دورية أكاديمية
Protein interaction network analysis of mTOR signaling reveals modular organization.
| العنوان: | Protein interaction network analysis of mTOR signaling reveals modular organization. |
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| المؤلفون: | Wehle DT; Graduate Program in Neuroscience, University of Washington, Seattle, Washington, USA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA., Bass CS; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA., Sulc J; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA., Mirzaa G; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA; Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA; Brotman Baty Institute for Precision Medicine, Seattle, Washington, USA., Smith SEP; Graduate Program in Neuroscience, University of Washington, Seattle, Washington, USA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA; Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA. Electronic address: seps@uw.edu. |
| المصدر: | The Journal of biological chemistry [J Biol Chem] 2023 Nov; Vol. 299 (11), pp. 105271. Date of Electronic Publication: 2023 Sep 21. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology |
| مواضيع طبية MeSH: | Signal Transduction* , TOR Serine-Threonine Kinases*/antagonists & inhibitors , TOR Serine-Threonine Kinases*/genetics , TOR Serine-Threonine Kinases*/metabolism, Animals ; Mice ; Phosphorylation ; Protein Interaction Maps ; Protein Kinase Inhibitors/pharmacology ; NIH 3T3 Cells ; Cells, Cultured ; Humans ; MAP Kinase Signaling System/drug effects ; Mutation |
| مستخلص: | 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. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.) |
| التعليقات: | Update of: bioRxiv. 2023 Aug 04;:. (PMID: 37577705) |
| معلومات مُعتمدة: | R01 MH113545 United States MH NIMH NIH HHS; R01 MH121487 United States MH NIMH NIH HHS |
| فهرسة مساهمة: | Keywords: PIK3CA; mTOR; mTORopathy; protein-protein interaction; signal transduction |
| المشرفين على المادة: | EC 2.7.11.1 (TOR Serine-Threonine Kinases) 0 (Protein Kinase Inhibitors) 0 (FR 180204) |
| تواريخ الأحداث: | Date Created: 20230923 Date Completed: 20231206 Latest Revision: 20240206 |
| رمز التحديث: | 20240206 |
| مُعرف محوري في PubMed: | PMC10594569 |
| DOI: | 10.1016/j.jbc.2023.105271 |
| PMID: | 37741456 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1083-351X |
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| DOI: | 10.1016/j.jbc.2023.105271 |