Ribosomal Protein S6 Phosphorylation in the Nervous System: From Regulation to Function.

Anne Biever,Emmanuel Valjent,Emma Puighermanal

doi:10.3389/fnmol.2015.00075

Abstract

Since the discovery of the phosphorylation of the 40S ribosomal protein S6 (rpS6) about four decades ago, much effort has been made to uncover the molecular mechanisms underlying the regulation of this post-translational modification. In the field of neuroscience, rpS6 phosphorylation is commonly used as a readout of the mammalian target of rapamycin complex 1 signaling activation or as a marker for neuronal activity. Nevertheless, its biological role in neurons still remains puzzling. Here we review the pharmacological and physiological stimuli regulating this modification in the nervous system as well as the pathways that transduce these signals into rpS6 phosphorylation. Altered rpS6 phosphorylation observed in various genetic and pathophysiological mouse models is also discussed. Finally, we examine the current state of knowledge on the physiological role of this post-translational modification and highlight the questions that remain to be addressed.

Highlights

The eukaryotic ribosome is composed of the small 40S and the large 60S subunits, comprising together 4 ribosomal RNA species and 79 ribosomal proteins (Kressler et al, 2010)
Despite the large debate regarding its physiological role, ribosomal protein S6 (rpS6) phosphorylation is commonly used as a marker for neuronal activity and a readout of mammalian target of rapamycin complex 1 activity (Meyuhas, 2008, 2015; Mahoney et al, 2009; Knight et al, 2012)
Since the molecular mechanisms regulating rpS6 phosphorylation have been recently extensively reviewed (Meyuhas, 2015), we focus on the contribution of S6 kinase 1 (S6K1)/2 kinases and the Protein Kinase A (PKA)/PP-1 pathway, being the main upstream mechanisms described to regulate rpS6 phosphorylation in the nervous system

Summary

Introduction

The eukaryotic ribosome is composed of the small 40S and the large 60S subunits, comprising together 4 ribosomal RNA species and 79 ribosomal proteins (Kressler et al, 2010). The blockade of canonical mTORC1/S6K signaling by the mTORC1 inhibitor rapamycin suppresses both basal and stimuli-induced rpS6 phosphorylation in various brain areas (Kelleher et al, 2004; Takei et al, 2004; Cota et al, 2006; Antion et al, 2008a; Gobert et al, 2008; Géranton et al, 2009; Santini et al, 2009; Zeng et al, 2009; Huang et al, 2010; Cao et al, 2011; Troca-Marín et al, 2011; Wu et al, 2011; Bailey et al, 2012; Bertran-Gonzalez et al, 2012; Meffre et al, 2012; Brewster et al, 2013; Macias et al, 2013; Bowling et al, 2014; Biever et al, 2015).

Results

Conclusion