Signal transduction at GPCRs: Allosteric activation of the ERK MAPK by β-arrestin
Recommended Citation
Kahsai AW, Shah KS, Shim PJ, Lee MA, Shreiber BN, Schwalb AM, Zhang X, Kwon HY, Huang LY, Soderblom EJ, Ahn S, and Lefkowitz RJ. Signal transduction at GPCRs: Allosteric activation of the ERK MAPK by β-arrestin. Proc Natl Acad Sci U S A 2023; 120(43):e2303794120.
Document Type
Article
Publication Date
10-24-2023
Publication Title
Proceedings of the National Academy of Sciences of the United States of America
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.
Medical Subject Headings
beta-Arrestins; beta-Arrestin 1; Arrestins; Allosteric Regulation; Signal Transduction; Receptors, G-Protein-Coupled; Phosphorylation; beta-Arrestin 2
PubMed ID
37844230
Volume
120
Issue
43
First Page
2303794120
Last Page
2303794120
