ArticleThe Journal of clinical investigation2010
Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade.
Article in The Journal of clinical investigation, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 132 papers, 1 of them a synthesis that pooled it.
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Who cites it
132 citing papers in PubMed, 1 synthesis or guideline pooled it, 231 citations in OpenAlex.
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- Cell differentiation-related signaling pathways: biological functions, diseases and therapeutic targets.Signal transduction and targeted therapy · 2026Review
- PI3K/AKT signaling pathway: molecular crossroads in tumorigenesis and therapeutic innovation.Signal transduction and targeted therapy · 2026Review
- A synthetic molecule targeting STAT3 against human oral squamous cell carcinoma cells.International journal of medical sciences · 2025Article
- Integrating Physical and Biochemical Cues for Muscle Engineering: Scaffolds and Graft Durability.Bioengineering (Basel, Switzerland) · 2024Review
- mTOR/miR-142-3p/PRAS40 signaling cascade is critical for tuberous sclerosis complex-associated renal cystogenesis.Cellular & molecular biology letters · 2024Article
- Augmented ERO1α upon mTORC1 activation induces ferroptosis resistance and tumor progression via upregulation of SLC7A11.Journal of experimental & clinical cancer research : CR · 2024Article
- Interfering with the AKT/mTOR/STAT3/ID1 signaling axis with usenamine A restrains the proliferative and invasive potential of human hepatocellular carcinoma cells.Chinese medicine · 2024Article
- Duct ligation/de-ligation model: exploring mechanisms for salivary gland injury and regeneration.Frontiers in cell and developmental biology · 2024Review
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- Targeting TREM1 augments antitumor T cell immunity by inhibiting myeloid-derived suppressor cells and restraining anti-PD-1 resistance.The Journal of clinical investigation · 2023Article
- The roles of JAK2/STAT3 signaling in fusion of the secondary palate.Disease models & mechanisms · 2023Article
- Polo-like kinase 1 promotes pulmonary hypertension.Respiratory research · 2023Article
- Specific Features of Focal Cortical Dysplasia in Tuberous Sclerosis Complex.Current issues in molecular biology · 2023Review
- Stiff matrix induces exosome secretion to promote tumour growth.Nature cell biology · 2023Article
- The Potential Therapeutic Role of Metformin in Diabetic and Non-Diabetic Bone Impairment.Pharmaceuticals (Basel, Switzerland) · 2022Review
- STAT3/miR-130b-3p/MBNL1 feedback loop regulated by mTORC1 signaling promotes angiogenesis and tumor growth.Journal of experimental & clinical cancer research : CR · 2022Article
72 more citing papers are in PubMed but not listed here.
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27 authors at 9 institutions in 4 countries.
Funding
Abstract
The receptor tyrosine kinase/PI3K/AKT/mammalian target of rapamycin (RTK/PI3K/AKT/mTOR) pathway is frequently altered in cancer, but the underlying mechanism leading to tumorigenesis by activated mTOR remains less clear. Here we show that mTOR is a positive regulator of Notch signaling in mouse and human cells, acting through induction of the STAT3/p63/Jagged signaling cascade. Furthermore, in response to differential cues from mTOR, we found that Notch served as a molecular switch to shift the balance between cell proliferation and differentiation. We determined that hyperactive mTOR signaling impaired cell differentiation of murine embryonic fibroblasts via potentiation of Notch signaling. Elevated mTOR signaling strongly correlated with enhanced Notch signaling in poorly differentiated but not in well-differentiated human breast cancers. Both human lung lymphangioleiomyomatosis (LAM) and mouse kidney tumors with hyperactive mTOR due to tumor suppressor TSC1 or TSC2 deficiency exhibited enhanced STAT3/p63/Notch signaling. Furthermore, tumorigenic potential of cells with uncontrolled mTOR signaling was suppressed by Notch inhibition. Our data therefore suggest that perturbation of cell differentiation by augmented Notch signaling might be responsible for the underdifferentiated phenotype displayed by certain tumors with an aberrantly activated RTK/PI3K/AKT/mTOR pathway. Additionally, the STAT3/p63/Notch axis may be a useful target for the treatment of cancers exhibiting hyperactive mTOR signaling.
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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.