Beta-arrestin-2 (arrestin-3) is a cytosolic adaptor protein of the arrestin family, abundant in neurons and spleen. After agonist activation and GRK phosphorylation of a G protein-coupled receptor, beta-arrestin-2 is recruited from the cytoplasm to the plasma membrane and binds the receptor. Binding sterically blocks G protein coupling, which desensitizes the receptor. Through C-terminal clathrin- and AP-2-binding motifs it acts as a clathrin-cargo adaptor that concentrates receptors in clathrin-coated pits for internalization. Class B receptors such as AT1R and V2R remain bound and travel with it to endosomes. Beta-arrestin-2 also serves as a signalling scaffold: it assembles receptor-associated ERK1/2 (and JNK3) modules and an AKT/PP2A complex, giving G protein-independent signals that in rat vascular smooth muscle cells, neurons, astrocytes and fibroblasts promote ERK activation, survival (BAD inactivation), proliferation and matrix synthesis. Additional adaptor roles include binding E3 ligases (MDM2, and ITCH via ARRDC1) to control ubiquitination of partner proteins, restraining TRAF6/NF-kappa-B signalling, and contributing to Smoothened trafficking to the primary cilium. In the nervous system it limits opioid receptor signalling, and knockdown enhances morphine analgesia.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001664 G protein-coupled receptor binding | ISO GO_REF:0000121 | ACCEPT | Summary: Binding to activated, GRK-phosphorylated GPCRs is the defining molecular activity of beta-arrestin-2. Reason: Transferred from human ARRB2; the rat protein has direct evidence for binding many GPCRs (AT1R, alpha1B-AR, D1, FSHR, PAFR). GPCR binding is the core interaction underlying desensitization, internalization and arrestin-dependent signalling. Supporting Evidence: UniProtKB:P29067 During homologous desensitization, beta-arrestins bind to the GPCR-phosphorylated receptor and sterically preclude its coupling to the cognate G protein PMID:18523139 RNA interference showed that beta-arrestin 2 plays a prominent role in alpha1b-AR endocytosis. PMID:19522833 Stimulation of isolated aortas with exogenous angiotensin II caused recruitment of beta-arrestin-2 in aortas from noncirrhotic rats |
| GO:0002029 desensitization of G protein-coupled receptor signaling pathway | ISO GO_REF:0000121 | ACCEPT | Summary: Desensitization of GPCR signalling is the canonical role of beta-arrestin-2. Reason: Rat beta-arrestin-2 was first characterized by its ability to quench beta2AR-Gs coupling in a reconstituted system; arrestin binding sterically blocks G protein coupling. Supporting Evidence: PMID:1517224 beta-Arrestin2 was equipotent to beta-arrestin1 and specifically inhibited beta 2AR function. UniProtKB:P29067 During homologous desensitization, beta-arrestins bind to the GPCR-phosphorylated receptor and sterically preclude its coupling to the cognate G protein |
| GO:0002031 G protein-coupled receptor internalization | IBA GO_REF:0000033 | ACCEPT | Summary: GPCR internalization via clathrin-coated pits is a core process of beta-arrestin-2. Reason: Beta-arrestin-2 is the clathrin/AP-2 cargo adaptor for agonist-occupied GPCRs; rat-cell RNAi and dominant-negative experiments show it drives endocytosis of the alpha1B-AR and mu-opioid receptor. The IBA node (PTN001370087) covers the beta-arrestin clade, and this gene sits inside it. Supporting Evidence: UniProtKB:P29067 The beta-arrestins target many receptors for internalization by acting as endocytic adapters (CLASPs, clathrin-associated sorting proteins) and recruiting the GPRCs to the adapter protein 2 complex 2 (AP-2) in clathrin-coated pits (CCPs). PMID:18523139 RNA interference showed that beta-arrestin 2 plays a prominent role in alpha1b-AR endocytosis. PMID:16120787 endocytosis induced by both ligands was inhibited by a dominant-negative mutant version of arrestin-3 (beta-arrestin-2). |
| GO:0002031 G protein-coupled receptor internalization | ISO GO_REF:0000121 | ACCEPT | Summary: GPCR internalization via clathrin-coated pits is a core process of beta-arrestin-2. Reason: Beta-arrestin-2 is the clathrin/AP-2 cargo adaptor for agonist-occupied GPCRs; rat-cell RNAi and dominant-negative experiments show it drives endocytosis of the alpha1B-AR and mu-opioid receptor. The IBA node (PTN001370087) covers the beta-arrestin clade, and this gene sits inside it. Supporting Evidence: UniProtKB:P29067 The beta-arrestins target many receptors for internalization by acting as endocytic adapters (CLASPs, clathrin-associated sorting proteins) and recruiting the GPRCs to the adapter protein 2 complex 2 (AP-2) in clathrin-coated pits (CCPs). PMID:18523139 RNA interference showed that beta-arrestin 2 plays a prominent role in alpha1b-AR endocytosis. PMID:16120787 endocytosis induced by both ligands was inhibited by a dominant-negative mutant version of arrestin-3 (beta-arrestin-2). |
| GO:0002092 positive regulation of receptor internalization | IMP PMID:16120787 Morphine promotes rapid, arrestin-dependent endocytosis of m... | MODIFY | Summary: Beta-arrestin-2 is the endocytic adaptor itself, so it participates in GPCR internalization rather than regulating it from outside. Reason: Dominant-negative arrestin-3 blocked morphine- and DAMGO-induced mu-opioid receptor endocytosis in rat striatal neurons. Because beta-arrestin-2 performs the cargo-adaptor step, GPCR internalization (GO:0002031, already accepted for this gene) is the better term than positive regulation of receptor internalization. Proposed replacements: G protein-coupled receptor internalization Supporting Evidence: PMID:16120787 endocytosis induced by both ligands was inhibited by a dominant-negative mutant version of arrestin-3 (beta-arrestin-2). UniProtKB:P29067 The beta-arrestins target many receptors for internalization by acting as endocytic adapters (CLASPs, clathrin-associated sorting proteins) and recruiting the GPRCs to the adapter protein 2 complex 2 (AP-2) in clathrin-coated pits (CCPs). |
| GO:0002092 positive regulation of receptor internalization | ISO GO_REF:0000121 | MODIFY | Summary: Beta-arrestin-2 is the endocytic adaptor itself, so it participates in GPCR internalization rather than regulating it from outside. Reason: Dominant-negative arrestin-3 blocked morphine- and DAMGO-induced mu-opioid receptor endocytosis in rat striatal neurons. Because beta-arrestin-2 performs the cargo-adaptor step, GPCR internalization (GO:0002031, already accepted for this gene) is the better term than positive regulation of receptor internalization. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: G protein-coupled receptor internalization Supporting Evidence: PMID:16120787 endocytosis induced by both ligands was inhibited by a dominant-negative mutant version of arrestin-3 (beta-arrestin-2). UniProtKB:P29067 The beta-arrestins target many receptors for internalization by acting as endocytic adapters (CLASPs, clathrin-associated sorting proteins) and recruiting the GPRCs to the adapter protein 2 complex 2 (AP-2) in clathrin-coated pits (CCPs). |
| GO:0005102 signaling receptor binding | ISO GO_REF:0000121 | MODIFY | Summary: Signaling receptor binding is correct but too general; the receptors bound are GPCRs. Reason: Replace with G protein-coupled receptor binding (GO:0001664), which the gene already carries. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: G protein-coupled receptor binding Supporting Evidence: UniProtKB:P29067 During homologous desensitization, beta-arrestins bind to the GPCR-phosphorylated receptor and sterically preclude its coupling to the cognate G protein |
| GO:0005515 protein binding | IPI PMID:16051150 An Akt/beta-arrestin 2/PP2A signaling complex mediates dopam... | MODIFY | Summary: Bare protein binding with GSK3 (IntAct, from the Akt/beta-arrestin-2/PP2A complex study); replace with protein kinase binding. Reason: Under the protein-binding policy GO:0005515 is uninformative. The partner is a protein kinase (GSK3) that is part of the beta-arrestin-2/Akt/PP2A signalling complex, so protein kinase binding (GO:0019901) is the informative term. Proposed replacements: protein kinase binding Supporting Evidence: PMID:16051150 D2 class-receptor-mediated Akt regulation involves the formation of signaling complexes containing beta-arrestin 2, PP2A, and Akt. |
| GO:0005515 protein binding | IPI PMID:16051150 An Akt/beta-arrestin 2/PP2A signaling complex mediates dopam... | MODIFY | Summary: Bare protein binding with GSK3 (IntAct, from the Akt/beta-arrestin-2/PP2A complex study); replace with protein kinase binding. Reason: Under the protein-binding policy GO:0005515 is uninformative. The partner is a protein kinase (GSK3) that is part of the beta-arrestin-2/Akt/PP2A signalling complex, so protein kinase binding (GO:0019901) is the informative term. Proposed replacements: protein kinase binding Supporting Evidence: PMID:16051150 D2 class-receptor-mediated Akt regulation involves the formation of signaling complexes containing beta-arrestin 2, PP2A, and Akt. |
| GO:0005515 protein binding | IPI PMID:17500066 Beta-arrestin-dependent regulation of the cofilin pathway do... | MODIFY | Summary: Bare protein binding with LIMK1; replace with protein kinase binding. Reason: Beta-arrestins scaffold LIMK and cofilin downstream of PAR-2; the partner is a kinase, so protein kinase binding (GO:0019901) is more informative than protein binding. Proposed replacements: protein kinase binding Supporting Evidence: PMID:17500066 can interact with cofilin, LIMK, and chronophin and colocalize with them in membrane protrusions |
| GO:0005515 protein binding | IPI PMID:17984062 beta-arrestin 2 oligomerization controls the Mdm2-dependent ... | MODIFY | Summary: Bare protein binding with MDM2; replace with ubiquitin protein ligase binding. Reason: Oligomeric beta-arrestin-2 binds the E3 ligase MDM2 and titrates it out of the nucleus. Ubiquitin protein ligase binding (GO:0031625, already annotated) is the informative term. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:17984062 the interaction with and subsequent titration out of the nucleus of the protooncogene Mdm2 specifically require beta-arr2 oligomers together with the previously characterized nucleocytoplasmic shuttling of beta-arr2. UniProtKB:P29067 Interacts with MDM2; the interaction is enhanced by activation of GPCRs. |
| GO:0005515 protein binding | IPI PMID:18191226 A beta-arrestin 2 signaling complex mediates lithium action ... | MODIFY | Summary: Bare protein binding with AKT1; replace with protein kinase B binding. Reason: Beta-arrestin-2 forms an Akt/beta-arrestin-2/PP2A signalling complex; protein kinase B binding (GO:0043422, already annotated by ISO) is the informative term. Proposed replacements: protein kinase B binding Supporting Evidence: PMID:18191226 by disrupting a signaling complex composed of Akt, beta-arrestin 2, and protein phosphatase 2A. PMID:16051150 D2 class-receptor-mediated Akt regulation involves the formation of signaling complexes containing beta-arrestin 2, PP2A, and Akt. |
| GO:0005515 protein binding | IPI PMID:18191226 A beta-arrestin 2 signaling complex mediates lithium action ... | MODIFY | Summary: Bare protein binding with MDM2; replace with ubiquitin protein ligase binding. Reason: Oligomeric beta-arrestin-2 binds the E3 ligase MDM2 and titrates it out of the nucleus. Ubiquitin protein ligase binding (GO:0031625, already annotated) is the informative term. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:17984062 the interaction with and subsequent titration out of the nucleus of the protooncogene Mdm2 specifically require beta-arr2 oligomers together with the previously characterized nucleocytoplasmic shuttling of beta-arr2. UniProtKB:P29067 Interacts with MDM2; the interaction is enhanced by activation of GPCRs. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Beta-arrestin-2 shuttles between nucleus and cytoplasm but is mainly cytoplasmic at steady state. Reason: Nucleocytoplasmic shuttling of beta-arrestin-2 is documented (it exports MDM2 from the nucleus), but nuclear presence is transient and peripheral to the core GPCR functions. Supporting Evidence: PMID:17984062 the interaction with and subsequent titration out of the nucleus of the protooncogene Mdm2 specifically require beta-arr2 oligomers together with the previously characterized nucleocytoplasmic shuttling of beta-arr2. UniProtKB:P29067 May serve as nuclear messenger for GPCRs. |
| GO:0005634 nucleus | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta-arrestin-2 shuttles between nucleus and cytoplasm but is mainly cytoplasmic at steady state. Reason: Nucleocytoplasmic shuttling of beta-arrestin-2 is documented (it exports MDM2 from the nucleus), but nuclear presence is transient and peripheral to the core GPCR functions. Supporting Evidence: PMID:17984062 the interaction with and subsequent titration out of the nucleus of the protooncogene Mdm2 specifically require beta-arr2 oligomers together with the previously characterized nucleocytoplasmic shuttling of beta-arr2. UniProtKB:P29067 May serve as nuclear messenger for GPCRs. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Resting beta-arrestin-2 is a soluble cytoplasmic protein that translocates to activated receptors. Reason: Cytoplasmic localization is supported by direct imaging (beta-arrestin-2-GFP in PMID:14757828), sucrose-gradient fractionation in Sertoli cells, the UniProt subcellular location and the IBA for the arrestin family. 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. UniProtKB:P29067 Translocates to the plasma membrane and colocalizes with antagonist-stimulated GPCRs. |
| GO:0005737 cytoplasm | IDA PMID:14757828 Heterodimerization of V1a and V2 vasopressin receptors deter... | ACCEPT | Summary: Resting beta-arrestin-2 is a soluble cytoplasmic protein that translocates to activated receptors. Reason: Cytoplasmic localization is supported by direct imaging (beta-arrestin-2-GFP in PMID:14757828), sucrose-gradient fractionation in Sertoli cells, the UniProt subcellular location and the IBA for the arrestin family. 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. UniProtKB:P29067 Translocates to the plasma membrane and colocalizes with antagonist-stimulated GPCRs. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Resting beta-arrestin-2 is a soluble cytoplasmic protein that translocates to activated receptors. Reason: Cytoplasmic localization is supported by direct imaging (beta-arrestin-2-GFP in PMID:14757828), sucrose-gradient fractionation in Sertoli cells, the UniProt subcellular location and the IBA for the arrestin family. 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. UniProtKB:P29067 Translocates to the plasma membrane and colocalizes with antagonist-stimulated GPCRs. |
| GO:0005737 cytoplasm | ISO GO_REF:0000121 | ACCEPT | Summary: Resting beta-arrestin-2 is a soluble cytoplasmic protein that translocates to activated receptors. Reason: Cytoplasmic localization is supported by direct imaging (beta-arrestin-2-GFP in PMID:14757828), sucrose-gradient fractionation in Sertoli cells, the UniProt subcellular location and the IBA for the arrestin family. 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. UniProtKB:P29067 Translocates to the plasma membrane and colocalizes with antagonist-stimulated GPCRs. |
| GO:0005768 endosome | IDA PMID:14757828 Heterodimerization of V1a and V2 vasopressin receptors deter... | ACCEPT | Summary: Beta-arrestin-2 traffics with class B GPCRs into endosomes. Reason: Live-cell imaging shows endosomal GPCR/beta-arrestin-2 complexes (V2R, bradykinin B2R); the rat T178 ERK motif regulates the stability of these endosomal complexes. Supporting Evidence: PMID:14757828 beta-arrestin remains associated with V2R in the endosomes 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. |
| GO:0005768 endosome | IDA PMID:25016018 Differential regulation of endosomal GPCR/Ξ²-arrestin complex... | ACCEPT | Summary: Beta-arrestin-2 traffics with class B GPCRs into endosomes. Reason: Live-cell imaging shows endosomal GPCR/beta-arrestin-2 complexes (V2R, bradykinin B2R); the rat T178 ERK motif regulates the stability of these endosomal complexes. Supporting Evidence: PMID:14757828 beta-arrestin remains associated with V2R in the endosomes 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. |
| GO:0005829 cytosol | ISO GO_REF:0000121 | ACCEPT | Summary: Cytosol is where inactive beta-arrestin-2 resides before receptor recruitment. Reason: Soluble protein without membrane anchors; recruited from the cytoplasm to the plasma membrane on receptor activation. 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:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Beta-arrestin-2 is recruited to the plasma membrane, where it binds activated receptors. Reason: Agonist-dependent translocation to the plasma membrane is shown for the FSH receptor in rat Sertoli cells, and is where receptor binding and coat recruitment occur. 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. UniProtKB:P29067 Translocates to the plasma membrane and colocalizes with antagonist-stimulated GPCRs. |
| GO:0005886 plasma membrane | ISO GO_REF:0000121 | ACCEPT | Summary: Beta-arrestin-2 is recruited to the plasma membrane, where it binds activated receptors. Reason: Agonist-dependent translocation to the plasma membrane is shown for the FSH receptor in rat Sertoli cells, and is where receptor binding and coat recruitment occur. 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. UniProtKB:P29067 Translocates to the plasma membrane and colocalizes with antagonist-stimulated GPCRs. |
| GO:0005905 clathrin-coated pit | IEA GO_REF:0000044 | ACCEPT | Summary: Beta-arrestin-2 concentrates receptors in clathrin-coated pits. Reason: The UniProt keyword mapping is consistent with the well-characterized clathrin- and AP-2-binding motifs of this protein (mutations abolish clathrin and AP2B1 binding). Supporting Evidence: UniProtKB:P29067 The beta-arrestins target many receptors for internalization by acting as endocytic adapters (CLASPs, clathrin-associated sorting proteins) and recruiting the GPRCs to the adapter protein 2 complex 2 (AP-2) in clathrin-coated pits (CCPs). UniProtKB:P29067 LIEF->AAEA: Abolishes interaction with CLTC; reduces interaction with AP2B1. |
| GO:0006366 transcription by RNA polymerase II | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: No evidence that beta-arrestin-2 participates in RNA polymerase II transcription. Reason: Nuclear transcriptional co-regulator roles are described mainly for beta-arrestin-1; for beta-arrestin-2 the nuclear role is MDM2 export and the UniProt text only says it may serve as a nuclear messenger. Participation in transcription by RNA polymerase II is not supported. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Supporting Evidence: UniProtKB:P29067 May serve as nuclear messenger for GPCRs. |
| GO:0006897 endocytosis | IDA PMID:12600992 A G protein-coupled receptor kinase induces Xenopus oocyte m... | MODIFY | Summary: Endocytosis is correct but general; the process beta-arrestin-2 drives is GPCR internalization. Reason: In Xenopus oocytes, rat beta-arrestin-2 (with GRK3) induced maturation in a way blocked by clathrin-endocytosis inhibitors, implying endocytosis of an endogenous GPCR. The more specific term GPCR internalization (GO:0002031) is already accepted for this gene. Proposed replacements: G protein-coupled receptor internalization Supporting Evidence: PMID:12600992 Several inhibitors of clathrin-mediated receptor endocytosis (the clathrin-binding domain of beta-arrestin-2, concanavalin A, and monodansyl cadaverine) significantly reduced the abilities of GRK3/beta-arrestin-2 to induce GVBD. UniProtKB:P29067 The beta-arrestins target many receptors for internalization by acting as endocytic adapters (CLASPs, clathrin-associated sorting proteins) and recruiting the GPRCs to the adapter protein 2 complex 2 (AP-2) in clathrin-coated pits (CCPs). |
| GO:0006897 endocytosis | IEA GO_REF:0000117 | MODIFY | Summary: Endocytosis (ARBA) is correct but general; the specific process is GPCR internalization. Reason: Same claim as the IDA row; replace with GO:0002031. Proposed replacements: G protein-coupled receptor internalization Supporting Evidence: UniProtKB:P29067 The beta-arrestins target many receptors for internalization by acting as endocytic adapters (CLASPs, clathrin-associated sorting proteins) and recruiting the GPRCs to the adapter protein 2 complex 2 (AP-2) in clathrin-coated pits (CCPs). |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | MODIFY | Summary: Signal transduction (InterPro2GO) is too general for beta-arrestin-2. Reason: Beta-arrestin-2 acts in GPCR signalling, both terminating G protein signalling and transducing arrestin-dependent signals; G protein-coupled receptor signaling pathway (GO:0007186) is the appropriate specific term. Proposed replacements: G protein-coupled receptor signaling pathway Supporting Evidence: UniProtKB:P29067 Belongs to the arrestin family. UniProtKB:P29067 During homologous desensitization, beta-arrestins bind to the GPCR-phosphorylated receptor and sterically preclude its coupling to the cognate G protein |
| GO:0007179 transforming growth factor beta receptor signaling pathway | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta-arrestin-2 mediates TGFBR3/TGFBR2 endocytosis and dampens TGF-beta signalling (human/mouse data). Reason: An extension of the adaptor role to a non-GPCR receptor; peripheral to the core GPCR functions. Supporting Evidence: UniProtKB:P29067 Involved in endocytosis of TGFBR2 and TGFBR3 and down-regulates TGF-beta signaling such as NF-kappa-B activation. |
| GO:0007186 G protein-coupled receptor signaling pathway | IDA PMID:157224 Partial purification of a bone-resorbing factor elaborated f... | ACCEPT | Summary: Beta-arrestin-2 acts in GPCR signalling pathways, both to terminate G protein signalling and to scaffold arrestin-dependent signals. Reason: The claim is correct and supported by PMID:1517224 (beta2AR desensitization). The cited PMID:157224 is a 1979 paper on a bone-resorbing factor and is almost certainly a typo for PMID:1517224; recorded as a source defect. Supporting Evidence: PMID:1517224 beta-Arrestin2 was equipotent to beta-arrestin1 and specifically inhibited beta 2AR function. UniProtKB:P29067 Acts as a signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2) and MAPK10 (JNK3). file:rat/Arrb2/Arrb2-deep-research-manual.md PMID:157224 (cited by RGD for GPCR signalling and postsynaptic membrane IDA) is a 1979 bone-resorbing-factor paper; almost certainly a typo of PMID:1517224. |
| GO:0007600 sensory perception | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Sensory perception is not an activity of beta-arrestin-2; ARBA rule propagates a phenotype-level process. Reason: Beta-arrestin-2 modulates opioid receptor signalling and therefore analgesia, but it does no work in perceiving a stimulus. The effect is captured by the opioid receptor signalling regulation terms. Supporting Evidence: PMID:21926413 We show here that intrathecal Ξ²-arrestin 2 siRNA in rats enhances analgesia and attenuates naloxone-induced withdrawal symptoms. |
| GO:0007623 circadian rhythm | IEP PMID:34919270 Disrupted circadian expression of Ξ²-arrestin 2 affects rewar... | MARK AS OVER ANNOTATED | Summary: Diurnal variation in Arrb2 mRNA does not show that beta-arrestin-2 takes part in the circadian rhythm. Reason: IEP from a diurnal transcription pattern in nucleus accumbens. Rhythmic expression is a consequence of the clock, not participation in it. Supporting Evidence: PMID:34919270 we report daily rhythmicity for bArr2 expression linked to an inverse pattern of MOR |
| GO:0007628 adult walking behavior | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Adult walking behavior is a whole-animal phenotype of mouse Arrb2 knockout, not a process the protein performs. Reason: Locomotor phenotypes of knockout mice reflect altered dopamine receptor signalling (Akt/GSK3 scaffold); the behaviour term is too far downstream of the molecular function. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Supporting Evidence: PMID:16051150 D2 class-receptor-mediated Akt regulation involves the formation of signaling complexes containing beta-arrestin 2, PP2A, and Akt. |
| 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 is correct but general; the specific process is desensitization. Reason: The direct evidence (PMID:1517224, inhibition of beta2AR-Gs coupling) is desensitization of GPCR signalling (GO:0002029), already accepted for this gene. The ARBA and ISO rows make the same claim. 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. UniProtKB:P29067 During homologous desensitization, beta-arrestins bind to the GPCR-phosphorylated receptor and sterically preclude its coupling to the cognate G protein |
| GO:0008277 regulation of G protein-coupled receptor signaling pathway | IEA GO_REF:0000117 | MODIFY | Summary: Regulation of GPCR signaling is correct but general; the specific process is desensitization. Reason: The direct evidence (PMID:1517224, inhibition of beta2AR-Gs coupling) is desensitization of GPCR signalling (GO:0002029), already accepted for this gene. The ARBA and ISO rows make the same claim. 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. UniProtKB:P29067 During homologous desensitization, beta-arrestins bind to the GPCR-phosphorylated receptor and 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 is correct but general; the specific process is desensitization. Reason: The direct evidence (PMID:1517224, inhibition of beta2AR-Gs coupling) is desensitization of GPCR signalling (GO:0002029), already accepted for this gene. The ARBA and ISO rows make the same claim. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH 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. UniProtKB:P29067 During homologous desensitization, beta-arrestins bind to the GPCR-phosphorylated receptor and sterically preclude its coupling to the cognate G protein |
| GO:0009968 negative regulation of signal transduction | IEA GO_REF:0000117 | MODIFY | Summary: Negative regulation of signal transduction (ARBA) is correct but general. Reason: The specific negative-regulatory process is desensitization of GPCR signalling (GO:0002029), a descendant of this term. Proposed replacements: desensitization of G protein-coupled receptor signaling pathway Supporting Evidence: UniProtKB:P29067 During homologous desensitization, beta-arrestins bind to the GPCR-phosphorylated receptor and sterically preclude its coupling to the cognate G protein |
| GO:0010628 positive regulation of gene expression | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Positive regulation of gene expression is an indirect, downstream effect. Reason: Transferred from a mouse phenotype; beta-arrestin-2 is not a transcriptional regulator and any effect on gene expression is several steps downstream of receptor signalling. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Supporting Evidence: UniProtKB:P29067 ERK1/2 and JNK3 activated by the beta-arrestin scaffold are largely excluded from the nucleus and confined to cytoplasmic locations such as endocytic vesicles, also called beta-arrestin signalosomes. |
| GO:0014069 postsynaptic density | IDA PMID:1517224 Beta-arrestin2, a novel member of the arrestin/beta-arrestin... | KEEP AS NON CORE | Summary: Immunoelectron microscopy places beta-arrestin-2 at postsynaptic sites in rat brain (SynGO). Reason: A valid tissue-specific location for neurotransmitter receptor regulation, but peripheral to the cell-wide core function. Supporting Evidence: PMID:1517224 immunoelectron microscopy shows that the beta-arrestins are appropriately situated at postsynaptic sites to act in concert with beta ARK to regulate G protein-coupled neurotransmitter receptors. |
| GO:0016323 basolateral plasma membrane | IDA PMID:16899567 G protein-coupled receptor kinase 2 and beta-arrestins are r... | KEEP AS NON CORE | Summary: Recruitment of beta-arrestins to FSH receptor-containing membrane fractions in polarized Sertoli cells. Reason: The abstract describes recruitment to the plasma membrane; the basolateral assignment presumably reflects the basolateral FSH receptor in Sertoli cells, which the curator saw in full text. Context-specific 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: Beta-arrestin-2 acts as an adaptor that brings E3 ligases (e.g. MDM2) to substrates such as IGF1R. Reason: Beta-arrestin-2 does not catalyse ubiquitin transfer but contributes the adaptor that brings ligase and substrate together; a secondary role. Supporting Evidence: UniProtKB:P29067 Involved in ubiquitination of IGF1R. UniProtKB:P29067 Interacts with MDM2; the interaction is enhanced by activation of GPCRs. |
| GO:0019233 sensory perception of pain | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Sensory perception of pain is a phenotype-level process; beta-arrestin-2 modulates opioid receptor signalling rather than performing nociception. Reason: The PAINT node (PTN002623675) is seeded from rat Arrb2 itself (RGD:2157), whose experimental basis is the intrathecal siRNA analgesia study. That shows beta-arrestin-2 limits morphine antinociception, i.e. regulation of opioid receptor signalling, not a step of pain perception. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Supporting Evidence: PMID:21926413 We show here that intrathecal Ξ²-arrestin 2 siRNA in rats enhances analgesia and attenuates naloxone-induced withdrawal symptoms. |
| GO:0019899 enzyme binding | IEA GO_REF:0000117 | MODIFY | Summary: Enzyme binding is too general; the enzymes bound are protein kinases (ERK1/2, AKT) and E3 ligases (MDM2). Reason: Replace with the specific binding terms that this gene already carries. Proposed replacements: mitogen-activated protein kinase binding protein kinase B binding ubiquitin protein ligase binding Supporting Evidence: UniProtKB:P29067 Acts as a signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2) and MAPK10 (JNK3). UniProtKB:P29067 Interacts with MDM2; the interaction is enhanced by activation of GPCRs. |
| GO:0019899 enzyme binding | ISO GO_REF:0000121 | MODIFY | Summary: Enzyme binding is too general; the enzymes bound are protein kinases (ERK1/2, AKT) and E3 ligases (MDM2). Reason: Replace with the specific binding terms that this gene already carries. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: mitogen-activated protein kinase binding protein kinase B binding ubiquitin protein ligase binding Supporting Evidence: UniProtKB:P29067 Acts as a signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2) and MAPK10 (JNK3). UniProtKB:P29067 Interacts with MDM2; the interaction is enhanced by activation of GPCRs. |
| GO:0019904 protein domain specific binding | IPI PMID:12890920 Loss of intracellular dystrophin: a potential mechanism for ... | UNDECIDED | Summary: The cited paper does not appear to concern beta-arrestin-2 or the D2 dopamine receptor. Reason: PMID:12890920 is a short report on loss of dystrophin in reperfused rat myocardium; the abstract mentions neither arrestins nor dopamine receptors. Beta-arrestin-2 does bind the D2 receptor (UniProt SUBUNIT), but the claimed domain-specific binding cannot be verified from this reference. Flagged as a probable wrong reference. Supporting Evidence: PMID:12890920 Dystrophin was distributed exclusively in the sarcolemmal membrane of buffer-perfused rat cardiomyocytes file:rat/Arrb2/Arrb2-deep-research-manual.md is a dystrophin/reperfusion report with no arrestin content in the abstract. |
| GO:0030139 endocytic vesicle | ISO GO_REF:0000121 | ACCEPT | Summary: Beta-arrestin-2 travels with internalized receptors on endocytic vesicles, where it scaffolds ERK signalosomes. Reason: Consistent with the endosomal IDA rows and the beta-arrestin signalosome model. Supporting Evidence: UniProtKB:P29067 ERK1/2 and JNK3 activated by the beta-arrestin scaffold are largely excluded from the nucleus and confined to cytoplasmic locations such as endocytic vesicles, also called beta-arrestin signalosomes. PMID:14757828 beta-arrestin remains associated with V2R in the endosomes |
| GO:0030139 endocytic vesicle | ISS GO_REF:0000024 | ACCEPT | Summary: Beta-arrestin-2 travels with internalized receptors on endocytic vesicles, where it scaffolds ERK signalosomes. Reason: Consistent with the endosomal IDA rows and the beta-arrestin signalosome model. Supporting Evidence: UniProtKB:P29067 ERK1/2 and JNK3 activated by the beta-arrestin scaffold are largely excluded from the nucleus and confined to cytoplasmic locations such as endocytic vesicles, also called beta-arrestin signalosomes. PMID:14757828 beta-arrestin remains associated with V2R in the endosomes |
| GO:0030674 protein-macromolecule adaptor activity | ISO GO_REF:0000121 | MODIFY | Summary: Adaptor activity is correct but general; beta-arrestin-2 has two specific adaptor activities. Reason: Beta-arrestin-2 is a clathrin-cargo adaptor linking phosphorylated GPCRs to clathrin and AP-2 (GO:0035615) and a signalling adaptor/scaffold for ERK1/2, JNK3 and AKT (GO:0035591). Both are descendants of this term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: clathrin-cargo adaptor activity signaling adaptor activity Supporting Evidence: UniProtKB:P29067 The beta-arrestins target many receptors for internalization by acting as endocytic adapters (CLASPs, clathrin-associated sorting proteins) and recruiting the GPRCs to the adapter protein 2 complex 2 (AP-2) in clathrin-coated pits (CCPs). UniProtKB:P29067 LIEF->AAEA: Abolishes interaction with CLTC; reduces interaction with AP2B1. UniProtKB:P29067 Acts as a signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2) and MAPK10 (JNK3). |
| GO:0031396 regulation of protein ubiquitination | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Beta-arrestin-2 influences ubiquitination of partner proteins in both directions. Reason: It is an adaptor for E3 ligases (IGF1R/MDM2, Notch/ITCH via ARRDC1) but limits TRAF6 autoubiquitination and TRPV4 ubiquitination. The general term is as precise as warranted given both signs; a secondary role. Supporting Evidence: UniProtKB:P29067 Involved in ubiquitination of IGF1R. UniProtKB:P29067 Involved in Toll-like receptor and IL-1 receptor signaling through the interaction with TRAF6 which prevents TRAF6 autoubiquitination and oligomerization required for activation of NF-kappa-B and JUN. PMID:20650893 Surprisingly, knocking down Ξ²-arrestin 2 led to an increase in angiotensin-induced ubiquitination of TRPV4. |
| GO:0031397 negative regulation of protein ubiquitination | IMP PMID:20650893 Arresting a transient receptor potential (TRP) channel: beta... | KEEP AS NON CORE | Summary: Beta-arrestin-2 knockdown increased angiotensin-induced ubiquitination of TRPV4, opposite to beta-arrestin-1. Reason: Full text read: siRNA against beta-arrestin-2 increased TRPV4 ubiquitination whereas beta-arrestin-1 knockdown abolished it. A real but peripheral, context-specific effect. Supporting Evidence: PMID:20650893 Surprisingly, knocking down Ξ²-arrestin 2 led to an increase in angiotensin-induced ubiquitination of TRPV4. |
| GO:0031410 cytoplasmic vesicle | IEA GO_REF:0000044 | MODIFY | Summary: Cytoplasmic vesicle is correct but general; the vesicles are endocytic. Reason: Replace with endocytic vesicle (GO:0030139), already annotated for this gene. Proposed replacements: endocytic vesicle Supporting Evidence: UniProtKB:P29067 ERK1/2 and JNK3 activated by the beta-arrestin scaffold are largely excluded from the nucleus and confined to cytoplasmic locations such as endocytic vesicles, also called beta-arrestin signalosomes. |
| GO:0031410 cytoplasmic vesicle | ISO GO_REF:0000121 | MODIFY | Summary: Cytoplasmic vesicle is correct but general; the vesicles are endocytic. Reason: Replace with endocytic vesicle (GO:0030139), already annotated for this gene. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: endocytic vesicle Supporting Evidence: UniProtKB:P29067 ERK1/2 and JNK3 activated by the beta-arrestin scaffold are largely excluded from the nucleus and confined to cytoplasmic locations such as endocytic vesicles, also called beta-arrestin signalosomes. |
| GO:0031623 receptor internalization | ISO GO_REF:0000121 | MODIFY | Summary: Receptor internalization is correct but general; the receptors are mainly GPCRs. Reason: Replace with GPCR internalization (GO:0002031), already accepted. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: G protein-coupled receptor internalization Supporting Evidence: UniProtKB:P29067 The beta-arrestins target many receptors for internalization by acting as endocytic adapters (CLASPs, clathrin-associated sorting proteins) and recruiting the GPRCs to the adapter protein 2 complex 2 (AP-2) in clathrin-coated pits (CCPs). |
| GO:0031625 ubiquitin protein ligase binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta-arrestin-2 binds the E3 ligase MDM2. Reason: MDM2 binding underlies receptor and arrestin ubiquitination and the p53 regulation by beta-arrestin-2; secondary to the core GPCR functions. Supporting Evidence: UniProtKB:P29067 Interacts with MDM2; the interaction is enhanced by activation of GPCRs. PMID:17984062 the interaction with and subsequent titration out of the nucleus of the protooncogene Mdm2 specifically require beta-arr2 oligomers together with the previously characterized nucleocytoplasmic shuttling of beta-arr2. |
| GO:0031691 alpha-1A adrenergic receptor binding | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Beta-arrestins bind the alpha1A-adrenergic receptor, but only weakly. Reason: Co-immunoprecipitation and translocation assays show a much weaker agonist-induced interaction than with the alpha1B-AR, consistent with the poor endocytosis of the alpha1A subtype. A real but minor receptor partner. 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: Beta-arrestins bind the alpha1A-adrenergic receptor, but only weakly. Reason: Co-immunoprecipitation and translocation assays show a much weaker agonist-induced interaction than with the alpha1B-AR, consistent with the poor endocytosis of the alpha1A subtype. A real but minor receptor partner. 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... | ACCEPT | Summary: Beta-arrestin-2 binds the agonist-activated alpha1B-adrenergic receptor and drives its endocytosis. Reason: Interaction depends on receptor C-tail phosphorylation sites and RNAi shows beta-arrestin-2 is the main isoform for alpha1B-AR endocytosis; an instance of the core GPCR binding activity. Supporting Evidence: PMID:18523139 RNA interference showed that beta-arrestin 2 plays a prominent role in alpha1b-AR endocytosis. |
| GO:0031692 alpha-1B adrenergic receptor binding | IEA GO_REF:0000117 | ACCEPT | Summary: Beta-arrestin-2 binds the agonist-activated alpha1B-adrenergic receptor and drives its endocytosis. Reason: Interaction depends on receptor C-tail phosphorylation sites and RNAi shows beta-arrestin-2 is the main isoform for alpha1B-AR endocytosis; an instance of the core GPCR binding activity. Supporting Evidence: PMID:18523139 RNA interference showed that beta-arrestin 2 plays a prominent role in alpha1b-AR endocytosis. |
| GO:0031701 angiotensin receptor binding | IBA GO_REF:0000033 | ACCEPT | Summary: Beta-arrestin-2 binds the AT1 angiotensin receptor, a prototypical class B GPCR partner. Reason: Agonist-stimulated recruitment of beta-arrestin-2 to AT1R is shown by co-immunoprecipitation in rat aorta, and AT1R/beta-arrestin-2 signalling is characterized in rat VSMCs. The IBA node is seeded by human and rat beta-arrestin-2. Supporting Evidence: PMID:19522833 Stimulation of isolated aortas with exogenous angiotensin II caused recruitment of beta-arrestin-2 in aortas from noncirrhotic rats PMID:15498833 the agonist stimulation of native AT1R in vascular smooth muscle cells (VSMCs) induces the formation of an endogenous complex containing c-Src, beta-arrestins and AP-2. |
| GO:0031701 angiotensin receptor binding | ISO GO_REF:0000121 | ACCEPT | Summary: Beta-arrestin-2 binds the AT1 angiotensin receptor, a prototypical class B GPCR partner. Reason: Agonist-stimulated recruitment of beta-arrestin-2 to AT1R is shown by co-immunoprecipitation in rat aorta, and AT1R/beta-arrestin-2 signalling is characterized in rat VSMCs. The IBA node is seeded by human and rat beta-arrestin-2. Supporting Evidence: PMID:19522833 Stimulation of isolated aortas with exogenous angiotensin II caused recruitment of beta-arrestin-2 in aortas from noncirrhotic rats PMID:15498833 the agonist stimulation of native AT1R in vascular smooth muscle cells (VSMCs) induces the formation of an endogenous complex containing c-Src, beta-arrestins and AP-2. |
| GO:0031702 type 1 angiotensin receptor binding | IPI PMID:19522833 Vascular hyporesponsiveness to angiotensin II in rats with C... | ACCEPT | Summary: Beta-arrestin-2 binds the AT1 angiotensin receptor, a prototypical class B GPCR partner. Reason: Agonist-stimulated recruitment of beta-arrestin-2 to AT1R is shown by co-immunoprecipitation in rat aorta, and AT1R/beta-arrestin-2 signalling is characterized in rat VSMCs. The IBA node is seeded by human and rat beta-arrestin-2. Supporting Evidence: PMID:19522833 Stimulation of isolated aortas with exogenous angiotensin II caused recruitment of beta-arrestin-2 in aortas from noncirrhotic rats PMID:15498833 the agonist stimulation of native AT1R in vascular smooth muscle cells (VSMCs) induces the formation of an endogenous complex containing c-Src, beta-arrestins and AP-2. |
| GO:0031748 D1 dopamine receptor binding | IBA GO_REF:0000033 | ACCEPT | Summary: Beta-arrestin-2 binds the D1 dopamine receptor and scaffolds p-ERK in striatal neurons. Reason: Full text read: D1 receptor and p-ERK co-immunoprecipitate with beta-arrestin-2 in dopamine-treated rat striatal neurons. Supporting Evidence: PMID:19200235 We analyzed whether stimulation of D1 receptors in striatal neurons also results in the scaffold of D1 DA receptor, Ξ²-arrestin2 and p-ERK. |
| GO:0031748 D1 dopamine receptor binding | IPI PMID:19200235 Dopamine promotes striatal neuronal apoptotic death via ERK ... | ACCEPT | Summary: Beta-arrestin-2 binds the D1 dopamine receptor and scaffolds p-ERK in striatal neurons. Reason: Full text read: D1 receptor and p-ERK co-immunoprecipitate with beta-arrestin-2 in dopamine-treated rat striatal neurons. Supporting Evidence: PMID:19200235 We analyzed whether stimulation of D1 receptors in striatal neurons also results in the scaffold of D1 DA receptor, Ξ²-arrestin2 and p-ERK. |
| GO:0031748 D1 dopamine receptor binding | ISO GO_REF:0000121 | ACCEPT | Summary: Beta-arrestin-2 binds the D1 dopamine receptor and scaffolds p-ERK in striatal neurons. Reason: Full text read: D1 receptor and p-ERK co-immunoprecipitate with beta-arrestin-2 in dopamine-treated rat striatal neurons. Supporting Evidence: PMID:19200235 We analyzed whether stimulation of D1 receptors in striatal neurons also results in the scaffold of D1 DA receptor, Ξ²-arrestin2 and p-ERK. |
| GO:0031762 follicle-stimulating hormone receptor binding | IEA GO_REF:0000117 | ACCEPT | Summary: Endogenous beta-arrestins bind the activated FSH receptor in rat Sertoli cells. Reason: Agonist-dependent co-immunoprecipitation of FSH-binding activity with beta-arrestins at physiological expression levels. 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... | ACCEPT | Summary: Endogenous beta-arrestins bind the activated FSH receptor in rat Sertoli cells. Reason: Agonist-dependent co-immunoprecipitation of FSH-binding activity with beta-arrestins at physiological expression levels. 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:0031826 type 2A serotonin receptor binding | IPI PMID:19919577 Differences in the C-terminus contribute to variations in tr... | KEEP AS NON CORE | Summary: Beta-arrestin-2 binds the human 5-HT2A receptor via its primate-specific ASK motif. Reason: Both this positive row (human HTR2A, RGD:734107) and the NOT row (rat Htr2a, RGD:61800) from the same paper hold: the interaction depends on a C-terminal motif present in the human but not the rat receptor. Supporting Evidence: PMID:19919577 The interaction of beta arrestin-2 with the human receptor causes the delay in recycling and is dependent on a primate-specific ASK motif present in the C-terminus of the receptor. |
| GO:0031826 type 2A serotonin receptor binding | IPI NOT PMID:19919577 Differences in the C-terminus contribute to variations in tr... | KEEP AS NON CORE | Summary: Beta-arrestin-2 does not bind the rat 5-HT2A receptor, which lacks the primate-specific ASK motif. Reason: The negative result is specific to the rat receptor isoform, as the abstract explains; consistent with the positive annotation for the human receptor. Supporting Evidence: PMID:19919577 The interaction of beta arrestin-2 with the human receptor causes the delay in recycling and is dependent on a primate-specific ASK motif present in the C-terminus of the receptor. |
| GO:0031859 platelet activating factor receptor binding | IPI PMID:23911909 PAF enhances MMP-2 production in rat aortic VSMCs via a Ξ²-ar... | ACCEPT | Summary: Beta-arrestin-2 binds the PAF receptor in rat aortic VSMCs and forms a complex with p-ERK. Reason: Co-immunoprecipitation and colocalization with PAFR and P-ERK; depletion of beta-arrestin-2 reduces PAF-induced ERK activation. Supporting Evidence: PMID:23911909 Coimmunoprecipitation results suggest that Ξ²-arrestin2-bound PAFRs existed as a complex with P-ERK. PMID:23911909 PAF-induced ERK phosphorylation and MMP-2 production were significantly attenuated by Ξ²-arrestin2 depletion. |
| GO:0032226 positive regulation of synaptic transmission, dopaminergic | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta-arrestin-2 mediates D2-class dopamine receptor signalling through an Akt/PP2A complex (mouse). Reason: Knockout mice show reduced dopamine-dependent behaviours; the protein contributes to dopaminergic transmission through receptor signalling scaffolding. Peripheral, tissue-specific. Supporting Evidence: PMID:16051150 D2 class-receptor-mediated Akt regulation involves the formation of signaling complexes containing beta-arrestin 2, PP2A, and Akt. UniProtKB:P29067 Is involved in dopamine-stimulated AKT1 activity in the striatum by disrupting the association of AKT1 with its negative regulator PP2A. |
| GO:0032691 negative regulation of interleukin-1 beta production | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta-arrestin-2 dampens pro-inflammatory cytokine production (mouse data) via TRAF6/NF-kappa-B and NLRP3 regulation. Reason: Downstream consequences of its negative regulation of TLR/IL-1R-NF-kappa-B signalling and NLRP3 inflammasome activation; non-core. Supporting Evidence: UniProtKB:P29067 Involved in Toll-like receptor and IL-1 receptor signaling through the interaction with TRAF6 which prevents TRAF6 autoubiquitination and oligomerization required for activation of NF-kappa-B and JUN. UniProtKB:P29067 During the activation step of NLRP3 inflammasome, directly associates with NLRP3 leading to inhibition of pro-inflammatory cytokine release and inhibition of inflammation. |
| GO:0032695 negative regulation of interleukin-12 production | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta-arrestin-2 dampens pro-inflammatory cytokine production (mouse data) via TRAF6/NF-kappa-B and NLRP3 regulation. Reason: Downstream consequences of its negative regulation of TLR/IL-1R-NF-kappa-B signalling and NLRP3 inflammasome activation; non-core. Supporting Evidence: UniProtKB:P29067 Involved in Toll-like receptor and IL-1 receptor signaling through the interaction with TRAF6 which prevents TRAF6 autoubiquitination and oligomerization required for activation of NF-kappa-B and JUN. UniProtKB:P29067 During the activation step of NLRP3 inflammasome, directly associates with NLRP3 leading to inhibition of pro-inflammatory cytokine release and inhibition of inflammation. |
| GO:0032715 negative regulation of interleukin-6 production | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta-arrestin-2 dampens pro-inflammatory cytokine production (mouse data) via TRAF6/NF-kappa-B and NLRP3 regulation. Reason: Downstream consequences of its negative regulation of TLR/IL-1R-NF-kappa-B signalling and NLRP3 inflammasome activation; non-core. Supporting Evidence: UniProtKB:P29067 Involved in Toll-like receptor and IL-1 receptor signaling through the interaction with TRAF6 which prevents TRAF6 autoubiquitination and oligomerization required for activation of NF-kappa-B and JUN. UniProtKB:P29067 During the activation step of NLRP3 inflammasome, directly associates with NLRP3 leading to inhibition of pro-inflammatory cytokine release and inhibition of inflammation. |
| GO:0032720 negative regulation of tumor necrosis factor production | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta-arrestin-2 dampens pro-inflammatory cytokine production (mouse data) via TRAF6/NF-kappa-B and NLRP3 regulation. Reason: Downstream consequences of its negative regulation of TLR/IL-1R-NF-kappa-B signalling and NLRP3 inflammasome activation; non-core. Supporting Evidence: UniProtKB:P29067 Involved in Toll-like receptor and IL-1 receptor signaling through the interaction with TRAF6 which prevents TRAF6 autoubiquitination and oligomerization required for activation of NF-kappa-B and JUN. UniProtKB:P29067 During the activation step of NLRP3 inflammasome, directly associates with NLRP3 leading to inhibition of pro-inflammatory cytokine release and inhibition of inflammation. |
| GO:0032967 positive regulation of collagen biosynthetic process | IMP PMID:28274926 Ξ²-Arrestin-biased AT1R stimulation promotes extracellular ma... | KEEP AS NON CORE | Summary: Beta-arrestin-2 is required for SII-AT1R-stimulated collagen and fibronectin synthesis in rat kidney fibroblasts. Reason: A downstream outcome of AT1R/beta-arrestin-2/ERK signalling; non-core. Supporting Evidence: PMID:28274926 Transfection of siRNA targeting Ξ²-arrestin-2 decreased the effects of SII on ECM synthesis. PMID:28274926 Transfection of siRNA targeting Ξ²-arrestin-2 inhibited ERK phosphorylation. |
| GO:0034122 negative regulation of toll-like receptor signaling pathway | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta-arrestin-2 binds TRAF6 and limits TLR/IL-1R signalling to NF-kappa-B. Reason: Transferred from mouse; an established but secondary scaffold role. Supporting Evidence: UniProtKB:P29067 Involved in Toll-like receptor and IL-1 receptor signaling through the interaction with TRAF6 which prevents TRAF6 autoubiquitination and oligomerization required for activation of NF-kappa-B and JUN. |
| GO:0034392 negative regulation of smooth muscle cell apoptotic process | IMP PMID:19171933 {beta}-Arrestin-2 Mediates Anti-apoptotic Signaling through ... | KEEP AS NON CORE | Summary: AT1R/beta-arrestin-2 signalling protects rat vascular smooth muscle cells from apoptosis. Reason: Full text read: SII-stimulated anti-apoptotic signalling through ERK/p90RSK and PI3K/AKT converging on BAD is abrogated by beta-arrestin-2 siRNA in rat VSMCs. A downstream outcome of the ERK/AKT scaffold. Supporting Evidence: PMID:19171933 Receptor stimulation leads to concerted activation of two pathways, ERK/p90RSK and PI3K/AKT, which converge to phosphorylate and inactivate the pro-apoptotic protein BAD. PMID:19171933 are abrogated by beta-arrestin-2 small interfering RNA. |
| 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: Beta-arrestins are recruited to the FSH receptor and regulate FSH signalling in Sertoli cells. Reason: A receptor-specific instance of GPCR desensitization/signalling; non-core context. 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:0042699 follicle-stimulating hormone signaling pathway | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Beta-arrestins are recruited to the FSH receptor and regulate FSH signalling in Sertoli cells. Reason: A receptor-specific instance of GPCR desensitization/signalling; non-core context. 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:0042802 identical protein binding | IPI PMID:17984062 beta-arrestin 2 oligomerization controls the Mdm2-dependent ... | KEEP AS NON CORE | Summary: Beta-arrestin-2 forms IP6-stabilized homo-oligomers. Reason: Oligomerization is needed for MDM2 binding and nuclear export; a structural property rather than the core activity. Supporting Evidence: PMID:17984062 form constitutive homo- and heterooligomers stabilized by inositol 1,2,3,4,5,6-hexakisphosphate (IP6). |
| GO:0043124 negative regulation of canonical NF-kappaB signal transduction | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta-arrestin-2 attenuates NF-kappa-B signalling by stabilizing IkappaBalpha/CHUK and binding TRAF6. Reason: Transferred from human ARRB2; a secondary scaffold role. Supporting Evidence: UniProtKB:P29067 Involved in attenuation of NF-kappa-B-dependent transcription in response to GPCR or cytokine stimulation by interacting with and stabilizing CHUK. UniProtKB:P29067 Involved in Toll-like receptor and IL-1 receptor signaling through the interaction with TRAF6 which prevents TRAF6 autoubiquitination and oligomerization required for activation of NF-kappa-B and JUN. |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta-arrestin-2 acts as an adaptor that targets partner proteins (IGF1R via MDM2, Notch via ARRDC1/ITCH) for ubiquitin-dependent degradation. Reason: Contributes the adaptor that brings the ligase to the substrate; secondary to the GPCR roles. Supporting Evidence: UniProtKB:P29067 Involved in ubiquitination of IGF1R. PMID:23886940 Our data show for the first time that ARRDC1 and Ξ²-arrestins heterodimerize and cooperate in the same complex to promote non-activated Notch receptor degradation |
| GO:0043197 dendritic spine | IDA PMID:1517224 Beta-arrestin2, a novel member of the arrestin/beta-arrestin... | KEEP AS NON CORE | Summary: Neuronal postsynaptic localization in rat brain. Reason: Immunohistochemistry and immunoelectron microscopy place beta-arrestin-2 at postsynaptic sites; a valid tissue-specific location. Supporting Evidence: PMID:1517224 immunoelectron microscopy shows that the beta-arrestins are appropriately situated at postsynaptic sites to act in concert with beta ARK to regulate G protein-coupled neurotransmitter receptors. PMID:1517224 Immunohistochemical analysis of the tissue distribution of beta-arrestin1 and beta-arrestin2 in rat brain shows extensive, but heterogenous, neuronal labeling of the two proteins. |
| GO:0043278 response to morphine | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Arrb2 mRNA levels in rat brain change after morphine administration. Reason: The IEP reports regulated expression; it shows the gene responds to morphine, but not a mechanistic role. Beta-arrestin-2's mechanistic link to morphine is through opioid receptor signalling. Supporting Evidence: PMID:12614678 Our results thus demonstrated for the first time that opiate administration regulates level of beta-arrestin mRNAs in brain |
| GO:0043278 response to morphine | IEP PMID:12614678 Differential regulation of beta-arrestin 1 and beta-arrestin... | KEEP AS NON CORE | Summary: Arrb2 mRNA levels in rat brain change after morphine administration. Reason: The IEP reports regulated expression; it shows the gene responds to morphine, but not a mechanistic role. Beta-arrestin-2's mechanistic link to morphine is through opioid receptor signalling. Supporting Evidence: PMID:12614678 Our results thus demonstrated for the first time that opiate administration regulates level of beta-arrestin mRNAs in brain |
| GO:0043422 protein kinase B binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta-arrestin-2 binds AKT in an Akt/beta-arrestin-2/PP2A signalling complex. Reason: Supports the AKT scaffold role; a component of the signalling-adaptor function rather than a separate core activity. Supporting Evidence: PMID:18191226 by disrupting a signaling complex composed of Akt, beta-arrestin 2, and protein phosphatase 2A. UniProtKB:P29067 Is involved in dopamine-stimulated AKT1 activity in the striatum by disrupting the association of AKT1 with its negative regulator PP2A. |
| GO:0043524 negative regulation of neuron apoptotic process | IMP PMID:26621121 Beta-arrestin1 and 2 differently modulate metabotropic gluta... | KEEP AS NON CORE | Summary: Beta-arrestin-2-dependent ERK signalling downstream of mGluR7 protects neurons from sevoflurane-induced apoptosis. Reason: A downstream, context-specific outcome of arrestin-dependent ERK signalling. Supporting Evidence: PMID:26621121 Increased Ξ²-arr2-dependent Phospho-ERK1/2 signaling alleviated sevoflurane neurotoxicity by inhibiting bad phosphorylation. |
| GO:0044877 protein-containing complex binding | IDA PMID:15498833 c-Src regulates clathrin adapter protein 2 interaction with ... | MODIFY | Summary: Protein-containing complex binding is vague; the complex bound is the AP-2 clathrin adaptor. Reason: Beta-arrestin-2 associates with the beta subunit of AP-2 (stabilized by c-Src) and forms an endogenous c-Src/beta-arrestin/AP-2 complex in rat VSMCs. AP-2 adaptor complex binding (GO:0035612) is the specific term. Proposed replacements: AP-2 adaptor complex binding Supporting Evidence: PMID:15498833 c-Src stabilizes the agonist-independent association between beta-arrestin2 and the beta-subunit of AP-2 independently of the kinase activity of c-Src. PMID:15498833 the agonist stimulation of native AT1R in vascular smooth muscle cells (VSMCs) induces the formation of an endogenous complex containing c-Src, beta-arrestins and AP-2. UniProtKB:P29067 R->A: Abolishes interaction with AP2B1. |
| GO:0045211 postsynaptic membrane | IDA PMID:1517224 Beta-arrestin2, a novel member of the arrestin/beta-arrestin... | KEEP AS NON CORE | Summary: Beta-arrestin-2 is situated at postsynaptic membranes in rat brain neurons. Reason: Immunoelectron microscopy; a valid neuronal location, peripheral to the core function. Supporting Evidence: PMID:1517224 immunoelectron microscopy shows that the beta-arrestins are appropriately situated at postsynaptic sites to act in concert with beta ARK to regulate G protein-coupled neurotransmitter receptors. |
| GO:0045211 postsynaptic membrane | IDA PMID:157224 Partial purification of a bone-resorbing factor elaborated f... | KEEP AS NON CORE | Summary: Same claim as the PMID:1517224 postsynaptic membrane row; the cited PMID:157224 is a mistyped reference. Reason: The location is supported by PMID:1517224. PMID:157224 is unrelated (1979 bone-resorbing factor paper); recorded as a source defect. Supporting Evidence: PMID:1517224 immunoelectron microscopy shows that the beta-arrestins are appropriately situated at postsynaptic sites to act in concert with beta ARK to regulate G protein-coupled neurotransmitter receptors. file:rat/Arrb2/Arrb2-deep-research-manual.md PMID:157224 (cited by RGD for GPCR signalling and postsynaptic membrane IDA) is a 1979 bone-resorbing-factor paper; almost certainly a typo of PMID:1517224. |
| GO:0045880 positive regulation of smoothened signaling pathway | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta-arrestin-2 with GRK2 mediates activity-dependent SMO internalization and ciliary localization, supporting Hedgehog signalling. Reason: Transferred from mouse; a receptor-trafficking role for a GPCR-like receptor, but peripheral to the core functions. Supporting Evidence: UniProtKB:P29067 Involved in both localization to primary cilium and endocytosis of smoothened (SMO) in a GRK2-dependent process. |
| GO:0045880 positive regulation of smoothened signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Beta-arrestin-2 with GRK2 mediates activity-dependent SMO internalization and ciliary localization, supporting Hedgehog signalling. Reason: Transferred from mouse; a receptor-trafficking role for a GPCR-like receptor, but peripheral to the core functions. Supporting Evidence: UniProtKB:P29067 Involved in both localization to primary cilium and endocytosis of smoothened (SMO) in a GRK2-dependent process. |
| GO:0045953 negative regulation of natural killer cell mediated cytotoxicity | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta-arrestin-2 recruits SHP-1/SHP-2 to KIR2DL1 to enhance inhibitory signalling in NK cells. Reason: Transferred from human; an adaptor role in an immune context, non-core. Supporting Evidence: UniProtKB:P29067 Involved in regulation of inhibitory signaling of natural killer cells by recruiting PTPN6 and PTPN11 to KIR2DL1. |
| GO:0050804 modulation of chemical synaptic transmission | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Beta-arrestin-2 modulates neurotransmitter GPCR signalling at synapses. Reason: Follows from desensitization and signalling of neurotransmitter receptors at postsynaptic sites; a tissue-level context of the core function. Supporting Evidence: PMID:1517224 immunoelectron microscopy shows that the beta-arrestins are appropriately situated at postsynaptic sites to act in concert with beta ARK to regulate G protein-coupled neurotransmitter receptors. |
| GO:0050804 modulation of chemical synaptic transmission | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta-arrestin-2 modulates neurotransmitter GPCR signalling at synapses. Reason: Follows from desensitization and signalling of neurotransmitter receptors at postsynaptic sites; a tissue-level context of the core function. Supporting Evidence: PMID:1517224 immunoelectron microscopy shows that the beta-arrestins are appropriately situated at postsynaptic sites to act in concert with beta ARK to regulate G protein-coupled neurotransmitter receptors. |
| GO:0050965 detection of temperature stimulus involved in sensory perception of pain | IMP PMID:21926413 Antinociceptive potentiation and attenuation of tolerance by... | MODIFY | Summary: The phenotype (siRNA enhances morphine antinociception) shows regulation of opioid receptor signalling, not participation in temperature detection. Reason: Intrathecal beta-arrestin-2 siRNA increased tail-flick morphine analgesia and reduced tolerance. Beta-arrestin-2 limits mu-opioid receptor signalling; negative regulation of opioid receptor signaling pathway (GO:2000475, already annotated) captures this better than detection of temperature stimulus involved in sensory perception of pain. Proposed replacements: negative regulation of opioid receptor signaling pathway Supporting Evidence: PMID:21926413 We show here that intrathecal Ξ²-arrestin 2 siRNA in rats enhances analgesia and attenuates naloxone-induced withdrawal symptoms. |
| GO:0051019 mitogen-activated protein kinase binding | IPI PMID:19200235 Dopamine promotes striatal neuronal apoptotic death via ERK ... | ACCEPT | Summary: Beta-arrestin-2 binds activated ERK1/2 as part of its MAPK scaffold function. Reason: Full text read: in dopamine-stimulated rat striatal neurons beta-arrestin-2 co-immunoprecipitates with p-ERK1/2 and the D1 receptor. Supporting Evidence: PMID:19200235 In pERK immunoprecipitated extracts, Ξ²-arrestin2 was detected in a dose-dependent manner UniProtKB:P29067 Acts as a signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2) and MAPK10 (JNK3). |
| GO:0051019 mitogen-activated protein kinase binding | IPI PMID:19200235 Dopamine promotes striatal neuronal apoptotic death via ERK ... | ACCEPT | Summary: Beta-arrestin-2 binds activated ERK1/2 as part of its MAPK scaffold function. Reason: Full text read: in dopamine-stimulated rat striatal neurons beta-arrestin-2 co-immunoprecipitates with p-ERK1/2 and the D1 receptor. Supporting Evidence: PMID:19200235 In pERK immunoprecipitated extracts, Ξ²-arrestin2 was detected in a dose-dependent manner UniProtKB:P29067 Acts as a signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2) and MAPK10 (JNK3). |
| GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | IMP PMID:19171933 {beta}-Arrestin-2 Mediates Anti-apoptotic Signaling through ... | KEEP AS NON CORE | Summary: Beta-arrestin-2 is needed for AT1R-stimulated PI3K/AKT activation in rat VSMCs. Reason: Full text read (PMID:19171933): SII-stimulated PI3K/AKT and ERK activation are abrogated by beta-arrestin-2 siRNA. The AKT scaffold is a secondary signalling role. Supporting Evidence: PMID:19171933 Receptor stimulation leads to concerted activation of two pathways, ERK/p90RSK and PI3K/AKT, which converge to phosphorylate and inactivate the pro-apoptotic protein BAD. PMID:19171933 are abrogated by beta-arrestin-2 small interfering RNA. UniProtKB:P29067 Acts as a signaling scaffold for the AKT1 pathway. |
| GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta-arrestin-2 is needed for AT1R-stimulated PI3K/AKT activation in rat VSMCs. Reason: Full text read (PMID:19171933): SII-stimulated PI3K/AKT and ERK activation are abrogated by beta-arrestin-2 siRNA. The AKT scaffold is a secondary signalling role. Supporting Evidence: PMID:19171933 Receptor stimulation leads to concerted activation of two pathways, ERK/p90RSK and PI3K/AKT, which converge to phosphorylate and inactivate the pro-apoptotic protein BAD. PMID:19171933 are abrogated by beta-arrestin-2 small interfering RNA. UniProtKB:P29067 Acts as a signaling scaffold for the AKT1 pathway. |
| GO:0051928 positive regulation of calcium ion transport | IMP PMID:21078978 {Beta}-blocker drugs mediate calcium signaling in native cen... | KEEP AS NON CORE | Summary: A beta-arrestin-2-dependent calcium signal is triggered by beta-blockers in rat hippocampal neurons. Reason: Full text read: the carvedilol-induced cytoplasmic calcium rise was reduced by beta-arrestin-2 knockdown. The pathway raises cytoplasmic calcium; peripheral outcome of arrestin-biased signalling. Supporting Evidence: PMID:21078978 The carvedilol-induced increase in local cytoplasmic calcium was significantly reduced by this knockdown |
| GO:0060090 molecular adaptor activity | ISO GO_REF:0000121 | MODIFY | Summary: Adaptor activity is correct but general; beta-arrestin-2 has two specific adaptor activities. Reason: Beta-arrestin-2 is a clathrin-cargo adaptor linking phosphorylated GPCRs to clathrin and AP-2 (GO:0035615) and a signalling adaptor/scaffold for ERK1/2, JNK3 and AKT (GO:0035591). Both are descendants of this term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: clathrin-cargo adaptor activity signaling adaptor activity Supporting Evidence: UniProtKB:P29067 The beta-arrestins target many receptors for internalization by acting as endocytic adapters (CLASPs, clathrin-associated sorting proteins) and recruiting the GPRCs to the adapter protein 2 complex 2 (AP-2) in clathrin-coated pits (CCPs). UniProtKB:P29067 LIEF->AAEA: Abolishes interaction with CLTC; reduces interaction with AP2B1. UniProtKB:P29067 Acts as a signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2) and MAPK10 (JNK3). |
| GO:0060252 positive regulation of glial cell proliferation | IMP PMID:19014370 Kappa opioids promote the proliferation of astrocytes via Gb... | KEEP AS NON CORE | Summary: Beta-arrestin-2 is required for kappa-opioid-stimulated astrocyte proliferation. Reason: Full text read: siRNA against beta-arrestin-2 diminished sustained ERK activation and abolished proliferation. A downstream outcome of the ERK scaffold. Supporting Evidence: PMID:19014370 Proliferative actions of both agonists were abolished by either inhibition of ERK1/2, Gbetagamma subunits or beta-arrestin 2 |
| GO:0060326 cell chemotaxis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta-arrestin-2 contributes to chemokine- and AT1R-mediated chemotaxis. Reason: Transferred from human; arrestin scaffolding supports directed migration, a peripheral role. Supporting Evidence: UniProtKB:P29067 Involved in AGTR1-mediated chemotaxis. |
| GO:0070098 chemokine-mediated signaling pathway | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta-arrestin-2 regulates chemokine receptor (CCR5, CXCR4, CCR7) signalling and internalization. Reason: Chemokine receptors are GPCRs; this is a receptor-specific instance of the core function. Supporting Evidence: UniProtKB:P29067 Involved in AGTR1-mediated chemotaxis. |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IBA GO_REF:0000033 | ACCEPT | Summary: Beta-arrestin-2 scaffolds and promotes ERK1/2 activation downstream of GPCRs. Reason: Multiple rat-cell studies show beta-arrestin-2 knockdown reduces GPCR-stimulated ERK1/2 activation (AT1R in VSMCs and kidney fibroblasts, kappa-opioid in astrocytes); the IBA node is seeded by human and rat beta-arrestin-2. This is the best-characterized arrestin-dependent signalling output. Supporting Evidence: PMID:19254952 Activation by both ligands is diminished by depletion of beta-arrestin2 by small interfering RNA, although the effect is more complete with SII. PMID:19014370 small interfering RNA silencing of beta-arrestin 2 diminished sustained ERK activation induced by U69593. PMID:28274926 Transfection of siRNA targeting Ξ²-arrestin-2 inhibited ERK phosphorylation. UniProtKB:P29067 Acts as a signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2) and MAPK10 (JNK3). |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IMP PMID:19014370 Kappa opioids promote the proliferation of astrocytes via Gb... | ACCEPT | Summary: Beta-arrestin-2 scaffolds and promotes ERK1/2 activation downstream of GPCRs. Reason: Multiple rat-cell studies show beta-arrestin-2 knockdown reduces GPCR-stimulated ERK1/2 activation (AT1R in VSMCs and kidney fibroblasts, kappa-opioid in astrocytes); the IBA node is seeded by human and rat beta-arrestin-2. This is the best-characterized arrestin-dependent signalling output. Supporting Evidence: PMID:19254952 Activation by both ligands is diminished by depletion of beta-arrestin2 by small interfering RNA, although the effect is more complete with SII. PMID:19014370 small interfering RNA silencing of beta-arrestin 2 diminished sustained ERK activation induced by U69593. PMID:28274926 Transfection of siRNA targeting Ξ²-arrestin-2 inhibited ERK phosphorylation. UniProtKB:P29067 Acts as a signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2) and MAPK10 (JNK3). |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IMP PMID:19171933 {beta}-Arrestin-2 Mediates Anti-apoptotic Signaling through ... | ACCEPT | Summary: Beta-arrestin-2 scaffolds and promotes ERK1/2 activation downstream of GPCRs. Reason: Multiple rat-cell studies show beta-arrestin-2 knockdown reduces GPCR-stimulated ERK1/2 activation (AT1R in VSMCs and kidney fibroblasts, kappa-opioid in astrocytes); the IBA node is seeded by human and rat beta-arrestin-2. This is the best-characterized arrestin-dependent signalling output. Supporting Evidence: PMID:19254952 Activation by both ligands is diminished by depletion of beta-arrestin2 by small interfering RNA, although the effect is more complete with SII. PMID:19014370 small interfering RNA silencing of beta-arrestin 2 diminished sustained ERK activation induced by U69593. PMID:28274926 Transfection of siRNA targeting Ξ²-arrestin-2 inhibited ERK phosphorylation. UniProtKB:P29067 Acts as a signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2) and MAPK10 (JNK3). |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IMP PMID:19254952 Independent beta-arrestin2 and Gq/protein kinase Czeta pathw... | ACCEPT | Summary: Beta-arrestin-2 scaffolds and promotes ERK1/2 activation downstream of GPCRs. Reason: Multiple rat-cell studies show beta-arrestin-2 knockdown reduces GPCR-stimulated ERK1/2 activation (AT1R in VSMCs and kidney fibroblasts, kappa-opioid in astrocytes); the IBA node is seeded by human and rat beta-arrestin-2. This is the best-characterized arrestin-dependent signalling output. Supporting Evidence: PMID:19254952 Activation by both ligands is diminished by depletion of beta-arrestin2 by small interfering RNA, although the effect is more complete with SII. PMID:19014370 small interfering RNA silencing of beta-arrestin 2 diminished sustained ERK activation induced by U69593. PMID:28274926 Transfection of siRNA targeting Ξ²-arrestin-2 inhibited ERK phosphorylation. UniProtKB:P29067 Acts as a signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2) and MAPK10 (JNK3). |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IMP PMID:28274926 Ξ²-Arrestin-biased AT1R stimulation promotes extracellular ma... | ACCEPT | Summary: Beta-arrestin-2 scaffolds and promotes ERK1/2 activation downstream of GPCRs. Reason: Multiple rat-cell studies show beta-arrestin-2 knockdown reduces GPCR-stimulated ERK1/2 activation (AT1R in VSMCs and kidney fibroblasts, kappa-opioid in astrocytes); the IBA node is seeded by human and rat beta-arrestin-2. This is the best-characterized arrestin-dependent signalling output. Supporting Evidence: PMID:19254952 Activation by both ligands is diminished by depletion of beta-arrestin2 by small interfering RNA, although the effect is more complete with SII. PMID:19014370 small interfering RNA silencing of beta-arrestin 2 diminished sustained ERK activation induced by U69593. PMID:28274926 Transfection of siRNA targeting Ξ²-arrestin-2 inhibited ERK phosphorylation. UniProtKB:P29067 Acts as a signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2) and MAPK10 (JNK3). |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | ISO GO_REF:0000121 | ACCEPT | Summary: Beta-arrestin-2 scaffolds and promotes ERK1/2 activation downstream of GPCRs. Reason: Multiple rat-cell studies show beta-arrestin-2 knockdown reduces GPCR-stimulated ERK1/2 activation (AT1R in VSMCs and kidney fibroblasts, kappa-opioid in astrocytes); the IBA node is seeded by human and rat beta-arrestin-2. This is the best-characterized arrestin-dependent signalling output. Supporting Evidence: PMID:19254952 Activation by both ligands is diminished by depletion of beta-arrestin2 by small interfering RNA, although the effect is more complete with SII. PMID:19014370 small interfering RNA silencing of beta-arrestin 2 diminished sustained ERK activation induced by U69593. PMID:28274926 Transfection of siRNA targeting Ξ²-arrestin-2 inhibited ERK phosphorylation. UniProtKB:P29067 Acts as a signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2) and MAPK10 (JNK3). |
| GO:0071889 14-3-3 protein binding | IDA PMID:19008961 Targeting of beta-arrestin2 to the centrosome and primary ci... | KEEP AS NON CORE | Summary: Beta-arrestin-2 binds 14-3-3 proteins at the centrosome/cilium. Reason: Full text read: GST-beta-arrestin-2 pulls down 14-3-3 and co-immunoprecipitates 14-3-3zeta; interaction appears constitutive. Peripheral. Supporting Evidence: PMID:19008961 betaarr2 was found to interact and colocalize with 14-3-3 proteins and Kif3A |
| GO:0090201 negative regulation of release of cytochrome c from mitochondria | IMP PMID:19171933 {beta}-Arrestin-2 Mediates Anti-apoptotic Signaling through ... | KEEP AS NON CORE | Summary: Beta-arrestin-2 knockdown increases H2O2-induced cytochrome c release in rat VSMCs stimulated through AT1R. Reason: Full text read: part of the beta-arrestin-2-dependent anti-apoptotic pathway via BAD inactivation; a downstream outcome. Supporting Evidence: PMID:19171933 we next examined effects of AngII stimulation on the hydrogen peroxide-induced redistribution of cytochrome c in control or Ξ²-arrestin-2 siRNA-transfected VSMCs. PMID:19171933 Receptor stimulation leads to concerted activation of two pathways, ERK/p90RSK and PI3K/AKT, which converge to phosphorylate and inactivate the pro-apoptotic protein BAD. |
| GO:0097499 protein localization to non-motile cilium | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta-arrestin-2 is needed to localize activated SMO to the primary cilium (mouse). Reason: Supported by mouse data and consistent with rat beta-arrestin-2 at the basal body and axoneme of primary cilia; peripheral. Supporting Evidence: UniProtKB:P29067 Involved in both localization to primary cilium and endocytosis of smoothened (SMO) in a GRK2-dependent process. PMID:19008961 In quiescent cells, both in vitro and in vivo, betaarr2 was found at the basal body and axoneme of primary cilia. |
| GO:0097499 protein localization to non-motile cilium | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Beta-arrestin-2 is needed to localize activated SMO to the primary cilium (mouse). Reason: Supported by mouse data and consistent with rat beta-arrestin-2 at the basal body and axoneme of primary cilia; peripheral. Supporting Evidence: UniProtKB:P29067 Involved in both localization to primary cilium and endocytosis of smoothened (SMO) in a GRK2-dependent process. PMID:19008961 In quiescent cells, both in vitro and in vivo, betaarr2 was found at the basal body and axoneme of primary cilia. |
| GO:0098926 postsynaptic signal transduction | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta-arrestin-2 participates in signalling from postsynaptic GPCRs (SynGO, from mouse). Reason: A synaptic context of its GPCR signalling function; non-core. Supporting Evidence: PMID:1517224 immunoelectron microscopy shows that the beta-arrestins are appropriately situated at postsynaptic sites to act in concert with beta ARK to regulate G protein-coupled neurotransmitter receptors. |
| GO:0098978 glutamatergic synapse | IDA PMID:1517224 Beta-arrestin2, a novel member of the arrestin/beta-arrestin... | KEEP AS NON CORE | Summary: Beta-arrestin-2 is present at glutamatergic synapses (SynGO). Reason: Postsynaptic localization by immunoelectron microscopy; a valid neuronal location, peripheral to the core function. Supporting Evidence: PMID:1517224 immunoelectron microscopy shows that the beta-arrestins are appropriately situated at postsynaptic sites to act in concert with beta ARK to regulate G protein-coupled neurotransmitter receptors. |
| GO:0098978 glutamatergic synapse | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta-arrestin-2 is present at glutamatergic synapses (SynGO). Reason: Postsynaptic localization by immunoelectron microscopy; a valid neuronal location, peripheral to the core function. Supporting Evidence: PMID:1517224 immunoelectron microscopy shows that the beta-arrestins are appropriately situated at postsynaptic sites to act in concert with beta ARK to regulate G protein-coupled neurotransmitter receptors. |
| GO:1902533 positive regulation of intracellular signal transduction | IEA GO_REF:0000117 | MODIFY | Summary: Positive regulation of intracellular signal transduction is correct but general. Reason: The best-supported positive signalling output is positive regulation of ERK1 and ERK2 cascade (GO:0070374), a descendant already accepted for this gene. Proposed replacements: positive regulation of ERK1 and ERK2 cascade Supporting Evidence: UniProtKB:P29067 Acts as a signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2) and MAPK10 (JNK3). |
| GO:1904037 positive regulation of epithelial cell apoptotic process | IMP PMID:24719556 Reactive oxygen species are involved in regulating hypocontr... | UNDECIDED | Summary: The cited full text contains no data on epithelial cell apoptosis. Reason: PMID:24719556 studies mesenteric artery hypocontractility in cirrhotic rats (ROS, alpha1-AR/beta-arrestin-2 binding, ROCK). The full text was read and has no epithelial apoptosis experiments; apoptosis is mentioned only in the discussion of other work. The annotation cannot be verified from this reference. Supporting Evidence: PMID:24719556 The H2O2 decrease in mesenteric artery from rats with cirrhosis resulted in down regulation of the Ξ²-arrestin-2 expression and its binding ability with Ξ±1 adrenergic receptor file:rat/Arrb2/Arrb2-deep-research-manual.md the full text has no epithelial apoptosis data. |
| GO:1990763 arrestin family protein binding | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Beta-arrestin-2 heterodimerizes with the alpha-arrestin ARRDC1. Reason: ARRDC1-beta-arrestin heterodimers bridge ITCH to Notch for its degradation; a secondary adaptor role. Supporting Evidence: PMID:23886940 Our data show for the first time that ARRDC1 and Ξ²-arrestins heterodimerize and cooperate in the same complex to promote non-activated Notch receptor degradation UniProtKB:P29067 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: Beta-arrestin-2 heterodimerizes with the alpha-arrestin ARRDC1. Reason: ARRDC1-beta-arrestin heterodimers bridge ITCH to Notch for its degradation; a secondary adaptor role. Supporting Evidence: PMID:23886940 Our data show for the first time that ARRDC1 and Ξ²-arrestins heterodimerize and cooperate in the same complex to promote non-activated Notch receptor degradation UniProtKB:P29067 Interacts with ARRDC1; the interaction is direct (PubMed:23886940). |
| GO:2000475 negative regulation of opioid receptor signaling pathway | IDA PMID:34919270 Disrupted circadian expression of Ξ²-arrestin 2 affects rewar... | KEEP AS NON CORE | Summary: Beta-arrestin-2 limits mu-opioid receptor signalling. Reason: The cited abstract shows inverse daily patterns of Arrb2 expression and MOR binding/coupling, which is weak direct evidence, but limiting MOR signalling through desensitization is well established (e.g. siRNA enhancing morphine analgesia in PMID:21926413). A receptor-specific instance of desensitization. Supporting Evidence: PMID:34919270 we report daily rhythmicity for bArr2 expression linked to an inverse pattern of MOR PMID:21926413 We show here that intrathecal Ξ²-arrestin 2 siRNA in rats enhances analgesia and attenuates naloxone-induced withdrawal symptoms. |
| GO:2000476 positive regulation of opioid receptor signaling pathway | IMP PMID:19014370 Kappa opioids promote the proliferation of astrocytes via Gb... | KEEP AS NON CORE | Summary: Beta-arrestin-2 is required for sustained kappa-opioid receptor ERK signalling in astrocytes. Reason: An arrestin-dependent signalling output of a specific receptor; consistent with its dual role in opioid receptor signalling. Supporting Evidence: PMID:19014370 small interfering RNA silencing of beta-arrestin 2 diminished sustained ERK activation induced by U69593. |
| GO:2000573 positive regulation of DNA biosynthetic process | IMP PMID:19254952 Independent beta-arrestin2 and Gq/protein kinase Czeta pathw... | KEEP AS NON CORE | Summary: AT1R-stimulated DNA synthesis in rat VSMCs proceeds via an ERK cascade that depends partly on beta-arrestin-2. Reason: Full text read: angiotensin and SII induce DNA synthesis via ERK, and beta-arrestin-2 depletion reduces ERK activation. A downstream proliferative outcome. Supporting Evidence: PMID:19254952 Both ANG and SII induced DNA synthesis via the ERK activation cascade. PMID:19254952 Activation by both ligands is diminished by depletion of beta-arrestin2 by small interfering RNA, although the effect is more complete with SII. |
| GO:2000727 positive regulation of cardiac muscle cell differentiation | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Cardiac muscle cell differentiation is a distant developmental outcome transferred from mouse. Reason: No rat evidence; the link from GPCR scaffolding to cardiomyocyte differentiation is indirect, so this is better treated as an over-annotation. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Supporting Evidence: UniProtKB:P29067 Belongs to the arrestin family. |
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Download this section (compressed HTML)Q: Which reference did RGD intend for the GO:0019904 protein domain specific binding row with the D2 dopamine receptor (cited as PMID:12890920, a dystrophin paper)?
Q: What evidence underlies the GO:1904037 positive regulation of epithelial cell apoptotic process IMP row citing PMID:24719556, which contains no epithelial apoptosis data?
Q: The rat beta-arrestin-2 hinge carries an ERK regulatory motif (PET178P) absent from human beta-arrestin-2 (PMID:25016018). How much do rodent findings on endosomal receptor/arrestin-2 complex stability transfer to human?
Experiment: Compare endosomal GPCR/beta-arrestin-2 complex lifetime and sustained ERK signalling in rat cells expressing wild-type, T178A and T178D beta-arrestin-2 with endogenous protein knocked out.
Hypothesis: ERK phosphorylation at the rodent-specific T178 site controls the stability of endosomal receptor-arrestin complexes and the duration of arrestin-dependent signalling.
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