DallePezze2012 - TSC-independent mTORC2 regulation

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Model Identifier
BIOMD0000000581
Short description
DallePezze2012 - TSC-independent mTORC2 regulation

This model is described in the article:

Dalle Pezze P, Sonntag AG, Thien A, Prentzell MT, Gödel M, Fischer S, Neumann-Haefelin E, Huber TB, Baumeister R, Shanley DP, Thedieck K.
Sci Signal 2012 Mar; 5(217): ra25

Abstract:

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.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Format
SBML (L2V4)
Related Publication
  • A dynamic network model of mTOR signaling reveals TSC-independent mTORC2 regulation.
  • Dalle Pezze P, Sonntag AG, Thien A, Prentzell MT, Gödel M, Fischer S, Neumann-Haefelin E, Huber TB, Baumeister R, Shanley DP, Thedieck K
  • Science signaling , 3/ 2012 , Volume 5 , pages: ra25 , PubMed ID: 22457331
  • Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK.
  • 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.
Contributors
Piero Dalle Pezze

Metadata information

is
BioModels Database MODEL1506230001
BioModels Database BIOMD0000000581
isDescribedBy
PubMed 22457331
hasTaxon
Taxonomy Homo sapiens
Taxonomy Mus musculus
isVersionOf
occursIn
Brenda Tissue Ontology HeLa cell
Brenda Tissue Ontology C2C12 cell

Curation status
Curated

Tags
Name Description Size Actions

Model files

BIOMD0000000581_url.xml SBML L2V4 representation of DallePezze2012 - TSC-independent mTORC2 regulation 101.54 KB Preview | Download

Additional files

BIOMD0000000581_urn.xml Auto-generated SBML file with URNs 100.24 KB Preview | Download
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BIOMD0000000581-biopax3.owl Auto-generated BioPAX (Level 3) 103.88 KB Preview | Download
BIOMD0000000581.svg Auto-generated Reaction graph (SVG) 108.70 KB Preview | Download
BIOMD0000000581-biopax2.owl Auto-generated BioPAX (Level 2) 61.51 KB Preview | Download
BIOMD0000000581.m Auto-generated Octave file 15.90 KB Preview | Download
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  • Model originally submitted by : Piero Dalle Pezze
  • Submitted: 23-Jun-2015 10:32:05
  • Last Modified: 10-Sep-2015 13:52:15
Revisions
  • Version: 2 public model Download this version
    • Submitted on: 10-Sep-2015 13:52:15
    • Submitted by: Piero Dalle Pezze
    • With comment: Current version of DallePezze2012 - TSC-independent mTORC2 regulation
  • Version: 1 public model Download this version
    • Submitted on: 23-Jun-2015 10:32:05
    • Submitted by: Piero Dalle Pezze
    • With comment: Original import of mTOR model

(*) You might be seeing discontinuous revisions as only public revisions are displayed here. Any private revisions unpublished model revision of this model will only be shown to the submitter and their collaborators.

Legends
: Variable used inside SBML models


Species
Reactions
Reactions Rate Parameters
species_27 + species_7 => species_3 + species_7; species_27, species_7 compartment_2*k1*species_27*species_7 k1=0.699505
species_9 + species_4 => species_10 + species_4; species_9, species_4 compartment_2*k1*species_9*species_4 k1=1.00001E-4
species_47 + species_2 => species_17 + species_2; species_47, species_2 compartment_2*k1*species_47*species_2 k1=0.00573896
species_6 + species_4 => species_8 + species_4; species_6, species_4 compartment_2*k1*species_6*species_4 k1=1.00039E-4
species_14 => species_13; species_14 compartment_2*k1*species_14 k1=1.0
species_3 + species_14 => species_4 + species_14; species_3, species_14 compartment_2*k1*species_3*species_14 k1=5.90372
species_13 + species_21 => species_14 + species_21; species_13, species_21 k1*species_13*species_21 k1=0.1
species_18 + species_21 => species_16 + species_21; species_18, species_21 k1*species_18*species_21 k1=0.999985
species_16 => species_18; species_16 compartment_2*k1*species_16 k1=2.32165E-4
species_10 => species_9; species_10 compartment_2*k1*species_10 k1=0.999991
species_3 => species_27; species_3 compartment_2*k1*species_3 k1=4.0739
species_3 + species_22 => species_4 + species_22; species_3, species_22 compartment_2*k1*species_3*species_22 k1=4.50769
species_4 => species_3; species_4 compartment_2*k1*species_4 k1=7.52842
Curator's comment:
(added: 12 Aug 2015, 23:11:44, updated: 12 Aug 2015, 23:11:44)
Figure 2 of the reference publication has been reproduced. The model was simulated using Copasi v4.15 (Build 95).