RGS6 is a multidomain regulator of heterotrimeric G protein signaling in the R7 RGS subfamily. Its RGS domain accelerates G alpha inactivation, and its G gamma-like domain binds the atypical beta subunit GNB5 to assemble a signaling-regulatory complex. The RGS6βGNB5 complex has directly demonstrated GAP activity toward Go. DEP-domain partners and splice variation influence membrane, cytoplasmic and nuclear localization. RGS6 participates in neuronal signaling and in termination of cardiac muscarinic responses; native mouse experiments establish control of M2-dependent acetylcholine-activated potassium currents.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003924 GTPase activity | IEA GO_REF:0000117 | MODIFY | Summary: The G alpha substrate hydrolyzes GTP; RGS6 accelerates that reaction in partnership with GNB5. Reason: Refine the misassigned intrinsic GTPase activity to the existing GAP function. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: ARBA:ARBA00026818 UNRESOLVED The G alpha substrate hydrolyzes GTP; RGS6 accelerates that reaction in partnership with GNB5. Refine the misassigned intrinsic GTPase activity to the existing GAP function. Proposed replacements: GTPase activator activity Supporting Evidence: PMID:10521509 act as GTPase-activating proteins specifically toward Galpha(o) |
| GO:0003924 GTPase activity | TAS Reactome:R-HSA-8982020 | MODIFY | Summary: The G alpha substrate hydrolyzes GTP; RGS6 accelerates that reaction in partnership with GNB5. Reason: Refine the misassigned intrinsic GTPase activity to the existing GAP function. Proposed replacements: GTPase activator activity Supporting Evidence: PMID:10521509 act as GTPase-activating proteins specifically toward Galpha(o) |
| GO:0005096 GTPase activator activity | IBA GO_REF:0000033 | ACCEPT | Summary: RGS6βGNB5 purified complexes accelerate Go GTP hydrolysis (PMID:10521509), and native mouse Rgs6 deletion prolongs M2-linked GIRK signaling. Reason: These support GAP activity without assigning RGS4-like substrate breadth to every RGS6 complex. The conserved RGS domain and specific GNB5 partnership support the cross-species assignment. Supporting Evidence: PMID:10521509 act as GTPase-activating proteins specifically toward Galpha(o) |
| GO:0005096 GTPase activator activity | IDA PMID:10521509 Regulators of G protein signaling 6 and 7. Purification of c... | ACCEPT | Summary: RGS6βGNB5 purified complexes accelerate Go GTP hydrolysis (PMID:10521509), and native mouse Rgs6 deletion prolongs M2-linked GIRK signaling. Reason: These support GAP activity without assigning RGS4-like substrate breadth to every RGS6 complex. The conserved RGS domain and specific GNB5 partnership support the cross-species assignment. Supporting Evidence: PMID:10521509 act as GTPase-activating proteins specifically toward Galpha(o) |
| GO:0005096 GTPase activator activity | IEA GO_REF:0000120 | ACCEPT | Summary: RGS6βGNB5 purified complexes accelerate Go GTP hydrolysis (PMID:10521509), and native mouse Rgs6 deletion prolongs M2-linked GIRK signaling. Reason: These support GAP activity without assigning RGS4-like substrate breadth to every RGS6 complex. The conserved RGS domain and specific GNB5 partnership support the cross-species assignment. Supporting Evidence: PMID:10521509 act as GTPase-activating proteins specifically toward Galpha(o) |
| GO:0005096 GTPase activator activity | TAS PMID:10083744 The human regulator of G-protein signaling protein 6 gene (R... | ACCEPT | Summary: RGS6βGNB5 purified complexes accelerate Go GTP hydrolysis (PMID:10521509), and native mouse Rgs6 deletion prolongs M2-linked GIRK signaling. Reason: These support GAP activity without assigning RGS4-like substrate breadth to every RGS6 complex. The conserved RGS domain and specific GNB5 partnership support the cross-species assignment. Supporting Evidence: PMID:10521509 act as GTPase-activating proteins specifically toward Galpha(o) |
| GO:0005515 protein binding | IPI PMID:22939624 Quantitative analysis of HSP90-client interactions reveals p... | REMOVE | Summary: Remove uninformative bare protein binding under the project policy while retaining the specific GNB5-dependent GAP complex and supported biological functions. Reason: Remove uninformative bare protein binding under the project policy while retaining the specific GNB5-dependent GAP complex and supported biological functions. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Remove uninformative bare protein binding under the project policy while retaining the specific GNB5-dependent GAP complex and supported biological functions. Reason: Remove uninformative bare protein binding under the project policy while retaining the specific GNB5-dependent GAP complex and supported biological functions. |
| GO:0005634 nucleus | EXP PMID:12761221 Human RGS6 gene structure, complex alternative splicing, and... | KEEP AS NON CORE | Summary: Human RGS6 splice products exhibit different nuclear/cytoplasmic partitioning, and R7BP-dependent trafficking can redistribute R7βGNB5 assemblies. Reason: Retain the nuclear pool with product/partner dependence; this is not universal localization of every RGS6 product. Supporting Evidence: PMID:12761221 RGS6 protein variants displayed subcellular distribution patterns ranging from an exclusive cytoplasmic to exclusive nuclear/nucleolar localization PMID:15897264 R7BP binds the R7 subunit of the R7βGΞ²5 complex |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Human RGS6 splice products exhibit different nuclear/cytoplasmic partitioning, and R7BP-dependent trafficking can redistribute R7βGNB5 assemblies. Reason: Retain the nuclear pool with product/partner dependence; this is not universal localization of every RGS6 product. Supporting Evidence: PMID:12761221 RGS6 protein variants displayed subcellular distribution patterns ranging from an exclusive cytoplasmic to exclusive nuclear/nucleolar localization PMID:15897264 R7BP binds the R7 subunit of the R7βGΞ²5 complex |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: The existing nucleoplasmic assignment is compatible with independently observed nuclear RGS6 products. Reason: Retain this contextual pool, distinguishing the human imaging-based assignment from its conserved mouse inference and from the predominant membrane signaling role. Supporting Evidence: PMID:12761221 RGS6 protein variants displayed subcellular distribution patterns ranging from an exclusive cytoplasmic to exclusive nuclear/nucleolar localization |
| GO:0005737 cytoplasm | EXP PMID:12761221 Human RGS6 gene structure, complex alternative splicing, and... | ACCEPT | Summary: RGS6 has cytoplasmic and soluble pools supported by splice-product localization and RGS6βGNB5 biochemical studies. Reason: Membrane recruitment and nuclear redistribution coexist with these pools rather than disproving them. Supporting Evidence: PMID:10521509 act as GTPase-activating proteins specifically toward Galpha(o) PMID:12761221 RGS6 protein variants displayed subcellular distribution patterns ranging from an exclusive cytoplasmic to exclusive nuclear/nucleolar localization PMID:15897264 R7BP binds the R7 subunit of the R7βGΞ²5 complex |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: RGS6 has cytoplasmic and soluble pools supported by splice-product localization and RGS6βGNB5 biochemical studies. Reason: Membrane recruitment and nuclear redistribution coexist with these pools rather than disproving them. Supporting Evidence: PMID:10521509 act as GTPase-activating proteins specifically toward Galpha(o) PMID:12761221 RGS6 protein variants displayed subcellular distribution patterns ranging from an exclusive cytoplasmic to exclusive nuclear/nucleolar localization PMID:15897264 R7BP binds the R7 subunit of the R7βGΞ²5 complex |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: RGS6 has cytoplasmic and soluble pools supported by splice-product localization and RGS6βGNB5 biochemical studies. Reason: Membrane recruitment and nuclear redistribution coexist with these pools rather than disproving them. Supporting Evidence: PMID:10521509 act as GTPase-activating proteins specifically toward Galpha(o) PMID:12761221 RGS6 protein variants displayed subcellular distribution patterns ranging from an exclusive cytoplasmic to exclusive nuclear/nucleolar localization PMID:15897264 R7BP binds the R7 subunit of the R7βGΞ²5 complex |
| GO:0005829 cytosol | IDA PMID:10521509 Regulators of G protein signaling 6 and 7. Purification of c... | ACCEPT | Summary: RGS6 has cytoplasmic and soluble pools supported by splice-product localization and RGS6βGNB5 biochemical studies. Reason: Membrane recruitment and nuclear redistribution coexist with these pools rather than disproving them. Supporting Evidence: PMID:10521509 act as GTPase-activating proteins specifically toward Galpha(o) PMID:12761221 RGS6 protein variants displayed subcellular distribution patterns ranging from an exclusive cytoplasmic to exclusive nuclear/nucleolar localization PMID:15897264 R7BP binds the R7 subunit of the R7βGΞ²5 complex |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: RGS6 has cytoplasmic and soluble pools supported by splice-product localization and RGS6βGNB5 biochemical studies. Reason: Membrane recruitment and nuclear redistribution coexist with these pools rather than disproving them. Supporting Evidence: PMID:10521509 act as GTPase-activating proteins specifically toward Galpha(o) PMID:12761221 RGS6 protein variants displayed subcellular distribution patterns ranging from an exclusive cytoplasmic to exclusive nuclear/nucleolar localization PMID:15897264 R7BP binds the R7 subunit of the R7βGΞ²5 complex |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Membrane recruitment of R7 RGSβGNB5 complexes, including RGS6 binding to R7BP, supports the plasma-membrane signaling pool. Reason: Retain the supported compartment without manufacturing a topology-specific replacement from a recruitment assay. |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Membrane recruitment of R7 RGSβGNB5 complexes, including RGS6 binding to R7BP, supports the plasma-membrane signaling pool. Reason: Retain the supported compartment without manufacturing a topology-specific replacement from a recruitment assay. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8982012 | ACCEPT | Summary: Membrane recruitment of R7 RGSβGNB5 complexes, including RGS6 binding to R7BP, supports the plasma-membrane signaling pool. Reason: Retain the supported compartment without manufacturing a topology-specific replacement from a recruitment assay. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8982019 | ACCEPT | Summary: Membrane recruitment of R7 RGSβGNB5 complexes, including RGS6 binding to R7BP, supports the plasma-membrane signaling pool. Reason: Retain the supported compartment without manufacturing a topology-specific replacement from a recruitment assay. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8982020 | ACCEPT | Summary: Membrane recruitment of R7 RGSβGNB5 complexes, including RGS6 binding to R7BP, supports the plasma-membrane signaling pool. Reason: Retain the supported compartment without manufacturing a topology-specific replacement from a recruitment assay. |
| GO:0007186 G protein-coupled receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: RGS6 performs termination of GPCR signaling through its GAP complex. Reason: Native mouse M2 experiments support a specific cholinergic implementation; purified Go-directed activity establishes the molecular role independently. Supporting Evidence: PMID:10521509 act as GTPase-activating proteins specifically toward Galpha(o) |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000002 | ACCEPT | Summary: RGS6 performs termination of GPCR signaling through its GAP complex. Reason: Native mouse M2 experiments support a specific cholinergic implementation; purified Go-directed activity establishes the molecular role independently. Supporting Evidence: PMID:10521509 act as GTPase-activating proteins specifically toward Galpha(o) |
| GO:0007186 G protein-coupled receptor signaling pathway | TAS Reactome:R-HSA-388396 | ACCEPT | Summary: RGS6 performs termination of GPCR signaling through its GAP complex. Reason: Native mouse M2 experiments support a specific cholinergic implementation; purified Go-directed activity establishes the molecular role independently. Supporting Evidence: PMID:10521509 act as GTPase-activating proteins specifically toward Galpha(o) |
| GO:0008277 regulation of G protein-coupled receptor signaling pathway | IEA GO_REF:0000120 | ACCEPT | Summary: The regulation term captures the established RGS6 complex function. Reason: The physiological consequence depends on partner, receptor and cellular context; this broad process remains useful alongside positive regulation of GTPase activity. Supporting Evidence: PMID:10521509 act as GTPase-activating proteins specifically toward Galpha(o) |
| GO:0008277 regulation of G protein-coupled receptor signaling pathway | TAS PMID:10083744 The human regulator of G-protein signaling protein 6 gene (R... | ACCEPT | Summary: The regulation term captures the established RGS6 complex function. Reason: The physiological consequence depends on partner, receptor and cellular context; this broad process remains useful alongside positive regulation of GTPase activity. Supporting Evidence: PMID:10521509 act as GTPase-activating proteins specifically toward Galpha(o) |
| GO:0016020 membrane | IDA PMID:10521509 Regulators of G protein signaling 6 and 7. Purification of c... | MODIFY | Summary: The established membrane-associated signaling pool can be specified as plasma membrane, already separately annotated. Reason: This refinement does not exclude additional membrane compartments or erase the soluble pool. Proposed replacements: plasma membrane Supporting Evidence: PMID:15897264 R7BP binds the R7 subunit of the R7βGΞ²5 complex |
| GO:0016020 membrane | IEA GO_REF:0000044 | MODIFY | Summary: The established membrane-associated signaling pool can be specified as plasma membrane, already separately annotated. Reason: This refinement does not exclude additional membrane compartments or erase the soluble pool. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: UniProtKB-SubCell:SL-0162 SUPPORTS TRANSFER The established membrane-associated signaling pool can be specified as plasma membrane, already separately annotated. This refinement does not exclude additional membrane compartments or erase the soluble pool. Proposed replacements: plasma membrane Supporting Evidence: PMID:15897264 R7BP binds the R7 subunit of the R7βGΞ²5 complex |
| GO:0035556 intracellular signal transduction | IEA GO_REF:0000002 | MODIFY | Summary: For the represented core signaling function, RGS6 is specifically a regulator of GPCR signaling. Reason: Refine the very broad intracellular signal-transduction term to that established process rather than keep it merely as peripheral. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: InterPro:IPR000591 SUPPORTS TRANSFER For the represented core signaling function, RGS6 is specifically a regulator of GPCR signaling. Refine the very broad intracellular signal-transduction term to that established process rather than keep it merely as peripheral. Proposed replacements: regulation of G protein-coupled receptor signaling pathway Supporting Evidence: PMID:10521509 act as GTPase-activating proteins specifically toward Galpha(o) |
| GO:0043005 neuron projection | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The R7-family neuronal localization inference is compatible with neurite-associated RGS6βSCG10 function and neuronal RGS expression. Reason: Retain neuron projection as a contextual conserved location, not evidence that every human/mouse splice product occupies every neuronal projection. Supporting Evidence: PMID:12140291 the GGL domain of RGS6 as the SCG10-interacting region |
| GO:0043547 positive regulation of GTPase activity | IDA PMID:10521509 Regulators of G protein signaling 6 and 7. Purification of c... | ACCEPT | Summary: RGS6 directly accelerates G alpha GTPase activity in the purified RGS6βGNB5 complex. Reason: This positive regulation of GTP hydrolysis is the mechanism by which receptor signaling is terminated. Supporting Evidence: PMID:10521509 act as GTPase-activating proteins specifically toward Galpha(o) |
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