Protein interaction network analysis of mTOR signaling reveals modular organization
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved..
The mammalian target of rapamycin (mTOR) is a serine-threonine kinase that acts as a central mediator of translation and plays important roles in cell growth, synaptic plasticity, cancer, and a wide range of developmental disorders. The signaling cascade linking lipid kinases (phosphoinositide 3-kinases), protein kinases (AKT), and translation initiation complexes (EIFs) to mTOR has been extensively modeled, but does not fully describe mTOR system behavior. Here, we use quantitative multiplex coimmunoprecipitation to monitor a protein interaction network (PIN) composed of 300+ binary interactions among mTOR-related proteins. Using a simple model system of serum-deprived or fresh-media-fed mouse 3T3 fibroblasts, we observed extensive PIN remodeling involving 27+ individual protein interactions after 1 h, despite phosphorylation changes observed after only 5 min. Using small molecule inhibitors of phosphoinositide 3-kinase, AKT, mTOR, MEK and ERK, we define subsets of the PIN, termed "modules", that respond differently to each inhibitor. Using primary fibroblasts from individuals with overgrowth disorders caused by pathogenic PIK3CA or MTOR variants, we find that hyperactivation of mTOR pathway components is reflected in a hyperactive PIN. Our data define a "modular" organization of the mTOR PIN in which coordinated groups of interactions respond to the activation or inhibition of distinct nodes, and demonstrate that kinase inhibitors affect the modular network architecture in a complex manner, inconsistent with simple linear models of signal transduction.
| Errataetall: | |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:299 |
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| Enthalten in: |
The Journal of biological chemistry - 299(2023), 11 vom: 24. Nov., Seite 105271 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wehle, Devin T [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 06.12.2023 Date Revised 06.02.2024 published: Print-Electronic UpdateOf: bioRxiv. 2023 Aug 04;:. - PMID 37577705 Citation Status MEDLINE |
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| doi: |
10.1016/j.jbc.2023.105271 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM362379408 |
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| 500 | |a UpdateOf: bioRxiv. 2023 Aug 04;:. - PMID 37577705 | ||
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| 520 | |a Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a The mammalian target of rapamycin (mTOR) is a serine-threonine kinase that acts as a central mediator of translation and plays important roles in cell growth, synaptic plasticity, cancer, and a wide range of developmental disorders. The signaling cascade linking lipid kinases (phosphoinositide 3-kinases), protein kinases (AKT), and translation initiation complexes (EIFs) to mTOR has been extensively modeled, but does not fully describe mTOR system behavior. Here, we use quantitative multiplex coimmunoprecipitation to monitor a protein interaction network (PIN) composed of 300+ binary interactions among mTOR-related proteins. Using a simple model system of serum-deprived or fresh-media-fed mouse 3T3 fibroblasts, we observed extensive PIN remodeling involving 27+ individual protein interactions after 1 h, despite phosphorylation changes observed after only 5 min. Using small molecule inhibitors of phosphoinositide 3-kinase, AKT, mTOR, MEK and ERK, we define subsets of the PIN, termed "modules", that respond differently to each inhibitor. Using primary fibroblasts from individuals with overgrowth disorders caused by pathogenic PIK3CA or MTOR variants, we find that hyperactivation of mTOR pathway components is reflected in a hyperactive PIN. Our data define a "modular" organization of the mTOR PIN in which coordinated groups of interactions respond to the activation or inhibition of distinct nodes, and demonstrate that kinase inhibitors affect the modular network architecture in a complex manner, inconsistent with simple linear models of signal transduction | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 650 | 4 | |a mTOR | |
| 650 | 4 | |a mTORopathy | |
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| 700 | 1 | |a Sulc, Josef |e verfasserin |4 aut | |
| 700 | 1 | |a Mirzaa, Ghayda |e verfasserin |4 aut | |
| 700 | 1 | |a Smith, Stephen E P |e verfasserin |4 aut | |
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