead. Proposed replacements: PDZ domain binding Supporting Evidence: file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-pdz-interactome.md Distinct partners parsed from the GOA file: **22** (from 22 binding rows). Carrying at least one PDZ domain: **22**. file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-binding-evidence.md | PATJ | Q8NI35 | holdup assay (MI:2437) | direct interaction | |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Direct binding of ARHGAP6's C-terminal class I motif to a PDZ domain of DLG3; replace the generic term with PDZ domain binding. Reason: Generic protein binding is uninformative as a molecular function, but here the cited paper does support a more specific one, so this is a MODIFY rather than a REMOVE. PMID:36115835 is a holdup screen of a recombinant PDZome library against a library of C-terminal PDZ-binding motif peptides, and IntAct records this pair as a direct interaction detected by holdup assay (MI:2437). DLG3 carries 3 PDZ domains, and ARHGAP6 terminates in ...LPETLV, a canonical class I PDZ-binding motif. What was measured is therefore binding between ARHGAP6's C-terminal motif and a PDZ domain, which GO:0030165 states exactly. Nothing beyond that is asserted - no adaptor, scaffolding, localisation or signalling role - because interaction evidence alone would not support one. Note that the cached full text of PMID:36115835 never names ARHGAP6: the pair is in the supplementary peptide library, so the per-pair evidence above is read from IntAct's curated record of that paper rather than from its prose. Finally, this stays peripheral evidence: GO:0030165 is deliberately not promoted to a core function, and core_functions does not contain it. MODIFY has no field for that, which is the one thing KEEP_AS_NON_CORE did convey, so it is stated here instead. Proposed replacements: PDZ domain binding Supporting Evidence: file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-pdz-interactome.md Distinct partners parsed from the GOA file: **22** (from 22 binding rows). Carrying at least one PDZ domain: **22**. file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-binding-evidence.md | DLG3 | Q92796 | holdup assay (MI:2437) | direct interaction | |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Direct binding of ARHGAP6's C-terminal class I motif to a PDZ domain of SNX27; replace the generic term with PDZ domain binding. Reason: Generic protein binding is uninformative as a molecular function, but here the cited paper does support a more specific one, so this is a MODIFY rather than a REMOVE. PMID:36115835 is a holdup screen of a recombinant PDZome library against a library of C-terminal PDZ-binding motif peptides, and IntAct records this pair as a direct interaction (also typed physical association) detected by fps (MI:0053) and holdup assay (MI:2437). Two orthogonal direct measurements are recorded for this pair, which corroborates the same determinant rather than adding a second claim. SNX27 carries 1 PDZ domain, and ARHGAP6 terminates in ...LPETLV, a canonical class I PDZ-binding motif. What was measured is therefore binding between ARHGAP6's C-terminal motif and a PDZ domain, which GO:0030165 states exactly. Nothing beyond that is asserted - no adaptor, scaffolding, localisation or signalling role - because interaction evidence alone would not support one. Note that the cached full text of PMID:36115835 never names ARHGAP6: the pair is in the supplementary peptide library, so the per-pair evidence above is read from IntAct's curated record of that paper rather than from its prose. Finally, this stays peripheral evidence: GO:0030165 is deliberately not promoted to a core function, and core_functions does not contain it. MODIFY has no field for that, which is the one thing KEEP_AS_NON_CORE did convey, so it is stated here instead. Proposed replacements: PDZ domain binding Supporting Evidence: file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-pdz-interactome.md Distinct partners parsed from the GOA file: **22** (from 22 binding rows). Carrying at least one PDZ domain: **22**. file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-binding-evidence.md | SNX27 | Q96L92 | fps (MI:0053), holdup assay (MI:2437) | direct interaction, physical association | |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Direct binding of ARHGAP6's C-terminal class I motif to a PDZ domain of MAGI1; replace the generic term with PDZ domain binding. Reason: Generic protein binding is uninformative as a molecular function, but here the cited paper does support a more specific one, so this is a MODIFY rather than a REMOVE. PMID:36115835 is a holdup screen of a recombinant PDZome library against a library of C-terminal PDZ-binding motif peptides, and IntAct records this pair as a direct interaction detected by holdup assay (MI:2437). MAGI1 carries 6 PDZ domains, and ARHGAP6 terminates in ...LPETLV, a canonical class I PDZ-binding motif. What was measured is therefore binding between ARHGAP6's C-terminal motif and a PDZ domain, which GO:0030165 states exactly. Nothing beyond that is asserted - no adaptor, scaffolding, localisation or signalling role - because interaction evidence alone would not support one. Note that the cached full text of PMID:36115835 never names ARHGAP6: the pair is in the supplementary peptide library, so the per-pair evidence above is read from IntAct's curated record of that paper rather than from its prose. Finally, this stays peripheral evidence: GO:0030165 is deliberately not promoted to a core function, and core_functions does not contain it. MODIFY has no field for that, which is the one thing KEEP_AS_NON_CORE did convey, so it is stated here instead. Proposed replacements: PDZ domain binding Supporting Evidence: file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-pdz-interactome.md Distinct partners parsed from the GOA file: **22** (from 22 binding rows). Carrying at least one PDZ domain: **22**. file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-binding-evidence.md | MAGI1 | Q96QZ7 | holdup assay (MI:2437) | direct interaction | |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Direct binding of ARHGAP6's C-terminal class I motif to a PDZ domain of APBA2; replace the generic term with PDZ domain binding. Reason: Generic protein binding is uninformative as a molecular function, but here the cited paper does support a more specific one, so this is a MODIFY rather than a REMOVE. PMID:36115835 is a holdup screen of a recombinant PDZome library against a library of C-terminal PDZ-binding motif peptides, and IntAct records this pair as a direct interaction detected by holdup assay (MI:2437). APBA2 carries 2 PDZ domains, and ARHGAP6 terminates in ...LPETLV, a canonical class I PDZ-binding motif. What was measured is therefore binding between ARHGAP6's C-terminal motif and a PDZ domain, which GO:0030165 states exactly. Nothing beyond that is asserted - no adaptor, scaffolding, localisation or signalling role - because interaction evidence alone would not support one. Note that the cached full text of PMID:36115835 never names ARHGAP6: the pair is in the supplementary peptide library, so the per-pair evidence above is read from IntAct's curated record of that paper rather than from its prose. Finally, this stays peripheral evidence: GO:0030165 is deliberately not promoted to a core function, and core_functions does not contain it. MODIFY has no field for that, which is the one thing KEEP_AS_NON_CORE did convey, so it is stated here instead. Proposed replacements: PDZ domain binding Supporting Evidence: file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-pdz-interactome.md Distinct partners parsed from the GOA file: **22** (from 22 binding rows). Carrying at least one PDZ domain: **22**. file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-binding-evidence.md | APBA2 | Q99767 | holdup assay (MI:2437) | direct interaction | |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Direct binding of ARHGAP6's C-terminal class I motif to a PDZ domain of GRIP2; replace the generic term with PDZ domain binding. Reason: Generic protein binding is uninformative as a molecular function, but here the cited paper does support a more specific one, so this is a MODIFY rather than a REMOVE. PMID:36115835 is a holdup screen of a recombinant PDZome library against a library of C-terminal PDZ-binding motif peptides, and IntAct records this pair as a direct interaction detected by holdup assay (MI:2437). GRIP2 carries 7 PDZ domains, and ARHGAP6 terminates in ...LPETLV, a canonical class I PDZ-binding motif. What was measured is therefore binding between ARHGAP6's C-terminal motif and a PDZ domain, which GO:0030165 states exactly. Nothing beyond that is asserted - no adaptor, scaffolding, localisation or signalling role - because interaction evidence alone would not support one. Note that the cached full text of PMID:36115835 never names ARHGAP6: the pair is in the supplementary peptide library, so the per-pair evidence above is read from IntAct's curated record of that paper rather than from its prose. Finally, this stays peripheral evidence: GO:0030165 is deliberately not promoted to a core function, and core_functions does not contain it. MODIFY has no field for that, which is the one thing KEEP_AS_NON_CORE did convey, so it is stated here instead. Proposed replacements: PDZ domain binding Supporting Evidence: file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-pdz-interactome.md Distinct partners parsed from the GOA file: **22** (from 22 binding rows). Carrying at least one PDZ domain: **22**. file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-binding-evidence.md | GRIP2 | Q9C0E4 | holdup assay (MI:2437) | direct interaction | |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Direct binding of ARHGAP6's C-terminal class I motif to a PDZ domain of WHRN; replace the generic term with PDZ domain binding. Reason: Generic protein binding is uninformative as a molecular function, but here the cited paper does support a more specific one, so this is a MODIFY rather than a REMOVE. PMID:36115835 is a holdup screen of a recombinant PDZome library against a library of C-terminal PDZ-binding motif peptides, and IntAct records this pair as a direct interaction detected by holdup assay (MI:2437). WHRN carries 3 PDZ domains, and ARHGAP6 terminates in ...LPETLV, a canonical class I PDZ-binding motif. What was measured is therefore binding between ARHGAP6's C-terminal motif and a PDZ domain, which GO:0030165 states exactly. Nothing beyond that is asserted - no adaptor, scaffolding, localisation or signalling role - because interaction evidence alone would not support one. Note that the cached full text of PMID:36115835 never names ARHGAP6: the pair is in the supplementary peptide library, so the per-pair evidence above is read from IntAct's curated record of that paper rather than from its prose. Finally, this stays peripheral evidence: GO:0030165 is deliberately not promoted to a core function, and core_functions does not contain it. MODIFY has no field for that, which is the one thing KEEP_AS_NON_CORE did convey, so it is stated here instead. Proposed replacements: PDZ domain binding Supporting Evidence: file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-pdz-interactome.md Distinct partners parsed from the GOA file: **22** (from 22 binding rows). Carrying at least one PDZ domain: **22**. file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-binding-evidence.md | WHRN | Q9P202 | holdup assay (MI:2437) | direct interaction | |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Direct binding of ARHGAP6's C-terminal class I motif to a PDZ domain of GRIP1; replace the generic term with PDZ domain binding. Reason: Generic protein binding is uninformative as a molecular function, but here the cited paper does support a more specific one, so this is a MODIFY rather than a REMOVE. PMID:36115835 is a holdup screen of a recombinant PDZome library against a library of C-terminal PDZ-binding motif peptides, and IntAct records this pair as a direct interaction detected by holdup assay (MI:2437). GRIP1 carries 7 PDZ domains, and ARHGAP6 terminates in ...LPETLV, a canonical class I PDZ-binding motif. What was measured is therefore binding between ARHGAP6's C-terminal motif and a PDZ domain, which GO:0030165 states exactly. Nothing beyond that is asserted - no adaptor, scaffolding, localisation or signalling role - because interaction evidence alone would not support one. Note that the cached full text of PMID:36115835 never names ARHGAP6: the pair is in the supplementary peptide library, so the per-pair evidence above is read from IntAct's curated record of that paper rather than from its prose. Finally, this stays peripheral evidence: GO:0030165 is deliberately not promoted to a core function, and core_functions does not contain it. MODIFY has no field for that, which is the one thing KEEP_AS_NON_CORE did convey, so it is stated here instead. Proposed replacements: PDZ domain binding Supporting Evidence: file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-pdz-interactome.md Distinct partners parsed from the GOA file: **22** (from 22 binding rows). Carrying at least one PDZ domain: **22**. file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-binding-evidence.md | GRIP1 | Q9Y3R0 | holdup assay (MI:2437) | direct interaction | |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Cytoplasm, from the UniProt subcellular-location keyword mapping. Reason: Correct but uninformative: UniProt's SUBCELLULAR LOCATION for ARHGAP6 is Cytoplasm, experimentally attributed to PMID:10699171, and cytoplasm is a parent of both cytosol and actin cytoskeleton, which are the locations that say something. Kept, not core. Supporting Evidence: file:human/ARHGAP6/ARHGAP6-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:10699171}. |
| GO:0005737 cytoplasm | IMP PMID:10699171 Functional analysis of ARHGAP6, a novel GTPase-activating pr... | KEEP AS NON CORE | Summary: Cytoplasmic localisation from the primary functional paper. Reason: Supported by the primary paper, which localises the protein to actin filaments and to the processes the transfected cells extend. Cytoplasm is true and is the term UniProt records, but the informative location is the actin cytoskeleton, so this is kept as non-core rather than as a core location. Supporting Evidence: PMID:10699171 The ARHGAP6 protein co-localizes with actin filaments through an N-terminal domain and recruits F-actin into the growing processes. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Cytosolic localisation; true but not where the informative biology is. Reason: Human Protein Atlas immunofluorescence. A real observation, but cytosol is a compartment rather than a site of action for this protein, whose informative localisation is the actin cytoskeleton. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8981637 | KEEP AS NON CORE | Summary: Cytosolic localisation; true but not where the informative biology is. Reason: Cytosol asserted as the compartment of a Reactome reaction rather than measured. Consistent with the HPA result and with a protein that has no transmembrane segment or signal peptide, but not informative. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9018806 | KEEP AS NON CORE | Summary: Cytosolic localisation; true but not where the informative biology is. Reason: Cytosol asserted as the compartment of a Reactome reaction rather than measured. Consistent with the HPA result and with a protein that has no transmembrane segment or signal peptide, but not informative. |
| GO:0005884 actin filament | NAS PMID:10699171 Functional analysis of ARHGAP6, a novel GTPase-activating pr... | ACCEPT | Summary: Localisation to actin filaments - the informative location, though recorded with a weak evidence code. Reason: This is the one cellular-component term that captures what is distinctive about ARHGAP6: it co-localises with F-actin through an N-terminal region, independently of GAP catalysis. The evidence code (NAS) understates the support, since the claim is a result of the cited paper rather than an untraceable assertion, but the code cannot be changed from here. Supporting Evidence: PMID:10699171 The ARHGAP6 protein co-localizes with actin filaments through an N-terminal domain and recruits F-actin into the growing processes. |
| GO:0007015 actin filament organization | IBA GO_REF:0000033 | ACCEPT | Summary: Actin filament organization, propagated phylogenetically and matching the target's own experimental phenotype. Reason: The best available term for the GAP-independent arm of ARHGAP6: cells expressing it reorganise their actin, losing stress fibres and extending F-actin-filled processes, and the process-outgrowth half of that survives R433G. Mouse Arhgap6 carries the same term by IDA from the same paper, so the propagation is experimentally grounded at its source. Core. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:1196332 · Arhgap6 (Mus musculus) SUPPORTS TRANSFER acts_upstream_of_or_within GO:0007015 by IDA from PMID:10699171. PANTHER:PTN000973894 · PTN000973894 SUPPORTS TRANSFER Supporting Evidence: PMID:10699171 These results suggest that ARHGAP6 has two independent functions: one as a GAP with specificity for RhoA and the other as a cytoskeletal protein that promotes actin remodeling. file:human/ARHGAP6/ARHGAP6-deep-research-affinage.md ARHGAP6 co-localizes with actin filaments through its N-terminal domain and recruits F-actin into growing processes (filopodia-like), independent of its RhoA-GAP activity. |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Root-level signal transduction, mapped from the RhoGAP domain signature. Reason: InterPro2GO mapping from IPR000198 (RhoGAP domain). True of essentially every RhoGAP and of much of the proteome; it is subsumed by the specific Rho protein signal transduction term this gene already carries. Not wrong, so not removed, but it adds no information. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR000198 · RhoGAP domain SUPPORTS TRANSFER The domain really is present (UniProt Rho-GAP 401-602); the mapped term is simply generic. |
| GO:0007266 Rho protein signal transduction | NAS PMID:10699171 Functional analysis of ARHGAP6, a novel GTPase-activating pr... | ACCEPT | Summary: Rho protein signal transduction - the process the GAP arm acts in. Reason: ARHGAP6 terminates RhoA signalling by accelerating GTP hydrolysis, which is participation in the Rho signalling cassette. Directly supported by the cited paper's demonstration of RhoA-specific GAP activity and its arginine-finger dependence. Supporting Evidence: PMID:10699171 Mutation of a conserved arginine residue in the rhoGAP domain prevents the loss of stress fibers but has little effect on process outgrowth. |
| GO:0007266 Rho protein signal transduction | TAS PMID:9417914 Cloning and characterization of a novel rho-type GTPase-acti... | ACCEPT | Summary: Rho protein signal transduction, from the original cloning paper. Reason: The 1997 cloning paper identified ARHGAP6 as a rhoGAP-family gene from the Xp22.3 MLS critical region on sequence grounds; the functional confirmation came three years later. The term is right, and the later experimental work is what sustains it. Supporting Evidence: PMID:9417914 The predicted protein sequence of the gene, named ARHGAP6, contains homology to the GTPase-activating (GAP) domain of the rhoGAP family of proteins, which has been implicated in the regulation of actin polymerization at the plasma membrane in several cellular processes. |
| GO:0015629 actin cytoskeleton | IBA GO_REF:0000033 | ACCEPT | Summary: Active in the actin cytoskeleton - the compartment where both of ARHGAP6's arms operate. Reason: is_active_in is the right qualifier here: ARHGAP6 does not merely reside on the actin cytoskeleton, it acts there, both by clearing RhoA-dependent stress fibres and by recruiting F-actin into extending processes. The mouse source carries the same localisation by IDA. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:1196332 · Arhgap6 (Mus musculus) SUPPORTS TRANSFER located_in GO:0015629 by IDA from PMID:10699171. PANTHER:PTN000973894 · PTN000973894 SUPPORTS TRANSFER Supporting Evidence: PMID:10699171 The ARHGAP6 protein co-localizes with actin filaments through an N-terminal domain and recruits F-actin into the growing processes. |
| GO:0015629 actin cytoskeleton | IEA GO_REF:0000107 | ACCEPT | Summary: Actin cytoskeleton, transferred from the mouse ortholog. Reason: Ensembl Compara transfer of the mouse IDA localisation. Concordant with the IBA and ISS rows for the same term and with the human primary data, so it is redundant rather than informative, but sound. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:O54834 · Arhgap6 (Mus musculus) SUPPORTS TRANSFER |
| GO:0015629 actin cytoskeleton | ISS PMID:10699171 Functional analysis of ARHGAP6, a novel GTPase-activating pr... | ACCEPT | Summary: Actin cytoskeleton by sequence similarity to mouse Arhgap6. Reason: A BHF-UCL sequence-similarity call to mouse Arhgap6 anchored to the paper that localised both proteins. The human protein's own localisation is shown in the same paper, so the ISS is conservative rather than necessary. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:O54834 · Arhgap6 (Mus musculus) SUPPORTS TRANSFER Supporting Evidence: PMID:10699171 The ARHGAP6 protein co-localizes with actin filaments through an N-terminal domain and recruits F-actin into the growing processes. |
| GO:0030041 actin filament polymerization | NAS PMID:10699171 Functional analysis of ARHGAP6, a novel GTPase-activating pr... | MARK AS OVER ANNOTATED | Summary: Actin filament polymerization overstates what the cited paper measured. Reason: GO:0030041 is defined as assembly of actin filaments by addition of actin monomers to a filament. What the cited paper reports is recruitment of pre-existing F-actin into growing processes - no monomer addition, nucleation or elongation assay is described. The adjacent claim, actin filament organization, is separately annotated and is the supportable one. Flagged rather than removed: recruitment into a growing structure is compatible with polymerisation, so the term is unsupported rather than contradicted. Supporting Evidence: PMID:10699171 The ARHGAP6 protein co-localizes with actin filaments through an N-terminal domain and recruits F-actin into the growing processes. |
| GO:0051056 regulation of small GTPase mediated signal transduction | TAS Reactome:R-HSA-9012999 | KEEP AS NON CORE | Summary: Regulation of small GTPase mediated signal transduction; true, and strictly more general than terms already held. Reason: Reactome's RHO GTPase cycle event. The gene already carries the more specific Rho protein signal transduction term with literature behind it, so this parent adds coverage rather than information. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH |
| GO:0051497 negative regulation of stress fiber assembly | IMP PMID:10699171 Functional analysis of ARHGAP6, a novel GTPase-activating pr... | ACCEPT | Summary: Loss of stress fibres on ARHGAP6 expression, and the phenotype that R433G abolishes. Reason: The central experimental phenotype of the GAP arm, and the one used to demonstrate arginine-finger dependence: wild-type ARHGAP6 clears stress fibres, the R433G mutant does not. Core. Supporting Evidence: PMID:10699171 Transfected mammalian cells expressing ARHGAP6 lose their actin stress fibers, retract from the growth surface and extend thin, branching processes resembling filopodia. PMID:10699171 Mutation of a conserved arginine residue in the rhoGAP domain prevents the loss of stress fibers but has little effect on process outgrowth. |
| GO:0051895 negative regulation of focal adhesion assembly | IMP PMID:10699171 Functional analysis of ARHGAP6, a novel GTPase-activating pr... | ACCEPT | Summary: Negative regulation of focal adhesion assembly, curated from the full text of the primary paper. Reason: Consistent with the RhoA-off phenotype the paper describes - cells retract from the growth surface as stress fibres are lost, and focal adhesions are RhoA-dependent structures that disassemble with them. The specific focal adhesion measurement is in the full text, which our cache does not contain; per repository practice the BHF-UCL curator's experimental call is accepted rather than second-guessed from the abstract. Supporting Evidence: PMID:10699171 Transfected mammalian cells expressing ARHGAP6 lose their actin stress fibers, retract from the growth surface and extend thin, branching processes resembling filopodia. |
| GO:1902533 positive regulation of intracellular signal transduction | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: A vague positive-regulation term that reaches the human record by way of the mouse entry. Reason: Ensembl Compara transfer from mouse Arhgap6, whose row for this term is itself a BHF-UCL IDA from PMID:10699171 - a paper whose cell-biological experiments were done on human ARHGAP6. So this is human-derived evidence returning to the human record through the mouse ortholog. It is not asserted to be circular: the human record does not carry the term directly, so the transfer does add coverage. The objection is granularity - positive regulation of intracellular signal transduction does not say which cassette is regulated, and for a protein that both switches RhoA off and switches PLC-delta1 on, the unqualified sign is close to uninterpretable. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:O54834 · Arhgap6 (Mus musculus) SUPPORTS TRANSFER Carries involved_in GO:1902533 by IDA (BHF-UCL) from PMID:10699171. |
| GO:0016004 phospholipase activator activity | IDA PMID:18434237 Regulation of phospholipase C-delta1 by ARGHAP6, a GTPase-ac... | NEW | Summary: Direct activation of phospholipase C-delta1, shown with purified proteins and in cells. Reason: ARHGAP6 binds PLC-delta1 and increases its catalytic output, raising Vmax and Ca2+ responsiveness by occluding inhibitory phospholipid binding sites. The activation is reported under in vitro conditions as well as in cells, so it is an activity of ARHGAP6 rather than a downstream consequence of lowering RhoA-GTP. This is not new curation. It is an existing BHF-UCL annotation that is present in UniProt's GO cross-reference block for O43182 but absent from the current GOA/QuickGO record, and it is entered as NEW only because the review workflow seeds existing_annotations from the GOA download, so a row missing there would never be reviewed at all. The disappearance is not term obsolescence - the term is active on both OLS4 and api.geneontology.org - and the missing rows are still load-bearing: GOA currently serves six ISO annotations on mouse Arhgap6 (GO_REF:0000119) and rat Arhgap6 (GO_REF:0000121) whose WITH/FROM column names O43182 as the source for exactly these three terms, so those projections are orphaned from a human annotation that is no longer in the human record. Supporting Evidence: PMID:18434237 Under in vitro conditions, ARHGAP6 protein activated PLC-delta1. PMID:18434237 ARHGAP6 protein bound PLC-delta1 and regulated its activity by masking the binding sites for inhibitory phospholipids. file:human/ARHGAP6/ARHGAP6-bioinformatics/RESULTS-goa-divergence.md | GO:0016004 | F:phospholipase activator activity [IDA:BHF-UCL] | active / active | active | **2** | |
| GO:0043274 phospholipase binding | IPI PMID:18434237 Regulation of phospholipase C-delta1 by ARGHAP6, a GTPase-ac... | NEW | Summary: Physical complex with PLC-delta1, by co-immunoprecipitation from transfected cells and by direct binding in vitro. Reason: The interaction is shown two ways: ARHGAP6 protein binds PLC-delta1 under in vitro conditions, and ARHGAP6/PLC-delta1 complexes are recovered by immunoprecipitation from transfected Cos-7 cells. Unlike the 22 GO:0005515 rows, this binding has an identified functional consequence, which is why it is recorded with the informative phospholipase binding term rather than as generic protein binding. This is not new curation. It is an existing BHF-UCL annotation that is present in UniProt's GO cross-reference block for O43182 but absent from the current GOA/QuickGO record, and it is entered as NEW only because the review workflow seeds existing_annotations from the GOA download, so a row missing there would never be reviewed at all. The disappearance is not term obsolescence - the term is active on both OLS4 and api.geneontology.org - and the missing rows are still load-bearing: GOA currently serves six ISO annotations on mouse Arhgap6 (GO_REF:0000119) and rat Arhgap6 (GO_REF:0000121) whose WITH/FROM column names O43182 as the source for exactly these three terms, so those projections are orphaned from a human annotation that is no longer in the human record. Supporting Evidence: PMID:18434237 ARHGAP6 protein bound PLC-delta1 and regulated its activity by masking the binding sites for inhibitory phospholipids. PMID:18434237 our data indicate that ARHGAP6 protein binds to and up regulates PLC-delta1 both under in vitro and in vivo conditions |
| GO:0141214 positive regulation of phospholipase C/protein kinase C signal transduction | IDA PMID:18434237 Regulation of phospholipase C-delta1 by ARGHAP6, a GTPase-ac... | NEW | Summary: Cellular phospholipase C activity rises about six-fold when ARHGAP6 is overexpressed. Reason: The process-level counterpart of the phospholipase activator activity: PLC activity rises about six-fold in cells overexpressing ARHGAP6, and that manipulation is the basis of the IDA. The same paper separately reports raised ARHGAP6 alongside raised PLC activity, IP3 (1.6-fold) and DAG (2.3-fold) in mononuclear cells from hypertensive patients; that is a correlation in patient material rather than a manipulation, and it is not part of the support for this term. An independent lab reports that a GAP-independent ARHGAP6 effect on HERG surface expression is lost when PLC is inhibited, which is a second, differently designed observation that ARHGAP6 signals through PLC. This is not new curation. It is an existing BHF-UCL annotation that is present in UniProt's GO cross-reference block for O43182 but absent from the current GOA/QuickGO record, and it is entered as NEW only because the review workflow seeds existing_annotations from the GOA download, so a row missing there would never be reviewed at all. The disappearance is not term obsolescence - the term is active on both OLS4 and api.geneontology.org - and the missing rows are still load-bearing: GOA currently serves six ISO annotations on mouse Arhgap6 (GO_REF:0000119) and rat Arhgap6 (GO_REF:0000121) whose WITH/FROM column names O43182 as the source for exactly these three terms, so those projections are orphaned from a human annotation that is no longer in the human record. Supporting Evidence: PMID:18434237 The activity of PLC in cells overexpressing ARHGAP6 increased approximately 6-fold compared to control cells. PMID:19038263 However, ARHGAP6 lost effectiveness when PLC was inhibited. |
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Download this section (compressed HTML)Q: Is ARHGAP6 a GAP for any Rho-family GTPase other than RhoA? Reactome assigns it RAC3-directed GAP activity on the basis of a co-immunoprecipitation, and no study has measured its GAP activity against Rac3 directly.
Q: The GO molecular function GO:0005096 has no descendants, so a GAP's substrate cannot be recorded on the activity term. Should substrate be captured with has input on the GAP activity for ARHGAP6, and would that be applied consistently across the RhoGAP family?
Q: Three BHF-UCL annotations (GO:0016004, GO:0043274, GO:0141214) appear in UniProt's cross-references for O43182 but not in GOA, while mouse and rat ISO rows in GOA still name O43182 as their source for those same terms. Were the human annotations withdrawn deliberately, and if so should the dependent projections be withdrawn with them?
Q: What does the N-terminal region of ARHGAP6 bind in order to co-localise with F-actin and recruit it into extending processes? Is the interaction with actin direct?
Q: The published HERG result shows a GAP-independent, PLC-dependent reduction in channel surface expression, with both overexpression and knockdown arms. It is not proposed as an annotation here because it is a single laboratory working largely in heterologous systems and the effect is routed through PLC rather than exerted on the channel. Is that the right threshold, or is the knockdown in atrial myocytes sufficient?
Experiment: Measure GAP-stimulated GTP hydrolysis by purified ARHGAP6 Rho-GAP domain against RhoA, Rac1, Rac3 and Cdc42 side by side, with the R433G mutant as the negative control and a characterised RhoA GAP as the positive control. A binding-only result for Rac3 with no acceleration of hydrolysis would settle the Reactome assignment.
Hypothesis: ARHGAP6 is a GAP for RhoA but not for Rac3, and the pathway-database assignment of RAC3-directed GAP activity is an over-reading of a binding experiment.
Type: biochemical assay
Experiment: Co-sedimentation of purified N-terminal fragments with F-actin, with a titration to obtain an affinity, plus TIRF microscopy of the same fragments on actin filaments to distinguish binding from bundling and from nucleation. Include a fragment that fails to co-localise in cells as the negative control.
Hypothesis: The N-terminal region of ARHGAP6 binds filamentous actin directly.
Type: biochemical assay
Experiment: Deplete ARHGAP6 with independent siRNAs or a knockout in a cell line expressing both proteins endogenously, and measure PLC activity, IP3 and DAG. Rescue with wild-type and with the R433G mutant: PLC-delta1 activation should be restored by both if it is genuinely GAP-independent.
Hypothesis: Endogenous ARHGAP6 sets PLC-delta1 activity in a cell type where both are expressed.
Type: loss of function
Experiment: Compare the existing rhoGAP-domain-disrupted mouse with a full Arhgap6 null and with an N-terminal deletion that removes the actin-co-localising region, phenotyping the cytoskeleton and cell morphology in a tissue where expression is high (kidney, heart, skeletal muscle). The published rhoGAP-only disruption is normal, so a phenotype in the other two lines would localise the biology.
Hypothesis: The actin-remodelling arm, not the GAP arm, accounts for ARHGAP6's contribution to phenotype in vivo.
Type: genetic
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