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https://hdl.handle.net/2440/90852
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Type: | Journal article |
Title: | 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 |
Author: | Fonseca, B. Alain, T. Finestone, L. Huang, B. Rolfe, M. Jiang, T. Yao, Z. Hernandez, G. Bennett, C. Proud, C. |
Citation: | Journal of Biological Chemistry, 2011; 286(31):27111-27122 |
Publisher: | American Society for Biochemistry and Molecular Biology |
Issue Date: | 2011 |
ISSN: | 0021-9258 1083-351X |
Statement of Responsibility: | Bruno D. Fonseca, Tommy Alain, Leona K. Finestone, Brandon P. H. Huang, Mark Rolfe, Tian Jiang, Zhong Yao, Greco Hernandez, Christopher F. Bennett, and Christopher G. Proud |
Abstract: | 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 (p90RSK) 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 p90RSK (BI-D1870) inhibitors of improved specificity allowed us to address the roles of these protein kinases in controlling mTORC1 in a variety of human and rodent cell types. In parallel, we used specific shRNAs against p90RSK1 and p90RSK2 to further test their roles in regulating mTORC1 signaling. Our data indicate that p90RSKs 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. |
Keywords: | Cell Line NIH 3T3 Cells Animals Humans Mice Rats Rats, Sprague-Dawley Tetradecanoylphorbol Acetate Pteridines Protein Kinases Transcription Factors Protein Kinase Inhibitors Signal Transduction Phosphorylation |
Rights: | © 2011 by The American Society for Biochemistry and Molecular Biology, Inc. |
DOI: | 10.1074/jbc.M111.260794 |
Published version: | http://dx.doi.org/10.1074/jbc.m111.260794 |
Appears in Collections: | Aurora harvest 2 Molecular and Biomedical Science publications |
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