ARHGEF9 encodes collybistin, a Dbl-family guanine-nucleotide exchange factor and adaptor associated with inhibitory postsynaptic organization. Its exchange-factor activity promotes CDC42 activation. Through gephyrin and phosphoinositide interactions, collybistin recruits gephyrin to the postsynaptic membrane, helping organize inhibitory receptor scaffolds. This recruitment activity can operate independently of nucleotide exchange and is conformationally regulated through the SH3 and PH domains. Collybistin occupies cytosolic and postsynaptic pools. Pathogenic ARHGEF9 variants cause developmental and epileptic encephalopathy with intellectual disability; hyperekplexia and an exaggerated startle response occur in affected individuals.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005085 guanyl-nucleotide exchange factor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Human target evidence corroborates the inherited exchange-factor activity. Reason: Human hPEM-2/ARHGEF9 increases active cellular CDC42 in the original PMID:10559246 study, corroborating the inherited exchange activity. The actual PTN002911494 is retained with UNRESOLVED tracing; an ARHGEF4 descendant donor does not by itself invalidate the PAINT judgment. The original human assay measures cellular GTPase activation with effector pull-downs; it is not purified hPEM-2 nucleotide-exchange kinetics. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002911494 · PTN002911494 UNRESOLVED The actual seeded ancestral node is preserved. Independent target or species-explicit ortholog evidence corroborates this biological assertion, but the historical IBD, alignment and placement have not been reconstructed. Donor count and target self-inclusion are not failure criteria. Supporting Evidence: PMID:10559246 hPEM-2 specifically activates Cdc42 and not Rac or RhoA. |
| GO:0005085 guanyl-nucleotide exchange factor activity | IEA GO_REF:0000002 | ACCEPT | Summary: The DH-domain annotation is consistent with cellular CDC42 activation. Reason: The Dbl-homology domain mapping agrees with the original human cellular CDC42-activation result and its GEF interpretation. Retain the current broad GEF term; no obsolete Rho-GEF term or unmeasured Rac specificity is substituted. The cellular assay scope is documented in the exchange-factor assessment and gene notes. Supporting Evidence: PMID:10559246 hPEM-2 specifically activates Cdc42 and not Rac or RhoA. |
| GO:0005085 guanyl-nucleotide exchange factor activity | TAS Reactome:R-HSA-9013159 | ACCEPT | Summary: The CDC42 GEF event explicitly identifies ARHGEF9. Reason: The actual R-HSA-9013159 summary explicitly names ARHGEF9/hPEM-2 among CDC42 GEFs and cites the original target experiment. It distinguishes supported exchange factors from candidates and negative assays; the target cellular activation study corroborates the MF. The cellular assay scope is documented in the exchange-factor assessment and gene notes. Supporting Evidence: PMID:10559246 hPEM-2 specifically activates Cdc42 and not Rac or RhoA. Reactome:R-HSA-9013159 ARHGEF9 (also known as hPEM2) (Reid et al. 1999; Jaiswal et al. 2013; Müller et al. 2020) |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | UNDECIDED | Summary: The VEZF1 (Q14119) interaction requires its original pair-level evidence. Reason: The original HuRI PMID:32296183 assertion names VEZF1 (Q14119). The UniProt INTERACTION block corroborates this partner with NbExp=3, but the original source-specific pair record and assay controls remain unread. UNDECIDED follows the explicit instruction to retain uncertainty when relevant experimental evidence cannot be checked; genericity alone is not an incorrectness claim under the supplied REMOVE definition. The annotation is retained, and unrelated gephyrin adaptor experiments do not justify refining this partner-specific assertion. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | UNDECIDED | Summary: The TSGA10IP (Q3SY00) interaction requires its original pair-level evidence. Reason: The original HuRI PMID:32296183 assertion names TSGA10IP (Q3SY00). The UniProt INTERACTION block corroborates this partner with NbExp=3, but the original source-specific pair record and assay controls remain unread. UNDECIDED follows the explicit instruction to retain uncertainty when relevant experimental evidence cannot be checked; genericity alone is not an incorrectness claim under the supplied REMOVE definition. The annotation is retained, and unrelated gephyrin adaptor experiments do not justify refining this partner-specific assertion. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | UNDECIDED | Summary: The ZNF410 isoform Q86VK4-3 interaction requires its original pair-level evidence. Reason: The original HuRI PMID:32296183 assertion names ZNF410 isoform Q86VK4-3. The UniProt INTERACTION block corroborates this partner with NbExp=3, but the original source-specific pair record and assay controls remain unread. UNDECIDED follows the explicit instruction to retain uncertainty when relevant experimental evidence cannot be checked; genericity alone is not an incorrectness claim under the supplied REMOVE definition. The annotation is retained, and unrelated gephyrin adaptor experiments do not justify refining this partner-specific assertion. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | UNDECIDED | Summary: The FAM90A1 (Q86YD7) interaction requires its original pair-level evidence. Reason: The original HuRI PMID:32296183 assertion names FAM90A1 (Q86YD7). The UniProt INTERACTION block corroborates this partner with NbExp=3, but the original source-specific pair record and assay controls remain unread. UNDECIDED follows the explicit instruction to retain uncertainty when relevant experimental evidence cannot be checked; genericity alone is not an incorrectness claim under the supplied REMOVE definition. The annotation is retained, and unrelated gephyrin adaptor experiments do not justify refining this partner-specific assertion. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | UNDECIDED | Summary: The TBC1D22B (Q9NU19) interaction requires its original pair-level evidence. Reason: The original HuRI PMID:32296183 assertion names TBC1D22B (Q9NU19). The UniProt INTERACTION block corroborates this partner with NbExp=3, but the original source-specific pair record and assay controls remain unread. UNDECIDED follows the explicit instruction to retain uncertainty when relevant experimental evidence cannot be checked; genericity alone is not an incorrectness claim under the supplied REMOVE definition. The annotation is retained, and unrelated gephyrin adaptor experiments do not justify refining this partner-specific assertion. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | UNDECIDED | Summary: The FANCL (Q9NW38) interaction requires its original pair-level evidence. Reason: The original HuRI PMID:32296183 assertion names FANCL (Q9NW38). The UniProt INTERACTION block corroborates this partner with NbExp=3, but the original source-specific pair record and assay controls remain unread. UNDECIDED follows the explicit instruction to retain uncertainty when relevant experimental evidence cannot be checked; genericity alone is not an incorrectness claim under the supplied REMOVE definition. The annotation is retained, and unrelated gephyrin adaptor experiments do not justify refining this partner-specific assertion. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | UNDECIDED | Summary: The YWHAG (P61981) interaction requires its original pair-level evidence. Reason: The original neurodegeneration network PMID:32814053 assertion names YWHAG (P61981). The UniProt INTERACTION block corroborates this partner with NbExp=3, but the original source-specific pair record and assay controls remain unread. UNDECIDED follows the explicit instruction to retain uncertainty when relevant experimental evidence cannot be checked; genericity alone is not an incorrectness claim under the supplied REMOVE definition. The annotation is retained, and unrelated gephyrin adaptor experiments do not justify refining this partner-specific assertion. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | UNDECIDED | Summary: The SETDB1 isoform Q15047-2 interaction requires its original pair-level evidence. Reason: The original neurodegeneration network PMID:32814053 assertion names SETDB1 isoform Q15047-2. The UniProt INTERACTION block corroborates this partner with NbExp=3, but the original source-specific pair record and assay controls remain unread. UNDECIDED follows the explicit instruction to retain uncertainty when relevant experimental evidence cannot be checked; genericity alone is not an incorrectness claim under the supplied REMOVE definition. The annotation is retained, and unrelated gephyrin adaptor experiments do not justify refining this partner-specific assertion. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | UNDECIDED | Summary: The LMO3 isoform Q8TAP4-4 interaction requires its original pair-level evidence. Reason: The original neurodegeneration network PMID:32814053 assertion names LMO3 isoform Q8TAP4-4. The UniProt INTERACTION block corroborates this partner with NbExp=3, but the original source-specific pair record and assay controls remain unread. UNDECIDED follows the explicit instruction to retain uncertainty when relevant experimental evidence cannot be checked; genericity alone is not an incorrectness claim under the supplied REMOVE definition. The annotation is retained, and unrelated gephyrin adaptor experiments do not justify refining this partner-specific assertion. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | UNDECIDED | Summary: The KAT5 (Q92993) interaction requires its original pair-level evidence. Reason: The original neurodegeneration network PMID:32814053 assertion names KAT5 (Q92993). The UniProt INTERACTION block corroborates this partner with NbExp=3, but the original source-specific pair record and assay controls remain unread. UNDECIDED follows the explicit instruction to retain uncertainty when relevant experimental evidence cannot be checked; genericity alone is not an incorrectness claim under the supplied REMOVE definition. The annotation is retained, and unrelated gephyrin adaptor experiments do not justify refining this partner-specific assertion. Supporting Evidence: |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: A cytoplasmic pool is supported by target evidence. Reason: The UniProt cytoplasm mapping is independently consistent with current HPA human cytosolic localization. Cytoplasm is a supported pool, not an exclusive distribution. Supporting Evidence: file:human/ARHGEF9/ARHGEF9-notes.md Localized to the cytosol. |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Human cytosolic localization corroborates the inherited compartment. Reason: Current target HPA localization corroborates cytosol independently of the inherited annotation. Target self-inclusion among descendant evidence is expected grounding; actual PTN002911494 remains UNRESOLVED pending topology/IBD inspection. HPA establishes a location pool, not activity at that site; exact inherited placement remains distinct from this corroboration. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002911494 · PTN002911494 UNRESOLVED The actual seeded ancestral node is preserved. Independent target or species-explicit ortholog evidence corroborates this biological assertion, but the historical IBD, alignment and placement have not been reconstructed. Donor count and target self-inclusion are not failure criteria. Supporting Evidence: file:human/ARHGEF9/ARHGEF9-notes.md Localized to the cytosol. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: The current HPA record supports a human cytosolic pool. Reason: The original source is the HPA localization resource, and its current target summary explicitly identifies cytosol. Accept the human cytosolic pool without claiming an independent audit of each historical image or exclusivity. Supporting Evidence: file:human/ARHGEF9/ARHGEF9-notes.md Localized to the cytosol. |
| GO:0005829 cytosol | IEA GO_REF:0000117 | ACCEPT | Summary: Target localization corroborates the ARBA cytosol assertion. Reason: The ARBA cytosol assertion agrees with the current human target HPA summary. The complete historical rule is not reconstructed; acceptance rests on independent target corroboration. Supporting Evidence: file:human/ARHGEF9/ARHGEF9-notes.md Localized to the cytosol. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-205039 | ACCEPT | Summary: Independent target evidence supports the cytosolic pool; the event graph remains uninspected. Reason: The p75NTR-associated Reactome summary does not expose the exact ARHGEF9 participant inventory. Nevertheless, human target HPA independently supports the asserted cytosolic pool; acceptance does not claim that ARHGEF9-specific event graph or RAC exchange was verified. Supporting Evidence: file:human/ARHGEF9/ARHGEF9-notes.md Localized to the cytosol. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-419166 | ACCEPT | Summary: The compartment is supported independently of the broad Rho-family event. Reason: The RhoA/B/C Reactome summary is a broad GEF context, and the target-specific participant graph remains unread. The annotation asserts cytosol, independently supported by human target HPA; no RHOA exchange activity is inferred from this location row. Supporting Evidence: file:human/ARHGEF9/ARHGEF9-notes.md Localized to the cytosol. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9013159 | ACCEPT | Summary: The target-specific CDC42 event agrees with independent cytosolic localization. Reason: The CDC42 GEF event explicitly includes ARHGEF9 in its summary, consistent with a cytosolic exchange-factor pool. Current HPA independently corroborates cytosol; full event topology is not claimed to have been reconstructed. Supporting Evidence: file:human/ARHGEF9/ARHGEF9-notes.md Localized to the cytosol. Reactome:R-HSA-9013159 ARHGEF9 (also known as hPEM2) (Reid et al. 1999; Jaiswal et al. 2013; Müller et al. 2020) |
| GO:0005829 cytosol | TAS Reactome:R-HSA-975340 | ACCEPT | Summary: Cytosolic localization does not imply GABA-channel activity. Reason: The GABA-channel Reactome summary describes ion conductance without exposing the ARHGEF9-specific inventory. Independent human cytosolic localization supports the location assertion. It does not imply that collybistin is a channel or that the source graph has been independently closed. Supporting Evidence: file:human/ARHGEF9/ARHGEF9-notes.md Localized to the cytosol. |
| GO:0014069 postsynaptic density | IEA GO_REF:0000044 | ACCEPT | Summary: Rodent synaptic evidence corroborates the conserved postsynaptic pool. Reason: The UniProt subcellular mapping assigns postsynaptic density. Gephyrin recruitment and collybistin localization in rodent neuronal studies corroborate this conserved synaptic pool. Retain the annotation with the rodent functional scope explicit; no human endogenous microscopy or exclusive isoform claim is invented. Supporting Evidence: PMID:25082542 switchable adaptor that links gephyrin to plasma membrane phosphoinositides. PMID:15215304 gephyrin clustering in recombinant systems and cultured neurons requires both collybistin-gephyrin interactions and an intact collybistin pleckstrin homology domain. |
| GO:0014069 postsynaptic density | ISS GO_REF:0000024 | ACCEPT | Summary: The identified mouse donor supports a conserved postsynaptic location. Reason: The original ISS donor Q3UTH8 is mouse Arhgef9, independently confirmed in the MGI sequence record. Rodent postsynaptic gephyrin-recruitment evidence is coherent with this conservation-based location assertion; exact current human isoform mapping is not inferred. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q3UTH8 · mouse Arhgef9 UNRESOLVED The donor identity was verified in the MGI sequence record. Rodent neuronal studies corroborate postsynaptic localization; the exact historical donor evidence row and present human isoform mapping remain unresolved. Supporting Evidence: PMID:25082542 switchable adaptor that links gephyrin to plasma membrane phosphoinositides. PMID:15215304 gephyrin clustering in recombinant systems and cultured neurons requires both collybistin-gephyrin interactions and an intact collybistin pleckstrin homology domain. |
| GO:0051056 regulation of small GTPase mediated signal transduction | IEA GO_REF:0000117 | MODIFY | Summary: Refine the broad small-GTPase regulation assertion to the supported CDC42 pathway. Reason: The human hPEM-2 study reports selective cellular activation of CDC42 rather than Rac or RhoA. Exchange-factor activity performs the nucleotide-switch regulatory step, supporting the CDC42-specific child term. The complete historical ARBA rule remains uninspected; this refinement rests on independent target evidence. The gephyrin adaptor activity is not assumed to require CDC42 exchange. Proposed replacements: regulation of Cdc42 protein signal transduction Supporting Evidence: PMID:10559246 hPEM-2 specifically activates Cdc42 and not Rac or RhoA. |
| GO:0051056 regulation of small GTPase mediated signal transduction | TAS Reactome:R-HSA-9012999 | ACCEPT | Summary: The established exchange-factor role fits the GDP/GTP-cycle process. Reason: The pathway describes regulation of small GTPase GDP/GTP cycles. The supported ARHGEF9 exchange-factor activity supplies the relevant regulatory work; this does not assert every Rho-family substrate or every downstream morphological effect. The cellular assay scope is documented in the exchange-factor assessment and gene notes. Supporting Evidence: PMID:10559246 hPEM-2 specifically activates Cdc42 and not Rac or RhoA. |
| GO:0098982 GABA-ergic synapse | IBA GO_REF:0000033 | ACCEPT | Summary: Rodent inhibitory-synapse work supports the inherited location. Reason: Rodent collybistin-mediated gephyrin recruitment at inhibitory synapses supports the inherited GABAergic synapse location. Actual PTN002911496 remains UNRESOLVED for phylogenetic tracing; donor count is not used as a weakness criterion. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002911496 · PTN002911496 UNRESOLVED The actual seeded ancestral node is preserved. Independent target or species-explicit ortholog evidence corroborates this biological assertion, but the historical IBD, alignment and placement have not been reconstructed. Donor count and target self-inclusion are not failure criteria. Supporting Evidence: PMID:25082542 switchable adaptor that links gephyrin to plasma membrane phosphoinositides. PMID:15215304 gephyrin clustering in recombinant systems and cultured neurons requires both collybistin-gephyrin interactions and an intact collybistin pleckstrin homology domain. |
| GO:0099150 regulation of postsynaptic specialization assembly | IBA GO_REF:0000033 | ACCEPT | Summary: Gephyrin recruitment supplies regulatory work in postsynaptic organization. Reason: Collybistin contributes the membrane-recruitment work needed to organize gephyrin rather than merely showing a knockout association. Species-explicit rat construct experiments and mouse neuronal contexts corroborate this existing regulation term. Its synaptic work is distinguished from GEF activity; the exact PTN002911496 topology remains unread. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002911496 · PTN002911496 UNRESOLVED The actual seeded ancestral node is preserved. Independent target or species-explicit ortholog evidence corroborates this biological assertion, but the historical IBD, alignment and placement have not been reconstructed. Donor count and target self-inclusion are not failure criteria. Supporting Evidence: PMID:25082542 switchable adaptor that links gephyrin to plasma membrane phosphoinositides. PMID:15215304 gephyrin clustering in recombinant systems and cultured neurons requires both collybistin-gephyrin interactions and an intact collybistin pleckstrin homology domain. |
| GO:0099572 postsynaptic specialization | IBA GO_REF:0000033 | ACCEPT | Summary: Rodent neuronal evidence supports the inherited postsynaptic compartment. Reason: Rodent neuronal recruitment and localization place collybistin at postsynaptic specializations, supporting the conserved broad location. Exact PTN002911496 topology and individual human isoform localization remain unresolved, without evidence of target loss or divergence. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002911496 · PTN002911496 UNRESOLVED The actual seeded ancestral node is preserved. Independent target or species-explicit ortholog evidence corroborates this biological assertion, but the historical IBD, alignment and placement have not been reconstructed. Donor count and target self-inclusion are not failure criteria. Supporting Evidence: PMID:25082542 switchable adaptor that links gephyrin to plasma membrane phosphoinositides. PMID:15215304 gephyrin clustering in recombinant systems and cultured neurons requires both collybistin-gephyrin interactions and an intact collybistin pleckstrin homology domain. |
| GO:0043495 protein-membrane adaptor activity | ISS PMID:25678704 Lipid binding defects and perturbed synaptogenic activity of... | NEW | Summary: Collybistin links gephyrin to membrane phosphoinositides. Reason: Rat collybistin binds gephyrin and phosphoinositides and recruits gephyrin to the plasma membrane; the species-explicit rat mutation assays separate retained gephyrin binding and exchange activity from defective lipid affinity and membrane recruitment. Transfer to human ARHGEF9 is explicitly ISS, corroborated by conserved domain architecture, human disease context and the independent 2014 switch mechanism. No direct human assay or exact human isoform is claimed. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9QX73 · rat Arhgef9 SUPPORTS TRANSFER The primary 2015 Figure 1 caption explicitly identifies the tested rat collybistin isoforms, distinct from the human disease residue. Gephyrin binding, lipid binding and membrane recruitment support the conserved adaptor activity; no direct human assay or exact current human isoform assignment is asserted. Supporting Evidence: file:human/ARHGEF9/ARHGEF9-notes.md GFP-Gephyrin forms microclusters at the plasma membrane. PMID:25082542 switchable adaptor that links gephyrin to plasma membrane phosphoinositides. PMID:25678704 phosphatidylinositol 3-phosphate binding affinity of Cb PMID:20345913 lacking any detectable GEF activity towards Cdc42 was still fully active in inducing gephyrin scaffold formation |
Loading supporting content…
Download this section (compressed HTML)Q: Which current human ARHGEF9 isoforms reproduce the independently separable exchange-factor and membrane-adaptor activities demonstrated with the historical human and rat constructs?
Q: Do the original HuRI and neurodegeneration pair-level records verify the ten retained ARHGEF9 interactions, including the named partner isoforms?
Q: What experimental descendant evidence and ancestral placements underlie PTN002911494 and PTN002911496, and which exact ARHGEF9 participants support the p75NTR, RhoA/B/C and GABA-conductance location records?
Experiment: Compare accession-defined human ARHGEF9 isoforms in purified nucleotide-exchange assays and in cellular gephyrin recruitment assays, with separate loss-of-exchange and loss-of-lipid-binding mutants.
Experiment: Test endogenous human neuronal collybistin localization and gephyrin recruitment while separately measuring CDC42 activation, avoiding an assumption that these two activities are obligatorily coupled.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)