The University of Southampton
University of Southampton Institutional Repository

Pharmacological and genetic evaluation of proposed roles of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK), extracellular signal-regulated kinase (ERK), and p90(RSK) in the control of mTORC1 protein signaling by phorbol esters

Pharmacological and genetic evaluation of proposed roles of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK), extracellular signal-regulated kinase (ERK), and p90(RSK) in the control of mTORC1 protein signaling by phorbol esters
Pharmacological and genetic evaluation of proposed roles of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK), extracellular signal-regulated kinase (ERK), and p90(RSK) in the control of mTORC1 protein signaling by phorbol esters
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 mTORC1 in 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.
map kinases (mapks), mtor complex (mtorc), phorbol esters, protein kinase c (pkc), rsk, tuberous sclerosis (tsc)
0021-9258
27111-27122
Fonseca, Bruno D.
bd81f9c7-365f-4636-a043-d204a8c4ccb9
Alain, Tommy
8888ebec-cfa9-4994-b8c8-071c9953fbe4
Finestone, Leona K.
154e376f-5768-42d2-8127-0131aa979073
Huang, Brandon P H.
18f304f8-0d88-41d4-b2cd-c1d5bb4ba411
Rolfe, Mark
2617e79f-4aea-43c1-8981-9048b13dbd95
Jiang, Tian
afe41bc0-24c4-435d-baa1-4f95696c2394
Yao, Zhong
d8e96a4a-a98d-47d3-96b8-efd459aa7a62
Hernandez, Greco
71258ca5-89ae-42f0-a147-cf432f6c1356
Bennett, Christopher F.
21776399-116d-4a16-bf6f-9e8c3470fa24
Proud, Christopher G.
59dabfc8-4b44-4be8-a17f-578a58550cb3
Fonseca, Bruno D.
bd81f9c7-365f-4636-a043-d204a8c4ccb9
Alain, Tommy
8888ebec-cfa9-4994-b8c8-071c9953fbe4
Finestone, Leona K.
154e376f-5768-42d2-8127-0131aa979073
Huang, Brandon P H.
18f304f8-0d88-41d4-b2cd-c1d5bb4ba411
Rolfe, Mark
2617e79f-4aea-43c1-8981-9048b13dbd95
Jiang, Tian
afe41bc0-24c4-435d-baa1-4f95696c2394
Yao, Zhong
d8e96a4a-a98d-47d3-96b8-efd459aa7a62
Hernandez, Greco
71258ca5-89ae-42f0-a147-cf432f6c1356
Bennett, Christopher F.
21776399-116d-4a16-bf6f-9e8c3470fa24
Proud, Christopher G.
59dabfc8-4b44-4be8-a17f-578a58550cb3

Fonseca, Bruno D., Alain, Tommy, Finestone, Leona K., Huang, Brandon P H., Rolfe, Mark, Jiang, Tian, Yao, Zhong, Hernandez, Greco, Bennett, Christopher F. and Proud, Christopher G. (2011) Pharmacological and genetic evaluation of proposed roles of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK), extracellular signal-regulated kinase (ERK), and p90(RSK) in the control of mTORC1 protein signaling by phorbol esters. The Journal of Biological Chemistry, 286 (31), 27111-27122. (doi:10.1074/jbc.M111.260794). (PMID:21659537)

Record type: Article

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 (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 mTORC1 in 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.

Full text not available from this repository.

More information

e-pub ahead of print date: 9 June 2011
Published date: 2011
Keywords: map kinases (mapks), mtor complex (mtorc), phorbol esters, protein kinase c (pkc), rsk, tuberous sclerosis (tsc)
Organisations: Centre for Biological Sciences

Identifiers

Local EPrints ID: 350237
URI: http://eprints.soton.ac.uk/id/eprint/350237
ISSN: 0021-9258
PURE UUID: 5679177f-69e6-4085-9389-3f325d27ba6d

Catalogue record

Date deposited: 20 Mar 2013 11:56
Last modified: 16 Jul 2019 21:40

Export record

Altmetrics

Contributors

Author: Bruno D. Fonseca
Author: Tommy Alain
Author: Leona K. Finestone
Author: Brandon P H. Huang
Author: Mark Rolfe
Author: Tian Jiang
Author: Zhong Yao
Author: Greco Hernandez
Author: Christopher F. Bennett
Author: Christopher G. Proud

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×