PMID- 18215133
OWN - NLM
STAT- MEDLINE
DCOM- 20080415
LR  - 20211203
IS  - 1470-8728 (Electronic)
IS  - 0264-6021 (Linking)
VI  - 411
IP  - 1
DP  - 2008 Apr 1
TI  - The binding of PRAS40 to 14-3-3 proteins is not required for activation of mTORC1 
      signalling by phorbol esters/ERK.
PG  - 141-9
LID - 10.1042/BJ20071001 [doi]
AB  - 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 Thr(246), binding of 
      14-3-3 proteins to PRAS40 or its release from mTORC1. Mutation of Thr(246) 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 
      Thr(246), bind to 14-3-3 or be released from mTORC1. It is conceivable that 
      phorbol esters activate mTORC1 by 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.
FAU - Fonseca, Bruno D
AU  - Fonseca BD
AD  - Department of Biochemistry and Molecular Biology, University of British Columbia, 
      Vancouver, BC V6T1Z3, Canada.
FAU - Lee, Vivian H-Y
AU  - Lee VH
FAU - Proud, Christopher G
AU  - Proud CG
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Biochem J
JT  - The Biochemical journal
JID - 2984726R
RN  - 0 (14-3-3 Proteins)
RN  - 0 (AKT1S1 protein, human)
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Insulin)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Phorbol Esters)
RN  - 0 (Phosphoproteins)
RN  - 0 (Proteins)
RN  - 0 (Transcription Factors)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
SB  - IM
MH  - 14-3-3 Proteins/*metabolism
MH  - Adaptor Proteins, Signal Transducing
MH  - Cell Line
MH  - Extracellular Signal-Regulated MAP Kinases
MH  - Humans
MH  - Insulin
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Multiprotein Complexes
MH  - Phorbol Esters/*pharmacology
MH  - Phosphoproteins/*metabolism
MH  - Phosphorylation
MH  - Protein Binding
MH  - Proteins
MH  - Signal Transduction/*drug effects
MH  - TOR Serine-Threonine Kinases
MH  - Transcription Factors/*metabolism
EDAT- 2008/01/25 09:00
MHDA- 2008/04/16 09:00
CRDT- 2008/01/25 09:00
PHST- 2008/01/25 09:00 [pubmed]
PHST- 2008/04/16 09:00 [medline]
PHST- 2008/01/25 09:00 [entrez]
AID - BJ20071001 [pii]
AID - 10.1042/BJ20071001 [doi]
PST - ppublish
SO  - Biochem J. 2008 Apr 1;411(1):141-9. doi: 10.1042/BJ20071001.