ArticleCancer discovery2015
PtdIns(3,4,5)P3-Dependent Activation of the mTORC2 Kinase Complex.
Article in Cancer discovery, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 247 papers.
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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.
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Who cites it
247 citing papers in PubMed, 375 citations in OpenAlex.
- The role of mTORC2/RICTOR in immune cells and inflammatory diseases.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Review
- PTEN Regulates Microtubule Polymerization via mTORC2, But Not mTORC1, in Peripheral Sensory Neurons.eNeuro · 2026Article
- TNFAIP8 polarity proteins mediate T cell development by propagating lipid second messenger signaling in thymocytes.Cell death & disease · 2026Article
- Development of a SIN1 Targeting Inhibitor as a Novel Therapeutic Approach for the Treatment of Malignancies.Molecular cancer therapeutics · 2026Article
- Lipid transfer proteins and PI4KIIα initiate nuclear p53-phosphoinositide signaling.The Journal of biological chemistry · 2026Article
- SLAP controls mTORC2 integrity via UBE3C-mediated non-degradative mLST8 ubiquitination to suppress colorectal tumorigenesis.Cell death and differentiation · 2026Article
- Exploring the role of metabolic disorders and gut microbiome in immune checkpoint regulation in cancer: PI3K/AKT/mTOR focus.Journal of physiology and biochemistry · 2026Review
- Structural basis for the recruitment and selective phosphorylation of Akt by mTORC2.Science (New York, N.Y.) · 2026Article
- Liprin-α1 enhances PHLDB3 oncogenic function in colorectal cancer via activation of mTORC2-AKT1 pathway.Cell reports · 2026Article
- The mTOR Pathway in Hearing Disorders: Mechanistic Links to Aging, Regeneration, and Neurodegeneration.Molecular neurobiology · 2026Review
- Rhein protects against renal aging and fibrotic injury by multiple targets through inhibition of TNF-α-mediated autophagy and necroptosis crosstalk.Frontiers in pharmacology · 2026Article
- TRIM21 and OTUD6A orchestrate AKT K27-linked atypical ubiquitination to modulate cancer chemoresistance.Nature structural & molecular biology · 2026Article
- mTOR signaling networks: mechanistic insights and translational frontiers in disease therapeutics.Signal transduction and targeted therapy · 2025Review
- Sirolimus for the treatment of Graves' orbitopathy.Thyroid research · 2025Review
- DEPTOR regulates nucleus pulposus cell senescence through the mTORC1/S6K1/ATG1 pathway to alleviate intervertebral disk degeneration.Cell death discovery · 2025Article
- Review
- Stable Cas9 expression regulates cell growth by facilitating mTORC2 activation.Nucleic acids research · 2025Article
- The insulin signalling network.Nature metabolism · 2025Review
- Phosphorylation of USP33 by CDK1 stabilizes the mTORC2 component SIN1.Cell death & disease · 2025Article
- The dual role of mTOR signaling in lung development and adult lung diseases.Cell & bioscience · 2025Review
187 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
Abstract
unlabelledmTOR serves as a central regulator of cell growth and metabolism by forming two distinct complexes, mTORC1 and mTORC2. Although mechanisms of mTORC1 activation by growth factors and amino acids have been extensively studied, the upstream regulatory mechanisms leading to mTORC2 activation remain largely elusive. Here, we report that the pleckstrin homology (PH) domain of SIN1, an essential and unique component of mTORC2, interacts with the mTOR kinase domain to suppress mTOR activity. More importantly, PtdIns(3,4,5)P3, but not other PtdInsPn species, interacts with SIN1-PH to release its inhibition on the mTOR kinase domain, thereby triggering mTORC2 activation. Mutating critical SIN1 residues that mediate PtdIns(3,4,5)P3 interaction inactivates mTORC2, whereas mTORC2 activity is pathologically increased by patient-derived mutations in the SIN1-PH domain, promoting cell growth and tumor formation. Together, our study unravels a PI3K-dependent mechanism for mTORC2 activation, allowing mTORC2 to activate AKT in a manner that is regulated temporally and spatially by PtdIns(3,4,5)P3. SIGNIFICANCE: The SIN1-PH domain interacts with the mTOR kinase domain to suppress mTOR activity, and PtdIns(3,4,5)P3 binds the SIN1-PH domain to release its inhibition on the mTOR kinase domain, leading to mTORC2 activation. Cancer patient-derived SIN1-PH domain mutations gain oncogenicity by loss of suppressing mTOR activity as a means to facilitate tumorigenesis.
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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.