PMID- 22457331
OWN - NLM
STAT- MEDLINE
DCOM- 20120808
LR  - 20211203
IS  - 1937-9145 (Electronic)
IS  - 1945-0877 (Linking)
VI  - 5
IP  - 217
DP  - 2012 Mar 27
TI  - A dynamic network model of mTOR signaling reveals TSC-independent mTORC2 
      regulation.
PG  - ra25
LID - 10.1126/scisignal.2002469 [doi]
AB  - The kinase mammalian target of rapamycin (mTOR) exists in two multiprotein 
      complexes (mTORC1 and mTORC2) and is a central regulator of growth and 
      metabolism. Insulin activation of mTORC1, mediated by phosphoinositide 3-kinase 
      (PI3K), Akt, and the inhibitory tuberous sclerosis complex 1/2 (TSC1-TSC2), 
      initiates a negative feedback loop that ultimately inhibits PI3K. We present a 
      data-driven dynamic insulin-mTOR network model that integrates the entire core 
      network and used this model to investigate the less well understood mechanisms by 
      which insulin regulates mTORC2. By analyzing the effects of perturbations 
      targeting several levels within the network in silico and experimentally, we 
      found that, in contrast to current hypotheses, the TSC1-TSC2 complex was not a 
      direct or indirect (acting through the negative feedback loop) regulator of 
      mTORC2. Although mTORC2 activation required active PI3K, this was not affected by 
      the negative feedback loop. Therefore, we propose an mTORC2 activation pathway 
      through a PI3K variant that is insensitive to the negative feedback loop that 
      regulates mTORC1. This putative pathway predicts that mTORC2 would be refractory 
      to Akt, which inhibits TSC1-TSC2, and, indeed, we found that mTORC2 was 
      insensitive to constitutive Akt activation in several cell types. Our results 
      suggest that a previously unknown network structure connects mTORC2 to its 
      upstream cues and clarifies which molecular connectors contribute to mTORC2 
      activation.
FAU - Dalle Pezze, Piero
AU  - Dalle Pezze P
AD  - Institute for Ageing and Health, Newcastle University, Campus for Ageing and 
      Vitality, Newcastle upon Tyne, UK.
FAU - Sonntag, Annika G
AU  - Sonntag AG
FAU - Thien, Antje
AU  - Thien A
FAU - Prentzell, Mirja T
AU  - Prentzell MT
FAU - Godel, Markus
AU  - Godel M
FAU - Fischer, Sven
AU  - Fischer S
FAU - Neumann-Haefelin, Elke
AU  - Neumann-Haefelin E
FAU - Huber, Tobias B
AU  - Huber TB
FAU - Baumeister, Ralf
AU  - Baumeister R
FAU - Shanley, Daryl P
AU  - Shanley DP
FAU - Thedieck, Kathrin
AU  - Thedieck K
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120327
PL  - United States
TA  - Sci Signal
JT  - Science signaling
JID - 101465400
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Carrier Proteins)
RN  - 0 (Insulin)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (RICTOR protein, human)
RN  - 0 (RPTOR protein, human)
RN  - 0 (Rapamycin-Insensitive Companion of mTOR Protein)
RN  - 0 (Regulatory-Associated Protein of mTOR)
RN  - 0 (TSC1 protein, human)
RN  - 0 (TSC2 protein, human)
RN  - 0 (Tuberous Sclerosis Complex 1 Protein)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
CIN - Sci Signal. 2012;5(232):lc3; author reply lc4. PMID: 22786721
MH  - Adaptor Proteins, Signal Transducing/genetics/metabolism
MH  - Animals
MH  - Carrier Proteins/genetics/metabolism
MH  - Cell Line
MH  - Computer Simulation
MH  - Gene Knockdown Techniques
MH  - HeLa Cells
MH  - Humans
MH  - Immunoblotting
MH  - Immunoprecipitation
MH  - Insulin/metabolism/pharmacology
MH  - *Models, Biological
MH  - Multiprotein Complexes/genetics/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphorylation/drug effects
MH  - Protein Binding
MH  - Rapamycin-Insensitive Companion of mTOR Protein
MH  - Regulatory-Associated Protein of mTOR
MH  - Ribosomal Protein S6 Kinases, 70-kDa/metabolism
MH  - Signal Transduction/drug effects/*physiology
MH  - Software
MH  - TOR Serine-Threonine Kinases/genetics/*metabolism
MH  - Tuberous Sclerosis Complex 1 Protein
MH  - Tuberous Sclerosis Complex 2 Protein
MH  - Tumor Suppressor Proteins/genetics/metabolism
EDAT- 2012/03/30 06:00
MHDA- 2012/08/09 06:00
CRDT- 2012/03/30 06:00
PHST- 2012/03/30 06:00 [entrez]
PHST- 2012/03/30 06:00 [pubmed]
PHST- 2012/08/09 06:00 [medline]
AID - 5/217/ra25 [pii]
AID - 10.1126/scisignal.2002469 [doi]
PST - epublish
SO  - Sci Signal. 2012 Mar 27;5(217):ra25. doi: 10.1126/scisignal.2002469.