GRK5 is a serine/threonine kinase that phosphorylates activated G protein-coupled receptors and regulates their signaling. Phospholipid interactions and a C-terminal amphipathic region support its plasma-membrane association. GRK5 also enters the nucleus and phosphorylates non-receptor substrates, including p53, giving it context-dependent roles in stress responses, survival and proliferation. Its receptor recruitment differs from GRK2, and kinase activity does not imply the same regulatory outcome for every receptor or cell type.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004672 protein kinase activity | IBA GO_REF:0000033 | MODIFY | Summary: GRK5 is a serine/threonine kinase with GPCR and non-receptor substrates, including p53. Reason: Refine the generic kinase term to the supported residue specificity rather than restrict every catalytic row to GPCR substrates. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: PANTHER:PTN001219783 SUPPORTS TRANSFER GRK5 is a serine/threonine kinase with GPCR and non-receptor substrates, including p53. Refine the generic kinase term to the supported residue specificity rather than restrict every catalytic row to GPCR substrates. Proposed replacements: protein serine/threonine kinase activity |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:20124405 G-protein-coupled receptor kinase 5 phosphorylates p53 and i... | ACCEPT | Summary: Purified GRK5 phosphorylates activated beta2-adrenergic, M2-muscarinic and rhodopsin receptors using ATP, and independent experiments establish non-receptor serine/threonine substrates. Reason: Retain catalytic and ATP-binding functions with substrate-specific assay scope. |
| GO:0004674 protein serine/threonine kinase activity | IEA GO_REF:0000002 | ACCEPT | Summary: Purified GRK5 phosphorylates activated beta2-adrenergic, M2-muscarinic and rhodopsin receptors using ATP, and independent experiments establish non-receptor serine/threonine substrates. Reason: Retain catalytic and ATP-binding functions with substrate-specific assay scope. |
| GO:0004703 G protein-coupled receptor kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Purified GRK5 phosphorylates activated beta2-adrenergic, M2-muscarinic and rhodopsin receptors using ATP, and independent experiments establish non-receptor serine/threonine substrates. Reason: Retain catalytic and ATP-binding functions with substrate-specific assay scope. |
| GO:0005080 protein kinase C binding | TAS PMID:9813065 Structure-function analysis of G protein-coupled receptor ki... | UNDECIDED | Summary: The source establishes phosphorylation/regulation of GRK5 by protein kinase C, but the accessible text does not resolve whether an independently demonstrated binary PKC-binding interaction supports this specific binding term. Reason: Substrate phosphorylation alone does not specify the affinity/association claim; it remains unresolved. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:17986524 Characterization of G-protein coupled receptor kinase intera... | REMOVE | Summary: Remove bare protein binding as uninformative under the project policy, while preserving specific catalytic, lipid-binding and receptor-regulatory functions. Reason: Remove bare protein binding as uninformative under the project policy, while preserving specific catalytic, lipid-binding and receptor-regulatory functions. |
| GO:0005515 protein binding | IPI PMID:19008357 The G-protein-coupled receptor kinase 5 inhibits NFkappaB tr... | REMOVE | Summary: Remove bare protein binding as uninformative under the project policy, while preserving specific catalytic, lipid-binding and receptor-regulatory functions. Reason: Remove bare protein binding as uninformative under the project policy, while preserving specific catalytic, lipid-binding and receptor-regulatory functions. |
| GO:0005515 protein binding | IPI PMID:19661922 Beta-arrestin1 phosphorylation by GRK5 regulates G protein-i... | REMOVE | Summary: Remove bare protein binding as uninformative under the project policy, while preserving specific catalytic, lipid-binding and receptor-regulatory functions. Reason: Remove bare protein binding as uninformative under the project policy, while preserving specific catalytic, lipid-binding and receptor-regulatory functions. |
| GO:0005515 protein binding | IPI PMID:20124405 G-protein-coupled receptor kinase 5 phosphorylates p53 and i... | REMOVE | Summary: Remove bare protein binding as uninformative under the project policy, while preserving specific catalytic, lipid-binding and receptor-regulatory functions. Reason: Remove bare protein binding as uninformative under the project policy, while preserving specific catalytic, lipid-binding and receptor-regulatory functions. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: Purified GRK5 phosphorylates activated beta2-adrenergic, M2-muscarinic and rhodopsin receptors using ATP, and independent experiments establish non-receptor serine/threonine substrates. Reason: Retain catalytic and ATP-binding functions with substrate-specific assay scope. |
| GO:0005543 phospholipid binding | TAS PMID:9813065 Structure-function analysis of G protein-coupled receptor ki... | ACCEPT | Summary: The C-terminal region directly mediates phospholipid interaction and membrane-dependent regulation. Reason: This binding is integral to localization and catalysis rather than a peripheral annotation. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Nuclear GRK5 activity and p53 regulation support a nuclear pool independently of the predominant plasma-membrane role. Reason: Retain the compartment without asserting exclusively nuclear localization. Supporting Evidence: |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: GRK5 has an intracellular cytoplasmic pool and membrane-associated activity. Reason: Cellular localization studies support the broad cytoplasmic assertion without excluding the separately supported nuclear pool. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: GRK5 has an intracellular cytoplasmic pool and membrane-associated activity. Reason: Cellular localization studies support the broad cytoplasmic assertion without excluding the separately supported nuclear pool. |
| GO:0005737 cytoplasm | TAS PMID:7685906 Cloning and expression of GRK5: a member of the G protein-co... | ACCEPT | Summary: GRK5 has an intracellular cytoplasmic pool and membrane-associated activity. Reason: Cellular localization studies support the broad cytoplasmic assertion without excluding the separately supported nuclear pool. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: Full-length GRK5 localization and C-terminal amphipathic-region mutagenesis establish plasma-membrane targeting; NK1 experiments additionally show receptor preassociation. Reason: Retain this experimentally supported compartment. |
| GO:0005886 plasma membrane | IDA PMID:14976207 A predicted amphipathic helix mediates plasma membrane local... | ACCEPT | Summary: Full-length GRK5 localization and C-terminal amphipathic-region mutagenesis establish plasma-membrane targeting; NK1 experiments additionally show receptor preassociation. Reason: Retain this experimentally supported compartment. |
| GO:0005886 plasma membrane | IDA PMID:17986524 Characterization of G-protein coupled receptor kinase intera... | ACCEPT | Summary: Full-length GRK5 localization and C-terminal amphipathic-region mutagenesis establish plasma-membrane targeting; NK1 experiments additionally show receptor preassociation. Reason: Retain this experimentally supported compartment. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Full-length GRK5 localization and C-terminal amphipathic-region mutagenesis establish plasma-membrane targeting; NK1 experiments additionally show receptor preassociation. Reason: Retain this experimentally supported compartment. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8851797 | ACCEPT | Summary: Full-length GRK5 localization and C-terminal amphipathic-region mutagenesis establish plasma-membrane targeting; NK1 experiments additionally show receptor preassociation. Reason: Retain this experimentally supported compartment. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8982641 | ACCEPT | Summary: Full-length GRK5 localization and C-terminal amphipathic-region mutagenesis establish plasma-membrane targeting; NK1 experiments additionally show receptor preassociation. Reason: Retain this experimentally supported compartment. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8982645 | ACCEPT | Summary: Full-length GRK5 localization and C-terminal amphipathic-region mutagenesis establish plasma-membrane targeting; NK1 experiments additionally show receptor preassociation. Reason: Retain this experimentally supported compartment. |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | MODIFY | Summary: The protein has specifically established regulation of GPCR signaling, more informative than generic signal transduction or its regulation. Reason: Refine those broad terms while retaining separate non-receptor nuclear functions. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: InterPro:IPR000239 SUPPORTS TRANSFER The protein has specifically established regulation of GPCR signaling, more informative than generic signal transduction or its regulation. Refine those broad terms while retaining separate non-receptor nuclear functions. Proposed replacements: regulation of G protein-coupled receptor signaling pathway |
| GO:0007186 G protein-coupled receptor signaling pathway | TAS Reactome:R-HSA-388396 | ACCEPT | Summary: Direct phosphorylation of activated receptors and functional desensitization/coupling assays establish GPCR regulation as a core role. Reason: Regulatory outcomes depend on receptor and cellular context. |
| GO:0007188 adenylate cyclase-modulating G protein-coupled receptor signaling pathway | TAS PMID:8626574 Involvement of G protein-coupled receptor kinase 5 in homolo... | KEEP AS NON CORE | Summary: The rat thyroid-cell study demonstrates GRK5-dependent regulation of TSH receptor/cAMP responsiveness. Reason: Retain this comparative receptor-specific cyclase-modulating implementation, not direct phosphorylation or catalysis of adenylyl cyclase itself. Supporting Evidence: |
| GO:0007217 tachykinin receptor signaling pathway | IDA PMID:17986524 Characterization of G-protein coupled receptor kinase intera... | KEEP AS NON CORE | Summary: The NK1 study shows GRK5 preassociation and kinase-dependent receptor interaction changes, providing a tachykinin signaling implementation distinct from GRK2 recruitment. Reason: The NK1 study shows GRK5 preassociation and kinase-dependent receptor interaction changes, providing a tachykinin signaling implementation distinct from GRK2 recruitment. Supporting Evidence: |
| GO:0008277 regulation of G protein-coupled receptor signaling pathway | IEA GO_REF:0000117 | ACCEPT | Summary: Direct phosphorylation of activated receptors and functional desensitization/coupling assays establish GPCR regulation as a core role. Reason: Regulatory outcomes depend on receptor and cellular context. |
| GO:0008277 regulation of G protein-coupled receptor signaling pathway | TAS PMID:8288567 Expression, purification, and characterization of the G prot... | ACCEPT | Summary: Direct phosphorylation of activated receptors and functional desensitization/coupling assays establish GPCR regulation as a core role. Reason: Regulatory outcomes depend on receptor and cellular context. |
| GO:0008284 positive regulation of cell population proliferation | IMP PMID:22099983 G-protein coupled receptor kinase 5 regulates prostate tumor... | KEEP AS NON CORE | Summary: Human prostate-cancer cell knockdown/rescue experiments link GRK5 kinase activity to proliferation and cell-cycle progression. Reason: Retain these tested cellular effects without making them universal properties of every GRK5-expressing tissue. Supporting Evidence: |
| GO:0009966 regulation of signal transduction | IBA GO_REF:0000033 | MODIFY | Summary: The protein has specifically established regulation of GPCR signaling, more informative than generic signal transduction or its regulation. Reason: Refine those broad terms while retaining separate non-receptor nuclear functions. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: PANTHER:PTN001219785 SUPPORTS TRANSFER The protein has specifically established regulation of GPCR signaling, more informative than generic signal transduction or its regulation. Refine those broad terms while retaining separate non-receptor nuclear functions. Proposed replacements: regulation of G protein-coupled receptor signaling pathway |
| GO:0016607 nuclear speck | IDA GO_REF:0000052 | UNDECIDED | Summary: The HPA fine-localization annotations are preserved, but target-specific images for nuclear speckles/nuclear membrane were not inspected. Reason: Independent nuclear function supports nucleus, not either finer microdomain by itself; neither precise claim is rejected on the basis of plasma-membrane localization. Supporting Evidence: |
| GO:0031965 nuclear membrane | IDA GO_REF:0000052 | UNDECIDED | Summary: The HPA fine-localization annotations are preserved, but target-specific images for nuclear speckles/nuclear membrane were not inspected. Reason: Independent nuclear function supports nucleus, not either finer microdomain by itself; neither precise claim is rejected on the basis of plasma-membrane localization. Supporting Evidence: |
| GO:0043066 negative regulation of apoptotic process | IDA PMID:20124405 G-protein-coupled receptor kinase 5 phosphorylates p53 and i... | KEEP AS NON CORE | Summary: The paper concludes that GRK5 phosphorylation of p53 promotes p53 degradation and reduces p53-dependent apoptosis, with increased irradiation-induced apoptosis in GRK5-deficient mice. Reason: Retain the negative regulatory outcome; the abstract contains inconsistent knockdown wording, so this judgment follows the mechanistic results/discussion rather than that isolated sentence. Supporting Evidence: |
| GO:0045444 fat cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Grk5-null mouse fibroblasts and preadipocytes show impaired adipogenic differentiation under induction, supporting a conserved regulatory role. Reason: Retain the native-mouse/orthology scope rather than infer human adipogenesis from expression alone. Supporting Evidence: |
| GO:0047696 beta-adrenergic receptor kinase activity | IMP PMID:20038610 Role for the regulator of G-protein signaling homology domai... | ACCEPT | Summary: Purified GRK5 phosphorylates activated beta2-adrenergic, M2-muscarinic and rhodopsin receptors using ATP, and independent experiments establish non-receptor serine/threonine substrates. Reason: Retain catalytic and ATP-binding functions with substrate-specific assay scope. |
| GO:0047696 beta-adrenergic receptor kinase activity | TAS Reactome:R-HSA-8851797 | ACCEPT | Summary: Purified GRK5 phosphorylates activated beta2-adrenergic, M2-muscarinic and rhodopsin receptors using ATP, and independent experiments establish non-receptor serine/threonine substrates. Reason: Retain catalytic and ATP-binding functions with substrate-specific assay scope. |
| GO:0051726 regulation of cell cycle | IMP PMID:22099983 G-protein coupled receptor kinase 5 regulates prostate tumor... | KEEP AS NON CORE | Summary: Human prostate-cancer cell knockdown/rescue experiments link GRK5 kinase activity to proliferation and cell-cycle progression. Reason: Retain these tested cellular effects without making them universal properties of every GRK5-expressing tissue. Supporting Evidence: |
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