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World J Biol Chem. Dec 12, 2018; 9(3): 25-35
Published online Dec 12, 2018. doi: 10.4331/wjbc.v9.i3.25
Arrestin-mediated signaling: Is there a controversy?
Vsevolod V Gurevich, Eugenia V Gurevich
Vsevolod V Gurevich, Eugenia V Gurevich, Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, United States
Author contributions: Gurevich VV and Gurevich EV wrote the manuscript.
Supported by National Institutes of Health RO1 grants, No. EY011500; National Institutes of Health R35 grants, No. GM122491; and Cornelius Vanderbilt Endowed Chair (Vanderbilt University), No. NS065868 (to Gurevich VV) and No. DA030103 (to Gurevich EV).
Conflict-of-interest statement: The authors declare no conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author to: Vsevolod V Gurevich, PhD, Professor, Department of Pharmacology, Vanderbilt University, 2200 Pierce Ave, PRB Rm 417D, Nashville, TN 37232, United States. vsevolod.gurevich@vanderbilt.edu
Telephone: +1-615-3227070 Fax: +1-615-3436532
Received: August 28, 2018
Peer-review started: August 28, 2018
First decision: September 11, 2018
Revised: October 20, 2018
Accepted: November 3, 2018
Article in press: November 3,2018
Published online: December 12, 2018
Processing time: 106 Days and 17.1 Hours
Abstract

The activation of the mitogen-activated protein (MAP) kinases extracellular signal-regulated kinase (ERK)1/2 was traditionally used as a readout of signaling of G protein-coupled receptors (GPCRs) via arrestins, as opposed to conventional GPCR signaling via G proteins. Several recent studies using HEK293 cells where all G proteins were genetically ablated or inactivated, or both non-visual arrestins were knocked out, demonstrated that ERK1/2 phosphorylation requires G protein activity, but does not necessarily require the presence of non-visual arrestins. This appears to contradict the prevailing paradigm. Here we discuss these results along with the recent data on gene edited cells and arrestin-mediated signaling. We suggest that there is no real controversy. G proteins might be involved in the activation of the upstream-most MAP3Ks, although in vivo most MAP3K activation is independent of heterotrimeric G proteins, being initiated by receptor tyrosine kinases and/or integrins. As far as MAP kinases are concerned, the best-established role of arrestins is scaffolding of the three-tiered cascades (MAP3K-MAP2K-MAPK). Thus, it seems likely that arrestins, GPCR-bound and free, facilitate the propagation of signals in these cascades, whereas signal initiation via MAP3K activation may be independent of arrestins. Different MAP3Ks are activated by various inputs, some of which are mediated by G proteins, particularly in cell culture, where we artificially prevent signaling by receptor tyrosine kinases and integrins, thereby favoring GPCR-induced signaling. Thus, there is no reason to change the paradigm: Arrestins and G proteins play distinct non-overlapping roles in cell signaling.

Keywords: G protein-coupled receptors; Arrestin; G protein; Signaling; Extracellular signal-regulated kinase 1/2; c-Jun N-terminal kinase 3

Core tip: Both arrestins and G proteins play important roles in G protein-coupled receptor (GPCR) signaling, including GPCR-initiated activation of mitogen-activated protein (MAP) kinases extracellular signal-regulated kinase (ERK)1/2 and c-Jun N-terminal kinase 3 (JNK3). Their roles do not overlap. G proteins participate in signal initiation, by activating MAP3Ks. Arrestins, free and GPCR-bound, function as scaffolds of the three-tiered MAP kinase cascades, facilitating signal transduction. Cells express other scaffolds, so that no MAPK cascade relies solely on arrestins. Different experimental paradigms highlight the role of G proteins or arrestins in this process, and neither can be discounted based on available evidence.