Arrb1 encodes beta-arrestin-1 (arrestin-2), a cytosolic arrestin-family adaptor protein of 418 residues, expressed mainly in neurons and spleen. When a G protein-coupled receptor is activated and phosphorylated by GPCR kinases, beta-arrestin-1 moves from the cytoplasm to the plasma membrane. Its N-domain phosphate sensor binds the phosphorylated receptor tail or loops, releasing its C-terminus. Bound beta-arrestin-1 sterically blocks G protein coupling (desensitization) and, through clathrin and AP-2 beta2-appendage binding, acts as a clathrin-associated sorting protein that carries receptors into clathrin-coated pits and endosomes. It also recruits PDE4 to limit local cAMP. Receptor-beta-arrestin-1 complexes act as signaling scaffolds for Src, Raf-MEK-ERK1/2, AKT and cofilin-pathway enzymes; for some receptors, such as AT1R in vascular smooth muscle, beta-arrestin-1 opposes the beta-arrestin-2 pathway. Beta-arrestin-1 also bridges E3 ubiquitin ligases to substrates (AIP4/ITCH to TRPV4 and, with ARRDC1, to Notch; MDM2 to p53), promoting their ubiquitination and down-regulation. A nuclear pool recruits p300 to target promoters and interacts with CREB and Dishevelled to regulate transcription.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000785 chromatin | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Located in chromatin, propagated from human ARRB1 ChIP at the p27 and c-fos promoters after delta-opioid receptor stimulation. Reason: Signal-dependent nuclear translocation and promoter occupancy is documented for the human ortholog; it is a secondary, transcriptional role, not the core GPCR adaptor function. Supporting Evidence: PMID:16325578 betaarr1 translocates to the nucleus and is selectively enriched at specific promoters such as that of p27 and c-fos, where it facilitates the recruitment of histone acetyltransferase p300 file:rat/Arrb1/Arrb1-uniprot.txt Involved in OPRD1-stimulated transcriptional regulation by translocating to CDKN1B and FOS promoter regions and recruiting EP300 resulting in acetylation of histone H4. |
| GO:0001664 G protein-coupled receptor binding | IBA GO_REF:0000033 | ACCEPT | Summary: G protein-coupled receptor binding (IBA, PAINT node PTN001370087). Reason: GPCR binding is the defining activity of beta-arrestin-1: it binds agonist-activated, GRK-phosphorylated receptors through a phosphate-sensing N-domain groove. Rat beta-arrestin-1 itself has been crystallised and imaged by cryo-EM with GPCR phosphopeptides and receptors. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt sterically preclude its coupling to the cognate G protein PMID:23604254 Here we report the crystal structure of Ξ²-arrestin-1 (also called arrestin-2) in complex with a fully phosphorylated 29-amino-acid carboxy-terminal peptide derived from the human V2 vasopressin receptor (V2Rpp). PMID:37209686 These structures help identify a P-X-P-P type phosphorylation motif in GPCRs that interacts with a spatially organized K-K-R-R-K-K sequence in the N-domain of Ξ²arrs. |
| GO:0001664 G protein-coupled receptor binding | IDA PMID:37209686 Structural snapshots uncover a key phosphorylation motif in ... | ACCEPT | Summary: Cryo-EM structures of rat beta-arrestin-1 bound to phosphorylated GPCR C-tails or receptors. Reason: GPCR binding is the defining activity of beta-arrestin-1: it binds agonist-activated, GRK-phosphorylated receptors through a phosphate-sensing N-domain groove. The study used rat beta-arrestin-1 protein. Supporting Evidence: PMID:37209686 These structures help identify a P-X-P-P type phosphorylation motif in GPCRs that interacts with a spatially organized K-K-R-R-K-K sequence in the N-domain of Ξ²arrs. PMID:37209686 Full length rat Ξ²arr1, Ξ²arr2WT and bovine Ξ²arr2DM were cloned into pGEX-4T3 vector |
| GO:0001664 G protein-coupled receptor binding | IDA PMID:38175886 Molecular insights into atypical modes of Ξ²-arrestin interac... | ACCEPT | Summary: Cryo-EM structures of rat beta-arrestin-1 bound to phosphorylated GPCR C-tails or receptors. Reason: GPCR binding is the defining activity of beta-arrestin-1: it binds agonist-activated, GRK-phosphorylated receptors through a phosphate-sensing N-domain groove. The study used rat beta-arrestin-1 protein. Supporting Evidence: PMID:38175886 Our structures of M2R-Ξ²arr1 and M2Rpp-Ξ²arr2 underscore that the key interaction interface and the activation mechanism remains conserved despite distinct domains on the receptor being used to engage Ξ²arrs. PMID:38175886 their interaction is driven primarily by agonist-induced receptor activation and phosphorylation |
| GO:0001664 G protein-coupled receptor binding | ISO GO_REF:0000121 | ACCEPT | Summary: G protein-coupled receptor binding (ISO from human ARRB1). Reason: GPCR binding is the defining activity of beta-arrestin-1: it binds agonist-activated, GRK-phosphorylated receptors through a phosphate-sensing N-domain groove. Rat beta-arrestin-1 itself has been crystallised and imaged by cryo-EM with GPCR phosphopeptides and receptors. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt sterically preclude its coupling to the cognate G protein PMID:23604254 Here we report the crystal structure of Ξ²-arrestin-1 (also called arrestin-2) in complex with a fully phosphorylated 29-amino-acid carboxy-terminal peptide derived from the human V2 vasopressin receptor (V2Rpp). PMID:37209686 These structures help identify a P-X-P-P type phosphorylation motif in GPCRs that interacts with a spatially organized K-K-R-R-K-K sequence in the N-domain of Ξ²arrs. |
| GO:0001678 intracellular glucose homeostasis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Intracellular glucose homeostasis, propagated from human ARRB1 (MRGPRE signaling to ALDOA and GLP-1 secretion). Reason: A downstream physiological consequence of beta-arrestin-1 signaling from one receptor; plausible but distal from the adaptor activity. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Involved in some MRGPRE-mediated signaling required to improve glucose tolerance |
| GO:0001934 positive regulation of protein phosphorylation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of protein phosphorylation (ISS from human ARRB1). Reason: Beta-arrestin-1 scaffolds kinases (Src, Raf/MEK/ERK, AKT) and so promotes phosphorylation of downstream targets; the term is broad but the specific kinase-cascade terms (ERK1/2 cascade) sit in a different branch, so this row is kept as non-core rather than replaced. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Acts as a signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2). PMID:10725339 The complex, which contains internalized receptor, beta-arrestin, raf-1, and activated ERK, is required for ERK1/2 activation. |
| GO:0002029 desensitization of G protein-coupled receptor signaling pathway | IDA PMID:37209686 Structural snapshots uncover a key phosphorylation motif in ... | ACCEPT | Summary: Desensitization of G protein-coupled receptor signaling pathway. Reason: Beta-arrestin-1 binding to phosphorylated, activated receptors sterically blocks G protein coupling; this is direct participation in desensitization and a core function. Supporting Evidence: PMID:37209686 broadly conserved functional responses such as desensitization, endocytosis, and signaling file:rat/Arrb1/Arrb1-uniprot.txt sterically preclude its coupling to the cognate G protein |
| GO:0002029 desensitization of G protein-coupled receptor signaling pathway | IDA PMID:38175886 Molecular insights into atypical modes of Ξ²-arrestin interac... | ACCEPT | Summary: Desensitization of G protein-coupled receptor signaling pathway. Reason: Beta-arrestin-1 binding to phosphorylated, activated receptors sterically blocks G protein coupling; this is direct participation in desensitization and a core function. Supporting Evidence: PMID:38175886 their interaction is driven primarily by agonist-induced receptor activation and phosphorylation file:rat/Arrb1/Arrb1-uniprot.txt sterically preclude its coupling to the cognate G protein |
| GO:0002029 desensitization of G protein-coupled receptor signaling pathway | ISO GO_REF:0000121 | ACCEPT | Summary: Desensitization of G protein-coupled receptor signaling pathway. Reason: Beta-arrestin-1 binding to phosphorylated, activated receptors sterically blocks G protein coupling; this is direct participation in desensitization and a core function. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt sterically preclude its coupling to the cognate G protein PMID:1517224 beta-Arrestin2 was equipotent to beta-arrestin1 and specifically inhibited beta 2AR function. PMID:20705669 siRNA-mediated knockdown of arrestin2 attenuated UTP-stimulated P2Y-receptor desensitization, whereas arrestin3 depletion did not. |
| GO:0002031 G protein-coupled receptor internalization | IBA GO_REF:0000033 | ACCEPT | Summary: G protein-coupled receptor internalization (IBA). Reason: Beta-arrestin-1 acts as a clathrin/AP-2 cargo adaptor that links activated GPCRs to clathrin-coated pits, so it directly performs GPCR internalization. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt endocytic adapters (CLASPs, clathrin-associated sorting proteins) PMID:15728179 the only other beta2 appendage selective adaptor, beta-arrestin PMID:18523139 this interaction is the main event triggering receptor internalization |
| GO:0002031 G protein-coupled receptor internalization | ISO GO_REF:0000121 | ACCEPT | Summary: G protein-coupled receptor internalization (ISO from human ARRB1). Reason: Beta-arrestin-1 acts as a clathrin/AP-2 cargo adaptor that links activated GPCRs to clathrin-coated pits, so it directly performs GPCR internalization. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt endocytic adapters (CLASPs, clathrin-associated sorting proteins) PMID:17513300 we also show a functional consequence of the release of the C terminus of beta-arrestin1 by enhanced clathrin binding. |
| GO:0002092 positive regulation of receptor internalization | ISO GO_REF:0000121 | MODIFY | Summary: Positive regulation of receptor internalization (ISO from human ARRB1). Reason: Beta-arrestin-1 does not regulate internalization from outside the process; it is a clathrin-associated sorting protein that physically couples the receptor to AP-2 and clathrin, i.e. a participant. The direct-participation term GO:0002031, which this gene already carries, is the better description. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P49407 SUPPORTS TRANSFER Human ARRB1 IMP (PMID:22457824) is sound; the term casts the endocytic adaptor as a regulator rather than a participant. Proposed replacements: G protein-coupled receptor internalization Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt endocytic adapters (CLASPs, clathrin-associated sorting proteins) PMID:15728179 the only other beta2 appendage selective adaptor, beta-arrestin |
| GO:0002092 positive regulation of receptor internalization | ISS GO_REF:0000024 | MODIFY | Summary: Positive regulation of receptor internalization (ISS from human ARRB1). Reason: Beta-arrestin-1 does not regulate internalization from outside the process; it is a clathrin-associated sorting protein that physically couples the receptor to AP-2 and clathrin, i.e. a participant. The direct-participation term GO:0002031, which this gene already carries, is the better description. Proposed replacements: G protein-coupled receptor internalization Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt endocytic adapters (CLASPs, clathrin-associated sorting proteins) PMID:15728179 the only other beta2 appendage selective adaptor, beta-arrestin |
| GO:0003713 transcription coactivator activity | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Transcription coactivator activity, propagated from human ARRB1 (p300 recruitment at p27/c-fos promoters). Reason: Supported for the ortholog and consistent with rat data on CREB and LEF transcription, but a secondary nuclear role of a primarily cytoplasmic GPCR adaptor. Supporting Evidence: PMID:16325578 betaarr1 translocates to the nucleus and is selectively enriched at specific promoters such as that of p27 and c-fos, where it facilitates the recruitment of histone acetyltransferase p300 file:rat/Arrb1/Arrb1-uniprot.txt Involved in OPRD1-stimulated transcriptional regulation by translocating to CDKN1B and FOS promoter regions and recruiting EP300 resulting in acetylation of histone H4. |
| GO:0004402 histone acetyltransferase activity | ISO NOT GO_REF:0000121 | ACCEPT | Summary: NOT histone acetyltransferase activity (ISO from human ARRB1). Reason: Correct negative annotation: beta-arrestin-1 increases local histone H4 acetylation by recruiting the acetyltransferase p300, and has no catalytic HAT activity of its own. Supporting Evidence: PMID:16325578 betaarr1 translocates to the nucleus and is selectively enriched at specific promoters such as that of p27 and c-fos, where it facilitates the recruitment of histone acetyltransferase p300 |
| GO:0004869 cysteine-type endopeptidase inhibitor activity | ISO GO_REF:0000121 | REMOVE | Summary: Cysteine-type endopeptidase inhibitor activity, propagated from a mouse IMP (PMID:19915011) on GLP-1 anti-apoptotic signaling in beta-cells. Reason: The source paper shows that beta-arrestin-1 mediates GLP-1 anti-apoptotic signaling through ERK1/2-p90RSK phosphorylation of Bad. That is an upstream signaling effect, not direct inhibition of caspases; arrestins have no protease-inhibitor activity. A phenotype was mapped to a molecular function the protein does not have, and the error propagates to rat by ISO. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:99473 SOURCE BAD Mouse IMP (PMID:19915011) maps an anti-apoptotic signaling phenotype (ERK-p90RSK-Bad) to caspase inhibitor activity. Supporting Evidence: PMID:19915011 beta-Arrestin 1 is further found to mediate the antiapoptotic effect of GLP-1 in beta-cells through the ERK1/2-p90RSK-phosphorylation of Bad. |
| GO:0005096 GTPase activator activity | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: GTPase activator activity, propagated from human ARRB1 (IMP, PMID:15611106, RhoA activation with Galpha q/11). Reason: The underlying finding is that beta-arrestin-1 cooperates with Galpha q to activate RhoA for stress-fiber formation. RhoA activation means GTP loading (GEF-type), which is the opposite of what GTPase activator (GAP) activity means. The cellular effect is captured by the Rho signal transduction and stress fiber rows; no GAP activity has been shown. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P49407 SOURCE BAD Human IMP (PMID:15611106) shows RhoA activation with Galpha q, not GAP activity. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Involved in AGTR1-mediated stress fiber formation by acting together with GNAQ to activate RHOA. |
| GO:0005102 signaling receptor binding | IPI PMID:23604254 Structure of active Ξ²-arrestin-1 bound to a G-protein-couple... | MODIFY | Summary: Signaling receptor binding (IPI, PMID:23604254) with the phosphorylated V2 vasopressin receptor C-tail. Reason: Correct but too general. The crystal structure shows binding to the phosphorylated V2 vasopressin receptor C-terminus, so the specific term V2 vasopressin receptor binding (already on this gene), within GPCR binding, is the right one. Proposed replacements: V2 vasopressin receptor binding Supporting Evidence: PMID:23604254 Here we report the crystal structure of Ξ²-arrestin-1 (also called arrestin-2) in complex with a fully phosphorylated 29-amino-acid carboxy-terminal peptide derived from the human V2 vasopressin receptor (V2Rpp). |
| GO:0005159 insulin-like growth factor receptor binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Insulin-like growth factor receptor binding (ISO from human ARRB1). Reason: Beta-arrestin-1 binds IGF1R and links it to MDM2 ubiquitination and AKT/MAPK signaling; rat data show beta-arrestin-1 is needed for IGF-I-stimulated MAPK signaling. A real but non-core (non-GPCR) partner. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Interacts with IGF1R and MDM2. file:rat/Arrb1/Arrb1-uniprot.txt Is involved in IGF1-stimulated AKT1 signaling leading to increased protection from apoptosis. PMID:12167719 Ectopic expression of wild-type beta-arrestin-1 in insulin-treated cells in which endogenous beta-arrestin-1 had been downregulated rescued IGF-I- and LPA-stimulated MAP kinase phosphorylation. |
| GO:0005515 protein binding | IPI PMID:10725339 beta-arrestin-dependent endocytosis of proteinase-activated ... | MODIFY | Summary: Protein binding with RAF1 in a PAR2-beta-arrestin-ERK signalosome (IPI, PMID:10725339). Reason: Bare protein binding is uninformative. The interaction places beta-arrestin as the scaffold of a PAR2/Raf-1/ERK complex, best described as protein-macromolecule adaptor activity. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:10725339 The complex, which contains internalized receptor, beta-arrestin, raf-1, and activated ERK, is required for ERK1/2 activation. |
| GO:0005515 protein binding | IPI PMID:10725339 beta-arrestin-dependent endocytosis of proteinase-activated ... | MODIFY | Summary: Protein binding with the GPCR F2RL1/PAR2 (IPI, PMID:10725339). Reason: Bare protein binding is uninformative; PAR2 is a GPCR, so G protein-coupled receptor binding is the informative term. Proposed replacements: G protein-coupled receptor binding Supporting Evidence: PMID:10725339 The complex, which contains internalized receptor, beta-arrestin, raf-1, and activated ERK, is required for ERK1/2 activation. |
| GO:0005515 protein binding | IPI PMID:17500066 Beta-arrestin-dependent regulation of the cofilin pathway do... | MODIFY | Summary: Protein binding with LIMK1 in the PAR2 cofilin pathway (IPI, PMID:17500066). Reason: Bare protein binding is uninformative. Beta-arrestins bind cofilin, LIMK and chronophin and colocalize with them in protrusions, acting as a scaffold that spatially regulates the cofilin pathway; protein-macromolecule adaptor activity captures this. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:17500066 Beta-arrestins can interact with cofilin, LIMK, and chronophin and colocalize with them in membrane protrusions file:rat/Arrb1/Arrb1-uniprot.txt Involved in F2RL1-mediated cytoskeletal rearrangement and chemotaxis. |
| GO:0005515 protein binding | IPI PMID:17500066 Beta-arrestin-dependent regulation of the cofilin pathway do... | MODIFY | Summary: Protein binding with PDXP/chronophin in the PAR2 cofilin pathway (IPI, PMID:17500066). Reason: Bare protein binding is uninformative. Beta-arrestins bind cofilin, LIMK and chronophin and colocalize with them in protrusions, acting as a scaffold that spatially regulates the cofilin pathway; protein-macromolecule adaptor activity captures this. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:17500066 Beta-arrestins can interact with cofilin, LIMK, and chronophin and colocalize with them in membrane protrusions file:rat/Arrb1/Arrb1-uniprot.txt Involved in F2RL1-mediated cytoskeletal rearrangement and chemotaxis. |
| GO:0005515 protein binding | IPI PMID:21857681 A stress response pathway regulates DNA damage through Ξ²2-ad... | MODIFY | Summary: Protein binding with TP53 (IPI, PMID:21857681). Reason: Bare protein binding is uninformative. In the source study beta-arrestin-1 acts as a scaffold that promotes MDM2 binding to and degradation of p53, i.e. it bridges an E3 ligase to its substrate. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:21857681 Ξ²-arrestin-1 (ARRB1), activated via Ξ²(2)-adrenoreceptors, facilitates AKT-mediated activation of MDM2 and also promotes MDM2 binding to, and degradation of, p53, by acting as a molecular scaffold. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Nucleus (IBA). Reason: Beta-arrestin-1 shuttles into the nucleus (the monomeric form is predominantly nuclear) and functions there at promoters; a real but secondary location. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt The monomeric form is predominantly located in the nucleus. PMID:16325578 betaarr1 translocates to the nucleus and is selectively enriched at specific promoters such as that of p27 and c-fos, where it facilitates the recruitment of histone acetyltransferase p300 |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Nucleus (IEA, UniProt subcellular location). Reason: Beta-arrestin-1 shuttles into the nucleus (the monomeric form is predominantly nuclear) and functions there at promoters; a real but secondary location. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt The monomeric form is predominantly located in the nucleus. |
| GO:0005634 nucleus | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Nucleus (ISO from human ARRB1). Reason: Beta-arrestin-1 shuttles into the nucleus (the monomeric form is predominantly nuclear) and functions there at promoters; a real but secondary location. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt The monomeric form is predominantly located in the nucleus. PMID:16325578 betaarr1 translocates to the nucleus and is selectively enriched at specific promoters such as that of p27 and c-fos, where it facilitates the recruitment of histone acetyltransferase p300 |
| GO:0005654 nucleoplasm | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Nucleoplasm (ISO from human ARRB1, HPA). Reason: Beta-arrestin-1 shuttles into the nucleus (the monomeric form is predominantly nuclear) and functions there at promoters; a real but secondary location. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt The monomeric form is predominantly located in the nucleus. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Cytoplasm (IBA). Reason: Beta-arrestin-1 resides in the cytoplasm (cytosol) at rest and is recruited to activated receptors at the membrane. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt The oligomeric form is located in the cytoplasm. PMID:16899567 FSH induces the recruitment of the endogenous GRK 2 and beta-arrestin 1/2 from the cytoplasm to the plasma membrane of rat primary Sertoli cells. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Cytoplasm (IEA, UniProt subcellular location). Reason: Beta-arrestin-1 resides in the cytoplasm (cytosol) at rest and is recruited to activated receptors at the membrane. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt The oligomeric form is located in the cytoplasm. |
| GO:0005737 cytoplasm | ISO GO_REF:0000121 | ACCEPT | Summary: Cytoplasm (ISO). Reason: Beta-arrestin-1 resides in the cytoplasm (cytosol) at rest and is recruited to activated receptors at the membrane. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt The oligomeric form is located in the cytoplasm. PMID:16899567 FSH induces the recruitment of the endogenous GRK 2 and beta-arrestin 1/2 from the cytoplasm to the plasma membrane of rat primary Sertoli cells. |
| GO:0005768 endosome | IDA PMID:25016018 Differential regulation of endosomal GPCR/Ξ²-arrestin complex... | ACCEPT | Summary: Endosome (IDA, PMID:25016018): endosomal bradykinin B2 receptor/beta-arrestin-1 complexes. Reason: Class B receptors internalize with beta-arrestin and traffic with it to endosomes, where beta-arrestin-scaffolded signaling continues; the live-cell study visualizes endosomal receptor/beta-arrestin-1 complexes. Supporting Evidence: PMID:25016018 Here we show, in live cells, differential dynamic regulation of endosomal bradykinin B2 receptor (B2R) complexes with either Ξ²-arrestin-1 or -2. file:rat/Arrb1/Arrb1-uniprot.txt confined to cytoplasmic locations such as endocytic vesicles |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Cytosol (IBA). Reason: Beta-arrestin-1 resides in the cytoplasm (cytosol) at rest and is recruited to activated receptors at the membrane. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt The oligomeric form is located in the cytoplasm. PMID:16899567 FSH induces the recruitment of the endogenous GRK 2 and beta-arrestin 1/2 from the cytoplasm to the plasma membrane of rat primary Sertoli cells. |
| GO:0005829 cytosol | ISO GO_REF:0000121 | ACCEPT | Summary: Cytosol (ISO from mouse). Reason: Beta-arrestin-1 resides in the cytoplasm (cytosol) at rest and is recruited to activated receptors at the membrane. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt The oligomeric form is located in the cytoplasm. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Plasma membrane (IBA). Reason: Beta-arrestin-1 is recruited to the plasma membrane by agonist-activated receptors, where it binds and desensitizes them; shown for endogenous rat beta-arrestin-1 in Sertoli cells. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Translocates to the plasma membrane and colocalizes with antagonist-stimulated GPCRs. PMID:16899567 FSH induces the recruitment of the endogenous GRK 2 and beta-arrestin 1/2 from the cytoplasm to the plasma membrane of rat primary Sertoli cells. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Plasma membrane (IEA, UniProt subcellular location). Reason: Beta-arrestin-1 is recruited to the plasma membrane by agonist-activated receptors, where it binds and desensitizes them; shown for endogenous rat beta-arrestin-1 in Sertoli cells. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Translocates to the plasma membrane and colocalizes with antagonist-stimulated GPCRs. |
| GO:0005905 clathrin-coated pit | IEA GO_REF:0000044 | ACCEPT | Summary: Clathrin-coated pit (IEA, UniProt subcellular location). Reason: As a clathrin/AP-2 cargo adaptor beta-arrestin-1 delivers receptors to clathrin-coated pits; activated rat beta-arrestin-1 shows enhanced clathrin binding. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Membrane, clathrin-coated pit file:rat/Arrb1/Arrb1-uniprot.txt endocytic adapters (CLASPs, clathrin-associated sorting proteins) PMID:17513300 we also show a functional consequence of the release of the C terminus of beta-arrestin1 by enhanced clathrin binding. |
| GO:0005929 cilium | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Cilium (IEA, inferred from intraciliary retrograde transport). Reason: Ortholog data place beta-arrestins in primary-cilium trafficking (SMO localization, GPR161 export); a peripheral location for this gene. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Involved in smoothened (SMO) localization to primary cilium file:rat/Arrb1/Arrb1-uniprot.txt Interacts with (phosphorylated) GPR161; promoting ciliary export of GPR161 |
| GO:0006355 regulation of DNA-templated transcription | IDA PMID:11742073 beta-Arrestin1 modulates lymphoid enhancer factor transcript... | KEEP AS NON CORE | Summary: Regulation of DNA-templated transcription (IDA, PMID:11742073): beta-arrestin-1 with phosphorylated Dishevelled synergistically activates LEF reporter. Reason: Reporter-based evidence that beta-arrestin-1 regulates Dvl-dependent LEF transcription, acting upstream of GSK-3beta at the level of Dvl. Real but non-core. Supporting Evidence: PMID:11742073 These results identify betaarr1 as a regulator of Dvl-dependent LEF transcription |
| GO:0006357 regulation of transcription by RNA polymerase II | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Regulation of transcription by RNA polymerase II (ISO from human ARRB1). Reason: Nuclear beta-arrestin-1 recruits p300 at p27 and c-fos promoters; supported but secondary. Supporting Evidence: PMID:16325578 betaarr1 translocates to the nucleus and is selectively enriched at specific promoters such as that of p27 and c-fos, where it facilitates the recruitment of histone acetyltransferase p300 file:rat/Arrb1/Arrb1-uniprot.txt Involved in OPRD1-stimulated transcriptional regulation by translocating to CDKN1B and FOS promoter regions and recruiting EP300 resulting in acetylation of histone H4. |
| GO:0006511 ubiquitin-dependent protein catabolic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Ubiquitin-dependent protein catabolic process (ISO from mouse, Notch degradation). Reason: Beta-arrestins act as adaptors that recruit E3 ligases (ITCH/AIP4, MDM2) to substrates such as Notch, TRPV4, p53 and IGF1R, promoting their ubiquitination and degradation. The degradation itself is carried out by the ligase and the lysosome/proteasome; beta-arrestin-1 contributes the adaptor step, so this is kept as non-core. Supporting Evidence: PMID:23886940 we show that Ξ²-arrestins are necessary for Itch-Notch interaction and for Itch-driven ubiquitylation and degradation of Notch. file:rat/Arrb1/Arrb1-uniprot.txt Negatively regulates the NOTCH signaling pathway by mediating the ubiquitination and degradation of NOTCH1 by ITCH. |
| GO:0006511 ubiquitin-dependent protein catabolic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Ubiquitin-dependent protein catabolic process (ISO from human ARRB1). Reason: Beta-arrestins act as adaptors that recruit E3 ligases (ITCH/AIP4, MDM2) to substrates such as Notch, TRPV4, p53 and IGF1R, promoting their ubiquitination and degradation. Kept as non-core for the same reason. Supporting Evidence: PMID:23886940 we show that Ξ²-arrestins are necessary for Itch-Notch interaction and for Itch-driven ubiquitylation and degradation of Notch. file:rat/Arrb1/Arrb1-uniprot.txt Interacts with IGF1R and MDM2. |
| GO:0006511 ubiquitin-dependent protein catabolic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ubiquitin-dependent protein catabolic process (ISS from human ARRB1). Reason: Beta-arrestins act as adaptors that recruit E3 ligases (ITCH/AIP4, MDM2) to substrates such as Notch, TRPV4, p53 and IGF1R, promoting their ubiquitination and degradation. Kept as non-core for the same reason. Supporting Evidence: PMID:23886940 we show that Ξ²-arrestins are necessary for Itch-Notch interaction and for Itch-driven ubiquitylation and degradation of Notch. PMID:20650893 Ξ²-Arrestin 1 interacts with, and acts as an adaptor for AIP4, an E3 ubiquitin ligase responsible for TRPV4 ubiquitination. |
| GO:0006897 endocytosis | IDA PMID:12519791 Role of G protein-coupled receptor kinase 4 and beta-arresti... | MODIFY | Summary: Endocytosis (IDA, PMID:12519791): agonist-driven translocation of beta-arrestin to the membrane and internalization into vesicles in mGlu1-expressing cells. Reason: Correct but general. Beta-arrestin-1's endocytic role is as a cargo adaptor for GPCRs, so GPCR internalization (already on this gene) is the specific term. Note that in this study the dominant-negative beta-arrestin did not block mGlu1 internalization itself; the row is supported by the beta-arrestin trafficking data and by the broader literature. Proposed replacements: G protein-coupled receptor internalization Supporting Evidence: PMID:12519791 beta-arrestin was first recruited to plasma membranes, where it was co-localized with the mGlu(1) receptor, and then internalized in vesicles. file:rat/Arrb1/Arrb1-uniprot.txt endocytic adapters (CLASPs, clathrin-associated sorting proteins) |
| GO:0006897 endocytosis | IEA GO_REF:0000117 | MODIFY | Summary: Endocytosis (IEA, ARBA). Reason: Correct but general; the specific process for beta-arrestin-1 is GPCR internalization. Proposed replacements: G protein-coupled receptor internalization Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt endocytic adapters (CLASPs, clathrin-associated sorting proteins) PMID:18523139 this interaction is the main event triggering receptor internalization |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | MODIFY | Summary: Signal transduction (IEA, InterPro arrestin domain). Reason: True but very general. Beta-arrestin-1 acts in GPCR signaling, both terminating G protein signaling and scaffolding beta-arrestin-dependent signaling, so the GPCR desensitization and GPCR signaling pathway terms are the informative ones. Proposed replacements: desensitization of G protein-coupled receptor signaling pathway G protein-coupled receptor signaling pathway Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Belongs to the arrestin family. PMID:1517224 The primary structure of these proteins delineates a family of proteins that regulates receptor coupling to G proteins. |
| GO:0007166 cell surface receptor signaling pathway | ISO GO_REF:0000121 | MODIFY | Summary: Cell surface receptor signaling pathway (ISO from human ARRB1). Reason: True but general. The best-supported roles are in GPCR signaling (desensitization, internalization, ERK scaffolding); the GPCR pathway terms are more informative. Non-GPCR roles (IGF1R, Notch) are captured by separate rows. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P49407 SUPPORTS TRANSFER Human ARRB1 data support the claim; the term is broader than the GPCR-specific evidence. Proposed replacements: G protein-coupled receptor signaling pathway Supporting Evidence: PMID:12519791 beta-arrestin is directly involved in glutamate-stimulated MAP kinase activation by acting as a signaling molecule. file:rat/Arrb1/Arrb1-uniprot.txt Acts as a signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2). |
| GO:0007186 G protein-coupled receptor signaling pathway | IDA PMID:1517224 Beta-arrestin2, a novel member of the arrestin/beta-arrestin... | KEEP AS NON CORE | Summary: G protein-coupled receptor signaling pathway (IDA, PMID:1517224): reconstitution showing beta-arrestin-1 quenches coupling of phosphorylated beta2AR to Gs. Reason: The experiment shows beta-arrestin-1 terminates GPCR signaling (desensitization, accepted as core elsewhere). Beta-arrestin-1 also transmits GPCR signals as a scaffold, so participation in the pathway is correct; kept as non-core next to the more precise desensitization term. Supporting Evidence: PMID:1517224 beta-Arrestin2 was equipotent to beta-arrestin1 and specifically inhibited beta 2AR function. PMID:12519791 beta-arrestin is directly involved in glutamate-stimulated MAP kinase activation by acting as a signaling molecule. |
| GO:0007188 adenylate cyclase-modulating G protein-coupled receptor signaling pathway | TAS PMID:12519791 Role of G protein-coupled receptor kinase 4 and beta-arresti... | KEEP AS NON CORE | Summary: Adenylate cyclase-modulating GPCR signaling pathway (TAS, PMID:12519791). Reason: The cited paper concerns mGlu1 (Gq-coupled) receptor regulation, not adenylate cyclase signaling. Beta-arrestin-1 does act in cAMP-pathway GPCR signaling (beta2AR desensitization, PDE4 recruitment), so the claim is true of the gene, but the traceable statement here is weak. Kept as non-core. Supporting Evidence: PMID:12399592 We show that beta-arrestins coordinate both processes by recruiting PDEs to activated beta2-adrenergic receptors in the plasma membrane of mammalian cells. file:rat/Arrb1/Arrb1-uniprot.txt Involved in the degradation of cAMP by recruiting cAMP phosphodiesterases to ligand-activated receptors. |
| GO:0007600 sensory perception | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Sensory perception (IBA, PTN000927402). Reason: This node term mainly reflects visual arrestins (rod/cone arrestin and Drosophila Arr1/Arr2) in phototransduction. Beta-arrestin-1 regulates many neuronal GPCRs, but it performs no step specific to sensory perception, and rat beta-arrestin-1 is about 20-fold less effective than visual arrestin on rhodopsin. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000927402 SUPPORTS SOURCE BUT NOT TARGET Node evidence comes from visual arrestins (Drosophila Arr1/Arr2, rod/cone arrestin) acting in phototransduction; beta-arrestins diverged to regulate non-visual GPCRs. Supporting Evidence: PMID:1517224 beta-Arrestin2 was equipotent to beta-arrestin1 and specifically inhibited beta 2AR function. file:rat/Arrb1/Arrb1-uniprot.txt Belongs to the arrestin family. |
| GO:0007600 sensory perception | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Sensory perception (IEA, ARBA). Reason: Same as the IBA row: a visual-arrestin property propagated to a non-visual arrestin. Supporting Evidence: PMID:1517224 beta-Arrestin2 was equipotent to beta-arrestin1 and specifically inhibited beta 2AR function. |
| GO:0007602 phototransduction | ISO GO_REF:0000121 | REMOVE | Summary: Phototransduction (ISO from mouse IMP, PMID:11853756). Reason: The source paper characterizes cone function in rod-transducin-alpha knockout mice and rod arrestin (Sag) knockout mice. The abstract (full text not available here) describes only these rod-arrestin-deleted and transducin-deleted strains and does not mention beta-arrestin-1. QuickGO lists the IMP from this paper on mouse Arrb1, not on Sag, so it looks like a gene mis-attribution by the source group (rod arrestin read as arrestin/Arrb1). The rat ISO row inherits it. Propagation Review Root cause: SOURCE BAD Failure modes: SOURCE MISCITATION Sources checked: MGI:MGI:99473 SOURCE BAD Mouse IMP (PMID:11853756) concerns rod arrestin (Sag) knockout mice; attributed to Arrb1. Supporting Evidence: PMID:11853756 mice with rod arrestin deleted (arrestin -/-) |
| GO:0008277 regulation of G protein-coupled receptor signaling pathway | IDA PMID:1517224 Beta-arrestin2, a novel member of the arrestin/beta-arrestin... | MODIFY | Summary: Regulation of GPCR signaling pathway (IDA, PMID:1517224). Reason: Beta-arrestin-1 regulates GPCR signaling by desensitizing receptors and switching them to beta-arrestin-dependent signaling. The term is correct but general; desensitization (already on this gene) is the specific, core process. Proposed replacements: desensitization of G protein-coupled receptor signaling pathway Supporting Evidence: PMID:1517224 beta-Arrestin2 was equipotent to beta-arrestin1 and specifically inhibited beta 2AR function. |
| GO:0008277 regulation of G protein-coupled receptor signaling pathway | IEA GO_REF:0000117 | MODIFY | Summary: Regulation of GPCR signaling pathway (IEA, ARBA). Reason: Beta-arrestin-1 regulates GPCR signaling by desensitizing receptors and switching them to beta-arrestin-dependent signaling. The term is correct but general; desensitization (already on this gene) is the specific, core process. Proposed replacements: desensitization of G protein-coupled receptor signaling pathway Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt sterically preclude its coupling to the cognate G protein |
| GO:0008277 regulation of G protein-coupled receptor signaling pathway | ISO GO_REF:0000121 | MODIFY | Summary: Regulation of GPCR signaling pathway (ISO from mouse, acts upstream of or within). Reason: Beta-arrestin-1 regulates GPCR signaling by desensitizing receptors and switching them to beta-arrestin-dependent signaling. The term is correct but general; desensitization (already on this gene) is the specific, core process. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:99473 SUPPORTS TRANSFER Mouse data support a role in GPCR signal regulation; the specific process is desensitization. Proposed replacements: desensitization of G protein-coupled receptor signaling pathway Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt sterically preclude its coupling to the cognate G protein |
| GO:0008277 regulation of G protein-coupled receptor signaling pathway | TAS PMID:12519791 Role of G protein-coupled receptor kinase 4 and beta-arresti... | MODIFY | Summary: Regulation of GPCR signaling pathway (TAS, PMID:12519791). Reason: Beta-arrestin-1 regulates GPCR signaling by desensitizing receptors and switching them to beta-arrestin-dependent signaling. The term is correct but general; desensitization (already on this gene) is the specific, core process. Proposed replacements: desensitization of G protein-coupled receptor signaling pathway Supporting Evidence: PMID:12519791 beta-arrestin is directly involved in glutamate-stimulated MAP kinase activation by acting as a signaling molecule. file:rat/Arrb1/Arrb1-uniprot.txt sterically preclude its coupling to the cognate G protein |
| GO:0008277 regulation of G protein-coupled receptor signaling pathway | TAS PMID:14519533 Presence of beta-arrestin-1 immunoreactivity in the cutaneou... | MODIFY | Summary: Regulation of GPCR signaling pathway (TAS, PMID:14519533). Reason: Beta-arrestin-1 regulates GPCR signaling by desensitizing receptors and switching them to beta-arrestin-dependent signaling. The term is correct but general; desensitization (already on this gene) is the specific, core process. Proposed replacements: desensitization of G protein-coupled receptor signaling pathway Supporting Evidence: PMID:14519533 beta-Arrestin-1 (betaArr1) plays a major role in the desensitization and internalization of G protein-coupled receptors. |
| GO:0008284 positive regulation of cell population proliferation | IMP PMID:25486571 The induction of thioredoxin-1 by epinephrine withdraws stre... | KEEP AS NON CORE | Summary: Positive regulation of cell population proliferation (IMP, PMID:25486571, PC12 cells). Reason: Knockdown of beta-arrestin-1 lowered PC12 cell viability and cyclin D1; a downstream, context-dependent effect of its signaling roles. Non-core. Supporting Evidence: PMID:25486571 Consequently, the downregulation of Ξ²-arrestin-1 suppressed the cell viability and the expressions of Ξ³-H2AX and cyclin D1, and increased p53 expression. |
| GO:0009410 response to xenobiotic stimulus | IEP PMID:21223624 Antidepressants elevate GDNF expression and release from Cβ ... | KEEP AS NON CORE | Summary: Response to xenobiotic stimulus (IEP, PMID:21223624): antidepressants raise cytosolic beta-arrestin-1 in C6 glioma cells. Reason: An expression response to drug treatment; the knockdown data place beta-arrestin-1 in the antidepressant-induced GDNF response. It says little about the gene's molecular role, so kept as non-core. Supporting Evidence: PMID:21223624 ADs significantly increased both GDNF expression and release from the cells, but were unable to induce such effects in Ξ²-arrestin1 knock-down cells. |
| GO:0009968 negative regulation of signal transduction | IEA GO_REF:0000117 | MODIFY | Summary: Negative regulation of signal transduction (IEA, ARBA). Reason: True but general: beta-arrestin-1 terminates GPCR signaling. The specific term is desensitization of GPCR signaling, already on this gene. Proposed replacements: desensitization of G protein-coupled receptor signaling pathway Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt sterically preclude its coupling to the cognate G protein |
| GO:0014069 postsynaptic density | IDA PMID:1517224 Beta-arrestin2, a novel member of the arrestin/beta-arrestin... | KEEP AS NON CORE | Summary: Postsynaptic density (IDA, SynGO, PMID:1517224): immuno-EM of rat brain. Reason: Immunoelectron microscopy places beta-arrestins at postsynaptic sites; a real neuronal location where it can regulate neurotransmitter GPCRs, but the antibody study does not fully separate beta-arrestin-1 from -2. Non-core location. Supporting Evidence: PMID:1517224 immunoelectron microscopy shows that the beta-arrestins are appropriately situated at postsynaptic sites |
| GO:0016323 basolateral plasma membrane | IDA PMID:16899567 G protein-coupled receptor kinase 2 and beta-arrestins are r... | KEEP AS NON CORE | Summary: Basolateral plasma membrane (IDA, PMID:16899567): rat Sertoli cell fractionation. Reason: The abstract reports FSH-induced recruitment of endogenous beta-arrestin-1 from cytoplasm to plasma membrane via sucrose-gradient fractionation; the basolateral detail presumably comes from the full text, which was not available. Deferred to the curator and kept as a non-core location. Supporting Evidence: PMID:16899567 FSH induces the recruitment of the endogenous GRK 2 and beta-arrestin 1/2 from the cytoplasm to the plasma membrane of rat primary Sertoli cells. |
| GO:0016567 protein ubiquitination | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Protein ubiquitination (ISO from human ARRB1). Reason: Beta-arrestin-1 promotes substrate ubiquitination by recruiting E3 ligases, without catalysing the transfer itself. Its contribution is better captured by the adaptor MF and by positive regulation of protein ubiquitination; kept as non-core. Supporting Evidence: PMID:20650893 Ξ²-Arrestin 1 interacts with, and acts as an adaptor for AIP4, an E3 ubiquitin ligase responsible for TRPV4 ubiquitination. PMID:21857681 Ξ²-arrestin-1 (ARRB1), activated via Ξ²(2)-adrenoreceptors, facilitates AKT-mediated activation of MDM2 and also promotes MDM2 binding to, and degradation of, p53, by acting as a molecular scaffold. |
| GO:0019899 enzyme binding | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Enzyme binding (IEA, ARBA). Reason: Beta-arrestin-1 binds many enzymes (PDE4D, Src, MDM2, GRK2). There is no more specific binding term for the PDE4 interaction that is the main experimental basis. Non-core. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Involved in the degradation of cAMP by recruiting cAMP phosphodiesterases to ligand-activated receptors. |
| GO:0019899 enzyme binding | IPI PMID:12399592 Targeting of cyclic AMP degradation to beta 2-adrenergic rec... | KEEP AS NON CORE | Summary: Enzyme binding (IPI, PMID:12399592) with cAMP phosphodiesterase PDE4D. Reason: Beta-arrestins recruit PDE4 to activated beta2-adrenergic receptors, coupling desensitization with local cAMP degradation. A real interaction that GO has no more specific binding term for; non-core. Supporting Evidence: PMID:12399592 We show that beta-arrestins coordinate both processes by recruiting PDEs to activated beta2-adrenergic receptors in the plasma membrane of mammalian cells. |
| GO:0030276 clathrin binding | IDA PMID:17513300 The active conformation of beta-arrestin1: direct evidence f... | ACCEPT | Summary: Clathrin binding (IDA, PMID:17513300): phosphopeptide-activated rat beta-arrestin-1 shows enhanced clathrin binding. Reason: Clathrin binding by the released C-terminus is a core part of the endocytic adaptor mechanism. Supporting Evidence: PMID:17513300 we also show a functional consequence of the release of the C terminus of beta-arrestin1 by enhanced clathrin binding. |
| GO:0030331 obsolete nuclear estrogen receptor binding | IPI PMID:19339617 17beta-estradiol-mediated neuroprotection and ERK activation... | KEEP AS NON CORE | Summary: Obsolete nuclear estrogen receptor binding (IPI, PMID:19339617): ER-alpha co-immunoprecipitates with beta-arrestin-1 in cortical neurons. Reason: The interaction (E2-induced ER-alpha/beta-arrestin-1/c-Src complex in neurons) is supported in the full text. The GO term is obsolete in the current ontology and should be re-mapped by the source, probably to nuclear receptor binding; kept as non-core. Supporting Evidence: PMID:19339617 E2 stimulation induces the formation of a ERΞ±Ξ²-arrestin-1 receptor complex |
| GO:0030674 protein-macromolecule adaptor activity | ISO GO_REF:0000121 | ACCEPT | Summary: Protein-macromolecule adaptor activity (ISO from human ARRB1). Reason: Beta-arrestin-1 is a multivalent adaptor that brings receptors together with clathrin/AP-2, kinases (Src, Raf, MEK, ERK, AKT), PDE4 and E3 ligases. Core MF, refined in the core functions to clathrin-cargo adaptor and ligase-substrate adaptor activities. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Acts as a signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2). PMID:10725339 The complex, which contains internalized receptor, beta-arrestin, raf-1, and activated ERK, is required for ERK1/2 activation. PMID:20650893 Ξ²-Arrestin 1 interacts with, and acts as an adaptor for AIP4, an E3 ubiquitin ligase responsible for TRPV4 ubiquitination. |
| GO:0031143 pseudopodium | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Pseudopodium (IEA, UniProt subcellular location). Reason: Ortholog data (mouse IDA) place beta-arrestin-1 in pseudopodia during chemotaxis; a peripheral location linked to its cytoskeletal scaffolding role. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Cell projection, pseudopodium. |
| GO:0031143 pseudopodium | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Pseudopodium (ISO from mouse). Reason: Ortholog data (mouse IDA) place beta-arrestin-1 in pseudopodia during chemotaxis; a peripheral location linked to its cytoskeletal scaffolding role. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Cell projection, pseudopodium. PMID:17500066 Beta-arrestins can interact with cofilin, LIMK, and chronophin and colocalize with them in membrane protrusions |
| GO:0031396 regulation of protein ubiquitination | IEA GO_REF:0000117 | MODIFY | Summary: Regulation of protein ubiquitination (IEA, ARBA). Reason: Correct but general: beta-arrestin-1 promotes ubiquitination of substrates by recruiting E3 ligases. Positive regulation of protein ubiquitination (already on this gene) is the supported specific term. Proposed replacements: positive regulation of protein ubiquitination Supporting Evidence: PMID:20650893 angiotensin stimulation results in ubiquitination of TRPV4, a process that requires Ξ²-arrestin 1 |
| GO:0031398 positive regulation of protein ubiquitination | IMP PMID:20650893 Arresting a transient receptor potential (TRP) channel: beta... | ACCEPT | Summary: Positive regulation of protein ubiquitination (IMP, PMID:20650893): angiotensin-induced TRPV4 ubiquitination requires beta-arrestin-1. Reason: Beta-arrestin-1 recruits AIP4 (ITCH) to TRPV4 in an AT1aR/TRPV4 complex; knockdown blocks angiotensin-induced TRPV4 ubiquitination. The E3 adaptor role is a well-supported core function. Supporting Evidence: PMID:20650893 angiotensin stimulation results in ubiquitination of TRPV4, a process that requires Ξ²-arrestin 1 PMID:20650893 Ξ²-Arrestin 1 interacts with, and acts as an adaptor for AIP4, an E3 ubiquitin ligase responsible for TRPV4 ubiquitination. |
| GO:0031410 cytoplasmic vesicle | IBA GO_REF:0000033 | ACCEPT | Summary: Cytoplasmic vesicle (IBA). Reason: Internalized receptor-beta-arrestin complexes traffic on endocytic vesicles (beta-arrestin signalosomes). Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt confined to cytoplasmic locations such as endocytic vesicles PMID:12519791 beta-arrestin was first recruited to plasma membranes, where it was co-localized with the mGlu(1) receptor, and then internalized in vesicles. |
| GO:0031410 cytoplasmic vesicle | IEA GO_REF:0000044 | ACCEPT | Summary: Cytoplasmic vesicle (IEA, UniProt subcellular location). Reason: Internalized receptor-beta-arrestin complexes traffic on endocytic vesicles (beta-arrestin signalosomes). Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt confined to cytoplasmic locations such as endocytic vesicles |
| GO:0031410 cytoplasmic vesicle | ISO GO_REF:0000121 | ACCEPT | Summary: Cytoplasmic vesicle (ISO from human ARRB1). Reason: Internalized receptor-beta-arrestin complexes traffic on endocytic vesicles (beta-arrestin signalosomes). Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt confined to cytoplasmic locations such as endocytic vesicles PMID:12519791 beta-arrestin was first recruited to plasma membranes, where it was co-localized with the mGlu(1) receptor, and then internalized in vesicles. |
| GO:0031434 mitogen-activated protein kinase kinase binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Mitogen-activated protein kinase kinase binding (ISO from mouse IDA, PMID:19915011). Reason: Beta-arrestins scaffold the Raf-MEK-ERK module; binding MEK is part of that scaffold. Non-core binding partner; the scaffold role is covered by adaptor activity. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Acts as a signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2). PMID:19915011 beta-Arrestin 1 is further found to mediate the antiapoptotic effect of GLP-1 in beta-cells through the ERK1/2-p90RSK-phosphorylation of Bad. |
| GO:0031625 ubiquitin protein ligase binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Ubiquitin protein ligase binding (ISO from human ARRB1, MDM2). Reason: Beta-arrestin-1 binds E3 ligases (MDM2, AIP4/ITCH) as part of its ligase-adaptor role; the adaptor MF is the more informative statement. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Interacts with IGF1R and MDM2. PMID:20650893 Ξ²-Arrestin 1 interacts with, and acts as an adaptor for AIP4, an E3 ubiquitin ligase responsible for TRPV4 ubiquitination. |
| GO:0031691 alpha-1A adrenergic receptor binding | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Alpha-1A adrenergic receptor binding (IEA, ARBA). Reason: Specific receptor-binding child of GPCR binding. Kept as non-core alongside the accepted core GPCR binding term. The alpha1a-AR interaction is weak. Supporting Evidence: PMID:18523139 the agonistinduced interaction of the alpha1a-AR with beta-arrestins was much weaker than that of the alpha1b-AR. |
| GO:0031691 alpha-1A adrenergic receptor binding | IPI PMID:18523139 Different internalization properties of the alpha1a- and alp... | KEEP AS NON CORE | Summary: Alpha-1A adrenergic receptor binding (IPI, PMID:18523139). Reason: Specific receptor-binding child of GPCR binding. Kept as non-core alongside the accepted core GPCR binding term. The alpha1a-AR interaction is weak compared with alpha1b-AR. Supporting Evidence: PMID:18523139 the agonistinduced interaction of the alpha1a-AR with beta-arrestins was much weaker than that of the alpha1b-AR. |
| GO:0031692 alpha-1B adrenergic receptor binding | IDA PMID:18523139 Different internalization properties of the alpha1a- and alp... | KEEP AS NON CORE | Summary: Alpha-1B adrenergic receptor binding (IDA, PMID:18523139). Reason: Specific receptor-binding child of GPCR binding. Kept as non-core alongside the accepted core GPCR binding term. Supporting Evidence: PMID:18523139 the agonistinduced interaction of the alpha1a-AR with beta-arrestins was much weaker than that of the alpha1b-AR. PMID:18523139 this interaction is the main event triggering receptor internalization |
| GO:0031692 alpha-1B adrenergic receptor binding | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Alpha-1B adrenergic receptor binding (IEA, ARBA). Reason: Specific receptor-binding child of GPCR binding. Kept as non-core alongside the accepted core GPCR binding term. Supporting Evidence: PMID:18523139 the agonistinduced interaction of the alpha1a-AR with beta-arrestins was much weaker than that of the alpha1b-AR. |
| GO:0031701 angiotensin receptor binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Angiotensin receptor binding (ISO from human ARRB1). Reason: Specific receptor-binding child of GPCR binding. Kept as non-core alongside the accepted core GPCR binding term. AT1R-beta-arrestin-1 signaling is documented in rat adrenal and vascular smooth muscle. Supporting Evidence: PMID:19289825 This pathway results in sustained ERK activation and subsequent up-regulation of steroidogenic acute regulatory protein PMID:20650893 AT1aR and TRPV4 form a constitutive complex in the plasma membrane, and angiotensin stimulation leads to recruitment of Ξ²-arrestin 1 to this complex. |
| GO:0031762 follicle-stimulating hormone receptor binding | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Follicle-stimulating hormone receptor binding (IEA, ARBA). Reason: Specific receptor-binding child of GPCR binding. Kept as non-core alongside the accepted core GPCR binding term. Supporting Evidence: PMID:16899567 a significant FSH-binding activity was co-immunoprecipitated with the endogenous beta-arrestins from agonist-stimulated but not from untreated Sertoli cell extracts. |
| GO:0031762 follicle-stimulating hormone receptor binding | IPI PMID:16899567 G protein-coupled receptor kinase 2 and beta-arrestins are r... | KEEP AS NON CORE | Summary: Follicle-stimulating hormone receptor binding (IPI, PMID:16899567): endogenous beta-arrestins co-immunoprecipitate FSH-binding activity from stimulated Sertoli cells. Reason: Specific receptor-binding child of GPCR binding. Kept as non-core alongside the accepted core GPCR binding term. Supporting Evidence: PMID:16899567 a significant FSH-binding activity was co-immunoprecipitated with the endogenous beta-arrestins from agonist-stimulated but not from untreated Sertoli cell extracts. |
| GO:0031896 V2 vasopressin receptor binding | IDA PMID:17513300 The active conformation of beta-arrestin1: direct evidence f... | KEEP AS NON CORE | Summary: V2 vasopressin receptor binding (IDA, PMID:17513300): the phosphorylated V2R C-tail peptide binds and activates rat beta-arrestin-1. Reason: Specific receptor-binding child of GPCR binding. Kept as non-core alongside the accepted core GPCR binding term. V2Rpp is the standard tool for activating beta-arrestin-1. Supporting Evidence: PMID:17513300 V(2)Rpp binds specifically to beta-arrestin1 causing significant conformational changes PMID:23604254 Here we report the crystal structure of Ξ²-arrestin-1 (also called arrestin-2) in complex with a fully phosphorylated 29-amino-acid carboxy-terminal peptide derived from the human V2 vasopressin receptor (V2Rpp). |
| GO:0032715 negative regulation of interleukin-6 production | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of interleukin-6 production (ISO from human ARRB1). Reason: Follows from beta-arrestin-1 attenuating NF-kappa-B signaling; a downstream immune effect. Non-core. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Involved in attenuation of NF-kappa-B-dependent transcription in response to GPCR or cytokine stimulation by interacting with and stabilizing CHUK. |
| GO:0032717 negative regulation of interleukin-8 production | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of interleukin-8 production (ISO from human ARRB1). Reason: Same basis as the IL-6 row; downstream of NF-kappa-B attenuation. Non-core. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Involved in attenuation of NF-kappa-B-dependent transcription in response to GPCR or cytokine stimulation by interacting with and stabilizing CHUK. |
| GO:0032960 regulation of inositol trisphosphate biosynthetic process | IMP PMID:20705669 G protein-coupled receptor kinase 2 and arrestin2 regulate a... | MODIFY | Summary: Regulation of inositol trisphosphate biosynthetic process (IMP, PMID:20705669): arrestin2 knockdown attenuates P2Y2 receptor desensitization of IP3 signaling in rat mesenteric smooth muscle. Reason: The measured effect is loss of P2Y2 receptor desensitization (the IP3 biosensor is the readout). Beta-arrestin-1 does not regulate IP3 synthesis enzymes directly; it desensitizes the receptor. Desensitization of GPCR signaling captures the finding. Proposed replacements: desensitization of G protein-coupled receptor signaling pathway Supporting Evidence: PMID:20705669 siRNA-mediated knockdown of arrestin2 attenuated UTP-stimulated P2Y-receptor desensitization, whereas arrestin3 depletion did not. |
| GO:0035025 positive regulation of Rho protein signal transduction | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of Rho protein signal transduction (ISO from human ARRB1). Reason: Beta-arrestin-1 with Galpha q activates RhoA downstream of AT1R; a supported scaffolding outcome but not core. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Involved in AGTR1-mediated stress fiber formation by acting together with GNAQ to activate RHOA. |
| GO:0035612 AP-2 adaptor complex binding | IDA PMID:15728179 Functional dissection of an AP-2 beta2 appendage-binding seq... | ACCEPT | Summary: AP-2 adaptor complex binding (IDA, PMID:15728179). Reason: Beta-arrestin binds the beta2-appendage of AP-2, which is central to its role as a clathrin-associated sorting protein. Supporting Evidence: PMID:15728179 the only other beta2 appendage selective adaptor, beta-arrestin file:rat/Arrb1/Arrb1-uniprot.txt endocytic adapters (CLASPs, clathrin-associated sorting proteins) |
| GO:0035615 clathrin-cargo adaptor activity | IDA PMID:15728179 Functional dissection of an AP-2 beta2 appendage-binding seq... | ACCEPT | Summary: Clathrin-cargo adaptor activity (IDA, PMID:15728179). Reason: Beta-arrestin-1 is a CLASP that couples activated GPCR cargo to AP-2 and clathrin. Core MF. Supporting Evidence: PMID:15728179 the only other beta2 appendage selective adaptor, beta-arrestin file:rat/Arrb1/Arrb1-uniprot.txt endocytic adapters (CLASPs, clathrin-associated sorting proteins) PMID:17513300 we also show a functional consequence of the release of the C terminus of beta-arrestin1 by enhanced clathrin binding. |
| GO:0035721 intraciliary retrograde transport | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Intraciliary retrograde transport (ISO from human ARRB1). Reason: Human data link beta-arrestins to export of phosphorylated GPR161 from cilia; a specialised, peripheral role. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Interacts with (phosphorylated) GPR161; promoting ciliary export of GPR161 |
| GO:0035774 positive regulation of insulin secretion involved in cellular response to glucose stimulus | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of insulin secretion involved in cellular response to glucose (ISO from mouse IMP, PMID:19915011). Reason: The mouse beta-cell study centres on GLP-1 anti-apoptotic ERK signaling; the insulin secretion data are presumably in the full text, which was not checked. Deferred to the MGI curator and kept non-core as a tissue-level outcome. Supporting Evidence: PMID:19915011 beta-Arrestin 1 is further found to mediate the antiapoptotic effect of GLP-1 in beta-cells through the ERK1/2-p90RSK-phosphorylation of Bad. |
| GO:0042699 follicle-stimulating hormone signaling pathway | IDA PMID:16899567 G protein-coupled receptor kinase 2 and beta-arrestins are r... | KEEP AS NON CORE | Summary: Follicle-stimulating hormone signaling pathway (IDA, PMID:16899567). Reason: FSH recruits endogenous beta-arrestin-1 to the plasma membrane in rat Sertoli cells, where it associates with FSHR and is dephosphorylated; consistent with a role in FSHR desensitization/signaling. A receptor-specific instance of the core role. Supporting Evidence: PMID:16899567 FSH induces the recruitment of the endogenous GRK 2 and beta-arrestin 1/2 from the cytoplasm to the plasma membrane of rat primary Sertoli cells. PMID:16899567 our data strongly suggest that the GRK/beta-arrestin machinery plays a physiologically relevant role in the regulation of the FSH signaling. |
| GO:0042699 follicle-stimulating hormone signaling pathway | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Follicle-stimulating hormone signaling pathway (IEA, ARBA). Reason: Same as the IDA row. Supporting Evidence: PMID:16899567 our data strongly suggest that the GRK/beta-arrestin machinery plays a physiologically relevant role in the regulation of the FSH signaling. |
| GO:0042981 regulation of apoptotic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Regulation of apoptotic process (ISO from mouse IMP, PMID:19915011). Reason: Beta-arrestin-1 effects on apoptosis are context dependent: anti-apoptotic in astrocytes and GLP-1-stimulated beta-cells, but pro-apoptotic in rat vascular smooth muscle where its knockdown reduced caspase-3 cleavage. These outcomes are downstream of its signaling scaffold roles. Supporting Evidence: PMID:19915011 beta-Arrestin 1 is further found to mediate the antiapoptotic effect of GLP-1 in beta-cells through the ERK1/2-p90RSK-phosphorylation of Bad. PMID:19171933 We have also found that Ξ²-arrestin-1 functionally opposes this signaling |
| GO:0043066 negative regulation of apoptotic process | IMP PMID:24378649 PAR-1 activation rescues astrocytes through the PI3K/Akt sig... | KEEP AS NON CORE | Summary: Negative regulation of apoptotic process (IMP, PMID:24378649): beta-arrestin-1 silencing increases staurosporine-induced astrocyte apoptosis. Reason: Beta-arrestin-1 effects on apoptosis are context dependent: anti-apoptotic in astrocytes and GLP-1-stimulated beta-cells, but pro-apoptotic in rat vascular smooth muscle where its knockdown reduced caspase-3 cleavage. These outcomes are downstream of its signaling scaffold roles. Supporting Evidence: PMID:24378649 This indicates that Ξ²-arrestin 1 is important to protect astrocytes from apoptosis. |
| GO:0043124 negative regulation of canonical NF-kappaB signal transduction | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of canonical NF-kappaB signal transduction (ISO from human ARRB1). Reason: Beta-arrestin-1 binds and stabilizes CHUK (IKK-alpha) and binds TRAF6, attenuating NF-kappa-B activation; supported for the ortholog, non-core. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Involved in attenuation of NF-kappa-B-dependent transcription in response to GPCR or cytokine stimulation by interacting with and stabilizing CHUK. |
| GO:0043149 stress fiber assembly | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Stress fiber assembly (ISO from human ARRB1). Reason: Beta-arrestin-1 with Galpha q activates RhoA for AT1R-induced stress fibers; a downstream cytoskeletal outcome. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Involved in AGTR1-mediated stress fiber formation by acting together with GNAQ to activate RHOA. |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Proteasome-mediated ubiquitin-dependent protein catabolic process (ISO from human ARRB1). Reason: Beta-arrestins act as adaptors that recruit E3 ligases (ITCH/AIP4, MDM2) to substrates such as Notch, TRPV4, p53 and IGF1R, promoting their ubiquitination and degradation. Kept as non-core: beta-arrestin-1 supplies the adaptor step, not the degradation. Supporting Evidence: PMID:21857681 Ξ²-arrestin-1 (ARRB1), activated via Ξ²(2)-adrenoreceptors, facilitates AKT-mediated activation of MDM2 and also promotes MDM2 binding to, and degradation of, p53, by acting as a molecular scaffold. file:rat/Arrb1/Arrb1-uniprot.txt Interacts with IGF1R and MDM2. |
| GO:0043197 dendritic spine | IDA PMID:1517224 Beta-arrestin2, a novel member of the arrestin/beta-arrestin... | KEEP AS NON CORE | Summary: Dendritic spine (IDA, PMID:1517224). Reason: Immuno-EM in rat brain places beta-arrestins at postsynaptic sites; non-core neuronal location. Supporting Evidence: PMID:1517224 immunoelectron microscopy shows that the beta-arrestins are appropriately situated at postsynaptic sites |
| GO:0043278 response to morphine | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Response to morphine (IEA, ARBA). Reason: Expression-level response; morphine lowers Arrb1 mRNA in locus coeruleus. Non-core. Supporting Evidence: PMID:12614678 In locus coeruleus, both acute and chronic morphine treatments resulted in significant decreases (over 50%) in beta-arrestin 1 mRNA level |
| GO:0043278 response to morphine | IEP PMID:12614678 Differential regulation of beta-arrestin 1 and beta-arrestin... | KEEP AS NON CORE | Summary: Response to morphine (IEP, PMID:12614678). Reason: In situ hybridization shows morphine lowers beta-arrestin-1 mRNA in rat locus coeruleus. A valid expression response, not a functional role. Supporting Evidence: PMID:12614678 In locus coeruleus, both acute and chronic morphine treatments resulted in significant decreases (over 50%) in beta-arrestin 1 mRNA level |
| GO:0043410 positive regulation of MAPK cascade | IDA PMID:12167719 Insulin induces heterologous desensitization of G-protein-co... | MODIFY | Summary: Positive regulation of MAPK cascade (IDA, PMID:12167719): beta-arrestin-1 is required for IGF-I-, LPA- and isoproterenol-stimulated MAPK phosphorylation. Reason: Correct but general; the readouts are ERK1/2 phosphorylation, so positive regulation of ERK1 and ERK2 cascade (already on this gene) is the specific term. Proposed replacements: positive regulation of ERK1 and ERK2 cascade Supporting Evidence: PMID:12167719 Ectopic expression of wild-type beta-arrestin-1 in insulin-treated cells in which endogenous beta-arrestin-1 had been downregulated rescued IGF-I- and LPA-stimulated MAP kinase phosphorylation. |
| GO:0043410 positive regulation of MAPK cascade | IDA PMID:12519791 Role of G protein-coupled receptor kinase 4 and beta-arresti... | MODIFY | Summary: Positive regulation of MAPK cascade (IDA, PMID:12519791): dominant-negative beta-arrestin reduces mGlu1-stimulated MAPK activation in Purkinje cells. Reason: Correct but general; the MAP kinases measured are ERK1/2, so the specific ERK1/2 cascade term is preferred. Proposed replacements: positive regulation of ERK1 and ERK2 cascade Supporting Evidence: PMID:12519791 beta-arrestin is directly involved in glutamate-stimulated MAP kinase activation by acting as a signaling molecule. |
| GO:0043524 negative regulation of neuron apoptotic process | IMP PMID:26621121 Beta-arrestin1 and 2 differently modulate metabotropic gluta... | KEEP AS NON CORE | Summary: Negative regulation of neuron apoptotic process (IMP, PMID:26621121): beta-arrestin-1 siRNA partly reduced mGluR7 agonist neuroprotection against sevoflurane. Reason: Beta-arrestin-1 effects on apoptosis are context dependent: anti-apoptotic in astrocytes and GLP-1-stimulated beta-cells, but pro-apoptotic in rat vascular smooth muscle where its knockdown reduced caspase-3 cleavage. These outcomes are downstream of its signaling scaffold roles. In this study ERK protection was beta-arrestin-2-dependent; the beta-arrestin-1 effect was partial. Supporting Evidence: PMID:26621121 this neuroprotective role of LAP4 could be partially reduced by Ξ²-arr1 small interfering RNA (siRNA) or Ξ²-arr2 siRNA transfection. |
| GO:0044325 transmembrane transporter binding | IPI PMID:20650893 Arresting a transient receptor potential (TRP) channel: beta... | KEEP AS NON CORE | Summary: Transmembrane transporter binding (IPI, PMID:20650893): beta-arrestin-1 interacts with the TRPV4 channel. Reason: Beta-arrestin-1 binds TRPV4 within an AT1aR/TRPV4 complex and bridges AIP4 to it. A substrate-recognition interaction of the ligase-adaptor function; kept as non-core next to the adaptor MF. Supporting Evidence: PMID:20650893 AT1aR and TRPV4 form a constitutive complex in the plasma membrane, and angiotensin stimulation leads to recruitment of Ξ²-arrestin 1 to this complex. PMID:20650893 Ξ²-Arrestin 1 interacts with, and acts as an adaptor for AIP4, an E3 ubiquitin ligase responsible for TRPV4 ubiquitination. |
| GO:0045211 postsynaptic membrane | IDA PMID:1517224 Beta-arrestin2, a novel member of the arrestin/beta-arrestin... | KEEP AS NON CORE | Summary: Postsynaptic membrane (IDA, PMID:1517224). Reason: Immuno-EM places beta-arrestins at postsynaptic sites; non-core location. Supporting Evidence: PMID:1517224 immunoelectron microscopy shows that the beta-arrestins are appropriately situated at postsynaptic sites |
| GO:0045309 protein phosphorylated amino acid binding | IDA PMID:17513300 The active conformation of beta-arrestin1: direct evidence f... | ACCEPT | Summary: Protein phosphorylated amino acid binding (IDA, PMID:17513300). Reason: The N-domain phosphate sensor recognises phosphorylated Ser/Thr residues of the receptor C-tail; this binding drives beta-arrestin-1 activation and is part of the core receptor-recognition mechanism. Supporting Evidence: PMID:17513300 consistent with previous studies suggesting the N-domain is responsible for recognizing phosphates in 7TMRs PMID:37209686 These structures help identify a P-X-P-P type phosphorylation motif in GPCRs that interacts with a spatially organized K-K-R-R-K-K sequence in the N-domain of Ξ²arrs. |
| GO:0045746 negative regulation of Notch signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Negative regulation of Notch signaling pathway (IBA). Reason: Beta-arrestins heterodimerize with ARRDC1, which recruits ITCH to non-activated Notch, promoting its ubiquitylation and lysosomal degradation and so limiting Notch signaling. Supported in mammals but secondary to the GPCR roles. Supporting Evidence: PMID:23886940 ARRDC1 and Ξ²-arrestins heterodimerize and cooperate in the same complex to promote non-activated Notch receptor degradation, thus acting as negative regulators of Notch signaling. file:rat/Arrb1/Arrb1-uniprot.txt Negatively regulates the NOTCH signaling pathway by mediating the ubiquitination and degradation of NOTCH1 by ITCH. |
| GO:0045746 negative regulation of Notch signaling pathway | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of Notch signaling pathway (ISO from mouse). Reason: Beta-arrestins heterodimerize with ARRDC1, which recruits ITCH to non-activated Notch, promoting its ubiquitylation and lysosomal degradation and so limiting Notch signaling. Supporting Evidence: PMID:23886940 ARRDC1 and Ξ²-arrestins heterodimerize and cooperate in the same complex to promote non-activated Notch receptor degradation, thus acting as negative regulators of Notch signaling. |
| GO:0045746 negative regulation of Notch signaling pathway | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of Notch signaling pathway (ISO from human ARRB1). Reason: Beta-arrestins heterodimerize with ARRDC1, which recruits ITCH to non-activated Notch, promoting its ubiquitylation and lysosomal degradation and so limiting Notch signaling. Supporting Evidence: PMID:23886940 ARRDC1 and Ξ²-arrestins heterodimerize and cooperate in the same complex to promote non-activated Notch receptor degradation, thus acting as negative regulators of Notch signaling. |
| GO:0045746 negative regulation of Notch signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Negative regulation of Notch signaling pathway (ISS from human ARRB1). Reason: Beta-arrestins heterodimerize with ARRDC1, which recruits ITCH to non-activated Notch, promoting its ubiquitylation and lysosomal degradation and so limiting Notch signaling. Supporting Evidence: PMID:23886940 we show that Ξ²-arrestins are necessary for Itch-Notch interaction and for Itch-driven ubiquitylation and degradation of Notch. file:rat/Arrb1/Arrb1-uniprot.txt Negatively regulates the NOTCH signaling pathway by mediating the ubiquitination and degradation of NOTCH1 by ITCH. |
| GO:0045880 positive regulation of smoothened signaling pathway | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of smoothened signaling pathway (ISO from mouse). Reason: Mouse data show beta-arrestins needed for SMO localization to the primary cilium and Hedgehog signaling; a specialised role. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Involved in smoothened (SMO) localization to primary cilium |
| GO:0045880 positive regulation of smoothened signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of smoothened signaling pathway (ISS from mouse). Reason: Mouse data show beta-arrestins needed for SMO localization to the primary cilium and Hedgehog signaling; a specialised role. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Involved in smoothened (SMO) localization to primary cilium |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:16325578 A nuclear function of beta-arrestin1 in GPCR signaling: regu... | KEEP AS NON CORE | Summary: Positive regulation of transcription by RNA polymerase II (IDA, PMID:16325578): nuclear beta-arrestin-1 recruits p300 to p27 and c-fos promoters. Reason: Well supported for the delta-opioid receptor-driven nuclear function, but secondary to the cytoplasmic GPCR adaptor roles. Supporting Evidence: PMID:16325578 betaarr1 translocates to the nucleus and is selectively enriched at specific promoters such as that of p27 and c-fos, where it facilitates the recruitment of histone acetyltransferase p300 |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of transcription by RNA polymerase II (ISO from human ARRB1). Reason: As for the IDA row; secondary nuclear role. Supporting Evidence: PMID:16325578 betaarr1 translocates to the nucleus and is selectively enriched at specific promoters such as that of p27 and c-fos, where it facilitates the recruitment of histone acetyltransferase p300 file:rat/Arrb1/Arrb1-uniprot.txt Involved in OPRD1-stimulated transcriptional regulation by translocating to CDKN1B and FOS promoter regions and recruiting EP300 resulting in acetylation of histone H4. |
| GO:0050975 sensory perception of touch | TAS PMID:14519533 Presence of beta-arrestin-1 immunoreactivity in the cutaneou... | MARK AS OVER ANNOTATED | Summary: Sensory perception of touch (TAS, PMID:14519533): beta-arrestin-1 immunoreactivity in cutaneous nerve fibres and Meissner corpuscles. Reason: The study is a localization study. The authors speculate that beta-arrestin-1 'may be involved' in tactile modulation, but no functional test was done. Presence in sensory terminals does not show it performs a step of touch perception. Supporting Evidence: PMID:14519533 Our observations thus indicate that betaArr1 may be involved in modulation of specific tactile stimulation from the skin in addition to nociception. |
| GO:0051219 phosphoprotein binding | IPI PMID:11742073 beta-Arrestin1 modulates lymphoid enhancer factor transcript... | KEEP AS NON CORE | Summary: Phosphoprotein binding (IPI, PMID:11742073) with phosphorylated DVL2. Reason: Phosphorylation of Dishevelled strongly enhances its binding to beta-arrestin-1; supports a Wnt/LEF regulatory role that is secondary to GPCR functions. Supporting Evidence: PMID:11742073 We find that phosphorylation of Dvl strongly enhances its interaction with betaarr1 |
| GO:0051219 phosphoprotein binding | IPI PMID:11742073 beta-Arrestin1 modulates lymphoid enhancer factor transcript... | KEEP AS NON CORE | Summary: Phosphoprotein binding (IPI, PMID:11742073) with phosphorylated DVL1. Reason: Phosphorylation of Dishevelled strongly enhances its binding to beta-arrestin-1; supports a Wnt/LEF regulatory role that is secondary to GPCR functions. Supporting Evidence: PMID:11742073 We find that phosphorylation of Dvl strongly enhances its interaction with betaarr1 |
| GO:0060090 molecular adaptor activity | IBA GO_REF:0000033 | MODIFY | Summary: Molecular adaptor activity (IBA). Reason: Correct but general. Beta-arrestin-1's adaptor roles are specifically clathrin-cargo adaptor activity (receptor to AP-2/clathrin) and ligase-substrate adaptor activity (AIP4-TRPV4, MDM2-p53), plus protein-macromolecule scaffolding of kinase modules. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P49407 SUPPORTS TRANSFER Adaptor activity is conserved and well supported; only the granularity is refined. Proposed replacements: clathrin-cargo adaptor activity ubiquitin-like ligase-substrate adaptor activity protein-macromolecule adaptor activity Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt endocytic adapters (CLASPs, clathrin-associated sorting proteins) PMID:15728179 the only other beta2 appendage selective adaptor, beta-arrestin PMID:20650893 Ξ²-Arrestin 1 interacts with, and acts as an adaptor for AIP4, an E3 ubiquitin ligase responsible for TRPV4 ubiquitination. |
| GO:0060090 molecular adaptor activity | ISO GO_REF:0000121 | MODIFY | Summary: Molecular adaptor activity (ISO from human ARRB1). Reason: As for the IBA row: correct but general; replace with the specific adaptor activities. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P49407 SUPPORTS TRANSFER Adaptor activity is conserved and well supported; only the granularity is refined. Proposed replacements: clathrin-cargo adaptor activity ubiquitin-like ligase-substrate adaptor activity protein-macromolecule adaptor activity Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt endocytic adapters (CLASPs, clathrin-associated sorting proteins) PMID:20650893 Ξ²-Arrestin 1 interacts with, and acts as an adaptor for AIP4, an E3 ubiquitin ligase responsible for TRPV4 ubiquitination. |
| GO:0070373 negative regulation of ERK1 and ERK2 cascade | IMP PMID:19254952 Independent beta-arrestin2 and Gq/protein kinase Czeta pathw... | KEEP AS NON CORE | Summary: Negative regulation of ERK1 and ERK2 cascade (IMP, PMID:19254952): beta-arrestin-1 knockdown in rat VSMCs raised early AngII-stimulated ERK activation. Reason: Matches the reciprocal regulation of AT1R-ERK signaling, where beta-arrestin-2 mediates and beta-arrestin-1 opposes the beta-arrestin-dependent pathway. The effect is limited to the 2-min time point and is receptor- and cell-type specific; positive ERK regulation is documented in other systems. Non-core. Supporting Evidence: PMID:19254952 In Ξ²-arrestin1 siRNA-transfected cells, ANG stimulation evokes a kinetic pattern of ERK activation similar to control but with significantly elevated levels of activation at the 2-min time point file:rat/Arrb1/Arrb1-uniprot.txt Inhibits ERK1/2 signaling in AGTR1- and AVPR2-mediated activation (reciprocal regulation). PMID:19171933 We have also found that Ξ²-arrestin-1 functionally opposes this signaling |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IBA GO_REF:0000033 | ACCEPT | Summary: Positive regulation of ERK1 and ERK2 cascade (IBA). Reason: Beta-arrestin-1 scaffolds Raf/MEK/ERK (and recruits Src) on internalized receptors, driving receptor-specific ERK1/2 activation (mGlu1 in Purkinje cells, AT1R in adrenal cortex, IGF-I/LPA signaling). Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Acts as a signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2). PMID:12519791 beta-arrestin is directly involved in glutamate-stimulated MAP kinase activation by acting as a signaling molecule. |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IMP PMID:19289825 An adrenal beta-arrestin 1-mediated signaling pathway underl... | ACCEPT | Summary: Positive regulation of ERK1 and ERK2 cascade (IMP, PMID:19289825): adrenal beta-arrestin-1 mediates sustained AT1R-dependent ERK activation and aldosterone production. Reason: Beta-arrestin-1 scaffolds Raf/MEK/ERK (and recruits Src) on internalized receptors, driving receptor-specific ERK1/2 activation (mGlu1 in Purkinje cells, AT1R in adrenal cortex, IGF-I/LPA signaling). Supporting Evidence: PMID:19289825 This pathway results in sustained ERK activation and subsequent up-regulation of steroidogenic acute regulatory protein |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | ISO GO_REF:0000121 | ACCEPT | Summary: Positive regulation of ERK1 and ERK2 cascade (ISO from mouse). Reason: Beta-arrestin-1 scaffolds Raf/MEK/ERK (and recruits Src) on internalized receptors, driving receptor-specific ERK1/2 activation (mGlu1 in Purkinje cells, AT1R in adrenal cortex, IGF-I/LPA signaling). Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Acts as a signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2). PMID:19915011 beta-Arrestin 1 is further found to mediate the antiapoptotic effect of GLP-1 in beta-cells through the ERK1/2-p90RSK-phosphorylation of Bad. |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | ISO GO_REF:0000121 | ACCEPT | Summary: Positive regulation of ERK1 and ERK2 cascade (ISO from human ARRB1). Reason: Beta-arrestin-1 scaffolds Raf/MEK/ERK (and recruits Src) on internalized receptors, driving receptor-specific ERK1/2 activation (mGlu1 in Purkinje cells, AT1R in adrenal cortex, IGF-I/LPA signaling). Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Acts as a signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2). PMID:10725339 The complex, which contains internalized receptor, beta-arrestin, raf-1, and activated ERK, is required for ERK1/2 activation. |
| GO:0097499 protein localization to non-motile cilium | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Protein localization to non-motile cilium (ISO from mouse). Reason: Ortholog data link beta-arrestins to ciliary trafficking of SMO and GPR161; specialised, non-core. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Involved in smoothened (SMO) localization to primary cilium |
| GO:0097499 protein localization to non-motile cilium | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Protein localization to non-motile cilium (ISS from mouse). Reason: Ortholog data link beta-arrestins to ciliary trafficking of SMO and GPR161; specialised, non-core. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Involved in smoothened (SMO) localization to primary cilium |
| GO:0098978 glutamatergic synapse | IDA PMID:1517224 Beta-arrestin2, a novel member of the arrestin/beta-arrestin... | KEEP AS NON CORE | Summary: Glutamatergic synapse (IDA, SynGO, PMID:1517224). Reason: Immuno-EM places beta-arrestins at postsynaptic sites in rat brain; a non-core neuronal location. Supporting Evidence: PMID:1517224 immunoelectron microscopy shows that the beta-arrestins are appropriately situated at postsynaptic sites |
| GO:1902533 positive regulation of intracellular signal transduction | IEA GO_REF:0000117 | MODIFY | Summary: Positive regulation of intracellular signal transduction (IEA, ARBA). Reason: Correct but general; the supported intracellular cascade is ERK1/2, already on this gene. Proposed replacements: positive regulation of ERK1 and ERK2 cascade Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Acts as a signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2). |
| GO:1903568 negative regulation of protein localization to ciliary membrane | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of protein localization to ciliary membrane (ISO from human ARRB1). Reason: Human data show beta-arrestins promote ciliary export of phosphorylated GPR161; specialised, non-core. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Interacts with (phosphorylated) GPR161; promoting ciliary export of GPR161 |
| GO:1990763 arrestin family protein binding | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Arrestin family protein binding (IEA, ARBA). Reason: Beta-arrestin-1 heterodimerizes with ARRDC1 (alpha-arrestin 1) and with beta-arrestin-2; the ARRDC1 interaction recruits ITCH in Notch degradation. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Interacts with ARRDC1; the interaction is direct (PubMed:23886940). |
| GO:1990763 arrestin family protein binding | IPI PMID:23886940 Ξ-arrestin 1 (ARRDC1) and Ξ²-arrestins cooperate to mediate N... | KEEP AS NON CORE | Summary: Arrestin family protein binding (IPI, PMID:23886940) with ARRDC1. Reason: Beta-arrestin-1 heterodimerizes with ARRDC1 (alpha-arrestin 1) and with beta-arrestin-2; the ARRDC1 interaction recruits ITCH in Notch degradation. Supporting Evidence: PMID:23886940 ARRDC1 and Ξ²-arrestins heterodimerize and cooperate in the same complex to promote non-activated Notch receptor degradation, thus acting as negative regulators of Notch signaling. |
| GO:1990763 arrestin family protein binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Arrestin family protein binding (ISO from human ARRB1). Reason: Beta-arrestin-1 heterodimerizes with ARRDC1 (alpha-arrestin 1) and with beta-arrestin-2; the ARRDC1 interaction recruits ITCH in Notch degradation. Supporting Evidence: file:rat/Arrb1/Arrb1-uniprot.txt Interacts with ARRDC1; the interaction is direct (PubMed:23886940). |
| GO:1990756 ubiquitin-like ligase-substrate adaptor activity | IDA PMID:20650893 Arresting a transient receptor potential (TRP) channel: beta... | NEW | Summary: Proposed: beta-arrestin-1 bridges the HECT E3 ligase AIP4 (ITCH) to the TRPV4 channel, which lacks a PY motif, after AT1aR activation. Reason: Direct-participation MF shown in rat vascular smooth muscle cells and HEK-293 cells: beta-arrestin-1 interacts constitutively with AIP4, is recruited to the AT1aR/TRPV4 complex, and its knockdown blocks the angiotensin-induced TRPV4-AIP4 interaction and TRPV4 ubiquitination. This is the activity itself, not a downstream phenotype, and is consistent with ortholog data (ARRDC1/ITCH-Notch, MDM2-p53). It is a sibling of clathrin-cargo adaptor activity, not an ancestor or descendant of any term on the gene. Supporting Evidence: PMID:20650893 Ξ²-Arrestin 1 interacts with, and acts as an adaptor for AIP4, an E3 ubiquitin ligase responsible for TRPV4 ubiquitination. PMID:20650893 angiotensin stimulation results in ubiquitination of TRPV4, a process that requires Ξ²-arrestin 1 PMID:21857681 Ξ²-arrestin-1 (ARRB1), activated via Ξ²(2)-adrenoreceptors, facilitates AKT-mediated activation of MDM2 and also promotes MDM2 binding to, and degradation of, p53, by acting as a molecular scaffold. |
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Download this section (compressed HTML)Q: The mouse Arrb1 IMP to phototransduction (PMID:11853756) appears to describe rod arrestin (Sag) knockout mice. Should MGI move it to Sag, so the rat and human ISO/IEA rows stop propagating?
Q: Should 'cysteine-type endopeptidase inhibitor activity' on mouse Arrb1 (PMID:19915011) be re-curated as regulation of apoptotic process, given that the mechanism is ERK1/2-p90RSK phosphorylation of Bad?
Q: For which rat receptors does beta-arrestin-1 promote and for which does it oppose ERK1/2 activation (reciprocal versus codependent regulation), and what structural features of the receptor set this?
Q: The GO:0030331 nuclear estrogen receptor binding row from PMID:19339617 uses an obsolete term; which current term should RGD use for the membrane ER-alpha/beta-arrestin-1 interaction?
Experiment: In rat vascular smooth muscle cells, compare beta-arrestin-1 and beta-arrestin-2 knockouts (CRISPR) with rescue by AP-2/clathrin-binding-deficient and phosphate-sensor mutants of beta-arrestin-1, to separate its desensitization, internalization and ERK-opposing roles downstream of AT1R.
Experiment: Reconstitute AIP4-mediated TRPV4 ubiquitination in vitro with purified beta-arrestin-1 (wild type and activation-deficient mutants), to test whether the ligase-substrate bridge needs receptor-induced beta-arrestin activation.
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