ArticleBiochemistry2011
A single mutation in arrestin-2 prevents ERK1/2 activation by reducing c-Raf1 binding.
Article in Biochemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed, 82 citations in OpenAlex.
- Atomic, structural and molecular insights into GPCR ligand binding and signalling.Nature reviews. Molecular cell biology · 2026Review
- Arrestins as programmable integrators of GPCR signaling: structural microstates, spatiotemporal logic, and therapeutic control.Cell discovery · 2026Review
- GPCR Phospho-Barcodes and Biased Signaling.Handbook of experimental pharmacology · 2026Review
- GPCR systems coordinate cellular resilience against aging-associated stress.Frontiers in molecular biosciences · 2026Review
- Arrestins as Possible Drug Targets.Biomolecules & therapeutics · 2025Review
- GPCR-dependent and -independent arrestin signaling.Trends in pharmacological sciences · 2024Review
- Arrestins: A Small Family of Multi-Functional Proteins.International journal of molecular sciences · 2024Review
- Molecular insights into atypical modes of β-arrestin interaction with seven transmembrane receptors.Science (New York, N.Y.) · 2024Article
- In-Cell Arrestin-Receptor Interaction Assays.Current protocols · 2023Article
- Review
- Article
- GPCR binding and JNK3 activation by arrestin-3 have different structural requirements.bioRxiv : the preprint server for biology · 2023Article
- Short Arrestin-3-Derived Peptides Activate JNK3 in Cells.International journal of molecular sciences · 2022Article
- The Two Non-Visual Arrestins Engage ERK2 Differently.Journal of molecular biology · 2022Article
- Structural evidence for visual arrestin priming via complexation of phosphoinositols.Structure (London, England : 1993) · 2022Article
- Scaffolding of Mitogen-Activated Protein Kinase Signaling by β-Arrestins.International journal of molecular sciences · 2022Review
- GPCRs Are Optimal Regulators of Complex Biological Systems and Orchestrate the Interface between Health and Disease.International journal of molecular sciences · 2021Review
- Structural Basis of Arrestin Selectivity for Active Phosphorylated G Protein-Coupled Receptors.International journal of molecular sciences · 2021Review
- Scaffolding mechanism of arrestin-2 in the cRaf/MEK1/ERK signaling cascade.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Structural studies of phosphorylation-dependent interactions between the V2R receptor and arrestin-2.Nature communications · 2021Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Arrestins regulate the signaling and trafficking of G protein-coupled receptors (GPCRs). GPCR complexes with both nonvisual arrestins channel signaling to G protein-independent pathways, one of which is the activation of extracellular signal regulated kinase 1/2 (ERK1/2). Here we used alanine-scanning mutagenesis of residues on the nonreceptor-binding surface conserved between arrestin-2 and arrestin-3. We show that an Arg307Ala mutation significantly reduced arrestin-2 binding to c-Raf1, whereas the binding of the mutant to active phosphorylated receptor and downstream kinases MEK1 and ERK2 was not affected. In contrast to wild-type arrestin-2, the Arg307Ala mutant failed to rescue arrestin-dependent ERK1/2 activation via β2-adrenergic receptor in arrestin-2/3 double knockout mouse embryonic fibroblasts. Thus, Arg307 plays a specific role in arrestin-2 binding to c-Raf1 and is indispensable in the productive scaffolding of c-Raf1-MEK1-ERK1/2 signaling cascade. Arg307Ala mutation specifically eliminates arrestin-2 signaling through ERK, which makes arrestin-2-Arg307Ala the first signaling-biased arrestin mutant constructed. In the crystal structure the side chain of homologous arrestin-3 residue Lys308 points in a different direction. Alanine substitution of Lys308 does not significantly affect c-Raf1 binding to arrestin-3 and its ability to promote ERK1/2 activation, suggesting that the two nonvisual arrestins perform the same function via distinct molecular mechanisms.
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Registered trials
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.