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https://hdl.handle.net/2440/82510
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Type: | Journal article |
Title: | The binding of PRAS40 to 14-3-3 proteins is not required for activation of mTORC1 signalling by phorbol esters/ERK |
Author: | Fonseca, B. Lee, V. Proud, C. |
Citation: | Biochemical Journal, 2008; 411(1):141-149 |
Publisher: | Portland Press |
Issue Date: | 2008 |
ISSN: | 0264-6021 1470-8728 |
Statement of Responsibility: | Bruno D. Fonseca, Vivian H.-Y. Lee and Christopher G. Proud |
Abstract: | PRAS40 binds to the mTORC1 (mammalian target of rapamycin complex 1) and is released in response to insulin. It has been suggested that this effect is due to 14-3-3 binding and leads to activation of mTORC1 signalling. In a similar manner to insulin, phorbol esters also activate mTORC1 signalling, in this case via PKC (protein kinase C) and ERK (extracellular-signal-regulated kinase). However, phorbol esters do not induce phosphorylation of PRAS40 at Thr246, binding of 14-3-3 proteins to PRAS40 or its release from mTORC1. Mutation of Thr246 to a serine residue permits phorbol esters to induce phosphorylation and binding to 14-3-3 proteins. Such phosphorylation is apparently mediated by RSKs (ribosomal S6 kinases), which lie downstream of ERK. However, although the PRAS40(T246S) mutant binds to 14-3-3 better than wild-type PRAS40, each inhibits mTORC1 signalling to a similar extent. Our results show that activation of mTORC1 signalling by phorbol esters does not require PRAS40 to be phosphorylated at Thr246, bind to 14-3-3 or be released from mTORC1. It is conceivable that phorbol esters activate mTORC1by a distinct mechanism not involving PRAS40. Indeed, our results suggest that PRAS40 may not actually be involved in controlling mTORC1, but rather be a downstream target of mTORC1 that is regulated in response only to specific stimuli, such as insulin. |
Keywords: | Mammalian target of rapamycin (mTOR) mammalian target of rapamycin complex 1 (mTORC1) MAPK (mitogen-activated protein kinase) proline-rich Akt substrate of 40 kDa (PRAS40) phosphorylation, 14-3-3 protein |
Rights: | © The Authors Journal compilation © 2008 Biochemical Society |
DOI: | 10.1042/BJ20071001 |
Published version: | http://dx.doi.org/10.1042/bj20071001 |
Appears in Collections: | Aurora harvest Molecular and Biomedical Science publications |
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