GRK2 is a serine/threonine protein kinase that phosphorylates activated G protein-coupled receptors, helping recruit arrestins and regulate receptor responsiveness and trafficking. Its membrane recruitment and activity depend on receptor engagement, phospholipids and G beta/gamma. GRK2 also has non-receptor substrates and kinase-independent regulatory interactions. Cytosolic and plasma-membrane pools participate in neurotransmitter and cardiovascular signaling, while mitochondrial-surface and ciliary pools support distinct metabolic and Hedgehog-related functions.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001664 G protein-coupled receptor binding | IBA GO_REF:0000033 | ACCEPT | Summary: GRK2 directly recognizes intracellular receptor regions as demonstrated by purified binding and receptor-dependent kinase activation. Reason: Retain this integral specific binding function alongside catalysis. Supporting Evidence: PMID:8798423 charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2 |
| GO:0002026 regulation of the force of heart contraction | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: GRK2 manipulation in human failing cardiomyocytes and cardiac transgenic mice alters adrenergic responsiveness, contractility and relaxation. Reason: Retain the specific cardiac process/regulation claims as signaling effects, not structural sarcomere membership. |
| GO:0002029 desensitization of G protein-coupled receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Receptor phosphorylation and arrestin-linked regulation establish GRK2-mediated desensitization. Reason: Some receptors additionally use kinase-independent GRK2 effects; these do not erase the well-supported catalytic desensitization mechanism. |
| GO:0002029 desensitization of G protein-coupled receptor signaling pathway | IDA PMID:14976224 Real-time detection of interactions between the human oxytoc... | ACCEPT | Summary: Receptor phosphorylation and arrestin-linked regulation establish GRK2-mediated desensitization. Reason: Some receptors additionally use kinase-independent GRK2 effects; these do not erase the well-supported catalytic desensitization mechanism. |
| GO:0002029 desensitization of G protein-coupled receptor signaling pathway | IDA PMID:16179383 Internalization and desensitization of the oxytocin receptor... | ACCEPT | Summary: Receptor phosphorylation and arrestin-linked regulation establish GRK2-mediated desensitization. Reason: Some receptors additionally use kinase-independent GRK2 effects; these do not erase the well-supported catalytic desensitization mechanism. |
| GO:0002029 desensitization of G protein-coupled receptor signaling pathway | IDA PMID:21799898 Regulation of C3a receptor signaling in human mast cells by ... | ACCEPT | Summary: Receptor phosphorylation and arrestin-linked regulation establish GRK2-mediated desensitization. Reason: Some receptors additionally use kinase-independent GRK2 effects; these do not erase the well-supported catalytic desensitization mechanism. |
| GO:0002029 desensitization of G protein-coupled receptor signaling pathway | IDA PMID:33859231 New phosphosite-specific antibodies to unravel the role of G... | ACCEPT | Summary: Receptor phosphorylation and arrestin-linked regulation establish GRK2-mediated desensitization. Reason: Some receptors additionally use kinase-independent GRK2 effects; these do not erase the well-supported catalytic desensitization mechanism. |
| GO:0002029 desensitization of G protein-coupled receptor signaling pathway | IEA GO_REF:0000117 | ACCEPT | Summary: Receptor phosphorylation and arrestin-linked regulation establish GRK2-mediated desensitization. Reason: Some receptors additionally use kinase-independent GRK2 effects; these do not erase the well-supported catalytic desensitization mechanism. |
| GO:0002029 desensitization of G protein-coupled receptor signaling pathway | IMP PMID:15102938 Regulation of mGlu4 metabotropic glutamate receptor signalin... | ACCEPT | Summary: Receptor phosphorylation and arrestin-linked regulation establish GRK2-mediated desensitization. Reason: Some receptors additionally use kinase-independent GRK2 effects; these do not erase the well-supported catalytic desensitization mechanism. |
| GO:0002029 desensitization of G protein-coupled receptor signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: Receptor phosphorylation and arrestin-linked regulation establish GRK2-mediated desensitization. Reason: Some receptors additionally use kinase-independent GRK2 effects; these do not erase the well-supported catalytic desensitization mechanism. |
| GO:0003108 negative regulation of the force of heart contraction by chemical signal | IMP PMID:15051637 Targeted beta-adrenergic receptor kinase (betaARK1) inhibiti... | KEEP AS NON CORE | Summary: GRK2 manipulation in human failing cardiomyocytes and cardiac transgenic mice alters adrenergic responsiveness, contractility and relaxation. Reason: Retain the specific cardiac process/regulation claims as signaling effects, not structural sarcomere membership. |
| GO:0004672 protein kinase activity | IEA GO_REF:0000120 | MODIFY | Summary: GRK2 phosphorylates serine/threonine residues on GPCR and non-GPCR substrates. Reason: Refine generic protein kinase to serine/threonine kinase, retaining the broader substrate range rather than narrowing every row exclusively to receptor kinase. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: UniProtKB:Q99MK8 SUPPORTS TRANSFER GRK2 phosphorylates serine/threonine residues on GPCR and non-GPCR substrates. Refine generic protein kinase to serine/threonine kinase, retaining the broader substrate range rather than narrowing every row exclusively to receptor kinase. InterPro:IPR008271 SUPPORTS TRANSFER GRK2 phosphorylates serine/threonine residues on GPCR and non-GPCR substrates. Refine generic protein kinase to serine/threonine kinase, retaining the broader substrate range rather than narrowing every row exclusively to receptor kinase. Proposed replacements: protein serine/threonine kinase activity |
| GO:0004672 protein kinase activity | IMP PMID:21983013 Mitochondrial localization unveils a novel role for GRK2 in ... | MODIFY | Summary: GRK2 phosphorylates serine/threonine residues on GPCR and non-GPCR substrates. Reason: Refine generic protein kinase to serine/threonine kinase, retaining the broader substrate range rather than narrowing every row exclusively to receptor kinase. Proposed replacements: protein serine/threonine kinase activity |
| GO:0004672 protein kinase activity | ISS GO_REF:0000024 | MODIFY | Summary: GRK2 phosphorylates serine/threonine residues on GPCR and non-GPCR substrates. Reason: Refine generic protein kinase to serine/threonine kinase, retaining the broader substrate range rather than narrowing every row exclusively to receptor kinase. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: UniProtKB:P21146 SUPPORTS TRANSFER GRK2 phosphorylates serine/threonine residues on GPCR and non-GPCR substrates. Refine generic protein kinase to serine/threonine kinase, retaining the broader substrate range rather than narrowing every row exclusively to receptor kinase. Proposed replacements: protein serine/threonine kinase activity |
| GO:0004674 protein serine/threonine kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Purified receptor phosphorylation and ATP-dependent kinase experiments establish GRK2 serine/threonine kinase activity, including beta-adrenergic and other GPCR substrates. Reason: These are integral catalytic/cofactor functions. PMID:15102938 additionally shows kinase-independent mGlu4 regulation and is not by itself proof of phosphorylation of that receptor. Supporting Evidence: PMID:8798423 charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2 |
| GO:0004703 G protein-coupled receptor kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Purified receptor phosphorylation and ATP-dependent kinase experiments establish GRK2 serine/threonine kinase activity, including beta-adrenergic and other GPCR substrates. Reason: These are integral catalytic/cofactor functions. PMID:15102938 additionally shows kinase-independent mGlu4 regulation and is not by itself proof of phosphorylation of that receptor. Supporting Evidence: PMID:8798423 charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2 |
| GO:0004703 G protein-coupled receptor kinase activity | IDA PMID:14976224 Real-time detection of interactions between the human oxytoc... | ACCEPT | Summary: Purified receptor phosphorylation and ATP-dependent kinase experiments establish GRK2 serine/threonine kinase activity, including beta-adrenergic and other GPCR substrates. Reason: These are integral catalytic/cofactor functions. PMID:15102938 additionally shows kinase-independent mGlu4 regulation and is not by itself proof of phosphorylation of that receptor. Supporting Evidence: PMID:8798423 charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2 |
| GO:0004703 G protein-coupled receptor kinase activity | IDA PMID:16179383 Internalization and desensitization of the oxytocin receptor... | ACCEPT | Summary: Purified receptor phosphorylation and ATP-dependent kinase experiments establish GRK2 serine/threonine kinase activity, including beta-adrenergic and other GPCR substrates. Reason: These are integral catalytic/cofactor functions. PMID:15102938 additionally shows kinase-independent mGlu4 regulation and is not by itself proof of phosphorylation of that receptor. Supporting Evidence: PMID:8798423 charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2 |
| GO:0004703 G protein-coupled receptor kinase activity | IDA PMID:21799898 Regulation of C3a receptor signaling in human mast cells by ... | ACCEPT | Summary: Purified receptor phosphorylation and ATP-dependent kinase experiments establish GRK2 serine/threonine kinase activity, including beta-adrenergic and other GPCR substrates. Reason: These are integral catalytic/cofactor functions. PMID:15102938 additionally shows kinase-independent mGlu4 regulation and is not by itself proof of phosphorylation of that receptor. Supporting Evidence: PMID:8798423 charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2 |
| GO:0004703 G protein-coupled receptor kinase activity | IDA PMID:33859231 New phosphosite-specific antibodies to unravel the role of G... | ACCEPT | Summary: Purified receptor phosphorylation and ATP-dependent kinase experiments establish GRK2 serine/threonine kinase activity, including beta-adrenergic and other GPCR substrates. Reason: These are integral catalytic/cofactor functions. PMID:15102938 additionally shows kinase-independent mGlu4 regulation and is not by itself proof of phosphorylation of that receptor. Supporting Evidence: PMID:8798423 charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2 |
| GO:0004703 G protein-coupled receptor kinase activity | IDA PMID:39138140 GRK2 kinases in the primary cilium initiate SMOOTHENED-PKA s... | ACCEPT | Summary: Purified receptor phosphorylation and ATP-dependent kinase experiments establish GRK2 serine/threonine kinase activity, including beta-adrenergic and other GPCR substrates. Reason: These are integral catalytic/cofactor functions. PMID:15102938 additionally shows kinase-independent mGlu4 regulation and is not by itself proof of phosphorylation of that receptor. Supporting Evidence: PMID:8798423 charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2 |
| GO:0004703 G protein-coupled receptor kinase activity | IDA PMID:40384633 Ξ²-Arrestin mediates the export of ciliary GPR161 but not Smo... | ACCEPT | Summary: Purified receptor phosphorylation and ATP-dependent kinase experiments establish GRK2 serine/threonine kinase activity, including beta-adrenergic and other GPCR substrates. Reason: These are integral catalytic/cofactor functions. PMID:15102938 additionally shows kinase-independent mGlu4 regulation and is not by itself proof of phosphorylation of that receptor. Supporting Evidence: PMID:8798423 charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2 |
| GO:0004703 G protein-coupled receptor kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Purified receptor phosphorylation and ATP-dependent kinase experiments establish GRK2 serine/threonine kinase activity, including beta-adrenergic and other GPCR substrates. Reason: These are integral catalytic/cofactor functions. PMID:15102938 additionally shows kinase-independent mGlu4 regulation and is not by itself proof of phosphorylation of that receptor. Supporting Evidence: PMID:8798423 charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2 |
| GO:0004703 G protein-coupled receptor kinase activity | IMP PMID:15102938 Regulation of mGlu4 metabotropic glutamate receptor signalin... | ACCEPT | Summary: Purified receptor phosphorylation and ATP-dependent kinase experiments establish GRK2 serine/threonine kinase activity, including beta-adrenergic and other GPCR substrates. Reason: These are integral catalytic/cofactor functions. PMID:15102938 additionally shows kinase-independent mGlu4 regulation and is not by itself proof of phosphorylation of that receptor. Supporting Evidence: PMID:8798423 charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2 |
| GO:0004703 G protein-coupled receptor kinase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Purified receptor phosphorylation and ATP-dependent kinase experiments establish GRK2 serine/threonine kinase activity, including beta-adrenergic and other GPCR substrates. Reason: These are integral catalytic/cofactor functions. PMID:15102938 additionally shows kinase-independent mGlu4 regulation and is not by itself proof of phosphorylation of that receptor. Supporting Evidence: PMID:8798423 charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2 |
| GO:0005515 protein binding | IPI PMID:17006543 Mdm2 is involved in the ubiquitination and degradation of G-... | REMOVE | Summary: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. Reason: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. |
| GO:0005515 protein binding | IPI PMID:17006543 Mdm2 is involved in the ubiquitination and degradation of G-... | REMOVE | Summary: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. Reason: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. |
| GO:0005515 protein binding | IPI PMID:17986524 Characterization of G-protein coupled receptor kinase intera... | REMOVE | Summary: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. Reason: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. |
| GO:0005515 protein binding | IPI PMID:18369319 G protein-coupled receptor kinase 2 positively regulates epi... | REMOVE | Summary: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. Reason: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. |
| GO:0005515 protein binding | IPI PMID:19008357 The G-protein-coupled receptor kinase 5 inhibits NFkappaB tr... | REMOVE | Summary: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. Reason: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. |
| GO:0005515 protein binding | IPI PMID:19306925 Dual regulation of lysophosphatidic acid (LPA1) receptor sig... | REMOVE | Summary: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. Reason: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. |
| GO:0005515 protein binding | IPI PMID:19306925 Dual regulation of lysophosphatidic acid (LPA1) receptor sig... | REMOVE | Summary: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. Reason: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. |
| GO:0005515 protein binding | IPI PMID:19306925 Dual regulation of lysophosphatidic acid (LPA1) receptor sig... | REMOVE | Summary: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. Reason: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. |
| GO:0005515 protein binding | IPI PMID:19502428 Kinase activity-independent regulation of cyclin pathway by ... | REMOVE | Summary: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. Reason: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. |
| GO:0005515 protein binding | IPI PMID:22447027 Bidirectional regulation of neutrophil migration by mitogen-... | REMOVE | Summary: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. Reason: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. |
| GO:0005515 protein binding | IPI PMID:23455922 Interlaboratory reproducibility of large-scale human protein... | REMOVE | Summary: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. Reason: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. Reason: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. Reason: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. Reason: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. Reason: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. Reason: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. |
| 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 without denying the interactions; specific receptor-binding and catalytic functions remain represented. Reason: Remove uninformative bare protein binding under the project policy without denying the interactions; specific receptor-binding and catalytic functions remain represented. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: Purified receptor phosphorylation and ATP-dependent kinase experiments establish GRK2 serine/threonine kinase activity, including beta-adrenergic and other GPCR substrates. Reason: These are integral catalytic/cofactor functions. PMID:15102938 additionally shows kinase-independent mGlu4 regulation and is not by itself proof of phosphorylation of that receptor. Supporting Evidence: PMID:8798423 charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2 |
| GO:0005737 cytoplasm | IDA PMID:17986524 Characterization of G-protein coupled receptor kinase intera... | ACCEPT | Summary: GRK2 has a cytoplasmic/cytosolic pool that can be recruited to receptor-containing membranes. Reason: Localization and fractionation experiments support this distribution independently of additional mitochondrial or ciliary pools. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: GRK2 has a cytoplasmic/cytosolic pool that can be recruited to receptor-containing membranes. Reason: Localization and fractionation experiments support this distribution independently of additional mitochondrial or ciliary pools. |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | ACCEPT | Summary: GRK2 has a cytoplasmic/cytosolic pool that can be recruited to receptor-containing membranes. Reason: Localization and fractionation experiments support this distribution independently of additional mitochondrial or ciliary pools. |
| GO:0005829 cytosol | IDA PMID:21983013 Mitochondrial localization unveils a novel role for GRK2 in ... | ACCEPT | Summary: GRK2 has a cytoplasmic/cytosolic pool that can be recruited to receptor-containing membranes. Reason: Localization and fractionation experiments support this distribution independently of additional mitochondrial or ciliary pools. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8866268 | ACCEPT | Summary: GRK2 has a cytoplasmic/cytosolic pool that can be recruited to receptor-containing membranes. Reason: Localization and fractionation experiments support this distribution independently of additional mitochondrial or ciliary pools. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Agonist-dependent receptor recruitment and membrane-assisted kinase activity establish the plasma-membrane pool. Reason: Retain this experimentally warranted compartment without manufacturing a new finer location term. Supporting Evidence: PMID:8798423 charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2 |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Agonist-dependent receptor recruitment and membrane-assisted kinase activity establish the plasma-membrane pool. Reason: Retain this experimentally warranted compartment without manufacturing a new finer location term. Supporting Evidence: PMID:8798423 charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-111966 | ACCEPT | Summary: Agonist-dependent receptor recruitment and membrane-assisted kinase activity establish the plasma-membrane pool. Reason: Retain this experimentally warranted compartment without manufacturing a new finer location term. Supporting Evidence: PMID:8798423 charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-111970 | ACCEPT | Summary: Agonist-dependent receptor recruitment and membrane-assisted kinase activity establish the plasma-membrane pool. Reason: Retain this experimentally warranted compartment without manufacturing a new finer location term. Supporting Evidence: PMID:8798423 charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-416516 | ACCEPT | Summary: Agonist-dependent receptor recruitment and membrane-assisted kinase activity establish the plasma-membrane pool. Reason: Retain this experimentally warranted compartment without manufacturing a new finer location term. Supporting Evidence: PMID:8798423 charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8851797 | ACCEPT | Summary: Agonist-dependent receptor recruitment and membrane-assisted kinase activity establish the plasma-membrane pool. Reason: Retain this experimentally warranted compartment without manufacturing a new finer location term. Supporting Evidence: PMID:8798423 charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8982641 | ACCEPT | Summary: Agonist-dependent receptor recruitment and membrane-assisted kinase activity establish the plasma-membrane pool. Reason: Retain this experimentally warranted compartment without manufacturing a new finer location term. Supporting Evidence: PMID:8798423 charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8982645 | ACCEPT | Summary: Agonist-dependent receptor recruitment and membrane-assisted kinase activity establish the plasma-membrane pool. Reason: Retain this experimentally warranted compartment without manufacturing a new finer location term. Supporting Evidence: PMID:8798423 charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2 |
| GO:0005929 cilium | TAS Reactome:R-HSA-5633040 | KEEP AS NON CORE | Summary: The Hedgehog study directly establishes ciliary GRK2 participation at the membrane, with receptor phosphorylation enabling downstream signaling. Reason: Retain ciliary localization without assuming every GRK2 pool or ciliary receptor undergoes desensitization. Supporting Evidence: |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | MODIFY | Summary: GRK2 has an established role in GPCR signaling, more informative than generic signal transduction. Reason: Refine the term while preserving separately documented non-GPCR and Hedgehog functions. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: InterPro:IPR000239 SUPPORTS TRANSFER GRK2 has an established role in GPCR signaling, more informative than generic signal transduction. Refine the term while preserving separately documented non-GPCR and Hedgehog functions. Proposed replacements: G protein-coupled receptor signaling pathway |
| GO:0007186 G protein-coupled receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: GRK2 performs receptor phosphorylation and signal regulation within GPCR pathways. Reason: It is a signaling enzyme, not merely a downstream marker of receptor activation. |
| GO:0007186 G protein-coupled receptor signaling pathway | TAS Reactome:R-HSA-388396 | ACCEPT | Summary: GRK2 performs receptor phosphorylation and signal regulation within GPCR pathways. Reason: It is a signaling enzyme, not merely a downstream marker of receptor activation. |
| GO:0007213 G protein-coupled acetylcholine receptor signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Purified human M2 is an agonist-dependent GRK2 substrate in charged-phospholipid-containing preparations. Reason: Beta/gamma stimulation is lipid-dependent; this supports a cholinergic implementation without claiming uniform phosphorylation in every native tissue. Supporting Evidence: PMID:8798423 charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2 |
| GO:0007217 tachykinin receptor signaling pathway | IDA PMID:17986524 Characterization of G-protein coupled receptor kinase intera... | KEEP AS NON CORE | Summary: NK1-receptor BRET and recruitment experiments establish GRK2 participation in tachykinin signaling. Reason: GRK2 agonist-dependent recruitment differs from GRK5 preassociation in the same study. Supporting Evidence: |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MODIFY | Summary: Independent experiments establish plasma-membrane, mitochondrial-surface and ciliary-membrane pools. Reason: Refine generic membrane membership to the separately supported locations rather than choose an arbitrary exclusive compartment. Proposed replacements: plasma membrane cytoplasmic side of mitochondrial outer membrane non-motile cilium membrane Supporting Evidence: PMID:8798423 charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2 |
| GO:0016020 membrane | IEA GO_REF:0000107 | MODIFY | Summary: Independent experiments establish plasma-membrane, mitochondrial-surface and ciliary-membrane pools. Reason: Refine generic membrane membership to the separately supported locations rather than choose an arbitrary exclusive compartment. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: UniProtKB:Q99MK8 SUPPORTS TRANSFER Independent experiments establish plasma-membrane, mitochondrial-surface and ciliary-membrane pools. Refine generic membrane membership to the separately supported locations rather than choose an arbitrary exclusive compartment. Proposed replacements: plasma membrane cytoplasmic side of mitochondrial outer membrane non-motile cilium membrane Supporting Evidence: PMID:8798423 charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2 |
| GO:0016020 membrane | ISS GO_REF:0000024 | MODIFY | Summary: Independent experiments establish plasma-membrane, mitochondrial-surface and ciliary-membrane pools. Reason: Refine generic membrane membership to the separately supported locations rather than choose an arbitrary exclusive compartment. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: UniProtKB:P21146 SUPPORTS TRANSFER Independent experiments establish plasma-membrane, mitochondrial-surface and ciliary-membrane pools. Refine generic membrane membership to the separately supported locations rather than choose an arbitrary exclusive compartment. Proposed replacements: plasma membrane cytoplasmic side of mitochondrial outer membrane non-motile cilium membrane Supporting Evidence: PMID:8798423 charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2 |
| GO:0019079 viral genome replication | IMP PMID:23029581 G protein-coupled receptor kinase 2 promotes flaviviridae en... | KEEP AS NON CORE | Summary: RNAi and genetic studies show GRK2 contributes to flavivirus entry and genome replication. Reason: Retain host-factor participation with the tested virus/cell contexts; it is not viral polymerase activity or a general requirement of every virus. Supporting Evidence: |
| GO:0031623 receptor internalization | IDA PMID:20074556 Function of the cytoplasmic tail of human calcitonin recepto... | KEEP AS NON CORE | Summary: Receptor trafficking assays demonstrate a GRK2 contribution to ligand-induced internalization. Reason: This is a context-dependent consequence of kinase/adaptor signaling rather than direct membrane-scission catalysis. |
| GO:0031623 receptor internalization | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Receptor trafficking assays demonstrate a GRK2 contribution to ligand-induced internalization. Reason: This is a context-dependent consequence of kinase/adaptor signaling rather than direct membrane-scission catalysis. |
| GO:0031694 alpha-2A adrenergic receptor binding | ISS GO_REF:0000024 | ACCEPT | Summary: Purified GRK2 binds mapped intracellular regions of alpha2A-adrenergic receptor; mutations alter binding, phosphorylation and activation. Reason: The domain experiments directly support specific receptor recognition rather than generic protein association. Supporting Evidence: |
| GO:0031755 Edg-2 lysophosphatidic acid receptor binding | IDA PMID:19306925 Dual regulation of lysophosphatidic acid (LPA1) receptor sig... | ACCEPT | Summary: LPA1/Edg-2 interaction and GRK2-dependent desensitization support specific receptor recognition in the reported cellular complex. Reason: This does not assert that RalA is dispensable or that every measured association is an isolated binary affinity assay. Supporting Evidence: |
| GO:0032473 cytoplasmic side of mitochondrial outer membrane | IDA PMID:21983013 Mitochondrial localization unveils a novel role for GRK2 in ... | KEEP AS NON CORE | Summary: The mitochondrial study localizes a GRK2 pool to the cytoplasmic mitochondrial outer surface and links it to metabolic regulation. Reason: Retain this topology-specific claim separately; it does not justify removing a root mitochondrion assertion elsewhere. Supporting Evidence: |
| GO:0033605 positive regulation of catecholamine secretion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Rat adrenal GRK2 overexpression increases catecholamine secretion by desensitizing inhibitory alpha2 autoreceptors, whereas betaARKct reduces secretion. Reason: Retain this experimentally resolved positive regulatory outcome: desensitization of an inhibitory receptor can increase secretion. Supporting Evidence: |
| GO:0035721 intraciliary retrograde transport | IDA PMID:40384633 Ξ²-Arrestin mediates the export of ciliary GPR161 but not Smo... | KEEP AS NON CORE | Summary: The GPR161 ciliary-export study identifies a GRK2-dependent regulatory contribution to receptor exit and retrograde trafficking. Reason: Retain these process/regulation terms with that substrate context; GRK2 is not itself an intraflagellar transport motor. Supporting Evidence: |
| GO:0045880 positive regulation of smoothened signaling pathway | IDA PMID:39138140 GRK2 kinases in the primary cilium initiate SMOOTHENED-PKA s... | KEEP AS NON CORE | Summary: GRK2 phosphorylation of Smoothened enables binding/sequestration of PKA catalytic subunits in the ciliary Hedgehog pathway. Reason: This positive signaling implementation differs from classical arrestin-associated receptor desensitization. Supporting Evidence: |
| GO:0045880 positive regulation of smoothened signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: GRK2 phosphorylation of Smoothened enables binding/sequestration of PKA catalytic subunits in the ciliary Hedgehog pathway. Reason: This positive signaling implementation differs from classical arrestin-associated receptor desensitization. Supporting Evidence: |
| GO:0045988 negative regulation of striated muscle contraction | IMP PMID:15051637 Targeted beta-adrenergic receptor kinase (betaARK1) inhibiti... | KEEP AS NON CORE | Summary: GRK2 manipulation in human failing cardiomyocytes and cardiac transgenic mice alters adrenergic responsiveness, contractility and relaxation. Reason: Retain the specific cardiac process/regulation claims as signaling effects, not structural sarcomere membership. |
| GO:0046718 symbiont entry into host cell | IMP PMID:23029581 G protein-coupled receptor kinase 2 promotes flaviviridae en... | KEEP AS NON CORE | Summary: RNAi and genetic studies show GRK2 contributes to flavivirus entry and genome replication. Reason: Retain host-factor participation with the tested virus/cell contexts; it is not viral polymerase activity or a general requirement of every virus. Supporting Evidence: |
| GO:0047696 beta-adrenergic receptor kinase activity | EXP PMID:19715378 Role of the amino terminus of G protein-coupled receptor kin... | ACCEPT | Summary: Purified receptor phosphorylation and ATP-dependent kinase experiments establish GRK2 serine/threonine kinase activity, including beta-adrenergic and other GPCR substrates. Reason: These are integral catalytic/cofactor functions. PMID:15102938 additionally shows kinase-independent mGlu4 regulation and is not by itself proof of phosphorylation of that receptor. Supporting Evidence: PMID:8798423 charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2 |
| GO:0047696 beta-adrenergic receptor kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Purified receptor phosphorylation and ATP-dependent kinase experiments establish GRK2 serine/threonine kinase activity, including beta-adrenergic and other GPCR substrates. Reason: These are integral catalytic/cofactor functions. PMID:15102938 additionally shows kinase-independent mGlu4 regulation and is not by itself proof of phosphorylation of that receptor. Supporting Evidence: PMID:8798423 charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2 |
| GO:0047696 beta-adrenergic receptor kinase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Purified receptor phosphorylation and ATP-dependent kinase experiments establish GRK2 serine/threonine kinase activity, including beta-adrenergic and other GPCR substrates. Reason: These are integral catalytic/cofactor functions. PMID:15102938 additionally shows kinase-independent mGlu4 regulation and is not by itself proof of phosphorylation of that receptor. Supporting Evidence: PMID:8798423 charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2 |
| GO:0047696 beta-adrenergic receptor kinase activity | TAS Reactome:R-HSA-8851797 | ACCEPT | Summary: Purified receptor phosphorylation and ATP-dependent kinase experiments establish GRK2 serine/threonine kinase activity, including beta-adrenergic and other GPCR substrates. Reason: These are integral catalytic/cofactor functions. PMID:15102938 additionally shows kinase-independent mGlu4 regulation and is not by itself proof of phosphorylation of that receptor. Supporting Evidence: PMID:8798423 charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2 |
| GO:0047696 beta-adrenergic receptor kinase activity | TAS Reactome:R-HSA-8866268 | ACCEPT | Summary: Purified receptor phosphorylation and ATP-dependent kinase experiments establish GRK2 serine/threonine kinase activity, including beta-adrenergic and other GPCR substrates. Reason: These are integral catalytic/cofactor functions. PMID:15102938 additionally shows kinase-independent mGlu4 regulation and is not by itself proof of phosphorylation of that receptor. Supporting Evidence: PMID:8798423 charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2 |
| GO:0060048 cardiac muscle contraction | IMP PMID:15051637 Targeted beta-adrenergic receptor kinase (betaARK1) inhibiti... | KEEP AS NON CORE | Summary: GRK2 manipulation in human failing cardiomyocytes and cardiac transgenic mice alters adrenergic responsiveness, contractility and relaxation. Reason: Retain the specific cardiac process/regulation claims as signaling effects, not structural sarcomere membership. |
| GO:0060170 ciliary membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: The Hedgehog study directly establishes ciliary GRK2 participation at the membrane, with receptor phosphorylation enabling downstream signaling. Reason: Retain ciliary localization without assuming every GRK2 pool or ciliary receptor undergoes desensitization. Supporting Evidence: |
| GO:0098793 presynapse | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Native rat-brain ultrastructure localizes betaARK1/GRK2 at postsynaptic densities and presynaptic terminals. Reason: Retain the conserved synaptic pools without presenting the rat immunolocalization as direct human microscopy. Supporting Evidence: |
| GO:0098793 presynapse | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Native rat-brain ultrastructure localizes betaARK1/GRK2 at postsynaptic densities and presynaptic terminals. Reason: Retain the conserved synaptic pools without presenting the rat immunolocalization as direct human microscopy. Supporting Evidence: |
| GO:0098794 postsynapse | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Native rat-brain ultrastructure localizes betaARK1/GRK2 at postsynaptic densities and presynaptic terminals. Reason: Retain the conserved synaptic pools without presenting the rat immunolocalization as direct human microscopy. Supporting Evidence: |
| GO:0098794 postsynapse | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Native rat-brain ultrastructure localizes betaARK1/GRK2 at postsynaptic densities and presynaptic terminals. Reason: Retain the conserved synaptic pools without presenting the rat immunolocalization as direct human microscopy. Supporting Evidence: |
| GO:0098804 non-motile cilium membrane | IDA PMID:39138140 GRK2 kinases in the primary cilium initiate SMOOTHENED-PKA s... | KEEP AS NON CORE | Summary: The Hedgehog study directly establishes ciliary GRK2 participation at the membrane, with receptor phosphorylation enabling downstream signaling. Reason: Retain ciliary localization without assuming every GRK2 pool or ciliary receptor undergoes desensitization. Supporting Evidence: |
| GO:1901081 negative regulation of relaxation of smooth muscle | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Airway smooth-muscle photorelaxation experiments show increased relaxation after GRK2 inhibition. Reason: Retain negative regulation in that tested receptor/light context rather than infer the same sign for all smooth-muscle stimuli. Supporting Evidence: |
| GO:1901081 negative regulation of relaxation of smooth muscle | IMP PMID:30284927 Airway smooth muscle photorelaxation via opsin receptor acti... | KEEP AS NON CORE | Summary: Airway smooth-muscle photorelaxation experiments show increased relaxation after GRK2 inhibition. Reason: Retain negative regulation in that tested receptor/light context rather than infer the same sign for all smooth-muscle stimuli. Supporting Evidence: |
| GO:1903568 negative regulation of protein localization to ciliary membrane | IDA PMID:40384633 Ξ²-Arrestin mediates the export of ciliary GPR161 but not Smo... | KEEP AS NON CORE | Summary: The GPR161 ciliary-export study identifies a GRK2-dependent regulatory contribution to receptor exit and retrograde trafficking. Reason: Retain these process/regulation terms with that substrate context; GRK2 is not itself an intraflagellar transport motor. Supporting Evidence: |
| GO:1905801 positive regulation of intraciliary retrograde transport | IDA PMID:40384633 Ξ²-Arrestin mediates the export of ciliary GPR161 but not Smo... | KEEP AS NON CORE | Summary: The GPR161 ciliary-export study identifies a GRK2-dependent regulatory contribution to receptor exit and retrograde trafficking. Reason: Retain these process/regulation terms with that substrate context; GRK2 is not itself an intraflagellar transport motor. Supporting Evidence: |
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