ArticleProceedings of the National Academy of Sciences of the United States of America2023
Signal transduction at GPCRs: Allosteric activation of the ERK MAPK by β-arrestin.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 54 citations in OpenAlex.
- Actin cytoskeletal dynamics in hepatic myofibroblasts and fibrosis.Nature reviews. Gastroenterology & hepatology · 2026Review
- Novel fenoterol derivatives as suppressors of ERK1/2 phosphorylation in melanoma.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Arrestins as programmable integrators of GPCR signaling: structural microstates, spatiotemporal logic, and therapeutic control.Cell discovery · 2026Review
- Small-molecule modulation of β-arrestins.Nature · 2026Article
- The Endoterpenoid System: A Membrane-Based Logic Framework for Integrating Cannabinoid, Olfactory, and Lipid-Sensitive Receptor Crosstalk.Journal of neuroscience research · 2026Review
- Erk inhibitors intercept Erk-mediated negative feedback while imposing cell-cycle arrest and activating p38.iScience · 2026Article
- Targeting tumor-associated G-protein coupled receptors: beyond single-axis inhibition toward multidimensional regulation.Cellular oncology (Dordrecht, Netherlands) · 2026Review
- Biased signaling at NTSR1 differentially regulates inhibitory synaptic transmission in the extended amygdala and suppresses motivated feeding in mice.bioRxiv : the preprint server for biology · 2026Article
- Location-biased β-arrestin conformations direct GPCR signaling.Science signaling · 2026Article
- The Mechanism of G Protein-Coupled Receptor Regulation of Ferroptosis in Hepatic Ischemia-Reperfusion Injury.International journal of molecular sciences · 2026Review
- Phosphoregulation of the novel hemi-arrestin MAPK scaffold Sms1 prevents untimely mating.Nature communications · 2026Article
- GPR39-mediated molecular signaling by bile acids.The Journal of biological chemistry · 2026Article
- Mechanism of beta-arrestin 1 mediated Src activation via Src SH3 domain revealed by cryo-electron microscopy.Nature communications · 2026Article
- IGF-1 protects against acute pancreatitis by suppressing NF-κB activation through the β-arrestin1/STAT3 pathway.Molecular and cellular biochemistry · 2026Article
- MAPK signaling pathways in host immune regulation during Mycobacterium tuberculosis infection.Frontiers in immunology · 2026Review
- Biased Allosteric Modulation in GPCR Drug Discovery.Handbook of experimental pharmacology · 2026Review
- Decoding GPCR signaling in living cells to advance early therapeutic discovery for neurological disorders.Frontiers in molecular neuroscience · 2026Review
- The role and mechanism of ARRB1 in simulated space radiation and microgravity-induced lung carcinogenesis.NPJ microgravity · 2025Article
- GPR107: A key driver of breast cancer invasion and metastasis through collagen IV modulation.Cancer gene therapy · 2025Article
- Article
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 1 country.
Funding
Abstract
β-arrestins are multivalent adaptor proteins that bind active phosphorylated G protein-coupled receptors (GPCRs) to inhibit G protein signaling, mediate receptor internalization, and initiate alternative signaling events. β-arrestins link agonist-stimulated GPCRs to downstream signaling partners, such as the c-Raf-MEK1-ERK1/2 cascade leading to ERK1/2 activation. β-arrestins have been thought to transduce signals solely via passive scaffolding by facilitating the assembly of multiprotein signaling complexes. Recently, however, β-arrestin 1 and 2 were shown to activate two downstream signaling effectors, c-Src and c-Raf, allosterically. Over the last two decades, ERK1/2 have been the most intensely studied signaling proteins scaffolded by β-arrestins. Here, we demonstrate that β-arrestins play an active role in allosterically modulating ERK kinase activity in vitro and within intact cells. Specifically, we show that β-arrestins and their GPCR-mediated active states allosterically enhance ERK2 autophosphorylation and phosphorylation of a downstream ERK2 substrate, and we elucidate the mechanism by which β-arrestins do so. Furthermore, we find that allosteric stimulation of dually phosphorylated ERK2 by active-state β-arrestin 2 is more robust than by active-state β-arrestin 1, highlighting differential capacities of β-arrestin isoforms to regulate effector signaling pathways downstream of GPCRs. In summary, our study provides strong evidence for a new paradigm in which β-arrestins function as active "catalytic" scaffolds to allosterically unlock the enzymatic activity of signaling components downstream of GPCR activation.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.