Pharmacological and Genetic Evaluation of Proposed Roles of Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase Kinase (MEK), Extracellular Signal-regulated Kinase (ERK), and p90RSK in the Control of mTORC1 Protein Signaling by Phorbol Esters

被引:40
作者
Fonseca, Bruno D. [1 ,2 ,3 ,5 ]
Alain, Tommy [5 ]
Finestone, Leona K. [5 ]
Huang, Brandon P. H. [2 ,3 ]
Rolfe, Mark [1 ]
Jiang, Tian [2 ,3 ]
Yao, Zhong [2 ,3 ]
Hernandez, Greco [5 ]
Bennett, Christopher F. [5 ]
Proud, Christopher G. [1 ,2 ,3 ,4 ]
机构
[1] Univ Dundee, Coll Life Sci, Div Mol Physiol, Dundee DD1 5EH, Scotland
[2] Univ British Columbia, Inst Life Sci, Dept Biochem & Mol Biol, Vancouver, BC V6T 1Z3, Canada
[3] Univ British Columbia, Inst Life Sci, Diabet Res Grp, Vancouver, BC V6T 1Z3, Canada
[4] Univ Southampton, Sch Biol Sci, Southampton SO16 7PX, Hants, England
[5] McGill Univ, Dept Biochem, Rosalind & Morris Goodman Canc Ctr, Montreal, PQ H3A 1A3, Canada
基金
加拿大健康研究院;
关键词
RIBOSOMAL S6 KINASE; TUMOR-SUPPRESSOR COMPLEX; TUBEROUS SCLEROSIS; MAMMALIAN TARGET; CARDIAC-HYPERTROPHY; ADULT CARDIOMYOCYTES; 3-KINASE/AKT PATHWAY; CELL-GROWTH; RAG GTPASES; IN-VITRO;
D O I
10.1074/jbc.M111.260794
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The mammalian target of rapamycin complex 1 (mTORC1) links the control of mRNA translation, cell growth, and metabolism to diverse stimuli. Inappropriate activation of mTORC1 can lead to cancer. Phorbol esters are naturally occurring products that act as potent tumor promoters. They activate isoforms of protein kinase C (PKCs) and stimulate the oncogenic MEK/ERK signaling cascade. They also activate mTORC1 signaling. Previous work indicated that mTORC1 activation by the phorbol ester PMA (phorbol 12-myristate 13-acetate) depends upon PKCs and may involve MEK. However, the precise mechanism(s) through which they activate mTORC1 remains unclear. Recent studies have implicated both the ERKs and the ERK-activated 90-kDa ribosomal S6 kinases (p90(RSK)) in activating mTORC1 signaling via phosphorylation of TSC2 (a regulator of mTORC1) and/or the mTORC1 component raptor. However, the relative importance of each of these kinases and phosphorylation events for the activation of mTORC1 signaling is unknown. The recent availability of MEK (PD184352) and p90(RSK) (BI-D1870) inhibitors of improved specificity allowed us to address the roles of these protein kinases in controlling mTORC1in a variety of human and rodent cell types. In parallel, we used specific shRNAs against p90(RSK1) and p90(RSK2) to further test their roles in regulating mTORC1 signaling. Our data indicate that p90(RSKs) are dispensable for the activation of mTORC1 signaling by phorbol esters in all cell types tested. Our data also reveal striking diversity in the requirements for MEK/ERK in the control of mTORC1 between different cell types, pointing to additional signaling connections between phorbol esters and mTORC1, which do not involve MEK/ERK. This study provides important information for the design of efficient strategies to combat the hyperactivation of mTORC1 signaling by oncogenic pathways.
引用
收藏
页码:27111 / 27122
页数:12
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