Inhibition of ERK1/2 Restores GSK3β Activity and Protein Synthesis Levels in a Model of Tuberous Sclerosis

被引：16

作者：

Pal, Rituraj ^{[1
,2
]}

Bondar, Vitaliy V. ^{[2
]}

Adamski, Carolyn J. ^{[2
]}

Rodney, George G. ^{[1
,4
,5
]}

Sardiello, Marco ^{[2
,3
]}

机构：

[1] Baylor Coll Med, Dept Mol Physiol & Biophys, 1 Baylor Plaza, Houston, TX 77030 USA

[2] Baylor Coll Med, Dept Mol & Human Genet, One Baylor Plaza, Houston, TX 77030 USA

[3] Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Houston, TX 77030 USA

[4] Baylor Coll Med, Cardiovasc Res Inst, One Baylor Plaza, Houston, TX 77030 USA

[5] Baylor Coll Med, Ctr Space Med, Biosci Res Collaborat, Houston, TX 77030 USA

来源：

SCIENTIFIC REPORTS | 2017年 / 7卷

基金：

美国国家卫生研究院;

关键词：

PHOSPHORYLATION; MTORC1; INACTIVATION; INITIATION; GSK3; DEGRADATION; INTEGRATION; AUTOPHAGY; INSULIN; TARGET;

D O I：

10.1038/s41598-017-04528-5

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 3 beta (GSK3 beta) 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 GSK3 beta, resulting in increased protein synthesis that is independent of Akt/mTORC1 activity. Inhibition of ERK1/2 in Tsc2(-/-) cells-a model of TS-rescues GSK3 beta activity and protein synthesis levels, thus highlighting ERK1/2 as a potential therapeutic target for the treatment of TS.

引用

页数：10

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