Inhibition of ERK1/2 Restores GSK3\u03b2 Activity and Protein Synthesis Levels in a Model of Tuberous Sclerosis

Rituraj Pal,Carolyn J Adamski,George G Rodney,Vitaliy V Bondar,Marco Sardiello

doi:10.1038/s41598-017-04528-5

Abstract

Tuberous sclerosis (TS) is a multi-organ autosomal dominant disorder that is best characterized by neurodevelopmental deficits and the presence of benign tumors. TS pathology is caused by mutations in tuberous sclerosis complex (TSC) genes and is associated with insulin resistance, decreased glycogen synthase kinase 3β (GSK3β) activity, activation of the mammalian target of rapamycin complex 1 (mTORC1), and subsequent increase in protein synthesis. Here, we show that extracellular signal–regulated kinases (ERK1/2) respond to insulin stimulation and integrate insulin signaling to phosphorylate and thus inactivate GSK3β, resulting in increased protein synthesis that is independent of Akt/mTORC1 activity. Inhibition of ERK1/2 in Tsc2−/− cells—a model of TS—rescues GSK3β activity and protein synthesis levels, thus highlighting ERK1/2 as a potential therapeutic target for the treatment of TS.

Highlights

Glycogen synthase kinase 3 (GSK3) is implicated in multiple biological processes including regulation of protein synthesis, cell proliferation and survival[12,13,14] and is found to be phosphorylated and inactivated in multiple cancer types[15, 16]
A previous study reported that ERK phosphorylates TSC2, but at an amino acid residue that is different from the Akt target sites[25]
Consistent with previous studies, we observed that TSC2 was predominantly localized at lysosomes in serum-starved cells[2, 10], which was significantly reduced upon insulin stimulation

Summary

Introduction

Glycogen synthase kinase 3 (GSK3) is implicated in multiple biological processes including regulation of protein synthesis, cell proliferation and survival[12,13,14] and is found to be phosphorylated and inactivated in multiple cancer types[15, 16]. Previous studies have shown that ERK1/2 integrates IGF1 signal to phosphorylate and inactivate GSKβ in an Akt-independent manner[26, 27]. Together, these findings suggest that ERK1/2 could possibly play a significant role in insulin regulation of GSKβ activity and protein synthesis in TS. We show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2−/− MEFs to normal levels. Together, these findings highlight ERK1/2 as a potential therapeutic target for the treatment of tuberous sclerosis

Methods

Results

Conclusion