G protein‐dependent signaling triggers a β‐arrestin‐scaffolded p70S6K/ rpS6 module that controls 5'TOP mRNA translation

Abstract

Many interaction partners of b-arrestins intervene in the control of mRNA translation. However, how b-arrestins regulate this cellular process has been poorly explored. In this study, we show that b-arrestins constitutively assemble a p70S6K/ribosomal protein S6 (rpS6) complex in HEK293 cells and in primary Sertoli cells of the testis. We demonstrate that this interaction is direct, and experimentally validate the interaction interface between b-arrestin 1 and p70S6K predicted by our docking algorithm. Like most GPCRs, the biological function of folliclestimulating hormone receptor (FSHR) is transduced by G proteins and b-arrestins. Upon follicle-stimulating hormone (FSH) stimulation, activation of G protein-dependent signaling enhances p70S6K activity within the b-arrestin/p70S6K/rpS6 preassembled complex, which is not recruited to the FSHR. In agreement, FSH-induced rpS6 phosphorylation within the b-arrestin scaffold was decreased in cells depleted of Ga s . Integration of the cooperative action of b-arrestin and G proteins led to the translation of 59 oligopyrimidine track mRNA with high efficacy within minutes of FSH input. Hence, this work highlights new relationships between G proteins and b-arrestins when acting cooperatively on a common signaling pathway, contrasting with their previously shown parallel action on the ERK MAP kinase pathway. In addition, this study provides insights into how GPCR can exert trophic effects in the

FSH for the Treatment of Male Infertility

“…So far, however, upon FSHR stimulation, only the extracellular-regulated (ERK) mitogen-activated protein (MAP) kinase-and ribosomal protein S6 kinase beta-1 (p70S6K)-dependent signaling has been demonstrated to be partly mediated by β-arrestins. Of note, when comparing the mode of activation of both of these pathways in HEK293 cells, ERKs are activated sequentially through Gαs and β-arrestins [16], whereas the p70S6K pathway is activated concomitantly by these two transducing mechanisms [27]. This observation emphasizes the role of GPCR transducers to coordinate the dynamics of the downstream signaling network and has potential implications regarding the action of FSHR biased ligands described in the next sub-sections of this review.…”

“…As for the p70S6K pathway, the role of β-arrestins in its activation in seminiferous tubules or in follicles has not been clarified yet, although in Sertoli cells, β-arrestin 1 and p70S6K can be identified in common protein complexes [27]. p70S6K activation relies on protein kinase B (Akt) [28,32], and activation of this pathway is presumably responsible for enhancing mRNA translation measured in response to FSH [33,34], as a hallmark of FSH anabolic function and trophic role.…”

Follicle-Stimulating Hormone (FSH) Action on Spermatogenesis: A Focus on Physiological and Therapeutic Roles

“…Their action is important because they sequentially dictate the kinetics of ERK activation profile, which is more sustained than the transient Gs-mediated ERK activation [65]. In contrast, β-arrestins and Gα s act cooperatively to stimulate the ribosomal protein S6 kinase beta-1 (p70S6K) in response to FSH in a complex including one of the enzyme substrates (ribosomal protein S6) [68]. Although p70S6K and β-arrestin 1 are identified in common protein complexes in Sertoli cells, to date, the role that β-arrestins could play as regulators of the kinetics and spatial organization of FSH-dependent signalling network has not been conclusively proven in these cells.…”

Prostaglandin EP2 receptor: Novel therapeutic target for human cancers (Review)

“…The signals initiated by the EP2 receptors can be transduced by the same G s α stimulating protein and the concentration of cAMP in cells is increased by activation of EP2 (63). cluster of differentiation (cd)4 + Th cells are a key effector in the adaptive immune system to control cancer (64) and the increase in cAMP is associated with a decrease in Th1 cells and IFN-γ (65).…”