ArticleThe Journal of biological chemistry2016
Mechanistic Target of Rapamycin Complex 1 (mTORC1) and mTORC2 as Key Signaling Intermediates in Mesenchymal Cell Activation.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 46 citations in OpenAlex.
- Single-cell multiomic analysis of mesenchymal cells reveals molecular signatures and regulators of lung allograft fibrosis.JCI insight · 2026Article
- In vitro study of TSC1 deficiency in preadipocytes: insights into development and treatment options for tuberous sclerosis related lipomatosis.Orphanet journal of rare diseases · 2026Article
- 4E-BP1 acts as a molecular rheostat balancing regenerative healing and fibrotic scarring.Experimental & molecular medicine · 2026Article
- Pathological Interplay of ROS With Myofibroblasts: An Impediment to Corneal Restitution.Oxidative medicine and cellular longevity · 2026Review
- 4EBP1 phosphorylation mediates TGF-β1-induced hepatic fibrosis and upregulates HIF-1α expression.iScience · 2025Article
- Quantitative Proteomic Study Reveals Amygdalin Alleviates Liver Fibrosis Through Inhibiting mTOR/PDCD4/JNK Pathway in Hepatic Stellate Cells.Drug design, development and therapy · 2025Article
- MNK-driven eIF4E phosphorylation regulates the fibrogenic transformation of mesenchymal cells and chronic lung allograft dysfunction.The Journal of clinical investigation · 2024Article
- IL-4/IL-4R axis signaling drives resistance to immunotherapy by inducing the upregulation of Fcγ receptor IIB in M2 macrophages.Cell death & disease · 2024Article
- Piezo1 Activation Drives Enhanced Collagen Synthesis in Aged Animal Skin Induced by Poly L-Lactic Acid Fillers.International journal of molecular sciences · 2024Article
- Metabolic requirements of pulmonary fibrosis: role of fibroblast metabolism.The FEBS journal · 2021Review
- Interleukin 6 trans-signaling is a critical driver of lung allograft fibrosis.American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons · 2021Article
- β1 integrin, ILK and mTOR regulate collagen synthesis in mechanically loaded tendon cells.Scientific reports · 2020Article
- mTOR inhibitor everolimus reduces invasiveness of melanoma cells.Human cell · 2020Article
- Transforming growth factor β1 alters the 3'-UTR of mRNA to promote lung fibrosis.The Journal of biological chemistry · 2019Article
- mTORC1 amplifies the ATF4-dependent de novo serine-glycine pathway to supply glycine during TGF-βScience signaling · 2019Article
- The mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis.Nature communications · 2019Article
- P27 Promotes TGF-Canadian respiratory journal · 2019Article
- c-Jun N-terminal kinase (JNK)-mediated induction of mSin1 expression and mTORC2 activation in mesenchymal cells during fibrosis.The Journal of biological chemistry · 2018Article
- Combined treatment with sinomenine and acupuncture on collagen-induced arthritis through the NF-κB and MAPK signaling pathway.Oncology letters · 2018Article
- The Role of the Mammalian Target of Rapamycin (mTOR) in Pulmonary Fibrosis.International journal of molecular sciences · 2018Review
Corrections and comments
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
Fibrotic diseases display mesenchymal cell (MC) activation with pathologic deposition of matrix proteins such as collagen. Here we investigate the role of mTOR complex 1 (mTORC1) and mTORC2 in regulating MC collagen expression, a hallmark of fibrotic disease. Relative to normal MCs (non-Fib MCs), MCs derived from fibrotic human lung allografts (Fib-MCs) demonstrated increased phosphoinositide-3kinase (PI3K) dependent activation of both mTORC1 and mTORC2, as measured by increased phosphorylation of S6K1 and 4E-BP1 (mTORC1 substrates) and AKT (an mTORC2 substrate). Dual ATP-competitive TORC1/2 inhibitor AZD8055, in contrast to allosteric mTORC1-specific inhibitor rapamycin, strongly inhibited 4E-BP1 phosphorylation and collagen I expression in Fib-MCs. In non-Fib MCs, increased mTORC1 signaling was shown to augment collagen I expression. mTORC1/4E-BP1 pathway was identified as an important driver of collagen I expression in Fib-MCs in experiments utilizing raptor gene silencing and overexpression of dominant-inhibitory 4E-BP1. Furthermore, siRNA-mediated knockdown of rictor, an mTORC2 partner protein, reduced mTORC1 substrate phosphorylation and collagen expression in Fib-, but not non-Fib MCs, revealing a dependence of mTORC1 signaling on mTORC2 function in activated MCs. Together these studies suggest a novel paradigm where fibrotic activation in MCs increases PI3K dependent mTORC1 and mTORC2 signaling and leads to increased collagen I expression via the mTORC1-dependent 4E-BP1/eIF4E pathway. These data provide rationale for targeting specific components of mTORC pathways in fibrotic states and underscore the need to further delineate mTORC2 signaling in activated cell states.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.