DallePezze2012 - TSC-independent mTORC2 regulation
This model is described in the article:
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.
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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.
Metadata information
| Name | Description | Size | Actions |
|---|---|---|---|
Model files |
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| BIOMD0000000581_url.xml | SBML L2V4 representation of DallePezze2012 - TSC-independent mTORC2 regulation | 101.54 KB | Preview | Download |
Additional files |
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| BIOMD0000000581_urn.xml | Auto-generated SBML file with URNs | 100.24 KB | Preview | Download |
| BIOMD0000000581.pdf | Auto-generated PDF file | 345.33 KB | Preview | Download |
| 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 |
| BIOMD0000000581.png | Auto-generated Reaction graph (PNG) | 711.57 KB | Preview | Download |
| BIOMD0000000581.sci | Auto-generated Scilab file | 154.00 Bytes | Preview | Download |
| BIOMD0000000581.xpp | Auto-generated XPP file | 12.04 KB | Preview | Download |
| BIOMD0000000581.vcml | Auto-generated VCML file | 897.00 Bytes | Preview | Download |
- Model originally submitted by : Piero Dalle Pezze
- Submitted: 23-Jun-2015 10:32:05
- Last Modified: 10-Sep-2015 13:52:15
Revisions
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Version: 2
- Submitted on: 10-Sep-2015 13:52:15
- Submitted by: Piero Dalle Pezze
- With comment: Current version of DallePezze2012 - TSC-independent mTORC2 regulation
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Version: 1
- Submitted on: 23-Jun-2015 10:32:05
- Submitted by: Piero Dalle Pezze
- With comment: Original import of mTOR model
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: Variable used inside SBML models
| Species | Initial Concentration/Amount |
|---|---|
| species 27 RAC-alpha serine/threonine-protein kinase |
144.13 dimensionless |
| species 4 RAC-alpha serine/threonine-protein kinase |
0.0 dimensionless |
| species 47 Ribosomal protein S6 kinase beta-1 |
127.0725 dimensionless |
| species 8 Tuberin ; Hamartin |
0.0 dimensionless |
| species 13 MAP kinase-activated protein kinase 2 ; DNA-dependent protein kinase catalytic subunit ; Serine-protein kinase ATM ; Serine/threonine-protein kinase PAK 1 |
12.1175 dimensionless |
| species 14 DNA-dependent protein kinase catalytic subunit ; Serine-protein kinase ATM ; Serine/threonine-protein kinase PAK 1 ; MAP kinase-activated protein kinase 2 |
0.0 dimensionless |
| species 16 Phosphatidylinositol 3-kinase regulatory subunit alpha |
0.0 dimensionless |
| species 18 Phosphatidylinositol 3-kinase regulatory subunit alpha |
2.965 dimensionless |
| species 10 Proline-rich AKT1 substrate 1 |
0.0 dimensionless |
| 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 |
(added: 12 Aug 2015, 23:11:44, updated: 12 Aug 2015, 23:11:44)