ArticleNature cell biology2013
Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis.
Article in Nature cell biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 167 papers, 2 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
167 citing papers in PubMed, 2 syntheses or guidelines pooled it, 254 citations in OpenAlex.
- Molecular mechanisms of sex hormones in Hepatocellular Carcinoma: a systematic review.Molecular biology reports · 2025Pooled it
- PI3K/AKT/mTOR Targeting in Colorectal Cancer Radiotherapy: A Systematic Review.Journal of gastrointestinal cancer · 2025Pooled it
- Review
- RMC-6272, a selective third-generation bi-steric mTORC1 inhibitor, improves cardiac function in pressure overload-induced cardiac hypertrophy.Journal of molecular and cellular cardiology plus · 2026Article
- A novel quinazolinone insulin receptor inhibitor and its synergy with an EGFR inhibitor in glucose-driven glioblastoma.Molecular oncology · 2026Article
- Metabolic regulation by tanycyte-derived extracellular vesicles through insulin precursor-mediated neuronal recognition and mTORC component delivery.Nature metabolism · 2026Article
- The mTORC2 component SIN1 post-transcriptionally regulates TYMS levels and modulates P53 activity in response to 5-FU chemotherapy.Cell communication and signaling : CCS · 2026Article
- TRIM21 and OTUD6A orchestrate AKT K27-linked atypical ubiquitination to modulate cancer chemoresistance.Nature structural & molecular biology · 2026Article
- SIN1 facilitates glioma progression and is associated with the KRAS/ERK pathway.Journal of neuro-oncology · 2025Article
- Phosphorylation of USP33 by CDK1 stabilizes the mTORC2 component SIN1.Cell death & disease · 2025Article
- Targeting the PI3K/AKT/mTOR pathway in lung cancer: mechanisms and therapeutic targeting.Frontiers in pharmacology · 2025Review
- Insulin restores retinal ganglion cell functional connectivity and promotes visual recovery in glaucoma.Science advances · 2024Article
- The mTORC2 signaling network: targets and cross-talks.The Biochemical journal · 2024Review
- A New Concept in Antidiabetic Therapeutics: A Concerted Removal of Labile Iron and Intracellular Deposition of Zinc.Diabetes & metabolism journal · 2024Article
- Metabolic plasticity sustains the robustness of Caenorhabditis elegans embryogenesis.EMBO reports · 2023Article
- Inhibitors of phosphoinositide 3-kinase (PI3K) and phosphoinositide 3-kinase-related protein kinase family (PIKK).Journal of enzyme inhibition and medicinal chemistry · 2023Review
- mTOR Signaling Pathway and Gut Microbiota in Various Disorders: Mechanisms and Potential Drugs in Pharmacotherapy.International journal of molecular sciences · 2023Review
- AMPK-dependent phosphorylation of the GATOR2 component WDR24 suppresses glucose-mediated mTORC1 activation.Nature metabolism · 2023Article
- Cell cycle control by the insulin-like growth factor signal: at the crossroad between cell growth and mitotic regulation.Cell cycle (Georgetown, Tex.) · 2023Review
- Look who's TORking: mTOR-mediated integration of cell status and external signals during limb development and endochondral bone growth.Frontiers in cell and developmental biology · 2023Review
107 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
- Erratum issued
Authors and funding
21 authors at 5 institutions in 1 country.
Funding
Abstract
The mechanistic target of rapamycin (mTOR) functions as a critical regulator of cellular growth and metabolism by forming multi-component, yet functionally distinct complexes mTORC1 and mTORC2. Although mTORC2 has been implicated in mTORC1 activation, little is known about how mTORC2 is regulated. Here we report that phosphorylation of Sin1 at Thr 86 and Thr 398 suppresses mTORC2 kinase activity by dissociating Sin1 from mTORC2. Importantly, Sin1 phosphorylation, triggered by S6K or Akt, in a cellular context-dependent manner, inhibits not only insulin- or IGF-1-mediated, but also PDGF- or EGF-induced Akt phosphorylation by mTORC2, demonstrating a negative regulation of mTORC2 independent of IRS-1 and Grb10. Finally, a cancer-patient-derived Sin1-R81T mutation impairs Sin1 phosphorylation, leading to hyper-activation of mTORC2 by bypassing this negative regulation. Together, our results reveal a Sin1-phosphorylation-dependent mTORC2 regulation, providing a potential molecular mechanism by which mutations in the mTORC1-S6K-Sin1 signalling axis might cause aberrant hyper-activation of the mTORC2-Akt pathway, which facilitates tumorigenesis.
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What OpenQuestion holds
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.