دورية أكاديمية
Molecular determinants of Ras-mTORC2 signaling.
| العنوان: | Molecular determinants of Ras-mTORC2 signaling. |
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| المؤلفون: | Smith SF; Department of Chemistry and Biochemistry, University of Arizona, Tucson, Arizona, USA., Islam AFMT; Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona, USA., Alimukhamedov S; Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona, USA., Weiss ET; Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona, USA., Charest PG; Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona, USA; Department of Chemistry and Biochemistry, University of Arizona, Tucson, Arizona, USA; University of Arizona Cancer Center, Tucson, Arizona, USA. Electronic address: pcharest@arizona.edu. |
| المصدر: | The Journal of biological chemistry [J Biol Chem] 2024 Jul; Vol. 300 (7), pp. 107423. Date of Electronic Publication: 2024 May 28. |
| نوع المنشور: | Journal Article |
| 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: | Dictyostelium*/metabolism , Dictyostelium*/genetics , Mechanistic Target of Rapamycin Complex 2*/metabolism , Mechanistic Target of Rapamycin Complex 2*/genetics , Signal Transduction* , ras Proteins*/metabolism, Protozoan Proteins/metabolism ; Protozoan Proteins/genetics ; Protozoan Proteins/chemistry ; Cyclic AMP/metabolism |
| مستخلص: | Recent research has identified the mechanistic Target of Rapamycin Complex 2 (mTORC2) as a conserved direct effector of Ras proteins. While previous studies suggested the involvement of the Switch I (SWI) effector domain of Ras in binding mTORC2 components, the regulation of the Ras-mTORC2 pathway is not entirely understood. In Dictyostelium, mTORC2 is selectively activated by the Ras protein RasC, and the RasC-mTORC2 pathway then mediates chemotaxis to cAMP and cellular aggregation by regulating the actin cytoskeleton and promoting cAMP signal relay. Here, we investigated the role of specific residues in RasC's SWI, C-terminal allosteric domain, and hypervariable region (HVR) related to mTORC2 activation. Interestingly, our results suggest that RasC SWI residue A31, which was previously implicated in RasC-mediated aggregation, regulates RasC's specific activation by the Aimless RasGEF. On the other hand, our investigation identified a crucial role for RasC SWI residue T36, with secondary contributions from E38 and allosteric domain residues. Finally, we found that conserved basic residues and the adjacent prenylation site in the HVR, which are crucial for RasC's membrane localization, are essential for RasC-mTORC2 pathway activation by allowing for both RasC's own cAMP-induced activation and its subsequent activation of mTORC2. Therefore, our findings revealed new determinants of RasC-mTORC2 pathway specificity in Dictyostelium, contributing to a deeper understanding of Ras signaling regulation in eukaryotic cells. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.) |
| فهرسة مساهمة: | Keywords: Dictyostelium; HVR; RasC; allosteric domain; hypervariable region; mTOR; mechanistic Target of Rapamycin complex 2; switch I |
| المشرفين على المادة: | EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2) EC 3.6.5.2 (ras Proteins) 0 (Protozoan Proteins) E0399OZS9N (Cyclic AMP) |
| تواريخ الأحداث: | Date Created: 20240530 Date Completed: 20240725 Latest Revision: 20240725 |
| رمز التحديث: | 20240726 |
| مُعرف محوري في PubMed: | PMC11255897 |
| DOI: | 10.1016/j.jbc.2024.107423 |
| PMID: | 38815864 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1083-351X |
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| DOI: | 10.1016/j.jbc.2024.107423 |