id: P07550 gene_symbol: ADRB2 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: ADRB2 encodes the beta-2 adrenergic receptor, a seven-transmembrane catecholamine GPCR that acts mainly at the plasma membrane. Epinephrine and norepinephrine binding activate bifurcated G protein signaling, especially Gs/cAMP/PKA and context-dependent Gi branches, with downstream effects on MAPK signaling, smooth-muscle and cardiovascular physiology, thermogenesis, and adipocyte lipolysis. Activated receptors are regulated by arrestin- and ubiquitin-dependent endocytosis, recycling, lysosomal sorting, and Golgi-associated palmitoylation-dependent trafficking. Beyond terminating signaling, internalized beta-arrestin-bound receptors can sustain G protein signaling from endosomes, so receptor output is shaped by subcellular location as well as ligand. references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000024 title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:10734107 title: The beta(2)-adrenergic receptor mediates extracellular signal-regulated kinase activation via assembly of a multi-receptor complex with the epidermal growth factor receptor. findings: - statement: Beta2AR stimulation induces EGFR transactivation and ERK1/2 activation through a multi-receptor/endocytic signaling complex. - id: PMID:12297500 title: G protein-coupled receptors form stable complexes with inwardly rectifying potassium channels and adenylyl cyclase. findings: - statement: Beta2AR forms stable receptor-effector complexes with Kir3 potassium channels and adenylyl cyclase. - id: PMID:12387862 title: Beta(1)/beta(2)/beta(3)-adrenoceptor knockout mice are obese and cold-sensitive but have normal lipolytic responses to fasting. findings: - statement: Beta1/beta2/beta3 adrenoceptor triple-knockout mice show obesity and cold intolerance, supporting beta-adrenergic signaling broadly rather than an ADRB2-specific thermogenesis assignment. - id: PMID:1371121 title: Ligand-regulated internalization and recycling of human beta 2-adrenergic receptors between the plasma membrane and endosomes containing transferrin receptors. findings: [] - id: PMID:15123695 title: Hetero-oligomerization between beta2- and beta3-adrenergic receptors generates a beta-adrenergic signaling unit with distinct functional properties. findings: - statement: Beta2 adrenergic receptor can homo- and hetero-oligomerize, stimulate adenylyl cyclase, recruit beta-arrestin, and alter G protein coupling in beta2/beta3 receptor signaling units. - id: PMID:15518545 title: Biochemical and biophysical characterization of serotonin 5-HT2C receptor homodimers on the plasma membrane of living cells. findings: [] - id: PMID:17148612 title: A system for quantifying dynamic protein interactions defines a role for Herceptin in modulating ErbB2 interactions. findings: [] - id: PMID:17170700 title: Dosage-dependent switch from G protein-coupled to G protein-independent signaling by a GPCR. findings: [] - id: PMID:19424180 title: The deubiquitinases USP33 and USP20 coordinate beta2 adrenergic receptor recycling and resensitization. findings: - statement: USP20 and USP33 regulate beta2AR post-endocytic sorting by reversing ubiquitination and promoting recycling/resensitization over lysosomal degradation. - id: PMID:19584355 title: Oxygen-regulated beta(2)-adrenergic receptor hydroxylation by EGLN3 and ubiquitylation by pVHL. findings: [] - id: PMID:19710023 title: Structure of an arrestin2-clathrin complex reveals a novel clathrin binding domain that modulates receptor trafficking. findings: [] - id: PMID:19763081 title: Ligand-regulated oligomerization of beta(2)-adrenoceptors in a model lipid bilayer. findings: [] - id: PMID:20353789 title: Beta-2 adrenergic receptor mediated ERK activation is regulated by interaction with MAGI-3. findings: [] - id: PMID:20395454 title: Binding of amyloid beta peptide to beta2 adrenergic receptor induces PKA-dependent AMPA receptor hyperactivity. findings: - statement: Soluble amyloid beta binds beta2AR and induces G protein/cAMP/PKA signaling in an AMPA receptor postsynaptic complex. - id: PMID:20559325 title: Arrestin domain-containing protein 3 recruits the NEDD4 E3 ligase to mediate ubiquitination of the beta2-adrenergic receptor. findings: [] - id: PMID:20590567 title: Physical and functional interaction between CB1 cannabinoid receptors and beta2-adrenoceptors. findings: [] - id: PMID:20733053 title: SNX27 mediates PDZ-directed sorting from endosomes to the plasma membrane. findings: - statement: SNX27 mediates PDZ-directed beta2AR recycling from early endosomes to the plasma membrane. - id: PMID:23166351 title: MARCH2 promotes endocytosis and lysosomal sorting of carvedilol-bound β(2)-adrenergic receptors. findings: - statement: MARCH2 promotes ligand-specific beta2AR ubiquitination, endocytosis, lysosomal sorting, and degradation. - id: PMID:23208550 title: Distinct roles for β-arrestin2 and arrestin-domain-containing proteins in β2 adrenergic receptor trafficking. findings: [] - id: PMID:23236378 title: Mammalian α arrestins link activated seven transmembrane receptors to Nedd4 family e3 ubiquitin ligases and interact with β arrestins. findings: [] - id: PMID:23291003 title: Adenosine A1 receptors heterodimerize with β1- and β2-adrenergic receptors creating novel receptor complexes with altered G protein coupling and signaling. findings: [] - id: PMID:23382219 title: Structural basis for endosomal trafficking of diverse transmembrane cargos by PX-FERM proteins. findings: [] - id: PMID:23708524 title: β-adrenergic receptor-stimulated lipolysis requires the RAB7-mediated autolysosomal lipid degradation. findings: - statement: ADRB2-cAMP stimulation increases autophagy-targeted lipid droplets and contributes to hormone-stimulated lipolysis, while RAB7 is the direct factor mediating autolysosomal lipid degradation. - id: PMID:24405750 title: CNIH4 interacts with newly synthesized GPCR and controls their export from the endoplasmic reticulum. findings: [] - id: PMID:25220262 title: Insights into β2-adrenergic receptor binding from structures of the N-terminal lobe of ARRDC3. findings: [] - id: PMID:27481942 title: S-Palmitoylation of a Novel Site in the β2-Adrenergic Receptor Associated with a Novel Intracellular Itinerary. findings: - statement: Activated beta2AR can traffic through the Golgi complex and undergo Cys-265 palmitoylation/depalmitoylation affecting plasma-membrane stability and receptor down-regulation. - id: PMID:2823249 title: 'Structure of the gene for human beta 2-adrenergic receptor: expression and promoter characterization.' findings: [] - id: PMID:28298427 title: Systematic protein-protein interaction mapping for clinically relevant human GPCRs. findings: [] - id: PMID:2831218 title: Site-directed mutagenesis and continuous expression of human beta-adrenergic receptors. Identification of a conserved aspartate residue involved in agonist binding and receptor activation. findings: - statement: Human beta-2 adrenergic receptor mutagenesis supports catecholamine binding, Gs coupling, adenylate cyclase stimulation, and beta-adrenergic receptor activation. - id: PMID:32814053 title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. findings: [] - id: PMID:36115835 title: Quantitative fragmentomics allow affinity mapping of interactomes. findings: [] - id: PMID:39083597 title: Multiplexed mapping of the interactome of GPCRs with receptor activity-modifying proteins. findings: [] - id: PMID:7915137 title: Amino-terminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonist-promoted regulatory properties. findings: [] - id: PMID:9235896 title: A novel interaction between adrenergic receptors and the alpha-subunit of eukaryotic initiation factor 2B. findings: [] - id: PMID:9507004 title: Role of clathrin-mediated endocytosis in agonist-induced down-regulation of the beta2-adrenergic receptor. findings: - statement: Beta2AR undergoes agonist-induced internalization and down-regulation through clathrin-coated pit/endosomal trafficking to lysosomes. - id: PMID:9560162 title: The beta2-adrenergic receptor interacts with the Na+/H+-exchanger regulatory factor to control Na+/H+ exchange. findings: - statement: Beta2AR interacts with NHERF to regulate Na+/H+ exchange independently of canonical PKA signaling. - id: PMID:9671706 title: A C-terminal motif found in the beta2-adrenergic receptor, P2Y1 receptor and cystic fibrosis transmembrane conductance regulator determines binding to the Na+/H+ exchanger regulatory factor family of PDZ proteins. findings: [] - id: PMID:38643023 title: 'Beneath the surface: endosomal GPCR signaling.' full_text_unavailable: true findings: - statement: Some GPCRs, including beta2-adrenergic receptor, continue to activate G proteins after internalization into endosomes, and a single receptor can simultaneously engage G protein via its transmembrane core and beta-arrestin via its phosphorylated tail in a megaplex assembly, so endosomes can be a signaling-competent compartment rather than only a degradation/recycling route. - id: PMID:39408565 title: Update on the Role of beta2AR and TRPV1 in Respiratory Diseases. full_text_unavailable: true findings: - statement: In respiratory tissues beta2AR couples to Gs/cAMP/PKA driving bronchodilation, mucociliary clearance, and anti-inflammatory effects, while GRK/beta-arrestin signaling drives desensitization and internalization and links to ERK, p38 MAPK, and NF-kB inflammatory transcriptional programs. - id: Reactome:R-HSA-379044 title: Liganded Gs-activating GPCR acts as a GEF for Gs findings: [] - id: Reactome:R-HSA-5696968 title: USP20, USP33 deubiquitinate ADRB2 findings: [] - id: Reactome:R-HSA-744886 title: The Ligand:GPCR:Gs complex dissociates findings: [] - id: Reactome:R-HSA-744887 title: Liganded Gs-activating GPCRs bind inactive heterotrimeric Gs findings: [] - id: Reactome:R-HSA-8851797 title: ADRB2 in ADRB2:GRK complex is phosphorylated findings: [] - id: Reactome:R-HSA-8852167 title: ADRB2:Catecholamine binds ARRB1, ARRB2 findings: [] - id: Reactome:R-HSA-8866269 title: ARRB bind GPCRs findings: [] - id: Reactome:R-HSA-8866283 title: ARBB recruits GPCRs into clathrin-coated pits findings: [] - id: Reactome:R-HSA-8867754 title: F- and N- BAR domain proteins bind the clathrin-coated pit findings: [] - id: Reactome:R-HSA-8867756 title: CLASP proteins and cargo are recruited to the nascent clathrin-coated pit findings: [] - id: Reactome:R-HSA-8868071 title: Clathrin recruits PIK3C2A findings: [] - id: Reactome:R-HSA-8868072 title: Clathrin-associated PIK3C2A phosphorylates PI(4)P to PI(3,4)P2 findings: [] - id: Reactome:R-HSA-8868230 title: SNX9 recruits components of the actin polymerizing machinery findings: [] - id: Reactome:R-HSA-8868236 title: BAR domain proteins recruit dynamin findings: [] - id: Reactome:R-HSA-8868648 title: SYNJ hydrolyze PI(4,5)P2 to PI(4)P findings: [] - id: Reactome:R-HSA-8868651 title: Endophilins recruit synaptojanins to the clathrin-coated pit findings: [] - id: Reactome:R-HSA-8868658 title: HSPA8-mediated ATP hydrolysis promotes vesicle uncoating findings: [] - id: Reactome:R-HSA-8868659 title: Clathrin recruits auxilins to the clathrin-coated vesicle findings: [] - id: Reactome:R-HSA-8868660 title: Auxilin recruits HSPA8:ATP to the clathrin-coated vesicle findings: [] - id: Reactome:R-HSA-8868661 title: Dynamin-mediated GTP hydrolysis promotes vesicle scission findings: [] - id: Reactome:R-HSA-8869438 title: Dissociation of clathrin-associated proteins findings: [] - id: Reactome:R-HSA-8871193 title: Dissociation of AAK1 and dephosphorylation of AP-2 mu2 findings: [] - id: Reactome:R-HSA-8871194 title: RAB5 and GAPVD1 bind AP-2 findings: [] - id: Reactome:R-HSA-8982641 title: ADRB2:GRK complex dissociates to Phosphorylated ADRB2 findings: [] - id: Reactome:R-HSA-8982645 title: GRKs bind ADRB2:Catecholamine findings: [] - id: Reactome:R-HSA-9609310 title: β-blockers bind ADRB1,2,3 findings: [] - id: Reactome:R-HSA-9611751 title: β1,2-agonists bind ADRB1,2 findings: [] - id: Reactome:R-HSA-9611851 title: ADRB2 bind ADR,NAd findings: [] - id: file:human/ADRB2/ADRB2-uniprot.txt title: UniProtKB record for human ADRB2 findings: - statement: UniProt summarizes ADRB2 as a catecholamine GPCR that couples to Gs and Gi proteins, binds epinephrine with higher affinity than norepinephrine, localizes primarily to the cell membrane, and undergoes endosomal, lysosomal, and Golgi-associated trafficking. - id: file:human/ADRB2/ADRB2-notes.md title: ADRB2 review notes findings: - statement: Manual notes document the failed Falcon/fallback deep-research attempt and the conservative conclusion that ADRB2 supports positive regulation of lipophagy but should not be upgraded to direct lipophagy. existing_annotations: - term: id: GO:0005886 label: plasma membrane evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: &id003 - file:human/ADRB2/ADRB2-uniprot.txt - PMID:2831218 supported_by: &id004 - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cell membrane' - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: Multi-pass membrane protein - reference_id: PMID:2831218 supporting_text: expression of the human beta 2-adrenergic receptor in mouse L cells - term: id: GO:0043410 label: positive regulation of MAPK cascade evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Positive regulation of MAPK cascade is a supported ADRB2 signaling branch. action: ACCEPT reason: ADRB2 activates ERK/MAPK through beta-arrestin/Src/EGFR-associated receptor complexes, so this is a real receptor signaling output rather than a project-level inference. additional_reference_ids: &id034 - PMID:10734107 - PMID:15123695 supported_by: &id035 - reference_id: PMID:10734107 supporting_text: beta(2)-Adrenergic receptor (beta(2)AR) stimulation of COS-7 cells induces EGFR dimerization - reference_id: PMID:10734107 supporting_text: beta(2)AR-dependent signaling to ERK1/2 - reference_id: PMID:15123695 supporting_text: regulate adenylyl cyclase and extracellular signal-regulated kinase activity - term: id: GO:0071880 label: adenylate cyclase-activating adrenergic receptor signaling pathway evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Adenylate cyclase-activating adrenergic receptor signaling is a core ADRB2 function. action: ACCEPT reason: The core beta-2 adrenergic receptor activity couples catecholamine binding to Gs, cAMP/PKA, and adenylate cyclase signaling. additional_reference_ids: &id009 - file:human/ADRB2/ADRB2-uniprot.txt - PMID:2831218 - PMID:15123695 supported_by: &id010 - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: G protein-coupled receptor for catecholamines that couples to - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: both G(s) and G(i) proteins, activating bifurcated signaling pathways - reference_id: PMID:2831218 supporting_text: associated with high affinity ligand binding, Gs coupling, and adenylate cyclase - reference_id: PMID:15123695 supporting_text: isoproterenol to stimulate adenylyl cyclase - term: id: GO:0002025 label: norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Systemic blood-pressure vasodilation is plausible phylogenetic physiology context, but not a core ADRB2 molecular function. action: KEEP_AS_NON_CORE reason: This IBA row is retained as non-core physiology context from phylogenetic/curated annotation. The cached MARCH2 paper only provides background about vascular tone and is not used as experimental support for this term; the local review does not identify direct human ADRB2 vasodilation experiments among the cached sources. additional_reference_ids: - file:human/ADRB2/ADRB2-uniprot.txt - GO_REF:0000033 supported_by: - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: G protein-coupled receptor for catecholamines that couples to - term: id: GO:0004941 label: beta2-adrenergic receptor activity evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: Beta2-adrenergic receptor activity is the core ADRB2 molecular function. action: ACCEPT reason: ADRB2 is the beta-2 adrenergic receptor; mutagenesis and UniProt evidence support catecholamine binding, Gs/Gi coupling, and adenylate cyclase signaling. additional_reference_ids: &id001 - file:human/ADRB2/ADRB2-uniprot.txt - PMID:2831218 supported_by: &id002 - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: G protein-coupled receptor for catecholamines that couples to - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: both G(s) and G(i) proteins, activating bifurcated signaling pathways - reference_id: PMID:2831218 supporting_text: associated with high affinity ligand binding, Gs coupling, and adenylate cyclase - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: ADRB2 binds epinephrine (Epi) with an - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: approximately 30-fold greater affinity than norepinephrine (NE) - reference_id: PMID:2831218 supporting_text: affinity for isoproterenol, epinephrine, and norepinephrine - term: id: GO:0051380 label: norepinephrine binding evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: Norepinephrine binding is supported as part of the catecholamine receptor activity. action: ACCEPT reason: ADRB2 binds catecholamines including norepinephrine, although epinephrine has higher affinity. This ligand-binding term supports the core beta-2 adrenergic receptor activity. additional_reference_ids: &id036 - file:human/ADRB2/ADRB2-uniprot.txt - PMID:2831218 supported_by: &id037 - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: ADRB2 binds epinephrine (Epi) with an - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: approximately 30-fold greater affinity than norepinephrine (NE) - reference_id: PMID:2831218 supporting_text: affinity for isoproterenol, epinephrine, and norepinephrine - term: id: GO:0004930 label: G protein-coupled receptor activity evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: Generic GPCR activity is correct but too broad for ADRB2. action: MODIFY reason: Replace the broad GPCR activity term with the more specific beta2-adrenergic receptor activity already supported for ADRB2. proposed_replacement_terms: - id: GO:0004941 label: beta2-adrenergic receptor activity additional_reference_ids: - file:human/ADRB2/ADRB2-uniprot.txt - PMID:2831218 supported_by: - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: G protein-coupled receptor for catecholamines that couples to - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: both G(s) and G(i) proteins, activating bifurcated signaling pathways - reference_id: PMID:2831218 supporting_text: associated with high affinity ligand binding, Gs coupling, and adenylate cyclase - term: id: GO:0004935 label: adrenergic receptor activity evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: Generic adrenergic receptor activity is correct but less specific than beta2-adrenergic receptor activity. action: MODIFY reason: ADRB2 is specifically the beta-2 adrenergic receptor, so the specific child term should be used rather than a broader adrenergic receptor activity term. proposed_replacement_terms: - id: GO:0004941 label: beta2-adrenergic receptor activity additional_reference_ids: - file:human/ADRB2/ADRB2-uniprot.txt - PMID:2831218 supported_by: - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: G protein-coupled receptor for catecholamines that couples to - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: both G(s) and G(i) proteins, activating bifurcated signaling pathways - reference_id: PMID:2831218 supporting_text: associated with high affinity ligand binding, Gs coupling, and adenylate cyclase - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: ADRB2 binds epinephrine (Epi) with an - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: approximately 30-fold greater affinity than norepinephrine (NE) - reference_id: PMID:2831218 supporting_text: affinity for isoproterenol, epinephrine, and norepinephrine - term: id: GO:0004939 label: beta-adrenergic receptor activity evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: enables review: summary: Beta-adrenergic receptor activity is correct but less specific than beta2-adrenergic receptor activity. action: MODIFY reason: ADRB2 should be annotated to beta2-adrenergic receptor activity rather than the broader beta-adrenergic receptor parent. proposed_replacement_terms: - id: GO:0004941 label: beta2-adrenergic receptor activity additional_reference_ids: - file:human/ADRB2/ADRB2-uniprot.txt - PMID:2831218 supported_by: - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: G protein-coupled receptor for catecholamines that couples to - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: both G(s) and G(i) proteins, activating bifurcated signaling pathways - reference_id: PMID:2831218 supporting_text: associated with high affinity ligand binding, Gs coupling, and adenylate cyclase - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: ADRB2 binds epinephrine (Epi) with an - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: approximately 30-fold greater affinity than norepinephrine (NE) - reference_id: PMID:2831218 supporting_text: affinity for isoproterenol, epinephrine, and norepinephrine - term: id: GO:0004941 label: beta2-adrenergic receptor activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: Beta2-adrenergic receptor activity is the core ADRB2 molecular function. action: ACCEPT reason: ADRB2 is the beta-2 adrenergic receptor; mutagenesis and UniProt evidence support catecholamine binding, Gs/Gi coupling, and adenylate cyclase signaling. additional_reference_ids: *id001 supported_by: *id002 - term: id: GO:0005794 label: Golgi apparatus evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Golgi apparatus is a supported receptor itinerary location but not the primary active signaling location. action: KEEP_AS_NON_CORE reason: Activated ADRB2 can traffic through the Golgi in a palmitoylation-dependent itinerary, but the primary core location for receptor signaling is the plasma membrane. additional_reference_ids: &id019 - file:human/ADRB2/ADRB2-uniprot.txt - PMID:27481942 supported_by: &id020 - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: Golgi apparatus - reference_id: PMID:27481942 supporting_text: traffics along a previously undescribed intracellular itinerary via the Golgi complex - reference_id: PMID:27481942 supporting_text: Cys-265 S-palmitoylation is mediated by the Golgi-resident palmitoyl transferases - term: id: GO:0005886 label: plasma membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0006940 label: regulation of smooth muscle contraction evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: Regulation of smooth muscle contraction is broad vascular physiology context and is not directly supported by the cached ADRB2 experiments. action: MARK_AS_OVER_ANNOTATED reason: The previous MARCH2 citation was introductory background rather than experimental support. Because the cached evidence directly supports ADRB2 receptor signaling and trafficking rather than smooth-muscle contraction regulation, this broad IEA physiology row should be treated as over-annotated. additional_reference_ids: - file:human/ADRB2/ADRB2-uniprot.txt supported_by: - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: G protein-coupled receptor for catecholamines that couples to - term: id: GO:0007186 label: G protein-coupled receptor signaling pathway evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: Generic GPCR signaling is too broad for ADRB2. action: MODIFY reason: Replace the broad GPCR signaling pathway with adrenergic receptor signaling and, where appropriate, the adenylate cyclase-activating adrenergic receptor signaling pathway. proposed_replacement_terms: - id: GO:0071875 label: adrenergic receptor signaling pathway - id: GO:0071880 label: adenylate cyclase-activating adrenergic receptor signaling pathway additional_reference_ids: - file:human/ADRB2/ADRB2-uniprot.txt - PMID:2831218 supported_by: - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: G protein-coupled receptor for catecholamines that couples to - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: both G(s) and G(i) proteins, activating bifurcated signaling pathways - reference_id: PMID:2831218 supporting_text: associated with high affinity ligand binding, Gs coupling, and adenylate cyclase - term: id: GO:0007189 label: adenylate cyclase-activating G protein-coupled receptor signaling pathway evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: Generic adenylate cyclase-activating GPCR signaling is too broad for ADRB2. action: MODIFY reason: Use the adrenergic receptor-specific adenylate cyclase-activating pathway term for ADRB2 rather than the generic GPCR parent. proposed_replacement_terms: - id: GO:0071880 label: adenylate cyclase-activating adrenergic receptor signaling pathway additional_reference_ids: - file:human/ADRB2/ADRB2-uniprot.txt - PMID:2831218 supported_by: - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: G protein-coupled receptor for catecholamines that couples to - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: both G(s) and G(i) proteins, activating bifurcated signaling pathways - reference_id: PMID:2831218 supporting_text: associated with high affinity ligand binding, Gs coupling, and adenylate cyclase - term: id: GO:0016020 label: membrane evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: Membrane is correct but too broad for ADRB2 localization. action: MODIFY reason: ADRB2 is a multi-pass receptor whose core location is the plasma membrane; the generic membrane term should be replaced with plasma membrane. proposed_replacement_terms: &id025 - id: GO:0005886 label: plasma membrane additional_reference_ids: &id026 - file:human/ADRB2/ADRB2-uniprot.txt - PMID:2831218 supported_by: &id027 - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cell membrane' - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: Multi-pass membrane protein - reference_id: PMID:2831218 supporting_text: expression of the human beta 2-adrenergic receptor in mouse L cells - term: id: GO:0097746 label: blood vessel diameter maintenance evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: Blood vessel diameter maintenance is broad vascular physiology context and is not directly supported by the cached ADRB2 experiments. action: MARK_AS_OVER_ANNOTATED reason: The previous MARCH2 citation was introductory background rather than experimental support. The reviewed evidence supports catecholamine receptor signaling, but not a direct ADRB2-specific blood-vessel-diameter maintenance assay, so this IEA row is over-annotated. additional_reference_ids: - file:human/ADRB2/ADRB2-uniprot.txt supported_by: - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: G protein-coupled receptor for catecholamines that couples to - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17148612 qualifier: enables review: summary: Generic protein binding is not an informative ADRB2 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs. additional_reference_ids: &id005 - file:human/ADRB2/ADRB2-notes.md supported_by: &id006 - reference_id: file:human/ADRB2/ADRB2-notes.md supporting_text: Generic `protein binding` rows are not informative ADRB2 molecular functions - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17170700 qualifier: enables review: summary: Generic protein binding is not an informative ADRB2 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs. additional_reference_ids: *id005 supported_by: *id006 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20353789 qualifier: enables review: summary: Generic protein binding is not an informative ADRB2 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs. additional_reference_ids: *id005 supported_by: *id006 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23208550 qualifier: enables review: summary: Generic protein binding is not an informative ADRB2 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs. additional_reference_ids: *id005 supported_by: *id006 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23236378 qualifier: enables review: summary: Generic protein binding is not an informative ADRB2 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs. additional_reference_ids: *id005 supported_by: *id006 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23291003 qualifier: enables review: summary: Generic protein binding is not an informative ADRB2 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs. additional_reference_ids: *id005 supported_by: *id006 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28298427 qualifier: enables review: summary: Generic protein binding is not an informative ADRB2 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs. additional_reference_ids: *id005 supported_by: *id006 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32814053 qualifier: enables review: summary: Generic protein binding is not an informative ADRB2 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs. additional_reference_ids: *id005 supported_by: *id006 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36115835 qualifier: enables review: summary: Generic protein binding is not an informative ADRB2 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs. additional_reference_ids: *id005 supported_by: *id006 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:39083597 qualifier: enables review: summary: Generic protein binding is not an informative ADRB2 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs. additional_reference_ids: *id005 supported_by: *id006 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:9671706 qualifier: enables review: summary: Generic protein binding is not an informative ADRB2 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs. additional_reference_ids: *id005 supported_by: *id006 - term: id: GO:0042802 label: identical protein binding evidence_type: IPI original_reference_id: PMID:15518545 qualifier: enables review: summary: Identical protein binding reflects receptor oligomerization, but it is not ADRB2 core function. action: KEEP_AS_NON_CORE reason: ADRB2 oligomerization/hetero-oligomerization is supported, but the core molecular function remains catecholamine receptor activity and downstream GPCR signaling. additional_reference_ids: &id007 - PMID:15123695 - PMID:19763081 supported_by: &id008 - reference_id: PMID:15123695 supporting_text: hetero-oligomerization between beta(2)AR and beta(3)AR forms a beta-adrenergic signaling unit - reference_id: PMID:19763081 supporting_text: Ligand-regulated oligomerization of beta(2)-adrenoceptors - term: id: GO:0042802 label: identical protein binding evidence_type: IPI original_reference_id: PMID:19763081 qualifier: enables review: summary: Identical protein binding reflects receptor oligomerization, but it is not ADRB2 core function. action: KEEP_AS_NON_CORE reason: ADRB2 oligomerization/hetero-oligomerization is supported, but the core molecular function remains catecholamine receptor activity and downstream GPCR signaling. additional_reference_ids: *id007 supported_by: *id008 - term: id: GO:0042802 label: identical protein binding evidence_type: IPI original_reference_id: PMID:20590567 qualifier: enables review: summary: Identical protein binding reflects receptor oligomerization, but it is not ADRB2 core function. action: KEEP_AS_NON_CORE reason: ADRB2 oligomerization/hetero-oligomerization is supported, but the core molecular function remains catecholamine receptor activity and downstream GPCR signaling. additional_reference_ids: *id007 supported_by: *id008 - term: id: GO:0005634 label: nucleus evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Nucleus is not supported as a primary ADRB2 location. action: MARK_AS_OVER_ANNOTATED reason: The reviewed UniProt and publication evidence supports plasma membrane, endosomal/lysosomal trafficking, and Golgi itinerary contexts, not a nuclear ADRB2 location. additional_reference_ids: - file:human/ADRB2/ADRB2-uniprot.txt supported_by: - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cell membrane' - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: Golgi apparatus - term: id: GO:0008179 label: adenylate cyclase binding evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: Adenylate cyclase binding is supported as receptor-effector complex context but is not the core MF term. action: KEEP_AS_NON_CORE reason: ADRB2 can associate with adenylyl cyclase and channel-effector complexes, but beta2-adrenergic receptor activity is the more direct core molecular function. additional_reference_ids: - PMID:12297500 supported_by: - reference_id: PMID:12297500 supporting_text: beta(2)-adrenergic receptors (beta(2)-AR) form stable complexes with Kir3 channels - reference_id: PMID:12297500 supporting_text: beta(2)AR interacts directly with Kir3.1/3.4 and Kir3.1/3.2c heterotetramers as well as with adenylyl cyclase - term: id: GO:0010666 label: positive regulation of cardiac muscle cell apoptotic process evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Positive regulation of cardiac muscle cell apoptosis is a context-specific signaling output. action: KEEP_AS_NON_CORE reason: Cardiomyocyte apoptotic/survival effects derive from bifurcated Gs/Gi signaling and are tissue-context outputs rather than the core receptor activity. additional_reference_ids: &id011 - file:human/ADRB2/ADRB2-uniprot.txt supported_by: &id012 - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: In the heart, Epi- and NE-activated ADRB2 induces rapid and slow cardiomyocyte - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: Both NE and Epi promote coupling to G(s)/PKA pathway to regulate myocyte contraction rate - term: id: GO:0010667 label: negative regulation of cardiac muscle cell apoptotic process evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Negative regulation of cardiac muscle cell apoptosis is a context-specific signaling output. action: KEEP_AS_NON_CORE reason: Cardiomyocyte apoptotic/survival effects derive from bifurcated Gs/Gi signaling and are tissue-context outputs rather than the core receptor activity. additional_reference_ids: &id013 - file:human/ADRB2/ADRB2-uniprot.txt supported_by: &id014 - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: In the heart, Epi- and NE-activated ADRB2 induces rapid and slow cardiomyocyte - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: Both NE and Epi promote coupling to G(s)/PKA pathway to regulate myocyte contraction rate - term: id: GO:0016324 label: apical plasma membrane evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Apical plasma membrane is plausible specialized plasma-membrane context, but not the primary localization term. action: KEEP_AS_NON_CORE reason: ADRB2 is primarily a plasma-membrane GPCR; apical plasma membrane can be retained as cell-type context but should not replace the core plasma membrane annotation. additional_reference_ids: - file:human/ADRB2/ADRB2-uniprot.txt supported_by: - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cell membrane' - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: Multi-pass membrane protein - reference_id: PMID:2831218 supporting_text: expression of the human beta 2-adrenergic receptor in mouse L cells - term: id: GO:0019899 label: enzyme binding evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: Generic enzyme binding is not an informative ADRB2 molecular function. action: MARK_AS_OVER_ANNOTATED reason: ADRB2 has specific signaling and trafficking partners, but generic enzyme binding should not be used as a functional endpoint when beta2-adrenergic receptor activity and specific pathway terms are available. additional_reference_ids: - file:human/ADRB2/ADRB2-notes.md supported_by: - reference_id: file:human/ADRB2/ADRB2-notes.md supporting_text: Specific interaction contexts such as receptor oligomerization - term: id: GO:0061885 label: positive regulation of mini excitatory postsynaptic potential evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Positive regulation of mini excitatory postsynaptic potential is a neuronal downstream context. action: KEEP_AS_NON_CORE reason: The amyloid-beta/AMPA receptor study supports a neuronal beta2AR signaling complex affecting excitatory postsynaptic currents, but this is a specialized context rather than the core ADRB2 function. additional_reference_ids: - PMID:20395454 supported_by: - reference_id: PMID:20395454 supporting_text: soluble Abeta binds to beta(2)AR - reference_id: PMID:20395454 supporting_text: binding is required to induce G-protein/cAMP/protein kinase A (PKA) signaling - reference_id: PMID:20395454 supporting_text: beta(2)AR and GluR1 also form a complex - term: id: GO:0071880 label: adenylate cyclase-activating adrenergic receptor signaling pathway evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Adenylate cyclase-activating adrenergic receptor signaling is a core ADRB2 function. action: ACCEPT reason: The core beta-2 adrenergic receptor activity couples catecholamine binding to Gs, cAMP/PKA, and adenylate cyclase signaling. additional_reference_ids: *id009 supported_by: *id010 - term: id: GO:0071881 label: adenylate cyclase-inhibiting adrenergic receptor signaling pathway evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Adenylate cyclase-inhibiting adrenergic receptor signaling is supportable as the Gi arm of ADRB2 signaling. action: ACCEPT reason: UniProt describes ADRB2 coupling to both Gs and Gi proteins; the Gi branch is part of bifurcated beta-2 adrenergic receptor signaling even if it is more context-dependent than the canonical Gs/cAMP arm. additional_reference_ids: &id015 - file:human/ADRB2/ADRB2-uniprot.txt - PMID:15123695 supported_by: &id016 - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: G protein-coupled receptor for catecholamines that couples to - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: both G(s) and G(i) proteins, activating bifurcated signaling pathways - reference_id: PMID:2831218 supporting_text: associated with high affinity ligand binding, Gs coupling, and adenylate cyclase - term: id: GO:0098992 label: neuronal dense core vesicle evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: is_active_in review: summary: Neuronal dense core vesicle is not supported as a primary ADRB2 active location. action: MARK_AS_OVER_ANNOTATED reason: The local evidence supports plasma membrane receptor activity and endosomal/Golgi trafficking. Dense-core vesicle activity is not established by the reviewed ADRB2 publications. additional_reference_ids: - file:human/ADRB2/ADRB2-uniprot.txt supported_by: - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cell membrane' - term: id: GO:0106134 label: positive regulation of cardiac muscle cell contraction evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Positive regulation of cardiac muscle cell contraction is a downstream tissue-specific output. action: KEEP_AS_NON_CORE reason: Cardiomyocyte contraction-rate regulation is a physiological output of beta-adrenergic signaling and is secondary to the core receptor activity. additional_reference_ids: &id017 - file:human/ADRB2/ADRB2-uniprot.txt supported_by: &id018 - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: In the heart, Epi- and NE-activated ADRB2 induces rapid and slow cardiomyocyte - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: Both NE and Epi promote coupling to G(s)/PKA pathway to regulate myocyte contraction rate - term: id: GO:0120162 label: positive regulation of cold-induced thermogenesis evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Cold-induced thermogenesis is not supported as an ADRB2-specific annotation by the cited triple-knockout study. action: MARK_AS_OVER_ANNOTATED reason: PMID:12387862 tests beta1/beta2/beta3 adrenoceptor triple-knockout mice, so its cold-intolerance phenotype supports beta-adrenergic signaling broadly, not ADRB2 specifically. ADRB2-specific adipocyte evidence supports cAMP-stimulated lipolysis, but not direct positive regulation of cold-induced thermogenesis at the gene level. additional_reference_ids: &id023 - PMID:23708524 supported_by: &id024 - reference_id: PMID:12387862 supporting_text: TKO mice exhibited normophagic obesity and cold-intolerance - reference_id: PMID:12387862 supporting_text: beta-adrenergic signalling is essential for the resistance to obesity and cold - reference_id: PMID:23708524 supporting_text: ADRB2-cAMP-stimulated lipolysis in fat cells - term: id: GO:1904646 label: cellular response to amyloid-beta evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Cellular response to amyloid-beta is a supported disease-context signaling response. action: KEEP_AS_NON_CORE reason: A beta binds beta2AR and induces PKA-dependent AMPA receptor hyperactivity, but this Alzheimer-disease-related context is not ADRB2 core physiology. additional_reference_ids: &id028 - PMID:20395454 supported_by: &id029 - reference_id: PMID:20395454 supporting_text: soluble Abeta binds to beta(2)AR - reference_id: PMID:20395454 supporting_text: binding is required to induce G-protein/cAMP/protein kinase A (PKA) signaling - reference_id: PMID:20395454 supporting_text: beta(2)AR and GluR1 also form a complex - term: id: GO:0005886 label: plasma membrane evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0005886 label: plasma membrane evidence_type: EXP original_reference_id: PMID:20559325 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0005886 label: plasma membrane evidence_type: EXP original_reference_id: PMID:25220262 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0005886 label: plasma membrane evidence_type: EXP original_reference_id: PMID:2831218 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0005886 label: plasma membrane evidence_type: EXP original_reference_id: PMID:7915137 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0071875 label: adrenergic receptor signaling pathway evidence_type: IGI original_reference_id: PMID:20395454 qualifier: involved_in review: summary: Adrenergic receptor signaling pathway is a core ADRB2 signaling annotation. action: ACCEPT reason: ADRB2 transduces catecholamine binding into adrenergic receptor signaling through G protein, cAMP/PKA, beta-arrestin, and MAPK-associated branches. additional_reference_ids: &id030 - file:human/ADRB2/ADRB2-uniprot.txt - PMID:2831218 - PMID:10734107 supported_by: &id031 - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: G protein-coupled receptor for catecholamines that couples to - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: both G(s) and G(i) proteins, activating bifurcated signaling pathways - reference_id: PMID:2831218 supporting_text: associated with high affinity ligand binding, Gs coupling, and adenylate cyclase - reference_id: PMID:10734107 supporting_text: beta(2)-Adrenergic receptor (beta(2)AR) stimulation of COS-7 cells induces EGFR dimerization - reference_id: PMID:10734107 supporting_text: beta(2)AR-dependent signaling to ERK1/2 - reference_id: PMID:15123695 supporting_text: regulate adenylyl cyclase and extracellular signal-regulated kinase activity - term: id: GO:1900451 label: positive regulation of glutamate receptor signaling pathway evidence_type: IGI original_reference_id: PMID:20395454 qualifier: involved_in review: summary: Positive regulation of glutamate receptor signaling is a neuronal amyloid-beta context. action: KEEP_AS_NON_CORE reason: The amyloid-beta study supports beta2AR/AMPA receptor complex signaling, but this is a specialized neuronal disease-context output rather than the central ADRB2 function. additional_reference_ids: - PMID:20395454 supported_by: - reference_id: PMID:20395454 supporting_text: soluble Abeta binds to beta(2)AR - reference_id: PMID:20395454 supporting_text: binding is required to induce G-protein/cAMP/protein kinase A (PKA) signaling - reference_id: PMID:20395454 supporting_text: beta(2)AR and GluR1 also form a complex - term: id: GO:0071880 label: adenylate cyclase-activating adrenergic receptor signaling pathway evidence_type: IGI original_reference_id: PMID:20395454 qualifier: involved_in review: summary: Adenylate cyclase-activating adrenergic receptor signaling is a core ADRB2 function. action: ACCEPT reason: The core beta-2 adrenergic receptor activity couples catecholamine binding to Gs, cAMP/PKA, and adenylate cyclase signaling. additional_reference_ids: *id009 supported_by: *id010 - term: id: GO:0004941 label: beta2-adrenergic receptor activity evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: enables review: summary: Beta2-adrenergic receptor activity is the core ADRB2 molecular function. action: ACCEPT reason: ADRB2 is the beta-2 adrenergic receptor; mutagenesis and UniProt evidence support catecholamine binding, Gs/Gi coupling, and adenylate cyclase signaling. additional_reference_ids: *id001 supported_by: *id002 - term: id: GO:0004941 label: beta2-adrenergic receptor activity evidence_type: IMP original_reference_id: PMID:2831218 qualifier: enables review: summary: Beta2-adrenergic receptor activity is the core ADRB2 molecular function. action: ACCEPT reason: ADRB2 is the beta-2 adrenergic receptor; mutagenesis and UniProt evidence support catecholamine binding, Gs/Gi coupling, and adenylate cyclase signaling. additional_reference_ids: *id001 supported_by: *id002 - term: id: GO:0005886 label: plasma membrane evidence_type: IDA original_reference_id: PMID:19584355 qualifier: is_active_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0010666 label: positive regulation of cardiac muscle cell apoptotic process evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Positive regulation of cardiac muscle cell apoptosis is a context-specific signaling output. action: KEEP_AS_NON_CORE reason: Cardiomyocyte apoptotic/survival effects derive from bifurcated Gs/Gi signaling and are tissue-context outputs rather than the core receptor activity. additional_reference_ids: *id011 supported_by: *id012 - term: id: GO:0010667 label: negative regulation of cardiac muscle cell apoptotic process evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Negative regulation of cardiac muscle cell apoptosis is a context-specific signaling output. action: KEEP_AS_NON_CORE reason: Cardiomyocyte apoptotic/survival effects derive from bifurcated Gs/Gi signaling and are tissue-context outputs rather than the core receptor activity. additional_reference_ids: *id013 supported_by: *id014 - term: id: GO:0071880 label: adenylate cyclase-activating adrenergic receptor signaling pathway evidence_type: IC original_reference_id: PMID:2831218 qualifier: involved_in review: summary: Adenylate cyclase-activating adrenergic receptor signaling is a core ADRB2 function. action: ACCEPT reason: The core beta-2 adrenergic receptor activity couples catecholamine binding to Gs, cAMP/PKA, and adenylate cyclase signaling. additional_reference_ids: *id009 supported_by: *id010 - term: id: GO:0071881 label: adenylate cyclase-inhibiting adrenergic receptor signaling pathway evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Adenylate cyclase-inhibiting adrenergic receptor signaling is supportable as the Gi arm of ADRB2 signaling. action: ACCEPT reason: UniProt describes ADRB2 coupling to both Gs and Gi proteins; the Gi branch is part of bifurcated beta-2 adrenergic receptor signaling even if it is more context-dependent than the canonical Gs/cAMP arm. additional_reference_ids: *id015 supported_by: *id016 - term: id: GO:0106134 label: positive regulation of cardiac muscle cell contraction evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Positive regulation of cardiac muscle cell contraction is a downstream tissue-specific output. action: KEEP_AS_NON_CORE reason: Cardiomyocyte contraction-rate regulation is a physiological output of beta-adrenergic signaling and is secondary to the core receptor activity. additional_reference_ids: *id017 supported_by: *id018 - term: id: GO:0042803 label: protein homodimerization activity evidence_type: IPI original_reference_id: PMID:15123695 qualifier: enables review: summary: Protein homodimerization activity is supported receptor oligomerization context but not core function. action: KEEP_AS_NON_CORE reason: ADRB2 can form receptor oligomers, but oligomerization is secondary to catecholamine receptor activity and signaling. additional_reference_ids: - PMID:15123695 - PMID:19763081 supported_by: - reference_id: PMID:15123695 supporting_text: hetero-oligomerization between beta(2)AR and beta(3)AR forms a beta-adrenergic signaling unit - reference_id: PMID:19763081 supporting_text: Ligand-regulated oligomerization of beta(2)-adrenoceptors - term: id: GO:0044877 label: protein-containing complex binding evidence_type: IPI original_reference_id: PMID:20395454 qualifier: enables review: summary: Protein-containing complex binding is supported by the amyloid-beta/AMPA receptor complex context. action: KEEP_AS_NON_CORE reason: The amyloid-beta study supports beta2AR participation in a postsynaptic signaling complex, but this generic binding term is less informative than receptor activity and pathway-specific signaling terms. additional_reference_ids: - PMID:20395454 supported_by: - reference_id: PMID:20395454 supporting_text: soluble Abeta binds to beta(2)AR - reference_id: PMID:20395454 supporting_text: binding is required to induce G-protein/cAMP/protein kinase A (PKA) signaling - reference_id: PMID:20395454 supporting_text: beta(2)AR and GluR1 also form a complex - term: id: GO:0098990 label: AMPA selective glutamate receptor signaling pathway evidence_type: IGI original_reference_id: PMID:20395454 qualifier: involved_in review: summary: AMPA-selective glutamate receptor signaling is a specialized neuronal output. action: KEEP_AS_NON_CORE reason: Beta2AR can mediate amyloid-beta-induced AMPA receptor hyperactivity, but this is a disease/neuron signaling branch rather than ADRB2 core function. additional_reference_ids: - PMID:20395454 supported_by: - reference_id: PMID:20395454 supporting_text: soluble Abeta binds to beta(2)AR - reference_id: PMID:20395454 supporting_text: binding is required to induce G-protein/cAMP/protein kinase A (PKA) signaling - reference_id: PMID:20395454 supporting_text: beta(2)AR and GluR1 also form a complex - term: id: GO:0045744 label: negative regulation of G protein-coupled receptor signaling pathway evidence_type: IDA original_reference_id: PMID:15123695 qualifier: involved_in review: summary: Negative regulation of GPCR signaling is supported as receptor regulation/desensitization context. action: KEEP_AS_NON_CORE reason: Hetero-oligomerization and beta-arrestin/endocytic regulation can dampen ADRB2 signaling, but the central function remains receptor activation of adrenergic signaling pathways. additional_reference_ids: - PMID:15123695 - PMID:9507004 supported_by: - reference_id: PMID:15123695 supporting_text: hetero-oligomerization between beta(2)AR and beta(3)AR forms a beta-adrenergic signaling unit - reference_id: PMID:19763081 supporting_text: Ligand-regulated oligomerization of beta(2)-adrenoceptors - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: internalized into endosomes prior to their degradation in lysosomes - term: id: GO:0071880 label: adenylate cyclase-activating adrenergic receptor signaling pathway evidence_type: IDA original_reference_id: PMID:15123695 qualifier: involved_in review: summary: Adenylate cyclase-activating adrenergic receptor signaling is a core ADRB2 function. action: ACCEPT reason: The core beta-2 adrenergic receptor activity couples catecholamine binding to Gs, cAMP/PKA, and adenylate cyclase signaling. additional_reference_ids: *id009 supported_by: *id010 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23166351 qualifier: enables review: summary: Generic protein binding is not an informative ADRB2 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs. additional_reference_ids: *id005 supported_by: *id006 - term: id: GO:0005886 label: plasma membrane evidence_type: IDA original_reference_id: PMID:23166351 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0005794 label: Golgi apparatus evidence_type: IDA original_reference_id: PMID:27481942 qualifier: located_in review: summary: Golgi apparatus is a supported receptor itinerary location but not the primary active signaling location. action: KEEP_AS_NON_CORE reason: Activated ADRB2 can traffic through the Golgi in a palmitoylation-dependent itinerary, but the primary core location for receptor signaling is the plasma membrane. additional_reference_ids: *id019 supported_by: *id020 - term: id: GO:0005886 label: plasma membrane evidence_type: IDA original_reference_id: PMID:27481942 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0030669 label: clathrin-coated endocytic vesicle membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8868658 qualifier: located_in review: summary: Clathrin-coated endocytic vesicle membrane is a supported receptor trafficking location. action: KEEP_AS_NON_CORE reason: Activated ADRB2 is internalized through clathrin-coated pits/vesicles during receptor down-regulation and sorting, but this is receptor lifecycle context rather than the core active signaling location. additional_reference_ids: &id021 - PMID:9507004 - file:human/ADRB2/ADRB2-uniprot.txt supported_by: &id022 - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: internalized into endosomes prior to their degradation in lysosomes - reference_id: PMID:9507004 supporting_text: agonist-induced internalization and down-regulation of the beta2AR - reference_id: PMID:9507004 supporting_text: trafficking of the beta2AR via the clathrin-coated pit endosomal pathway to lysosomes - term: id: GO:0030669 label: clathrin-coated endocytic vesicle membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8868659 qualifier: located_in review: summary: Clathrin-coated endocytic vesicle membrane is a supported receptor trafficking location. action: KEEP_AS_NON_CORE reason: Activated ADRB2 is internalized through clathrin-coated pits/vesicles during receptor down-regulation and sorting, but this is receptor lifecycle context rather than the core active signaling location. additional_reference_ids: *id021 supported_by: *id022 - term: id: GO:0030669 label: clathrin-coated endocytic vesicle membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8868660 qualifier: located_in review: summary: Clathrin-coated endocytic vesicle membrane is a supported receptor trafficking location. action: KEEP_AS_NON_CORE reason: Activated ADRB2 is internalized through clathrin-coated pits/vesicles during receptor down-regulation and sorting, but this is receptor lifecycle context rather than the core active signaling location. additional_reference_ids: *id021 supported_by: *id022 - term: id: GO:0030669 label: clathrin-coated endocytic vesicle membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8868661 qualifier: located_in review: summary: Clathrin-coated endocytic vesicle membrane is a supported receptor trafficking location. action: KEEP_AS_NON_CORE reason: Activated ADRB2 is internalized through clathrin-coated pits/vesicles during receptor down-regulation and sorting, but this is receptor lifecycle context rather than the core active signaling location. additional_reference_ids: *id021 supported_by: *id022 - term: id: GO:0030669 label: clathrin-coated endocytic vesicle membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8869438 qualifier: located_in review: summary: Clathrin-coated endocytic vesicle membrane is a supported receptor trafficking location. action: KEEP_AS_NON_CORE reason: Activated ADRB2 is internalized through clathrin-coated pits/vesicles during receptor down-regulation and sorting, but this is receptor lifecycle context rather than the core active signaling location. additional_reference_ids: *id021 supported_by: *id022 - term: id: GO:0030669 label: clathrin-coated endocytic vesicle membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8871193 qualifier: located_in review: summary: Clathrin-coated endocytic vesicle membrane is a supported receptor trafficking location. action: KEEP_AS_NON_CORE reason: Activated ADRB2 is internalized through clathrin-coated pits/vesicles during receptor down-regulation and sorting, but this is receptor lifecycle context rather than the core active signaling location. additional_reference_ids: *id021 supported_by: *id022 - term: id: GO:0030669 label: clathrin-coated endocytic vesicle membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8871194 qualifier: located_in review: summary: Clathrin-coated endocytic vesicle membrane is a supported receptor trafficking location. action: KEEP_AS_NON_CORE reason: Activated ADRB2 is internalized through clathrin-coated pits/vesicles during receptor down-regulation and sorting, but this is receptor lifecycle context rather than the core active signaling location. additional_reference_ids: *id021 supported_by: *id022 - term: id: GO:0120162 label: positive regulation of cold-induced thermogenesis evidence_type: ISS original_reference_id: PMID:12387862 qualifier: involved_in review: summary: Cold-induced thermogenesis is not supported as an ADRB2-specific annotation by the cited triple-knockout study. action: MARK_AS_OVER_ANNOTATED reason: PMID:12387862 tests beta1/beta2/beta3 adrenoceptor triple-knockout mice, so its cold-intolerance phenotype supports beta-adrenergic signaling broadly, not ADRB2 specifically. ADRB2-specific adipocyte evidence supports cAMP-stimulated lipolysis, but not direct positive regulation of cold-induced thermogenesis at the gene level. additional_reference_ids: *id023 supported_by: *id024 - term: id: GO:0001540 label: amyloid-beta binding evidence_type: IDA original_reference_id: PMID:20395454 qualifier: enables review: summary: Amyloid-beta binding is direct but disease-context and not a core ADRB2 function. action: KEEP_AS_NON_CORE reason: Soluble amyloid beta binding to beta2AR is experimentally supported, but it is a specialized Alzheimer-disease-related interaction rather than ADRB2 canonical catecholamine receptor function. additional_reference_ids: - PMID:20395454 supported_by: - reference_id: PMID:20395454 supporting_text: soluble Abeta binds to beta(2)AR - reference_id: PMID:20395454 supporting_text: binding is required to induce G-protein/cAMP/protein kinase A (PKA) signaling - reference_id: PMID:20395454 supporting_text: beta(2)AR and GluR1 also form a complex - term: id: GO:0004941 label: beta2-adrenergic receptor activity evidence_type: NAS original_reference_id: PMID:20395454 qualifier: enables review: summary: Beta2-adrenergic receptor activity is the core ADRB2 molecular function. action: ACCEPT reason: ADRB2 is the beta-2 adrenergic receptor; mutagenesis and UniProt evidence support catecholamine binding, Gs/Gi coupling, and adenylate cyclase signaling. additional_reference_ids: *id001 supported_by: *id002 - term: id: GO:0016020 label: membrane evidence_type: NAS original_reference_id: PMID:20395454 qualifier: located_in review: summary: Membrane is correct but too broad for ADRB2 localization. action: MODIFY reason: ADRB2 is a multi-pass receptor whose core location is the plasma membrane; the generic membrane term should be replaced with plasma membrane. proposed_replacement_terms: *id025 additional_reference_ids: *id026 supported_by: *id027 - term: id: GO:1904646 label: cellular response to amyloid-beta evidence_type: IGI original_reference_id: PMID:20395454 qualifier: involved_in review: summary: Cellular response to amyloid-beta is a supported disease-context signaling response. action: KEEP_AS_NON_CORE reason: A beta binds beta2AR and induces PKA-dependent AMPA receptor hyperactivity, but this Alzheimer-disease-related context is not ADRB2 core physiology. additional_reference_ids: *id028 supported_by: *id029 - term: id: GO:1990911 label: response to psychosocial stress evidence_type: TAS original_reference_id: PMID:20395454 qualifier: involved_in review: summary: Response to psychosocial stress is too high-level for a direct ADRB2 gene annotation from the reviewed evidence. action: MARK_AS_OVER_ANNOTATED reason: The supporting ADRB2 evidence is receptor signaling and amyloid-beta neuronal signaling; a broad organismal psychosocial-stress response annotation is not a precise gene-product function. additional_reference_ids: - PMID:20395454 supported_by: - reference_id: PMID:20395454 supporting_text: non-neurotransmitter Abeta has a binding capacity to beta(2)AR - term: id: GO:0004941 label: beta2-adrenergic receptor activity evidence_type: IDA original_reference_id: PMID:19710023 qualifier: enables review: summary: Beta2-adrenergic receptor activity is the core ADRB2 molecular function. action: ACCEPT reason: ADRB2 is the beta-2 adrenergic receptor; mutagenesis and UniProt evidence support catecholamine binding, Gs/Gi coupling, and adenylate cyclase signaling. additional_reference_ids: *id001 supported_by: *id002 - term: id: GO:0005886 label: plasma membrane evidence_type: IDA original_reference_id: PMID:19710023 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0071875 label: adrenergic receptor signaling pathway evidence_type: IDA original_reference_id: PMID:19710023 qualifier: involved_in review: summary: Adrenergic receptor signaling pathway is a core ADRB2 signaling annotation. action: ACCEPT reason: ADRB2 transduces catecholamine binding into adrenergic receptor signaling through G protein, cAMP/PKA, beta-arrestin, and MAPK-associated branches. additional_reference_ids: *id030 supported_by: *id031 - term: id: GO:0010008 label: endosome membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-5696968 qualifier: located_in review: summary: Endosome membrane is a supported post-endocytic receptor trafficking location. action: KEEP_AS_NON_CORE reason: Internalized ADRB2 is sorted between recycling and lysosomal routes from endosomes, but this is secondary to the plasma-membrane receptor signaling role. additional_reference_ids: - PMID:9507004 - PMID:19424180 - file:human/ADRB2/ADRB2-uniprot.txt supported_by: - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: internalized into endosomes prior to their degradation in lysosomes - reference_id: PMID:9507004 supporting_text: agonist-induced internalization and down-regulation of the beta2AR - reference_id: PMID:9507004 supporting_text: trafficking of the beta2AR via the clathrin-coated pit endosomal pathway to lysosomes - reference_id: PMID:19424180 supporting_text: sort internalized receptors to the lysosomes for degradation - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8851797 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8852167 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8866269 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8866283 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8867754 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8867756 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8868071 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8868072 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8868230 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8868236 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8868648 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8868651 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8868661 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8982641 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:1901098 label: positive regulation of autophagosome maturation evidence_type: IDA original_reference_id: PMID:23708524 qualifier: involved_in review: summary: Positive regulation of autophagosome maturation is supported in ADRB2-stimulated adipocyte lipolysis but is non-core. action: KEEP_AS_NON_CORE reason: ADRB2 stimulation increases autophagy-targeted lipid droplets, but the direct lipophagy machinery in the paper is RAB7; therefore this is retained as an upstream adipocyte signaling output rather than a core ADRB2 function. additional_reference_ids: - PMID:23708524 - file:human/ADRB2/ADRB2-notes.md supported_by: - reference_id: PMID:23708524 supporting_text: ADRB2-stimulated lipolysis was reduced after inhibition of early or late autophagy - reference_id: PMID:23708524 supporting_text: ADRB2 stimulation has caused a marked increase in the autophagy-targeted LDs for lysosomal degradation - reference_id: PMID:23708524 supporting_text: during ADRB2 stimulation, a subset of LDs are packaged into autophagosomes and delivered to the lysosomes for degradation - reference_id: PMID:23708524 supporting_text: RAB7 plays a pivotal role in the regulation of this autolysosome-mediated lipid degradation in fat cells - reference_id: file:human/ADRB2/ADRB2-notes.md supporting_text: do not add direct `lipophagy` for ADRB2 - term: id: GO:1904504 label: positive regulation of lipophagy evidence_type: IDA original_reference_id: PMID:23708524 qualifier: involved_in review: summary: Positive regulation of lipophagy is supported as upstream ADRB2 adipocyte signaling, but should not be upgraded to direct lipophagy. action: KEEP_AS_NON_CORE reason: The PN projection to direct lipophagy is not accepted for ADRB2. PMID:23708524 supports ADRB2 stimulation as an upstream signal that increases lipophagy/autophagy-targeted lipid droplets, while RAB7 is the direct lipid-droplet recruitment and autolysosomal degradation factor. additional_reference_ids: - PMID:23708524 - file:human/ADRB2/ADRB2-notes.md supported_by: - reference_id: PMID:23708524 supporting_text: ADRB2-stimulated lipolysis was reduced after inhibition of early or late autophagy - reference_id: PMID:23708524 supporting_text: ADRB2 stimulation has caused a marked increase in the autophagy-targeted LDs for lysosomal degradation - reference_id: PMID:23708524 supporting_text: during ADRB2 stimulation, a subset of LDs are packaged into autophagosomes and delivered to the lysosomes for degradation - reference_id: PMID:23708524 supporting_text: RAB7 plays a pivotal role in the regulation of this autolysosome-mediated lipid degradation in fat cells - reference_id: file:human/ADRB2/ADRB2-notes.md supporting_text: do not add direct `lipophagy` for ADRB2 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:24405750 qualifier: enables review: summary: Generic protein binding is not an informative ADRB2 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs. additional_reference_ids: *id005 supported_by: *id006 - term: id: GO:0043235 label: signaling receptor complex evidence_type: IDA original_reference_id: PMID:23382219 qualifier: part_of review: summary: Signaling receptor complex is a supported core context for ADRB2 signaling. action: ACCEPT reason: ADRB2 functions in receptor-effector and receptor-scaffold complexes that support beta-adrenergic signaling, including beta2/beta3 receptor signaling units and postsynaptic complexes. additional_reference_ids: &id032 - PMID:15123695 - PMID:12297500 supported_by: &id033 - reference_id: PMID:15123695 supporting_text: hetero-oligomerization between beta(2)AR and beta(3)AR forms a beta-adrenergic signaling unit - reference_id: PMID:19763081 supporting_text: Ligand-regulated oligomerization of beta(2)-adrenoceptors - reference_id: PMID:12297500 supporting_text: beta(2)-adrenergic receptors (beta(2)-AR) form stable complexes with Kir3 channels - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20733053 qualifier: enables review: summary: Generic protein binding is not an informative ADRB2 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs. additional_reference_ids: *id005 supported_by: *id006 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-379044 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-744886 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-744887 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8982645 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-9609310 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-9611751 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-9611851 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19584355 qualifier: enables review: summary: Generic protein binding is not an informative ADRB2 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs. additional_reference_ids: *id005 supported_by: *id006 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19424180 qualifier: enables review: summary: Generic protein binding is not an informative ADRB2 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs. additional_reference_ids: *id005 supported_by: *id006 - term: id: GO:0005886 label: plasma membrane evidence_type: IDA original_reference_id: PMID:12297500 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0015459 label: potassium channel regulator activity evidence_type: IDA original_reference_id: PMID:12297500 qualifier: enables review: summary: Potassium channel regulator activity is supported receptor-effector context but not core ADRB2 function. action: KEEP_AS_NON_CORE reason: ADRB2 can form stable complexes with Kir3 potassium channels and adenylyl cyclase, but this specialized effector-complex role is secondary to beta2-adrenergic receptor activity. additional_reference_ids: - PMID:12297500 supported_by: - reference_id: PMID:12297500 supporting_text: beta(2)-adrenergic receptors (beta(2)-AR) form stable complexes with Kir3 channels - reference_id: PMID:12297500 supporting_text: beta(2)AR interacts directly with Kir3.1/3.4 and Kir3.1/3.2c heterotetramers as well as with adenylyl cyclase - term: id: GO:0005886 label: plasma membrane evidence_type: IDA original_reference_id: PMID:9235896 qualifier: located_in review: summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling. action: ACCEPT reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0004941 label: beta2-adrenergic receptor activity evidence_type: IDA original_reference_id: PMID:15123695 qualifier: enables review: summary: Beta2-adrenergic receptor activity is the core ADRB2 molecular function. action: ACCEPT reason: ADRB2 is the beta-2 adrenergic receptor; mutagenesis and UniProt evidence support catecholamine binding, Gs/Gi coupling, and adenylate cyclase signaling. additional_reference_ids: *id001 supported_by: *id002 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:15123695 qualifier: enables review: summary: Generic protein binding is not an informative ADRB2 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs. additional_reference_ids: *id005 supported_by: *id006 - term: id: GO:0006898 label: receptor-mediated endocytosis evidence_type: IDA original_reference_id: PMID:15123695 qualifier: involved_in review: summary: Receptor-mediated endocytosis is supported receptor lifecycle regulation. action: KEEP_AS_NON_CORE reason: Agonist-induced beta2AR internalization and down-regulation are well supported, but this is post-activation receptor trafficking rather than the primary receptor signaling function. additional_reference_ids: - PMID:9507004 - file:human/ADRB2/ADRB2-uniprot.txt supported_by: - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: internalized into endosomes prior to their degradation in lysosomes - reference_id: PMID:9507004 supporting_text: agonist-induced internalization and down-regulation of the beta2AR - reference_id: PMID:9507004 supporting_text: trafficking of the beta2AR via the clathrin-coated pit endosomal pathway to lysosomes - term: id: GO:0043235 label: signaling receptor complex evidence_type: IDA original_reference_id: PMID:15123695 qualifier: part_of review: summary: Signaling receptor complex is a supported core context for ADRB2 signaling. action: ACCEPT reason: ADRB2 functions in receptor-effector and receptor-scaffold complexes that support beta-adrenergic signaling, including beta2/beta3 receptor signaling units and postsynaptic complexes. additional_reference_ids: *id032 supported_by: *id033 - term: id: GO:0043410 label: positive regulation of MAPK cascade evidence_type: IDA original_reference_id: PMID:15123695 qualifier: involved_in review: summary: Positive regulation of MAPK cascade is a supported ADRB2 signaling branch. action: ACCEPT reason: ADRB2 activates ERK/MAPK through beta-arrestin/Src/EGFR-associated receptor complexes, so this is a real receptor signaling output rather than a project-level inference. additional_reference_ids: *id034 supported_by: *id035 - term: id: GO:0051380 label: norepinephrine binding evidence_type: IDA original_reference_id: PMID:15123695 qualifier: enables review: summary: Norepinephrine binding is supported as part of the catecholamine receptor activity. action: ACCEPT reason: ADRB2 binds catecholamines including norepinephrine, although epinephrine has higher affinity. This ligand-binding term supports the core beta-2 adrenergic receptor activity. additional_reference_ids: *id036 supported_by: *id037 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:9560162 qualifier: enables review: summary: Generic protein binding is not an informative ADRB2 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs. additional_reference_ids: *id005 supported_by: *id006 - term: id: GO:0005764 label: lysosome evidence_type: TAS original_reference_id: PMID:9507004 qualifier: located_in review: summary: Lysosome is a supported destination for down-regulated ADRB2. action: KEEP_AS_NON_CORE reason: Activated/internalized ADRB2 can be routed to lysosomes for degradation, but lysosome localization is receptor turnover context and not the core active signaling site. additional_reference_ids: - PMID:9507004 - PMID:19424180 - PMID:23166351 supported_by: - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: internalized into endosomes prior to their degradation in lysosomes - reference_id: PMID:9507004 supporting_text: agonist-induced internalization and down-regulation of the beta2AR - reference_id: PMID:9507004 supporting_text: trafficking of the beta2AR via the clathrin-coated pit endosomal pathway to lysosomes - reference_id: PMID:19424180 supporting_text: sort internalized receptors to the lysosomes for degradation - reference_id: PMID:20733053 supporting_text: recycling of the beta(2)-adrenoreceptor (beta(2)AR) from early endosomes - reference_id: PMID:23166351 supporting_text: Lysosomal degradation of ubiquitinated beta(2)-adrenergic receptors - term: id: GO:0005768 label: endosome evidence_type: TAS original_reference_id: PMID:10734107 qualifier: located_in review: summary: Endosome is a supported post-endocytic ADRB2 trafficking compartment. action: KEEP_AS_NON_CORE reason: Internalized ADRB2 traffics through endosomes for recycling or lysosomal degradation, but this is secondary to plasma-membrane signaling. additional_reference_ids: - PMID:9507004 - PMID:20733053 - file:human/ADRB2/ADRB2-uniprot.txt supported_by: - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: internalized into endosomes prior to their degradation in lysosomes - reference_id: PMID:9507004 supporting_text: agonist-induced internalization and down-regulation of the beta2AR - reference_id: PMID:9507004 supporting_text: trafficking of the beta2AR via the clathrin-coated pit endosomal pathway to lysosomes - reference_id: PMID:19424180 supporting_text: sort internalized receptors to the lysosomes for degradation - reference_id: PMID:20733053 supporting_text: recycling of the beta(2)-adrenoreceptor (beta(2)AR) from early endosomes - term: id: GO:0007166 label: cell surface receptor signaling pathway evidence_type: TAS original_reference_id: PMID:1371121 qualifier: involved_in review: summary: Generic cell-surface receptor signaling is too broad for ADRB2. action: MODIFY reason: Replace this broad parent with adrenergic receptor signaling pathway and the adenylate cyclase-activating adrenergic receptor signaling pathway where the evidence specifies cAMP/Gs signaling. proposed_replacement_terms: - id: GO:0071875 label: adrenergic receptor signaling pathway - id: GO:0071880 label: adenylate cyclase-activating adrenergic receptor signaling pathway additional_reference_ids: - file:human/ADRB2/ADRB2-uniprot.txt - PMID:2831218 supported_by: - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: G protein-coupled receptor for catecholamines that couples to - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: both G(s) and G(i) proteins, activating bifurcated signaling pathways - reference_id: PMID:2831218 supporting_text: associated with high affinity ligand binding, Gs coupling, and adenylate cyclase - term: id: GO:0007188 label: adenylate cyclase-modulating G protein-coupled receptor signaling pathway evidence_type: TAS original_reference_id: PMID:2823249 qualifier: involved_in review: summary: Generic adenylate cyclase-modulating GPCR signaling is too broad for ADRB2. action: MODIFY reason: ADRB2 should be represented by adrenergic receptor signaling and its activating/inhibiting adenylate cyclase adrenergic receptor branches rather than a generic GPCR signaling term. proposed_replacement_terms: - id: GO:0071880 label: adenylate cyclase-activating adrenergic receptor signaling pathway - id: GO:0071881 label: adenylate cyclase-inhibiting adrenergic receptor signaling pathway additional_reference_ids: - file:human/ADRB2/ADRB2-uniprot.txt - PMID:2831218 supported_by: - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: G protein-coupled receptor for catecholamines that couples to - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: both G(s) and G(i) proteins, activating bifurcated signaling pathways - reference_id: PMID:2831218 supporting_text: associated with high affinity ligand binding, Gs coupling, and adenylate cyclase - term: id: GO:0008333 label: endosome to lysosome transport evidence_type: TAS original_reference_id: PMID:9507004 qualifier: involved_in review: summary: Endosome to lysosome transport is a supported ADRB2 down-regulation route. action: KEEP_AS_NON_CORE reason: ADRB2 can be sorted from endosomes to lysosomes for degradation during receptor down-regulation, but this is a non-core receptor lifecycle process. additional_reference_ids: - PMID:9507004 - PMID:19424180 - PMID:23166351 supported_by: - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: internalized into endosomes prior to their degradation in lysosomes - reference_id: PMID:9507004 supporting_text: agonist-induced internalization and down-regulation of the beta2AR - reference_id: PMID:9507004 supporting_text: trafficking of the beta2AR via the clathrin-coated pit endosomal pathway to lysosomes - reference_id: PMID:19424180 supporting_text: sort internalized receptors to the lysosomes for degradation - reference_id: PMID:20733053 supporting_text: recycling of the beta(2)-adrenoreceptor (beta(2)AR) from early endosomes - reference_id: PMID:23166351 supporting_text: Lysosomal degradation of ubiquitinated beta(2)-adrenergic receptors core_functions: - molecular_function: id: GO:0004941 label: beta2-adrenergic receptor activity description: ADRB2 binds catecholamines at the plasma membrane and activates beta-2 adrenergic receptor signaling through Gs/cAMP/PKA, context-dependent Gi, and MAPK-associated signaling branches. directly_involved_in: - id: GO:0071880 label: adenylate cyclase-activating adrenergic receptor signaling pathway - id: GO:0071881 label: adenylate cyclase-inhibiting adrenergic receptor signaling pathway - id: GO:0043410 label: positive regulation of MAPK cascade locations: - id: GO:0005886 label: plasma membrane supported_by: - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: G protein-coupled receptor for catecholamines that couples to - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: both G(s) and G(i) proteins, activating bifurcated signaling pathways - reference_id: PMID:2831218 supporting_text: associated with high affinity ligand binding, Gs coupling, and adenylate cyclase - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: ADRB2 binds epinephrine (Epi) with an - reference_id: file:human/ADRB2/ADRB2-uniprot.txt supporting_text: approximately 30-fold greater affinity than norepinephrine (NE) - reference_id: PMID:2831218 supporting_text: affinity for isoproterenol, epinephrine, and norepinephrine - reference_id: PMID:10734107 supporting_text: beta(2)-Adrenergic receptor (beta(2)AR) stimulation of COS-7 cells induces EGFR dimerization - reference_id: PMID:10734107 supporting_text: beta(2)AR-dependent signaling to ERK1/2 proposed_new_terms: [] suggested_questions: - question: Should PN projection for ADRB2 remain at GO:1904504 positive regulation of lipophagy rather than direct GO:0061724 lipophagy? experts: - GO autophagy editors - Proteostasis Network curators - question: Which ADRB2 trafficking locations should remain gene-level GO annotations versus pathway-context annotations from receptor lifecycle studies? experts: - GO signaling editors - GPCR trafficking experts - question: Should endosomal/sustained beta2AR signaling (G protein activation from endosomes, beta-arrestin megaplexes) be captured as a distinct active location or signaling context for ADRB2, or treated as an emerging mechanism not yet at gene-annotation maturity? experts: - GO signaling editors - GPCR trafficking experts - question: Does ADRB2 biased agonism (e.g., beta-arrestin/NF-kB-selective outputs in immune cells) warrant separate biological-process annotations distinct from canonical Gs/cAMP/PKA signaling? experts: - GPCR pharmacology experts - GO signaling editors suggested_experiments: - description: Compare ADRB2 knockout/rescue and RAB7 knockout/rescue adipocytes during beta-adrenergic stimulation using lipid-droplet autophagosome recruitment and lysosomal flux reporters. hypothesis: ADRB2 acts upstream to stimulate lipophagy, whereas RAB7 is required for direct lipid-droplet autolysosomal delivery. - description: Measure endogenous ADRB2 routing to recycling versus lysosomal compartments after agonists and biased ligands while perturbing ARRDC3, NEDD4, MARCH2, USP20/USP33, and SNX27. hypothesis: Distinct trafficking adaptors determine whether activated ADRB2 is recycled/resensitized or degraded after internalization. - description: Use compartment-targeted cAMP/PKA biosensors with agonists and GRK/beta-arrestin perturbations to test whether internalized ADRB2 sustains G protein signaling from endosomes versus only at the plasma membrane. hypothesis: A fraction of agonist-activated ADRB2 continues to generate cAMP from endosomes in a beta-arrestin-dependent megaplex-like state, contributing a spatially distinct signaling output.