ArticleProceedings of the National Academy of Sciences of the United States of America2015
Receptor sequestration in response to β-arrestin-2 phosphorylation by ERK1/2 governs steady-state levels of GPCR cell-surface expression.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 48 citations in OpenAlex.
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- Rules of engagement: Determinants of chemokine receptor activation and selectivity by CCL27 and CCL28.The Journal of biological chemistry · 2025Article
- Traffic control: Mechanisms of ligand-specific internalization and intracellular distribution of CCR5.Molecular pharmacology · 2025Article
- Myeloid beta-arrestin 2 depletion attenuates metabolic dysfunction-associated steatohepatitis via the metabolic reprogramming of macrophages.Cell metabolism · 2024Article
- Computationally designed GPCR quaternary structures bias signaling pathway activation.Nature communications · 2022Article
- The α-Arrestin ARRDC3 Is an Emerging Multifunctional Adaptor Protein in Cancer.Antioxidants & redox signaling · 2022Review
- Delineating the interactions between the cannabinoid CBBritish journal of pharmacology · 2022Article
- Biochemical and physiological insights into TRH receptor-mediated signaling.Frontiers in cell and developmental biology · 2022Review
- The Role of Kisspeptin in the Control of the Hypothalamic-Pituitary-Gonadal Axis and Reproduction.Frontiers in endocrinology · 2022Review
- Bivalent ligands promote endosomal trafficking of the dopamine D3 receptor-neurotensin receptor 1 heterodimer.Communications biology · 2021Article
- Discovery of a dual Ras and ARF6 inhibitor from a GPCR endocytosis screen.Nature communications · 2021Article
- The RanBP2/RanGAP1-SUMO complex gates β-arrestin2 nuclear entry to regulate the Mdm2-p53 signaling axis.Oncogene · 2021Article
- Beta-Arrestins and Receptor Signaling in the Vascular Endothelium.Biomolecules · 2020Review
- Beta-arrestins operate an on/off control switch for focal adhesion kinase activity.Cellular and molecular life sciences : CMLS · 2020Article
- Modulation of polycystic kidney disease by G-protein coupled receptors and cyclic AMP signaling.Cellular signalling · 2020Review
- Novel peptide nanoparticle-biased antagonist of CCR3 blocks eosinophil recruitment and airway hyperresponsiveness.The Journal of allergy and clinical immunology · 2019Article
- Asymmetric Recruitment of β-Arrestin1/2 by the Angiotensin II Type I and Prostaglandin F2α Receptor Dimer.Frontiers in endocrinology · 2019Article
- Translating biased signaling in the ghrelin receptor system into differential in vivo functions.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Heterologous phosphorylation-induced formation of a stability lock permits regulation of inactive receptors by β-arrestins.The Journal of biological chemistry · 2018Article
- Differential phosphorylation signals control endocytosis of GPR15.Molecular biology of the cell · 2017Article
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
Abstract
MAPKs are activated in response to G protein-coupled receptor (GPCR) stimulation and play essential roles in regulating cellular processes downstream of these receptors. However, very little is known about the reciprocal effect of MAPK activation on GPCRs. To investigate possible crosstalk between the MAPK and GPCRs, we assessed the effect of ERK1/2 on the activity of several GPCR family members. We found that ERK1/2 activation leads to a reduction in the steady-state cell-surface expression of many GPCRs because of their intracellular sequestration. This subcellular redistribution resulted in a global dampening of cell responsiveness, as illustrated by reduced ligand-mediated G-protein activation and second-messenger generation as well as blunted GPCR kinases and β-arrestin recruitment. This ERK1/2-mediated regulatory process was observed for GPCRs that can interact with β-arrestins, such as type-2 vasopressin, type-1 angiotensin, and CXC type-4 chemokine receptors, but not for the prostaglandin F receptor that cannot interact with β-arrestin, implicating this scaffolding protein in the receptor's subcellular redistribution. Complementation experiments in mouse embryonic fibroblasts lacking β-arrestins combined with in vitro kinase assays revealed that β-arrestin-2 phosphorylation on Ser14 and Thr276 is essential for the ERK1/2-promoted GPCR sequestration. This previously unidentified regulatory mechanism was observed after constitutive activation as well as after receptor tyrosine kinase- or GPCR-mediated activation of ERK1/2, suggesting that it is a central node in the tonic regulation of cell responsiveness to GPCR stimulation, acting both as an effector and a negative regulator.
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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.