PMID- 20227368
OWN - NLM
STAT- MEDLINE
DCOM- 20100413
LR  - 20220227
IS  - 1097-4164 (Electronic)
IS  - 1097-2765 (Linking)
VI  - 37
IP  - 5
DP  - 2010 Mar 12
TI  - PP2A T61 epsilon is an inhibitor of MAP4K3 in nutrient signaling to mTOR.
PG  - 633-42
LID - 10.1016/j.molcel.2010.01.031 [doi]
AB  - The mammalian target of rapamycin (mTOR) pathway is activated by a variety of 
      stimuli, including nutrients such as glucose and amino acids. The Ste20 family 
      kinase MAP4K3 is regulated by amino acids and acts upstream of mTORC1. Here we 
      investigate how MAP4K3 activity is regulated by amino acid sufficiency. We 
      identify a transautophosphorylation site in the MAP4K3 kinase activation segment 
      (Ser170) that is required for MAP4K3 activity and its activation of mTORC1 
      signaling. Following amino acid withdrawal, Ser170 is dephosphorylated via PP2A 
      complexed to PR61 epsilon, a PP2A-targeting subunit. Inhibition of PR61 epsilon 
      expression prevents MAP4K3 Ser170 dephosphorylation and impairs mTORC1 inhibition 
      during amino acid withdrawal. We propose that during amino acid sufficiency 
      Ser170-phosphorylated MAP4K3 activates mTORC1, but that upon amino acid 
      restriction MAP4K3 preferentially interacts with PP2A(T61 epsilon), promoting 
      dephosphorylation of Ser170, MAP4K3 inhibition, and, subsequently, inhibition of 
      mTORC1 signaling.
CI  - (c) 2010 Elsevier Inc. All rights reserved.
FAU - Yan, Lijun
AU  - Yan L
AD  - Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 
      University Avenue, AB T6G IZ2, Canada.
FAU - Mieulet, Virginie
AU  - Mieulet V
FAU - Burgess, Darren
AU  - Burgess D
FAU - Findlay, Greg M
AU  - Findlay GM
FAU - Sully, Katherine
AU  - Sully K
FAU - Procter, Julia
AU  - Procter J
FAU - Goris, Jozef
AU  - Goris J
FAU - Janssens, Veerle
AU  - Janssens V
FAU - Morrice, Nick A
AU  - Morrice NA
FAU - Lamb, Richard F
AU  - Lamb RF
LA  - eng
GR  - Cancer Research UK/United Kingdom
GR  - Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Cell
JT  - Molecular cell
JID - 9802571
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Amino Acids)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Protein Subunits)
RN  - 0 (Proteins)
RN  - 0 (RPTOR protein, human)
RN  - 0 (RRAGC protein, human)
RN  - 0 (RRAGD protein, human)
RN  - 0 (Regulatory-Associated Protein of mTOR)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (MAP4K3 protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.3.16 (Protein Phosphatase 2)
RN  - EC 3.6.5.2 (Monomeric GTP-Binding Proteins)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing
MH  - Amino Acids/deficiency/*metabolism
MH  - Cell Line
MH  - Enzyme Activation
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/*metabolism
MH  - Monomeric GTP-Binding Proteins/metabolism
MH  - Mutation
MH  - Phosphorylation
MH  - Protein Binding
MH  - Protein Phosphatase 2/genetics/*metabolism
MH  - Protein Serine-Threonine Kinases/genetics/*metabolism
MH  - Protein Subunits
MH  - Proteins/metabolism
MH  - RNA Interference
MH  - Regulatory-Associated Protein of mTOR
MH  - *Signal Transduction
MH  - TOR Serine-Threonine Kinases
MH  - Transfection
EDAT- 2010/03/17 06:00
MHDA- 2010/04/14 06:00
CRDT- 2010/03/16 06:00
PHST- 2008/11/12 00:00 [received]
PHST- 2009/10/14 00:00 [revised]
PHST- 2010/01/06 00:00 [accepted]
PHST- 2010/03/16 06:00 [entrez]
PHST- 2010/03/17 06:00 [pubmed]
PHST- 2010/04/14 06:00 [medline]
AID - S1097-2765(10)00114-0 [pii]
AID - 10.1016/j.molcel.2010.01.031 [doi]
PST - ppublish
SO  - Mol Cell. 2010 Mar 12;37(5):633-42. doi: 10.1016/j.molcel.2010.01.031.