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BIOMD0000000581 - DallePezze2012 - TSC-independent mTORC2 regulation

 

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Reference Publication
Publication ID: 22457331
Dalle Pezze P, Sonntag AG, Thien A, Prentzell MT, Gödel M, Fischer S, Neumann-Haefelin E, Huber TB, Baumeister R, Shanley DP, Thedieck K.
A dynamic network model of mTOR signaling reveals TSC-independent mTORC2 regulation.
Sci Signal 2012 Mar; 5(217): ra25
Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK.  [more]
Model
Original Model: BIOMD0000000581.origin
Submitter: Piero Dalle Pezze
Submission ID: MODEL1506230001
Submission Date: 23 Jun 2015 09:32:05 UTC
Last Modification Date: 10 Sep 2015 12:52:15 UTC
Creation Date: 12 Aug 2015 22:15:02 UTC
Encoders:  Vijayalakshmi Chelliah
   Piero Dalle Pezze
set #1
bqbiol:isVersionOf Gene Ontology cellular response to insulin stimulus
set #2
bqbiol:occursIn Brenda Tissue Ontology C2C12 cell
Brenda Tissue Ontology BTO:0000567
set #3
bqbiol:hasTaxon Taxonomy Homo sapiens
Taxonomy Mus musculus
Notes
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.

Model
Publication ID: 22457331 Submission Date: 23 Jun 2015 09:32:05 UTC Last Modification Date: 10 Sep 2015 12:52:15 UTC Creation Date: 12 Aug 2015 22:15:02 UTC
Mathematical expressions
Reactions
TSC_p_clx_dephosphorylation p70S6K_T389_phosphorylation_by_mTORC1_pS2448 p70S6K_pT389_dephosphorylation IRS1_S636_phosphorylation_by_p70S6K_pT389
IRS1_PI3K_phosphorylation_by_IR_beta_pY1146 Akt_T308_phosphorylation_by_IRS1_phos_PI3K Akt_pT308_S473_phosphorylation_by_mTORC2_pS2481 TSC_clx_phosphorylation_by_Akt_pT308
mTORC1_S2448_activation_by_Amino_Acids IR_beta_Y1146_phosphorylation IRS1_p_pi3K_phosphorylation_by_p70S6K_pT389 IRS1_pS636_degradation
IRS1_p_PI3K_dephosphorylation Akt_pT308_pS473_dephosphorylation Akt_pT308_dephosphorylation mTORC2_pS2481_dephosphorylation
IR_beta_pY1146_dephosphorylation TSC_clx_phosphorylation_by_Akt_pT308_pS473 IRS1_synthesis IR_beta_ready
PRAS40_T246_phosphorylation_by_Akt_pT308_pS473 mTORC1_pS2448_dephosphorylation_by_TSC_clx PRAS40_T246_phosphorylation_by_Akt_pT308 PRAS40_pT246_dephosphorylation
PRAS40_pS183_dephosphorylation PRAS40_S183_phosphorylation_by_mTORC1_pS2448 mTORC2_S2481_phosphorylation_by_PI3K_variant_p Akt_pT308_S473_phosphorylation_by_PDK2
PDK2_p_dephosphorylation PDK2_phosphorylation PI3K_variant_phosphorylation_by_IR_beta_pY1146 PI3K_variant_p_dephosphorylation
Physical entities
Compartments Species
Membrane IR_beta IR_beta_pY1146 IR_beta_refractory
Insulin    
Cytoplasm Amino_Acids Sink mTORC2
mTORC1_pS2448 mTORC1 IRS1_pS636_PI3K
IRS1_p_PI3K mTORC2_pS2481 p70S6K_pT389
IRS1_PI3K Akt_pT308 TSC_clx
PRAS40 PRAS40_pS183 PRAS40_pT246
Akt Akt_pT308_pS473 p70S6K
TSC_p_clx PDK2 PDK2_p
PI3K_variant_p PI3K_variant PI3K
Reactions (32)
 
 TSC_p_clx_dephosphorylation [TSC_p_clx] → [TSC_clx];   {TSC_p_clx}
 
 p70S6K_T389_phosphorylation_by_mTORC1_pS2448 [p70S6K] + [mTORC1_pS2448] → [p70S6K_pT389] + [mTORC1_pS2448];   {p70S6K} , {mTORC1_pS2448}
 
 p70S6K_pT389_dephosphorylation [p70S6K_pT389] → [p70S6K];   {p70S6K_pT389}
 
 IRS1_S636_phosphorylation_by_p70S6K_pT389 [IRS1_PI3K] + [p70S6K_pT389] → [IRS1_pS636_PI3K] + [p70S6K_pT389];   {IRS1_PI3K} , {p70S6K_pT389}
 
 IRS1_PI3K_phosphorylation_by_IR_beta_pY1146 [IRS1_PI3K] + [IR_beta_pY1146] → [IRS1_p_PI3K] + [IR_beta_pY1146];   {IRS1_PI3K} , {IR_beta_pY1146}
 
 Akt_T308_phosphorylation_by_IRS1_phos_PI3K [Akt] + [IRS1_p_PI3K] → [Akt_pT308] + [IRS1_p_PI3K];   {Akt} , {IRS1_p_PI3K}
 
 Akt_pT308_S473_phosphorylation_by_mTORC2_pS2481 [Akt_pT308] + [mTORC2_pS2481] → [Akt_pT308_pS473] + [mTORC2_pS2481];   {Akt_pT308} , {mTORC2_pS2481}
 
 TSC_clx_phosphorylation_by_Akt_pT308 [TSC_clx] + [Akt_pT308] → [TSC_p_clx] + [Akt_pT308];   {TSC_clx} , {Akt_pT308}
 
 mTORC1_S2448_activation_by_Amino_Acids [mTORC1] + [Amino_Acids] → [mTORC1_pS2448];   {mTORC1} , {Amino_Acids}
 
 IR_beta_Y1146_phosphorylation [IR_beta] + [Insulin] → [IR_beta_pY1146];   {IR_beta} , {Insulin}
 
 IRS1_p_pi3K_phosphorylation_by_p70S6K_pT389 [IRS1_p_PI3K] + [p70S6K_pT389] → [IRS1_pS636_PI3K] + [p70S6K_pT389];   {IRS1_p_PI3K} , {p70S6K_pT389}
 
 IRS1_pS636_degradation [IRS1_pS636_PI3K] → [Sink];   {IRS1_pS636_PI3K}
 
 IRS1_p_PI3K_dephosphorylation [IRS1_p_PI3K] → [IRS1_PI3K];   {IRS1_p_PI3K}
 
 Akt_pT308_pS473_dephosphorylation [Akt_pT308_pS473] → [Akt_pT308];   {Akt_pT308_pS473}
 
 Akt_pT308_dephosphorylation [Akt_pT308] → [Akt];   {Akt_pT308}
 
 mTORC2_pS2481_dephosphorylation [mTORC2_pS2481] → [mTORC2];   {mTORC2_pS2481}
 
 IR_beta_pY1146_dephosphorylation [IR_beta_pY1146] → [IR_beta_refractory];   {IR_beta_pY1146}
 
 TSC_clx_phosphorylation_by_Akt_pT308_pS473 [TSC_clx] + [Akt_pT308_pS473] → [TSC_p_clx] + [Akt_pT308_pS473];   {TSC_clx} , {Akt_pT308_pS473}
 
 IRS1_synthesis [Sink] → [IRS1_PI3K];   {Sink}
 
 IR_beta_ready [IR_beta_refractory] → [IR_beta];   {IR_beta_refractory}
 
 PRAS40_T246_phosphorylation_by_Akt_pT308_pS473 [PRAS40] + [Akt_pT308_pS473] → [PRAS40_pT246] + [Akt_pT308_pS473];   {PRAS40} , {Akt_pT308_pS473}
 
 mTORC1_pS2448_dephosphorylation_by_TSC_clx [mTORC1_pS2448] + [TSC_clx] → [mTORC1] + [TSC_clx];   {mTORC1_pS2448} , {TSC_clx}
 
 PRAS40_T246_phosphorylation_by_Akt_pT308 [PRAS40] + [Akt_pT308] → [PRAS40_pT246] + [Akt_pT308];   {PRAS40} , {Akt_pT308}
 
 PRAS40_pT246_dephosphorylation [PRAS40_pT246] → [PRAS40];   {PRAS40_pT246}
 
 PRAS40_pS183_dephosphorylation [PRAS40_pS183] → [PRAS40];   {PRAS40_pS183}
 
 PRAS40_S183_phosphorylation_by_mTORC1_pS2448 [PRAS40] + [mTORC1_pS2448] → [PRAS40_pS183] + [mTORC1_pS2448];   {PRAS40} , {mTORC1_pS2448}
 
 mTORC2_S2481_phosphorylation_by_PI3K_variant_p [mTORC2] + [PI3K_variant_p] → [mTORC2_pS2481] + [PI3K_variant_p];   {mTORC2} , {PI3K_variant_p}
 
 Akt_pT308_S473_phosphorylation_by_PDK2 [Akt_pT308] + [PDK2_p] → [Akt_pT308_pS473] + [PDK2_p];   {Akt_pT308} , {PDK2_p}
 
 PDK2_p_dephosphorylation [PDK2_p] → [PDK2];   {PDK2_p}
 
 PDK2_phosphorylation [PDK2] + [IR_beta_pY1146] → [PDK2_p] + [IR_beta_pY1146];   {PDK2} , {IR_beta_pY1146}
 
 PI3K_variant_phosphorylation_by_IR_beta_pY1146 [PI3K_variant] + [IR_beta_pY1146] → [PI3K_variant_p] + [IR_beta_pY1146];   {PI3K_variant} , {IR_beta_pY1146}
 
 PI3K_variant_p_dephosphorylation [PI3K_variant_p] → [PI3K_variant];   {PI3K_variant_p}
 
 Membrane Spatial dimensions: 3.0  Compartment size: 1.0
 
 IR_beta
Compartment: Membrane
Initial concentration: 12.1175
 
 IR_beta_pY1146
Compartment: Membrane
Initial concentration: 0.0
 
 IR_beta_refractory
Compartment: Membrane
Initial concentration: 0.0
 
 Insulin
Compartment: Membrane
Initial concentration: 100.0
Constant
 
 Cytoplasm Spatial dimensions: 3.0  Compartment size: 1.0
 
 Amino_Acids
Compartment: Cytoplasm
Initial concentration: 100.0
Constant
 
 Sink
Compartment: Cytoplasm
Initial concentration: 0.0
 
 mTORC2
Compartment: Cytoplasm
Initial concentration: 6.2175
 
 mTORC1_pS2448
Compartment: Cytoplasm
Initial concentration: 0.0
 
 mTORC1
Compartment: Cytoplasm
Initial concentration: 4.3225
 
 IRS1_pS636_PI3K
Compartment: Cytoplasm
Initial concentration: 0.0
 
 IRS1_p_PI3K
Compartment: Cytoplasm
Initial concentration: 0.0
 
 mTORC2_pS2481
Compartment: Cytoplasm
Initial concentration: 0.0
 
 p70S6K_pT389
Compartment: Cytoplasm
Initial concentration: 0.0
 
 IRS1_PI3K
Compartment: Cytoplasm
Initial concentration: 2.965
 
 Akt_pT308
Compartment: Cytoplasm
Initial concentration: 0.0
 
 TSC_clx
Compartment: Cytoplasm
Initial concentration: 10.0
 
 PRAS40
Compartment: Cytoplasm
Initial concentration: 73.2175
 
 PRAS40_pS183
Compartment: Cytoplasm
Initial concentration: 0.0
 
 PRAS40_pT246
Compartment: Cytoplasm
Initial concentration: 0.0
 
 Akt
Compartment: Cytoplasm
Initial concentration: 144.13
 
 Akt_pT308_pS473
Compartment: Cytoplasm
Initial concentration: 0.0
 
 p70S6K
Compartment: Cytoplasm
Initial concentration: 127.0725
 
 TSC_p_clx
Compartment: Cytoplasm
Initial concentration: 0.0
 
 PDK2
Compartment: Cytoplasm
Initial concentration: 12.1175
 
 PDK2_p
Compartment: Cytoplasm
Initial concentration: 0.0
 
 PI3K_variant_p
Compartment: Cytoplasm
Initial concentration: 0.0
 
 PI3K_variant
Compartment: Cytoplasm
Initial concentration: 2.965
 
 PI3K
Compartment: Cytoplasm
Initial concentration: 2.965
Constant
 
TSC_p_clx_dephosphorylation (1)
 
   k1
Value: 0.00812537
Constant
 
p70S6K_T389_phosphorylation_by_mTORC1_pS2448 (1)
 
   k1
Value: 0.00573896
Constant
 
p70S6K_pT389_dephosphorylation (1)
 
   k1
Value: 0.00528455
Constant
 
IRS1_S636_phosphorylation_by_p70S6K_pT389 (1)
 
   k1
Value: 1.0
Constant
 
IRS1_PI3K_phosphorylation_by_IR_beta_pY1146 (1)
 
   k1
Value: 0.134664
Constant
 
Akt_T308_phosphorylation_by_IRS1_phos_PI3K (1)
 
   k1
Value: 0.699505
Constant
 
Akt_pT308_S473_phosphorylation_by_mTORC2_pS2481 (1)
 
   k1
Value: 4.50769
Constant
 
TSC_clx_phosphorylation_by_Akt_pT308 (1)
 
   k1
Value: 0.00627315
Constant
 
mTORC1_S2448_activation_by_Amino_Acids (1)
 
   k1
Value: 0.0513784
Constant
 
IR_beta_Y1146_phosphorylation (1)
 
   k1
Value: 0.0253763
Constant
 
IRS1_p_pi3K_phosphorylation_by_p70S6K_pT389 (1)
 
   k1
Value: 1.0E-4
Constant
 
IRS1_pS636_degradation (1)
 
   k1
Value: 1.00001E-4
Constant
 
IRS1_p_PI3K_dephosphorylation (1)
 
   k1
Value: 0.00328283
Constant
 
Akt_pT308_pS473_dephosphorylation (1)
 
   k1
Value: 7.52842
Constant
 
Akt_pT308_dephosphorylation (1)
 
   k1
Value: 4.0739
Constant
 
mTORC2_pS2481_dephosphorylation (1)
 
   k1
Value: 0.0255714
Constant
 
IR_beta_pY1146_dephosphorylation (1)
 
   k1
Value: 0.149328
Constant
 
TSC_clx_phosphorylation_by_Akt_pT308_pS473 (1)
 
   k1
Value: 1.00039E-4
Constant
 
IRS1_synthesis (1)
 
   k1
Value: 0.0999968
Constant
 
IR_beta_ready (1)
 
   k1
Value: 0.0309731
Constant
 
PRAS40_T246_phosphorylation_by_Akt_pT308_pS473 (1)
 
   k1
Value: 1.00001E-4
Constant
 
mTORC1_pS2448_dephosphorylation_by_TSC_clx (1)
 
   k1
Value: 0.999989
Constant
 
PRAS40_T246_phosphorylation_by_Akt_pT308 (1)
 
   k1
Value: 0.0239178
Constant
 
PRAS40_pT246_dephosphorylation (1)
 
   k1
Value: 0.999991
Constant
 
PRAS40_pS183_dephosphorylation (1)
 
   k1
Value: 0.403706
Constant
 
PRAS40_S183_phosphorylation_by_mTORC1_pS2448 (1)
 
   k1
Value: 0.073093
Constant
 
mTORC2_S2481_phosphorylation_by_PI3K_variant_p (1)
 
   k1
Value: 0.0318902
Constant
 
Akt_pT308_S473_phosphorylation_by_PDK2 (1)
 
   k1
Value: 5.90372
Constant
 
PDK2_p_dephosphorylation (1)
 
   k1
Value: 1.0
Constant
 
PDK2_phosphorylation (1)
 
   k1
Value: 0.1
Constant
 
PI3K_variant_phosphorylation_by_IR_beta_pY1146 (1)
 
   k1
Value: 0.999985
Constant
 
PI3K_variant_p_dephosphorylation (1)
 
   k1
Value: 2.32165E-4
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000581

Curator's comment: (updated: 12 Aug 2015 23:11:44 BST)

Figure 2 of the reference publication has been reproduced. The model was simulated using Copasi v4.15 (Build 95).

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