CHN1 encodes alpha-chimaerin Rac GTPase-activating proteins that promote GTP hydrolysis on Rac and restrain Rac-dependent cytoskeletal signaling. The alpha2 product contains an N-terminal SH2 domain in addition to a lipid-responsive C1 region and a C-terminal GAP domain; alpha1 has a different N terminus. Alpha2 associates with Eph receptors and couples guidance cues to spatially regulated Rac signaling in developing axons. Mouse and chick studies establish roles in growth-cone responses and motor-axon trajectory selection, while human dominant gain-of-function variants cause Duane retraction syndrome and strengthen Rac inactivation. Cytosolic alpha2 can redistribute toward membranes after stimulation. In human alpha2, C1-dependent diacylglycerol recognition helps control membrane recruitment, while intramolecular contacts restrain ligand access.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005096 GTPase activator activity | IBA GO_REF:0000033 | ACCEPT | Summary: Retain the conserved Rac-directed GAP function. Reason: PTN001141948 is a curated ancestral assertion, not a pairwise donor vote. Rat Chn2, human CHN2 and fish chn1 identities are consistent with chimaerin-family evidence; historical node placement remains uninspected. Independent PMID:8336731 purified human alpha2 assays establish Rac GAP activity, with Rho and CDC42Hs negative only in the tested conditions. GO:0005096 includes Rac GAP as a narrow synonym, without a narrower is_a molecular-function child. The old construct is not assigned to all current products. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001141948 UNRESOLVED The original PAINT ancestral identifier and curated propagation are preserved. Current target/ortholog experiments corroborate biological applicability, but historical tree placement, MSA and IBD provenance were not independently reconstructed. This is not a donor-count or self-source objection. Supporting Evidence: GO_REF:0000033 PMID:8336731 exhibited racGAP activity file:human/CHN1/CHN1-source-evidence.json |
| GO:0005096 GTPase activator activity | IEA GO_REF:0000002 | ACCEPT | Summary: Retain the chimaerin-domain GAP inference. Reason: Official IPR017356 and IPR037860 map to the original function and match the chimaerin family/domain. Independent purified human alpha2 Rac-GAP assays in PMID:8336731 establish target-specific applicability, beyond the domain name. PMID:18653847 corroborates reduced Rac-GTP in human cells but is not a purified turnover assay. Current GO:0005096 already encompasses Rac GAP; old constructs are not equated to all three products. Supporting Evidence: GO_REF:0000002 file:human/CHN1/CHN1-source-evidence.json |
| GO:0005096 GTPase activator activity | TAS Reactome:R-HSA-9013144 | ACCEPT | Summary: Retain the Reactome RAC1 GAP activity. Reason: Reaction R-HSA-9013144 uses catalyst9013174 and RAC1-GAP set9013175, whose explicit member2980571 is human CHN1/P15882 in the cytosol. CHN1 supplies GAP activity to the RAC1 substrate; intrinsic GTP hydrolysis by CHN1 is not claimed. Independent PMID:8336731 establishes purified human alpha2 Rac GAP, with separate rat-brain p45 and tested Rho/CDC42 limits. GO:0005096 includes this specificity. |
| GO:0005515 protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | KEEP AS NON CORE | Summary: Retain the source-specific NCK2 binding evidence. Reason: The exact original CHN1–NCK2 pair is present in MINT record line4 under PMID:21516116: human proteins, yeast two-hybrid, fusion constructs and negative=false. Original Methods remove autoactivators, use reporter/CHX controls and pairwise retesting. The original supplementary target table remained inaccessible, but the literal curated record resolves the pair. NCK2 is an adaptor, but the screen does not demonstrate CHN1 performing an adaptor activity or resolve the bound NCK2 domain. Independent 2007 GST/lysate association supports biological compatibility while leaving construct species and precise interface scope separate. Generic binding is retained as non-core under the campaign policy. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Retain the source-specific NCK2 binding evidence. Reason: Five exact IntAct records retain the human CHN1–NCK2 pair under PMID:25416956, including pooling/array and validated two-hybrid methods. Fresh normal full Results/Methods describe quadruplicate retesting and identity confirmation; selected main bytes are preserved even though they contain less of the paper. NCK2 is an adaptor, but the screen does not demonstrate CHN1 performing an adaptor activity or resolve the bound NCK2 domain. Independent 2007 GST/lysate association supports biological compatibility while leaving construct species and precise interface scope separate. Generic binding is retained as non-core under the campaign policy. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MODIFY | Summary: Refine the verified HEMK1 interaction to enzyme binding. Reason: Three exact IntAct records retain the human CHN1–HEMK1 pair under PMID:25416956. The full primary describes sequence-confirmed, repeatedly positive yeast two-hybrid pairs; orthogonal validation is a dataset-level assessment, not an independently established CHN1-specific mammalian assay. Exact partner Q9Y5R4 is the curated protein-glutamine methyltransferase HEMK1. GO:0019899 requires binding to an enzyme, not regulation or transfer of its chemistry. This is a non-core, assay-scoped class refinement; it does not place CHN1 in mitochondria or assign methyltransferase activity. Proposed replacements: enzyme binding |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | KEEP AS NON CORE | Summary: Retain the source-specific NCK2 binding evidence. Reason: Three exact IntAct records under PMID:25910212 retain CHN1–NCK2. Mutation annotations at CHN1 positions20/223/228/252 are recorded as no-effect in the literal features, alongside a pooling record. Original Methods compare matched wild-type and mutant human ORFs after autoactivator removal; do not assign these allele observations identically to every product. NCK2 is an adaptor, but the screen does not demonstrate CHN1 performing an adaptor activity or resolve the bound NCK2 domain. Independent 2007 GST/lysate association supports biological compatibility while leaving construct species and precise interface scope separate. Generic binding is retained as non-core under the campaign policy. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | KEEP AS NON CORE | Summary: Retain the source-specific NCK2 binding evidence. Reason: The exact PMID:31515488 CHN1–NCK2 record has a CHN1 position115 no-effect mutation feature. Actual Y2H Methods compare mutant and wild-type interactions with empty-vector autoactivation controls; this is a retained assay interaction, not proof of a native neuronal complex. NCK2 is an adaptor, but the screen does not demonstrate CHN1 performing an adaptor activity or resolve the bound NCK2 domain. Independent 2007 GST/lysate association supports biological compatibility while leaving construct species and precise interface scope separate. Generic binding is retained as non-core under the campaign policy. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | MODIFY | Summary: Refine the verified HEMK1 interaction to enzyme binding. Reason: Two exact PMID:31515488 CHN1–HEMK1 records contain disrupting CHN1 mutation features at positions115/200. Actual Methods define disruption relative to a positive wild-type interaction, require neither construct to autoactivate and reproduce reduced growth across three screens. Retain the wild-type interaction context; do not call the disruptive mutant interaction intact. Exact partner Q9Y5R4 is the curated protein-glutamine methyltransferase HEMK1. GO:0019899 requires binding to an enzyme, not regulation or transfer of its chemistry. This is a non-core, assay-scoped class refinement; it does not place CHN1 in mitochondria or assign methyltransferase activity. Proposed replacements: enzyme binding |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the source-specific NCK2 binding evidence. Reason: Six exact PMID:32296183 CHN1–NCK2 records are positive human ORF yeast two-hybrid results with N- or C-terminal Gal4 fusions. The primary describes three assay versions, quadruplicate retesting and sequence confirmation. No CHN1-specific endogenous co-immunoprecipitation or native bridge was established. NCK2 is an adaptor, but the screen does not demonstrate CHN1 performing an adaptor activity or resolve the bound NCK2 domain. Independent 2007 GST/lysate association supports biological compatibility while leaving construct species and precise interface scope separate. Generic binding is retained as non-core under the campaign policy. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Refine the verified kinase interaction to protein kinase binding. Reason: Three exact PMID:32296183 CHN1–MAPK1 records are positive human ORF yeast two-hybrid results with Gal4 fusion features. Original HuRI verification supports assay binding capability; endogenous pathway coupling and regulation of kinase activity are not inferred. GO:0019901 describes binding to a protein kinase. The exact positive pair plus independently verified partner class supports this non-core refinement, without claiming kinase activation, a native encounter or phosphorylation of CHN1. Proposed replacements: protein kinase binding |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Refine the verified kinase interaction to protein kinase binding. Reason: Three exact PMID:32296183 CHN1–ANKK1 records are positive human ORF yeast two-hybrid results with Gal4 fusion features. The exact Q8NFD2 UniProt record classifies ANKK1 as a protein serine/threonine kinase and records catalytic reactions; this curated class is distinguished from a new CHN1-specific kinase-turnover experiment. GO:0019901 describes binding to a protein kinase. The exact positive pair plus independently verified partner class supports this non-core refinement, without claiming kinase activation, a native encounter or phosphorylation of CHN1. Proposed replacements: protein kinase binding |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Refine the verified HEMK1 interaction to enzyme binding. Reason: Three exact PMID:32296183 CHN1–HEMK1 records are positive human ORF yeast two-hybrid results with Gal4 fusion features. Dataset-wide orthogonal validation does not establish a native CHN1–HEMK1 complex or regulation of methylation. Exact partner Q9Y5R4 is the curated protein-glutamine methyltransferase HEMK1. GO:0019899 requires binding to an enzyme, not regulation or transfer of its chemistry. This is a non-core, assay-scoped class refinement; it does not place CHN1 in mitochondria or assign methyltransferase activity. Proposed replacements: enzyme binding |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9013144 | ACCEPT | Summary: Retain the soluble cytosolic signaling pool. Reason: The authentic Reactome catalyst set explicitly contains CHN1/P15882 entity2980571 in the cytosol. Human-cell fractionation in PMID:18653847 also measures a cytosolic alpha2 pool and regulated membrane redistribution after PMA. A soluble pool is compatible with stimulus-dependent membrane recruitment; neither constant membrane residence nor all-product localization is inferred. |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | MODIFY | Summary: Refine broad signaling to small-GTPase signal regulation. Reason: IPR000198 is the Rho GTPase-activating protein domain and authentically maps to the broad signal-transduction term. Direct human Rac-GAP assays establish the better-scoped process GO:0051056. This is a source-preserving refinement converging with the distinct original ARBA/Reactome assertions, not a new process or a claim that the original InterPro mapping is malformed. This third source route adds provenance for the same function, not a third biological activity or a NEW annotation. Proposed replacements: regulation of small GTPase mediated signal transduction Supporting Evidence: GO_REF:0000002 file:human/CHN1/CHN1-source-evidence.json |
| GO:0008045 motor neuron axon guidance | IBA GO_REF:0000033 | ACCEPT | Summary: Retain conserved motor-neuron axon guidance. Reason: The preserved PTN002918248 propagation is consistent with experimental mouse Chn1 grounding; historical ancestral placement was not reconstructed. PMID:25673830 tests mouse and chick spinal motor axons: alpha2 loss, GAP-inactive constructs and altered dosage perturb EphA-dependent trajectory selection without changing motor-neuron number/type. Endogenous mouse spinal-cord co-IP supports EphA4/EphB1 association; the measured functional motor response is EphA-selective. These experiments establish performed GAP-dependent guidance, with alpha2-specific scope. Human PMID:18653847 adds mutant Rac regulation and dosage-dependent chick axon effects, not an endogenous human circuit assay. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002918248 UNRESOLVED The original PAINT ancestral identifier and curated propagation are preserved. Current target/ortholog experiments corroborate biological applicability, but historical tree placement, MSA and IBD provenance were not independently reconstructed. This is not a donor-count or self-source objection. Supporting Evidence: GO_REF:0000033 PMID:25673830 cell-autonomous GAP activity file:human/CHN1/CHN1-source-evidence.json |
| GO:0008045 motor neuron axon guidance | IEA GO_REF:0000107 | ACCEPT | Summary: Retain conserved motor-neuron axon guidance. Reason: The exact Q91V57/ENSMUSP00000107655 mouse donor fields remain unchanged; the automated orthology inference has positive experimental grounding. PMID:25673830 tests mouse and chick spinal motor axons: alpha2 loss, GAP-inactive constructs and altered dosage perturb EphA-dependent trajectory selection without changing motor-neuron number/type. Endogenous mouse spinal-cord co-IP supports EphA4/EphB1 association; the measured functional motor response is EphA-selective. These experiments establish performed GAP-dependent guidance, with alpha2-specific scope. Human PMID:18653847 adds mutant Rac regulation and dosage-dependent chick axon effects, not an endogenous human circuit assay. Supporting Evidence: GO_REF:0000107 PMID:25673830 cell-autonomous GAP activity file:human/CHN1/CHN1-source-evidence.json |
| GO:0008045 motor neuron axon guidance | ISS GO_REF:0000024 | ACCEPT | Summary: Retain conserved motor-neuron axon guidance. Reason: The original curator-reviewed Q91V57 orthology transfer has positive experimental grounding and remains unchanged. PMID:25673830 tests mouse and chick spinal motor axons: alpha2 loss, GAP-inactive constructs and altered dosage perturb EphA-dependent trajectory selection without changing motor-neuron number/type. Endogenous mouse spinal-cord co-IP supports EphA4/EphB1 association; the measured functional motor response is EphA-selective. These experiments establish performed GAP-dependent guidance, with alpha2-specific scope. Human PMID:18653847 adds mutant Rac regulation and dosage-dependent chick axon effects, not an endogenous human circuit assay. Supporting Evidence: GO_REF:0000024 PMID:25673830 cell-autonomous GAP activity file:human/CHN1/CHN1-source-evidence.json |
| GO:0046875 ephrin receptor binding | IBA GO_REF:0000033 | ACCEPT | Summary: Retain conserved ephrin-receptor binding. Reason: The source mouse Q91V57/Chn1 record includes experimental Eph-receptor binding under PMID:17719550 and PMID:17785183. The PMID:17719550 premise is its authentic abstract and literal donor record, not a full-body read. Independently recovered original PMID:17785182/17785183 Results demonstrate GST/lysate association with Eph receptors, including phosphorylation dependence for alpha2; failed co-immunoprecipitation in those conditions is reported separately. Independent PMID:25673830 provides endogenous mouse spinal-cord EphA4/EphB1 co-immunoprecipitation. These positive assays support conserved receptor binding without asserting a purified human binary interface, binding to every Eph receptor or equal behavior of all three human products. PTN000571682 remains an authenticated curated source identifier with uninspected historical placement. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000571682 UNRESOLVED The original PAINT ancestral identifier and curated propagation are preserved. Current target/ortholog experiments corroborate biological applicability, but historical tree placement, MSA and IBD provenance were not independently reconstructed. This is not a donor-count or self-source objection. Supporting Evidence: GO_REF:0000033 PMID:17785183 interacts with activated EphA4 file:human/CHN1/CHN1-source-evidence.json |
| GO:0046875 ephrin receptor binding | IEA GO_REF:0000107 | ACCEPT | Summary: Retain conserved ephrin-receptor binding. Reason: The source mouse Q91V57/Chn1 record includes experimental Eph-receptor binding under PMID:17719550 and PMID:17785183. The PMID:17719550 premise is its authentic abstract and literal donor record, not a full-body read. Independently recovered original PMID:17785182/17785183 Results demonstrate GST/lysate association with Eph receptors, including phosphorylation dependence for alpha2; failed co-immunoprecipitation in those conditions is reported separately. Independent PMID:25673830 provides endogenous mouse spinal-cord EphA4/EphB1 co-immunoprecipitation. These positive assays support conserved receptor binding without asserting a purified human binary interface, binding to every Eph receptor or equal behavior of all three human products. The exact mouse-protein/Ensembl donor pair remains intact. Supporting Evidence: GO_REF:0000107 PMID:17785183 interacts with activated EphA4 file:human/CHN1/CHN1-source-evidence.json |
| GO:0048013 ephrin receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Retain performed Eph-receptor signaling. Reason: Alpha2 chimaerin supplies a Rac-regulatory step downstream of Eph-receptor stimulation, supported by actual receptor association, growth-cone responses and GAP-domain perturbations. Mouse and chick motor-neuron assays specifically separate EphA-dependent responses from EphB responses, despite binding to both receptor classes. The existing broad pathway term is valid without claiming universal receptor activation of GAP activity. The original PTN002918248 propagation is retained without reconstructing the ancestral node. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002918248 UNRESOLVED The original PAINT ancestral identifier and curated propagation are preserved. Current target/ortholog experiments corroborate biological applicability, but historical tree placement, MSA and IBD provenance were not independently reconstructed. This is not a donor-count or self-source objection. Supporting Evidence: GO_REF:0000033 file:human/CHN1/CHN1-source-evidence.json |
| GO:0048013 ephrin receptor signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: Retain performed Eph-receptor signaling. Reason: Alpha2 chimaerin supplies a Rac-regulatory step downstream of Eph-receptor stimulation, supported by actual receptor association, growth-cone responses and GAP-domain perturbations. Mouse and chick motor-neuron assays specifically separate EphA-dependent responses from EphB responses, despite binding to both receptor classes. The existing broad pathway term is valid without claiming universal receptor activation of GAP activity. The source specifies mouse Q91V57-2; that donor field is preserved rather than copied into an unsupported human isoform tag. Supporting Evidence: GO_REF:0000024 file:human/CHN1/CHN1-source-evidence.json |
| GO:0050770 regulation of axonogenesis | IEA GO_REF:0000107 | ACCEPT | Summary: Retain regulation of axon growth and guidance. Reason: The ortholog source and actual mouse/chick experiments show CHN1-dependent growth-cone responses and altered axon trajectories, with GAP and SH2 functions tested. This is regulation performed through Rac signaling, not merely a disease phenotype. Human alpha2 overexpression also changes chick axon growth, but WT overexpression itself stalls axons, so dosage perturbation is not equated to normal human circuit function. The exact mouse donor and its product scope remain unchanged; no all-product functional equivalence is inferred. The broader regulation-of-axonogenesis term describes this core Rac-dependent control of axon growth and guidance; its exact identifier need not be repeated in the concise core process list. Supporting Evidence: GO_REF:0000107 file:human/CHN1/CHN1-source-evidence.json |
| GO:0050770 regulation of axonogenesis | ISS GO_REF:0000024 | ACCEPT | Summary: Retain regulation of axon growth and guidance. Reason: The ortholog source and actual mouse/chick experiments show CHN1-dependent growth-cone responses and altered axon trajectories, with GAP and SH2 functions tested. This is regulation performed through Rac signaling, not merely a disease phenotype. Human alpha2 overexpression also changes chick axon growth, but WT overexpression itself stalls axons, so dosage perturbation is not equated to normal human circuit function. The exact mouse donor and its product scope remain unchanged; no all-product functional equivalence is inferred. The broader regulation-of-axonogenesis term describes this core Rac-dependent control of axon growth and guidance; its exact identifier need not be repeated in the concise core process list. Supporting Evidence: GO_REF:0000024 file:human/CHN1/CHN1-source-evidence.json |
| GO:0051056 regulation of small GTPase mediated signal transduction | IEA GO_REF:0000120 | ACCEPT | Summary: Retain direct regulation of small-GTPase signaling. Reason: CHN1 promotes hydrolysis of GTP bound to Rac and thereby reduces the active Rac-GTP pool. Purified human alpha2 assays and independent human-cell measurements directly support this regulatory step. The authentic chimaerin InterPro family mapping supports applicability; the historical ARBA execution was not reconstructed. Supporting Evidence: GO_REF:0000120 file:human/CHN1/CHN1-source-evidence.json |
| GO:0051056 regulation of small GTPase mediated signal transduction | TAS Reactome:R-HSA-9012999 | ACCEPT | Summary: Retain direct regulation of small-GTPase signaling. Reason: CHN1 promotes hydrolysis of GTP bound to Rac and thereby reduces the active Rac-GTP pool. Purified human alpha2 assays and independent human-cell measurements directly support this regulatory step. The authentic Reactome RHO GTPase cycle contains the CHN1-bearing RAC1-GAP reaction. This does not make CHN1 a universal GAP for all RHO-family proteins. Supporting Evidence: Reactome:R-HSA-9012999 file:human/CHN1/CHN1-source-evidence.json |
| GO:0019992 diacylglycerol binding | IMP PMID:18826946 Identification of an autoinhibitory mechanism that restricts... | NEW | Summary: Add human alpha2 C1-dependent DAG recognition at the experimentally supported inference level. Reason: Actual PMID:18826946 Methods identify sequence-verified human alpha2 cloned from SW480 cells. In HeLa cells, EGF-induced membrane redistribution is inhibited by PLC inhibitor U73122 and lost with the ligand-deficient C1 mutant P216A (Fig. 8). Together with C1 ligand-response controls, this supports diacylglycerol recognition that helps anchor alpha2 at membranes. IMP records the perturbation-based inference: this paper does not directly measure purified human alpha2 DAG-binding affinity. Autoinhibition and additional inputs limit the response, so DAG binding is not equated with sufficient GAP activation or every recruitment pathway. No exact current-product sequence alignment or equal activity of all three products is asserted. PMID:8336731 phosphatidylserine stimulation and PMID:7518459 phorbol-ester binding are distinct observations, not direct DAG-binding assays. Supporting Evidence: PMID:18826946 DAG generation and binding to the C1 domain |
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Download this section (compressed HTML)Q: How do the three sequence-verified human CHN1 products differ in receptor coupling, Rac-substrate preference and membrane recruitment at endogenous expression?
Q: How does Eph-dependent recruitment control local Rac inactivation when receptor coexpression alone does not consistently increase bulk GAP activity?
Q: Do the verified CHN1 interactions with HEMK1, MAPK1 and ANKK1 occur in the same endogenous cellular compartment, and what consequence follows from binding?
Q: How do endogenous diacylglycerol species and additional receptor inputs regulate membrane recruitment and Rac-GAP activity of each sequence-verified human CHN1 product, and what are their direct ligand affinities?
Experiment: At matched endogenous expression, combine sequence-verified human alpha2, SH2-disruptive and GAP-inactive alleles with Eph stimulation and spatial Rac biosensors in human motor-neuron growth cones; measure local Rac kinetics, membrane recruitment and directional turning separately from total Rac-GTP.
Hypothesis: Spatial recruitment rather than a uniform increase in bulk catalytic activity controls the alpha2 guidance response.
Experiment: Purify all three sequence-verified human products and compare Rac, Rho and CDC42 hydrolysis across defined lipid conditions, with catalytic controls; independently test receptor association so that binding and enzyme activity remain separable.
Hypothesis: Human CHN1 products differ in regulated catalytic output.
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