ArticleOncotarget2016
VPS34 regulates TSC1/TSC2 heterodimer to mediate RheB and mTORC1/S6K1 activation and cellular transformation.
Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 27 citations in OpenAlex.
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- Class III Phosphatidylinositol-3 Kinase/Vacuolar Protein Sorting 34 in Cardiovascular Health and Disease.Journal of cardiovascular translational research · 2025Review
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- Structural and functional characterization of IgG- and non-IgG-based T-cell-engaging bispecific antibodies.Frontiers in immunology · 2024Article
- TRIM28 in cancer and cancer therapy.Frontiers in genetics · 2024Review
- Class 3 PI3K coactivates the circadian clock to promote rhythmic de novo purine synthesis.Nature cell biology · 2023Article
- LncRNA PVT-1 promotes osteosarcoma cancer stem-like properties through direct interaction with TRIM28 and TSC2 ubiquitination.Oncogene · 2022Article
- Comparative Characterization of Different Molecular Formats of Bispecific Antibodies Targeting EGFR and PD-L1.Pharmaceutics · 2022Article
- The Role of Phosphatidylinositol 3-Kinase Catalytic Subunit Type 3 in the Pathogenesis of Human Cancer.International journal of molecular sciences · 2021Review
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- The role of ubiquitination and deubiquitination in cancer metabolism.Molecular cancer · 2020Review
- Overexpression of BmFoxO inhibited larval growth and promoted glucose synthesis and lipolysis in silkworm.Molecular genetics and genomics : MGG · 2019Article
- VPS34 complexes from a structural perspective.Journal of lipid research · 2019Review
- PtdIns3P controls mTORC1 signaling through lysosomal positioning.The Journal of cell biology · 2017Article
- Lysosomal regulation of cholesterol homeostasis in tuberous sclerosis complex is mediated via NPC1 and LDL-R.Oncotarget · 2017Article
- Atezolizumab potentiates Tcell-mediated cytotoxicity and coordinates with FAK to suppress cell invasion and motility in PD-L1OncoimmunologyArticle
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
VPS34 is reported to activate S6K1 and is implicated in regulating cell growth, the mechanisms of which remain elusive. Here, we describe novel mechanisms by which VPS34 upregulates mTOR/S6K1 activity via downregulating TSC2 protein and activating RheB activity. Specifically, upregulation of VPS34 lipid kinase increases local production of ptdins(3)p in the plasma membrane, which recruits PIKFYVE, a FYVE domain containing protein, to ptdins(3)p enriched regions of the plasma membrane, where VPS34 forms a protein complex with PIKFYVE and TSC1. This in turn disengages TSC2 from the TSC1/TSC2 heterodimer, leading to TSC2 ubiquitination and degradation. Downregulation of TSC2 promotes the activation of RheB and mTOR/S6K1. When VPS34 lipid kinase activity is increased by introduction of an H868R mutation, ptdins(3)p production at the plasma membrane is dramatically increased, which recruits more PIKFYVE and TSC1 molecules to the plasma membrane. This results in the enhanced TSC2 ubiquitination and degradation, and subsequent activation of RheB and mTORC1/S6K1, leading to oncogenic transformation. The role played by VPS34 in regulating mTOR/S6K1 activity and cellular transformation is underscored by the fact that the VPS34 kinase dead mutant blocks VPS34-induced recruitment of PIKFYVE and TSC1 to the plasma membrane. This study provides mechanistic insight into the cellular function of VPS34 in regulating oncogenic transformation and important indications for identifying VPS34 specific mutations in human cancers.
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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 Socratic graph.