Affinage

PIK3C3

Phosphatidylinositol 3-kinase catalytic subunit type 3 · UniProt Q8NEB9

Length
887 aa
Mass
101.5 kDa
Annotated
2026-04-28
100 papers in source corpus 48 papers cited in narrative 48 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PIK3C3 (VPS34) is the sole class III phosphatidylinositol 3-kinase in mammals, generating PtdIns(3)P to control autophagosome biogenesis, endosomal sorting, retrograde membrane transport, lysosome reformation, and nutrient-dependent mTORC1 signaling. It functions obligately within two major multiprotein complexes: Complex I (VPS34–VPS15–Beclin-1–ATG14L–NRBF2), which drives autophagy initiation, and Complex II (VPS34–VPS15–Beclin-1–UVRAG), which governs endosomal trafficking and lysosome reformation; Rab GTPases (Rab5a for Complex II, Rab1a for Complex I) recruit these complexes to target membranes and relieve VPS15-mediated autoinhibition of the VPS34 catalytic domain through a conformational dislodging mechanism (PMID:11157979, PMID:33692360, PMID:28757208, PMID:26450213). VPS34 activity is extensively regulated by post-translational modifications including activating phosphorylation of its partners by ULK1 (Beclin-1 Ser14, VPS15 Ser861) and mTOR (UVRAG S550/S571 for lysosome reformation), inhibitory Cdk1 phosphorylation (VPS34 Thr159), SUMOylation at Lys840, lactylation at Lys356/Lys781, and ubiquitin-mediated degradation by FBXL20, KLHL20, and UBE3C counteracted by USP13/NEDD4-1 and TRABID (PMID:25593308, PMID:34121209, PMID:23569248, PMID:37267363, PMID:33637724). Tissue-specific deletion causes hepatomegaly with steatosis, cardiomegaly, neurodegeneration preferentially through endosomal dysfunction, and impaired T cell IL-7Rα recycling, demonstrating essential non-redundant roles in multiple organ systems (PMID:22308354, PMID:20439739, PMID:22021616).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1998 High

    Establishing that mammalian VPS34 is required for endosomal trafficking of internalized receptors and cell cycle progression answered whether class III PI3K has a functional role distinct from class I PI3Ks in mammalian cells.

    Evidence Microinjection of isoform-specific inhibitory antibodies and antisense knockdown in cultured cells with PDGFR trafficking and DNA synthesis readouts

    PMID:9852157

    Open questions at the time
    • Substrate specificity for PtdIns(3)P not yet formally demonstrated in these cells
    • Mechanism by which VPS34 promotes G1-S transition unresolved
  2. 2001 High

    The discovery that VPS34 assembles into two functionally distinct complexes—one with Apg14p for autophagy and another with Vps38p for vacuolar sorting—established the paradigm that a single lipid kinase generates pathway-specific PtdIns(3)P pools through complex-specific subunits.

    Evidence Reciprocal co-IP, mass spectrometry, and phenotypic analysis of deletion mutants in yeast

    PMID:11157979

    Open questions at the time
    • Mammalian equivalents of complex-specific subunits not yet identified at this point
    • How complex assembly is regulated was unknown
  3. 2002 High

    Demonstrating that Rab5 recruits VPS34/VPS15 to early endosomes through the VPS15 WD40 domain resolved how the kinase is targeted to specific compartments and linked Rab GTPase biology to PtdIns(3)P generation.

    Evidence Recombinant domain-mapping, subcellular fractionation, and EEA1 displacement assays in Rab5-expressing cells

    PMID:12010460

    Open questions at the time
    • Whether Rab7 independently recruits VPS34 to late endosomes was unresolved
    • Structural basis of the Rab–VPS15 interaction unknown
  4. 2003 High

    Identification of Ca²⁺/calmodulin as a direct activator of VPS34 on phagosomes, and its exploitation by M. tuberculosis to block phagosome maturation, revealed a signal-dependent activation mechanism with pathophysiological relevance, although the Ca²⁺/CaM requirement was later contested.

    Evidence In vitro PI3P production assay on liposomes, pharmacological Ca²⁺/CaM inhibition in macrophages

    PMID:12925680 PMID:18460336 PMID:18957027

    Open questions at the time
    • Conflicting data on whether Ca²⁺/CaM is required for VPS34 activity in reconstituted systems
    • Whether VPS15 co-expression accounts for the discrepancy was not fully resolved
  5. 2005 High

    Showing that VPS34 is a nutrient-regulated kinase required for mTORC1/S6K1 activation established a new role for class III PI3K upstream of growth signaling, beyond its vesicle trafficking functions.

    Evidence siRNA knockdown, antibody microinjection, FYVE-domain PI3P sequestration with S6K1/4EBP1 phosphorylation readouts

    PMID:16049009

    Open questions at the time
    • Direct mechanism linking PtdIns(3)P to mTORC1 activation unclear
    • Relative contribution of VPS34 versus class I PI3K to mTOR signaling debated
  6. 2006 High

    Systematic siRNA knockdown and yeast genetic studies revealed that VPS34 loss causes enlarged late endosomes with impaired intraluminal vesicle formation and EGFR degradation, and that VPS15 functions as a G-beta-like scaffold engaging G-alpha subunits, defining the endosomal sorting branch of VPS34 function.

    Evidence Electron microscopy, EGFR degradation assays in VPS34-depleted cells; genome-wide epistasis screen with Gpa1 and direct binding assays in yeast

    PMID:16522686 PMID:16839886

    Open questions at the time
    • How VPS34-dependent PtdIns(3)P recruits ESCRT machinery for ILV formation was not determined
    • Mammalian relevance of G-alpha regulation unknown
  7. 2007 High

    Demonstrating that myotubularin (MTM1) binds VPS15 WD40 in a manner mutually exclusive with Rab5/Rab7, and that VPS34-produced PtdIns(3)P is required for retrograde endosome-to-Golgi transport, defined a synthesis-degradation molecular switch and expanded the repertoire of VPS34-dependent trafficking pathways.

    Evidence Domain-mapping Co-IP of MTM1–VPS15, competitive binding with Rab GTPases, ricin retrograde transport assays with dominant-negative VPS34 and siRNA

    PMID:17319803 PMID:17651088

    Open questions at the time
    • How the MTM1–VPS15 switch is regulated temporally on endosomes was unknown
    • Sorting nexin effector mechanisms downstream of PtdIns(3)P not fully defined
  8. 2010 High

    Discovery that Cdk1 phosphorylates VPS34 at Thr159 to disrupt Beclin-1 binding during mitosis, and that neuronal VPS34 deletion causes neurodegeneration preferentially through endosomal rather than autophagic dysfunction, established cell-cycle-dependent regulation and revealed tissue-specific hierarchy of VPS34 functions.

    Evidence In vitro Cdk1 kinase assay with phosphomimetic mutants; conditional neuron-specific Pik3c3 KO with Pik3c3/Atg7 double-mutant epistasis

    PMID:20439739 PMID:20513426

    Open questions at the time
    • How neurons bypass VPS34 for autophagosome formation is mechanistically unclear
    • Whether Cdk1-mediated regulation extends to Complex II was not tested
  9. 2012 High

    Tissue-specific VPS34 knockouts in liver and heart demonstrated essential in vivo roles in autophagy and protein turnover, causing organ-specific pathology (hepatomegaly/steatosis, cardiomegaly), and confirmed VPS34 requirement for amino acid-stimulated but not basal mTOR signaling.

    Evidence Albumin-Cre and MCK-Cre conditional KO mice with metabolic and autophagy phenotyping

    PMID:22308354

    Open questions at the time
    • How VPS34 loss leads specifically to steatosis versus general proteotoxicity was unclear
    • Compensatory mechanisms in different tissues not defined
  10. 2013 High

    Identification of ULK1 phosphorylation of Beclin-1 Ser14 to activate Complex I, and reciprocal mTORC1 phosphorylation of ATG14 to inhibit Complex I specifically, established the molecular logic by which autophagy-initiating signals converge on VPS34 complex-specific activation.

    Evidence In vitro kinase assays with phosphosite mutagenesis, VPS34 complex-specific lipid kinase assays, cross-species validation in C. elegans

    PMID:23685627 PMID:24013218

    Open questions at the time
    • Full set of ULK1 phosphosites on VPS34 complex subunits not yet mapped
    • Quantitative contribution of each phosphorylation event to autophagy flux unknown
  11. 2013 High

    Discovery that acetylated Hsp70 recruits KAP1 to SUMOylate VPS34 at Lys840, enhancing its kinase activity, revealed a stress-responsive post-translational activation mechanism distinct from phosphorylation.

    Evidence Co-IP of Hsp70–Beclin-1–VPS34 complex, SUMOylation assay with K840R mutant, lipid kinase activity measurement in Hsp70 KO MEFs

    PMID:23569248

    Open questions at the time
    • Whether SUMOylation affects Complex I versus Complex II differentially was not tested
    • Identity of the SUMO protease reversing this modification was unknown
  12. 2014 High

    Identification of NRBF2 as a Complex I-specific subunit that binds VPS15 and promotes autophagy, and demonstration that VPS34-produced PtdIns(3)P recruits ankyrin-B for dynactin-dependent fast axonal transport, expanded the functional repertoire of VPS34 beyond canonical autophagy and endosomal sorting.

    Evidence Differential Co-IP of Complex I versus II with NRBF2 knockdown; AnkB KO mice with live axonal transport imaging

    PMID:24785657 PMID:25533844

    Open questions at the time
    • Structural basis of NRBF2 integration into Complex I unknown
    • Whether AnkB-dependent transport requires Complex I or Complex II was not determined
  13. 2015 High

    The 4.4 Å crystal structure of Complex II revealed VPS15 kinase domain engagement with the VPS34 activation loop as the basis of allosteric regulation, and additional studies defined mTOR-UVRAG phosphorylation for lysosome reformation, Rubicon RUN domain-mediated inhibition, and ubiquitin-dependent VPS34 degradation by FBXL20 and KLHL20.

    Evidence X-ray crystallography with HDX-MS on giant liposomes; in vitro mTOR kinase assay on UVRAG; Co-IP and in vitro kinase inhibition with Rubicon RUN domain mutants; ubiquitination assays linking p53–FBXL20 and Cul3–KLHL20 to VPS34 degradation

    PMID:21062745 PMID:25593308 PMID:26139536 PMID:26450213 PMID:26687681

    Open questions at the time
    • Structure of Complex I (with ATG14L) not yet solved
    • How Rubicon-mediated inhibition is relieved during autophagosome maturation was unclear
  14. 2016 High

    Leucyl-tRNA synthetase was identified as a leucine-dependent direct activator of VPS34 for mTORC1 signaling, and VPS34 was shown to activate SGK3 as an alternative to Akt under PI3K inhibition, revealing amino acid sensing and drug resistance mechanisms.

    Evidence In vitro VPS34 kinase assay with purified LRS and leucine; SGK3 PX domain–PtdIns(3)P binding with tumor xenograft studies

    PMID:27477288 PMID:27481935

    Open questions at the time
    • Whether LRS activates Complex I, Complex II, or both was not resolved
    • Structural basis of LRS–VPS34 interaction unknown
  15. 2017 High

    Electron microscopy and crosslinking MS revealed that the VPS34 catalytic domain undergoes a 'dislodging' conformational change controlled by VPS15, serving as a master allosteric switch for kinase activation, and kinase-dead knock-in mice showed VPS34 activity controls whole-body glucose metabolism.

    Evidence EM structural analysis with leashed VPS34 construct blocking activity in vitro and autophagy in yeast; Vps34 kinase-dead knock-in mice with metabolic flux assays

    PMID:28757208 PMID:29180704

    Open questions at the time
    • How upstream signals (Rab GTPases, ULK1) trigger the dislodging event was not defined
    • Tissue-specific metabolic consequences not fully characterized
  16. 2020 High

    Identification of NEDD4-1/USP13-mediated deubiquitination stabilizing VPS34 at Lys419, and HDX-MS demonstration that membrane composition differentially activates Complex I (via ATG14L BATS domain) versus Complex II (via Beclin-1 BARA loops), refined the regulatory and biophysical determinants of complex-specific activity.

    Evidence K29/K48 ubiquitin linkage assays on VPS34 K419 with NEDD4-1/USP13 KO; HDX-MS on defined-composition liposomes with BATS and BARA domain mutagenesis

    PMID:32101753 PMID:32602837

    Open questions at the time
    • How membrane curvature sensing is structurally coupled to kinase activation was not resolved
    • Whether additional deubiquitinases regulate VPS34 in specific tissues is unknown
  17. 2021 High

    Cryo-ET structures showed Rab5a activates Complex II and Rab1a activates Complex I through the same VPS34 interface by relieving VPS15-mediated inhibition; ULK1 phosphoproteomics identified six VPS15 sites (including Ser861) that enhance VPS34 activity; and UBE3C/TRABID K29/K48-branched ubiquitination was defined as a degradation-stabilization toggle for VPS34.

    Evidence Cryo-electron tomography on Rab-decorated vesicles with in vitro kinase assays; unbiased phosphoproteomics in Ulk1/2 KO MEFs with VPS15 phosphosite mutant activity assays; K29/K48 branched ubiquitination biochemistry with UBE3C KO and TRABID depletion

    PMID:33637724 PMID:33692360 PMID:34121209

    Open questions at the time
    • Full structural model of activated Complex I on membranes with all regulators not yet available
    • How ULK1-dependent VPS15 phosphorylation cooperates with Rab1a for Complex I activation is unclear
  18. 2023 High

    Discovery that ULK1 drives lactate production via LDHA Ser196 phosphorylation, enabling KAT5/TIP60-mediated lactylation of VPS34 at Lys356 and Lys781 to enhance complex assembly and kinase activity, revealed a metabolite-driven post-translational activation circuit linking glycolysis to autophagy.

    Evidence In vitro ULK1-LDHA kinase assay, lactylation assay at defined VPS34 lysines, VPS34 complex Co-IP and lipid kinase assay, autophagic flux measurement

    PMID:37267363

    Open questions at the time
    • Whether lactylation acts in concert with or independently of SUMOylation and phosphorylation is unknown
    • Tissue-specific relevance of VPS34 lactylation not established
  19. 2024 Medium

    Demonstration that cysteine oxidation by a vitamin K precursor suppresses VPS34 activity and ameliorates MTM1-deficiency phenotypes introduced redox regulation as a druggable axis of VPS34 control with therapeutic implications for myotubular myopathy.

    Evidence VPS34 cysteine oxidation biochemical assay, MTM1-deficient disease model rescue with dietary menadione sodium bisulfite, muscle histology and function

    PMID:39446948

    Open questions at the time
    • Identity of specific oxidized cysteines not fully mapped
    • Long-term efficacy and off-target effects of redox-based VPS34 modulation not established
    • Single study; independent replication pending

Open questions

Synthesis pass · forward-looking unresolved questions
  • A complete structural and kinetic model integrating all known post-translational modifications (phosphorylation, SUMOylation, lactylation, ubiquitination, oxidation), Rab GTPase recruitment, and membrane sensing into a unified quantitative framework for complex-specific VPS34 activation on native membranes remains unachieved.
  • No high-resolution structure of fully assembled, membrane-engaged Complex I with all regulatory subunits and Rab1a
  • Quantitative contribution of each PTM to VPS34 activity in vivo is unknown
  • How VPS34 activity is spatially restricted to specific membrane subdomains in real time is not resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 14 GO:0008289 lipid binding 2
Localization
GO:0005768 endosome 7 GO:0031410 cytoplasmic vesicle 3 GO:0005764 lysosome 2 GO:0005829 cytosol 2
Pathway
R-HSA-9612973 Autophagy 17 R-HSA-5653656 Vesicle-mediated transport 9 R-HSA-162582 Signal Transduction 5 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-5357801 Programmed Cell Death 2
Partners
ATG14BECN1NRBF2PIK3R4RAB5ARAB7ARUBCNUVRAG
Complex memberships
PI3KC3-C1 (VPS34-VPS15-Beclin1-ATG14L-NRBF2)PI3KC3-C2 (VPS34-VPS15-Beclin1-UVRAG)

Evidence

Reading pass · 48 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Two distinct Vps34/VPS34 (PIK3C3) PI3-kinase complexes exist in yeast: one containing Vps15p, Vps30p, and Apg14p that functions in autophagy, and another containing Vps15p, Vps30p, and Vps38p that functions in carboxypeptidase Y sorting to the vacuole. Co-immunoprecipitation, pull-down experiments, mass spectrometry, phenotypic analyses of deletion mutants The Journal of cell biology High 11157979
1998 hVPS34 (PIK3C3) is required for vesicular trafficking of internalized PDGF receptors to a perinuclear compartment and for proper localization of EEA1, but not for insulin-stimulated actin ruffling; both hVPS34 and p110α are required for insulin-stimulated DNA synthesis at distinct points in G1-S transition. Microinjection of isoform-specific inhibitory antibodies, antisense oligonucleotides, vesicular trafficking assays, actin cytoskeleton assays The Journal of cell biology High 9852157
2002 Rab5 GTPase recruits hVps34/p150 (PIK3C3/VPS15) to early endosomes; the p150 HEAT and WD40 domains are required for GTP-dependent Rab5 binding, and p150 is required for EEA1 targeting to endosomes. Co-localization in Rab5-expressing cells, recombinant fragment competition assays, subcellular fractionation, dominant-active Rab5 overexpression Traffic (Copenhagen, Denmark) High 12010460
2002 Vps34 PtdIns 3-kinase activity is required for both the cytoplasm-to-vacuole targeting (Cvt) pathway and macroautophagy; a novel PtdIns(3)P-binding effector Etf1 mediates Vps34 function specifically in the Cvt pathway through a basic amino acid motif (KKPAKK). Temperature-sensitive Vps34 inactivation, genetic selection for PtdIns(3)P-binding effectors, mutagenesis of Etf1 binding motif The Journal of cell biology High 12186856
2003 hVPS34 (PIK3C3) and its adaptor p150 are Rab7 interacting partners on late endosomes; hVPS34 activity is dependent on nucleotide cycling of Rab7, and Rab7 expression modulates total cellular PtdIns3P levels. Co-localization, co-immunoprecipitation, nucleotide-dependent binding assays, PtdIns3P level measurement Traffic (Copenhagen, Denmark) Medium 14617358
2003 A Ca2+/calmodulin-hVPS34 cascade is required for PtdIns3P production on phagosomes in macrophages; M. tuberculosis toxin LAM from virulent strains blocks cytosolic Ca2+ increase, thereby inhibiting calmodulin-dependent hVPS34 activation and phagosome maturation. In vitro PI3P production assay on liposomes, in vivo phagosome PtdIns3P measurement, pharmacological Ca2+/CaM inhibition The Journal of experimental medicine High 12925680
2005 hVps34 (PIK3C3) is a nutrient-regulated lipid kinase required for activation of S6K1 and mTOR signaling; it is inhibited by amino acid or glucose starvation and by AMPK activation, and lies upstream of mTOR. siRNA knockdown, anti-hVps34 antibody microinjection, FYVE-domain sequestration of PI3P, S6K1 and 4EBP1 phosphorylation assays The Journal of biological chemistry High 16049009
2006 The yeast Gα subunit Gpa1 directly interacts with both Vps34 and Vps15 at endosomes and stimulates increased PtdIns3P production; Vps15 (which has a WD-repeat structure similar to Gβ subunits) binds GDP-bound Gpa1, revealing a preformed effector-Gβ-like assembly at the endosome. Genome-wide genetic screen with constitutively active Gpa1(Q323L), direct binding assays, endosomal localization studies, PtdIns3P measurement Cell High 16839886
2006 siRNA-mediated knockdown of hVps34 (PIK3C3) causes accumulation of enlarged late endosomes with loss of intraluminal vesicle formation and impaired EGFR degradation, but does not affect early endocytic uptake, EEA1 localization on LAMP1-negative vesicles, or TGN-to-endosome cathepsin D trafficking. siRNA gene silencing, electron microscopy, EGF receptor degradation assays, GFP-2xFYVE probe for PtdIns3P, cathepsin D processing assay Journal of cell science High 16522686
2008 Amino acids activate mTORC1 via a Ca2+/calmodulin signaling pathway to hVps34; amino acids induce a rise in intracellular Ca2+ that triggers direct binding of Ca2+/calmodulin to an evolutionarily conserved motif in hVps34, which is required for lipid kinase activity and mTORC1 signaling. Ca2+ chelation, calmodulin binding assays, hVps34 lipid kinase activity assays, mutagenesis of CaM-binding motif, mTORC1 signaling readouts Cell metabolism High 18460336
2009 hVps15 (p150) is required for hVps34 (PIK3C3) lipid kinase activity in mammalian cells; co-expression with hVps15 markedly increases hVps34 activity and is necessary for Beclin-1/UVRAG activation of hVps34 and for nutrient regulation; contrary to a prior report, hVps34 activity is independent of Ca2+/CaM. In vitro lipid kinase assays with and without hVps15 co-expression, BAPTA/AM and W7 treatment, EDTA/EGTA washes, nutrient regulation assays The Biochemical journal High 18957027
2007 Myotubularin (MTM1) PI 3-phosphatase directly binds the hVPS15/hVPS34 complex on endosomes via the WD40 domain of hVPS15; this complex is mutually exclusive with Rab5 or Rab7 binding at the hVPS15 WD40 domain, forming a molecular switch controlling sequential PtdIns3P synthesis and degradation. Co-immunoprecipitation of membrane-bound complexes, domain-mapping binding assays, overexpression of wild-type vs. phosphatase-dead MTM1, endosomal PI(3)P level measurement Traffic (Copenhagen, Denmark) High 17651088
2007 hVps34 (PIK3C3) and its product PtdIns3P are required for retrograde transport of ricin from endosomes to the Golgi apparatus; sorting nexins SNX2 and SNX4 are effectors in this hVps34-dependent pathway. PI3K inhibitors, FYVE-domain PI3P sequestration, dominant-negative hVps34 mutants, siRNA knockdown, ricin transport assays Traffic (Copenhagen, Denmark) High 17319803
2010 Vps34 (PIK3C3) is phosphorylated on Thr159 by Cdk1 during mitosis, which negatively regulates its interaction with Beclin 1 and thereby suppresses class III PtdIns3K activity; Cdk5/p25 can also phosphorylate Thr159. In vitro kinase assays, phospho-specific analysis, co-immunoprecipitation of Vps34-Beclin1 interaction with phosphomimetic/non-phosphorylatable mutants Molecular cell High 20513426
2010 PIK3C3 (Vps34) deletion in sensory neurons causes rapid neurodegeneration preferentially through disruption of the endosomal pathway rather than autophagy; PIK3C3-deficient small-diameter neurons activate a noncanonical PIK3C3-independent, ATG7-dependent LC3-positive autophagosome formation pathway. Conditional neuron-specific Cre-mediated deletion, Pik3c3/Atg7 double mutant analysis, electron microscopy, LC3 puncta analysis Proceedings of the National Academy of Sciences of the United States of America High 20439739
2011 PIK3C3 (Vps34) is required for proper IL-7Rα intracellular trafficking and recycling in T lymphocytes; Vps34-deficient T cells have mislocalized EEA1, HGF-regulated tyrosine kinase substrate, and Vps36, preventing internalized IL-7Rα from entering the retromer pathway for surface display. T cell-specific conditional Vps34 knockout mice, flow cytometry for IL-7Rα surface expression, endosome marker localization, T cell survival assays Journal of immunology High 22021616
2011 PKD (protein kinase D) is activated by DAPk, forms a complex with Vps34 (PIK3C3), and phosphorylates Vps34 to activate it, leading to PtdIns3P formation and autophagosome formation in response to oxidative stress. Co-immunoprecipitation of PKD-Vps34 complex, in vitro Vps34 phosphorylation assay, PI(3)P formation measurement, LC3-positive autophagosome assay Cell death and differentiation High 22095288
2012 Vps34 (PIK3C3) is essential for starvation-induced autophagosome formation and endocytic degradation in mammals; liver-specific deletion causes hepatomegaly and hepatic steatosis with impaired protein turnover; heart-specific deletion causes cardiomegaly and decreased contractility; amino acid-stimulated mTOR activation is suppressed without affecting steady-state mTOR signaling. Tissue-specific conditional Vps34 knockout mice (Albumin-Cre, MCK-Cre), adenoviral Cre in MEFs, PI3P localization, autophagosome formation assays, mTOR signaling assays Proceedings of the National Academy of Sciences of the United States of America High 22308354
2012 A Fyn/STAT3/Vps34 pathway regulates fiber-type-specific macroautophagy in skeletal muscle; Fyn kinase induces STAT3-dependent reduction of Vps34 protein levels, decreasing Vps34/p150/Beclin1/Atg14 complex I and inhibiting autophagy specifically in glycolytic type II fibers. Fyn kinase overexpression and Fyn null mice, STAT3 phosphorylation analysis, Vps34 complex immunoprecipitation, autophagy flux assays in glycolytic vs. oxidative fibers Cell reports High 22745922
2013 ULK1 phosphorylates Beclin-1 on Ser14 following amino-acid starvation or mTOR inhibition, thereby enhancing the lipid kinase activity of ATG14L-containing VPS34 (PIK3C3) complexes and promoting autophagic induction. In vitro kinase assay, phospho-specific Beclin-1 Ser14 antibody, VPS34 complex immunoprecipitation and lipid kinase assay, C. elegans conservation experiments Nature cell biology High 23685627
2013 MTORC1 inhibits the PtdIns3-kinase activity of ATG14-containing PIK3C3 (but not ATG14-free complexes) by directly phosphorylating ATG14; MTORC1 inactivation during nutrient starvation activates the autophagy-specific PIK3C3 complex. In vitro MTORC1 phosphorylation of ATG14, PIK3C3 lipid kinase assay of ATG14-containing vs. UVRAG-containing complexes, immunoprecipitation under starvation conditions Autophagy High 24013218
2013 Acetylated Hsp70 binds the Beclin-1-Vps34 (PIK3C3) complex and recruits the E3 ligase KAP1, which induces SUMOylation of Vps34 at Lys840, increasing Vps34 lipid kinase activity during autophagy-inducing stress. Co-immunoprecipitation of Hsp70-Beclin1-Vps34 complex, KAP1 recruitment assay, SUMOylation assay at Lys840, Vps34 activity measurement, hsp70 knockout MEFs Proceedings of the National Academy of Sciences of the United States of America High 23569248
2014 SAR405, a highly selective VPS34 (PIK3C3) inhibitor, blocks VPS34 kinase activity and inhibits late endosome-lysosome compartments and autophagy; structural analysis reveals unique binding within the ATP-binding cleft of VPS34. Kinase binding assay (KD 1.5 nM), cellular autophagy assays, vesicle trafficking assays, structural analysis of VPS34-inhibitor interaction Nature chemical biology High 25326666
2014 NRBF2 is a subunit specific to Vps34 Complex I (autophagy complex) that binds Vps15 via its WD40 domain and other regions; NRBF2 knockdown inhibits starvation-induced autophagy and LC3-II formation without affecting UVRAG-containing Complex II. Co-immunoprecipitation distinguishing Complex I vs. II, GFP-LC3 puncta assay, LC3-II/p62 western blot, NRBF2 siRNA knockdown The Biochemical journal High 24785657
2014 PIK3C3 (VPS34) produces PtdIns(3)P that recruits ankyrin-B (AnkB) to organelle membranes; AnkB links dynactin (via p62 subunit) to PtdIns(3)P-containing membranes to promote fast axonal transport of synaptic vesicles, mitochondria, endosomes, and lysosomes. AnkB knockout mice, PIK3C3 loss-of-function, dynactin membrane association assays, live imaging of organelle transport in hippocampal neurons, 3D-STORM imaging The Journal of cell biology High 25533844
2015 Crystal structure of the 385-kDa endosomal VPS34 complex II (PIK3C3-CII: Vps34, Vps15/p150, Vps30/Beclin1, Vps38/UVRAG) at 4.4 Å reveals a Y-shaped complex centered on the Vps34 C2 domain; the Vps15 kinase domain engages the Vps34 activation loop to regulate its activity; HDX-MS reveals a Vps30 loop critical for complex II activity on giant liposomes. X-ray crystallography (4.4 Å), hydrogen-deuterium exchange mass spectrometry (HDX-MS), giant liposome lipid kinase assay, nanobody-assisted crystallography Science (New York, N.Y.) High 26450213
2015 MTOR directly phosphorylates UVRAG (at S550 and S571), which activates VPS34 (PIK3C3) lipid kinase activity; this VPS34-UVRAG complex is required for autolysosomal tubulation and lysosome reformation (ALR); loss of these phosphorylation sites impairs lysosomal tubulation and causes cell death. In vitro mTOR kinase assay on UVRAG, VPS34 lipid kinase assay with phosphomimetic/non-phosphorylatable UVRAG, VPS34-specific inhibitor (VPS34-IN1), lysosomal tubulation imaging The EMBO journal High 26139536
2015 The RUN domain of Rubicon directly interacts with the PIK3C3 (hVps34) catalytic subunit and inhibits its lipid kinase activity; the RUN domain is required for Rubicon-mediated suppression of autophagosome maturation. Co-immunoprecipitation of Rubicon-hVps34 interaction, in vitro lipid kinase assays with RUN domain deletion mutants, autophagy rescue assays in Rubicon-depleted cells The Journal of biological chemistry High 21062745
2015 FBXL20 (an F-box protein in the SCF ubiquitin ligase complex) ubiquitinates and promotes proteasomal degradation of Vps34 (PIK3C3) following CDK-mediated phosphorylation during DNA damage; FBXL20 expression is regulated by p53-dependent transcription, linking DNA damage to VPS34 degradation and inhibition of autophagy and receptor endocytosis. Co-immunoprecipitation of FBXL20-Vps34 complex, ubiquitination assays, proteasome inhibitor rescue, p53-dependent FBXL20 expression analysis, CDK phosphorylation assays Genes & development High 25593308
2015 Cul3-KLHL20 ubiquitin ligase targets ULK1 (via autophosphorylation-facilitated KLHL20 binding) and also promotes degradation of ATG13, VPS34, Beclin-1, and ATG14 during prolonged starvation, terminating autophagy. Ubiquitination assays, ULK1 autophosphorylation analysis, KLHL20 knockdown and reconstitution, VPS34 stability measurement Molecular cell High 26687681
2016 Leucyl-tRNA synthetase (LRS) acts as a leucine sensor that directly activates Vps34 (PIK3C3) in amino acid sensing upstream of mTORC1; LRS physically interacts with Vps34 in non-autophagic complexes and purified LRS activates Vps34 kinase in vitro in a leucine-dependent manner. Co-immunoprecipitation of LRS-Vps34 complex, in vitro Vps34 kinase assay with purified LRS and leucine, PI(3)P level measurement, PLD1 translocation assays Cell reports High 27477288
2016 hVps34 (PIK3C3) generates PtdIns(3)P that activates SGK3 by enabling its PDK1-dependent phosphorylation via SGK3's PX domain binding to PtdIns(3)P; under sustained PI3K/Akt inhibition, the hVps34-SGK3 pathway substitutes for Akt by phosphorylating TSC2 to activate mTORC1. PI3P measurement, SGK3 phosphorylation assays, PX-domain binding to PtdIns(3)P, tumor xenograft studies, SGK3 inhibitor (14h) characterization The EMBO journal High 27481935
2016 VPS34 (PIK3C3) regulates Rab7 activity at late endosomes by recruiting the Rab7 GAP Armus (TBC1D2) through PtdIns(3)P; loss of Vps34 leads to Rab7 hyperactivation, enlarged late endosomes, impaired intraluminal vesicle formation, and decreased EGFR degradation. Vps34-null MEF analysis, protein-lipid overlay and liposome-binding assays for Armus PH domain-PI3P interaction, Rab7-GTP pulldown, Rab7 siRNA and Armus overexpression rescue Journal of cell science High 27793976
2017 The VPS34 catalytic domain undergoes dislodging from the PI3KC3-C1 complex while remaining tethered by an intrinsically disordered linker; this conformational state is a master allosteric switch controlled by VPS15, and preventing dislodging (via a 'leashed' construct) blocks enzyme activity in vitro and autophagy induction in yeast. Electron microscopy, crosslinking mass spectrometry, in vitro lipid kinase assay with leashed construct, yeast autophagy induction assay Molecular cell High 28757208
2017 Vps34 (PIK3C3) inactivation in skeletal muscle triggers a metabolic switch from oxidative phosphorylation towards glycolysis and enhanced glucose uptake; in liver, Vps34 inactivation mildly dampens autophagy and reduces gluconeogenesis via AMPK activation; heterozygous kinase-dead mice have enhanced insulin sensitivity. Vps34 kinase-dead knock-in mice, Vps34 selective inhibitor in wild-type mice, metabolic flux assays, AMPK activation measurement Nature communications High 29180704
2018 ULK1 O-GlcNAcylation at Thr754 by OGT upon glucose starvation is required for ULK1 to bind and phosphorylate ATG14L, which activates VPS34 (PIK3C3) lipid kinase activity and initiates phagophore formation; this occurs downstream of mTOR-dependent dephosphorylation at Ser757 by PP1 and AMPK phosphorylation of ULK1. O-GlcNAcylation assay, site-specific mutagenesis, co-immunoprecipitation of ULK1-ATG14L, VPS34 lipid kinase assay, PI(3)P measurement, LC3 puncta formation Cell reports High 30517873
2019 SUMO1-mediated SUMOylation of Vps34 (PIK3C3) at K840 promotes assembly of the Beclin-1-Vps34-Atg14 complex and induces autophagy; Vps34 K840R mutation reduces SUMOylation and inhibits vascular smooth muscle cell dedifferentiation. SUMOylation assay with Vps34 K840R mutant, Beclin-1-Vps34-Atg14 complex immunoprecipitation, autophagy and VSMC dedifferentiation assays Pulmonary pharmacology & therapeutics Medium 30703554
2020 NEDD4-1 undergoes K29-linked auto-ubiquitination and acts as a scaffold to recruit USP13, which removes K48-linked poly-ubiquitin chains from VPS34 (PIK3C3) at Lys419, stabilizing VPS34 and promoting autophagy. Ubiquitination assays (K29 auto-ubiquitin and K48 on VPS34 K419), co-immunoprecipitation of NEDD4-1-USP13-VPS34 complex, VPS34 stability assays, NEDD4-1/USP13 knockout analysis Cell reports High 32101753
2020 PDPK1 directly binds PIK3C3 (VPS34); this interaction inhibits PDPK1 SUMOylation, allowing non-SUMOylated PDPK1 to tether LC3 to the ER and initiate autophagosome biogenesis. Co-immunoprecipitation of PDPK1-PIK3C3 complex, SUMOylation assay, LC3-ER colocalization imaging, autophagosome biogenesis assays Autophagy Medium 32876514
2021 Rab5a-GTP recruits and activates endocytic VPS34 complex II by binding between the VPS34 C2 and VPS15 WD40 domains, releasing the VPS34 kinase domain from inhibition by VPS15; Rab1a specifically recruits and activates autophagy complex I (but not complex II) via the same VPS34 interface. Electron cryotomography of complexes on Rab5a-decorated vesicles, in vitro lipid kinase assays, crosslinking mass spectrometry, GTPase-specific binding assays Nature communications High 33692360
2021 ULK1 phosphorylates VPS15 at six sites (including the major site Ser861), which increases VPS34 activity in vitro and promotes autophagosome formation; VPS15 knockout cells show ULK-dependent phenotypes including starvation-independent ULK substrate accumulation. Unbiased phosphoproteomics in Ulk1/2 KO MEFs, in vitro VPS34 complex kinase assay with VPS15 phosphosite mutants, VPS15 KO cell analysis The EMBO journal High 34121209
2021 UBE3C catalyzes K29/K48-branched ubiquitination of VPS34 (PIK3C3), enhancing its binding to proteasomes for degradation; deubiquitinating enzyme TRABID reverses this modification to stabilize VPS34; under ER and proteotoxic stress, UBE3C dissociates from phagophores reducing VPS34 ubiquitination and elevating autophagy. K29/K48 branched ubiquitination assay on VPS34, Co-IP of VPS34-proteasome interaction, UBE3C and TRABID knockdown/KO, VPS34 stability assays, liver metabolic phenotyping Nature communications High 33637724
2021 SRSF1 inhibits autophagy by directly interacting with PIK3C3 (VPS34) to disrupt its interaction with Beclin1, and independently promotes Bcl-xL splicing to sequester Beclin1 away from PIK3C3. Co-immunoprecipitation of SRSF1-PIK3C3 complex, Beclin1-PIK3C3 disruption assay, alternative splicing analysis, autophagosome formation assays Signal transduction and targeted therapy Medium 33664238
2021 AHCYL1 senses S-adenosyl-L-homocysteine (SAH) through its C-terminus; SAH binding promotes AHCYL1 N-terminus interaction with the catalytic domain of PIK3C3 (VPS34), inhibiting PIK3C3 activity and autophagy in an MTORC1-independent manner. Co-immunoprecipitation of AHCYL1-PIK3C3, domain-mapping binding assays, PIK3C3 activity assay, SAH treatment and methionine metabolism manipulation, in vivo validation Autophagy High 33993848
2022 VPS34 (PIK3C3) produces PtdIns(3)P that serves as substrate for PIKfyve to generate PI(3,5)P2 on endosomes; this coordinated VPS34-PIKfyve cascade is required for SNX17-Retriever-WASH-CCC-dependent recycling of integrins and other cargoes from endosomes to the plasma membrane. VPS34 and PIKfyve inhibition, colocalization of PIKfyve with retromer/CCC complexes, integrin recycling assays, Retriever/CCC displacement from endosomes eLife High 35040777
2023 ULK1 phosphorylates LDHA at Ser196 upon nutrient deprivation, promoting lactate production; lactate drives KAT5/TIP60-mediated lactylation of Vps34 at Lys356 and Lys781, which enhances Vps34 association with Beclin1, Atg14L, and UVRAG, and increases Vps34 lipid kinase activity to promote autophagic flux and endolysosomal trafficking. In vitro ULK1-LDHA phosphorylation assay, lactylation assay at defined Vps34 lysines, co-immunoprecipitation of Vps34 complexes, Vps34 lipid kinase assay, autophagic flux assays Science advances High 37267363
2020 Physicochemical membrane properties (lipid unsaturation, negative charge, curvature) strongly modulate VPS34 complex activity; the ATG14L BATS domain makes complex I more active than complex II on membranes; the Beclin1 BARA domain membrane-interacting loops are critical for complex II but not complex I. HDX-MS of complexes on membranes, in vitro lipid kinase assays on liposomes of defined composition, mutagenesis of BATS and BARA domains eLife High 32602837
2024 A pro-oxidant vitamin K precursor (menadione sodium bisulfite) suppresses VPS34 (PIK3C3) activity through oxidation of key cysteines in VPS34, antagonizing endosome identity and sorting; in a myotubular myopathy model driven by loss of the VPS34-antagonizing phosphatase MTM1, dietary MSB improved muscle function. VPS34 cysteine oxidation biochemical assay, MTM1-deficient model rescue, muscle histology and functional testing Science (New York, N.Y.) Medium 39446948

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nature cell biology 1290 23685627
2001 Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae. The Journal of cell biology 841 11157979
2010 The Beclin 1-VPS34 complex--at the crossroads of autophagy and beyond. Trends in cell biology 649 20356743
2008 The regulation and function of Class III PI3Ks: novel roles for Vps34. The Biochemical journal 523 18215151
2005 hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase. The Journal of biological chemistry 430 16049009
2014 A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy. Nature chemical biology 397 25326666
2012 Class III PI3K Vps34 plays an essential role in autophagy and in heart and liver function. Proceedings of the National Academy of Sciences of the United States of America 312 22308354
2008 Amino acids activate mTOR complex 1 via Ca2+/CaM signaling to hVps34. Cell metabolism 293 18460336
2003 Tuberculosis toxin blocking phagosome maturation inhibits a novel Ca2+/calmodulin-PI3K hVPS34 cascade. The Journal of experimental medicine 258 12925680
2013 Regulation of PIK3C3/VPS34 complexes by MTOR in nutrient stress-induced autophagy. Autophagy 225 24013218
2020 Inhibition of Vps34 reprograms cold into hot inflamed tumors and improves anti-PD-1/PD-L1 immunotherapy. Science advances 209 32494661
2010 Deletion of PIK3C3/Vps34 in sensory neurons causes rapid neurodegeneration by disrupting the endosomal but not the autophagic pathway. Proceedings of the National Academy of Sciences of the United States of America 203 20439739
2016 The intricate regulation and complex functions of the Class III phosphoinositide 3-kinase Vps34. The Biochemical journal 194 27470591
2015 Structure and flexibility of the endosomal Vps34 complex reveals the basis of its function on membranes. Science (New York, N.Y.) 192 26450213
2023 ULK1-mediated metabolic reprogramming regulates Vps34 lipid kinase activity by its lactylation. Science advances 188 37267363
2006 Activation of the phosphatidylinositol 3-kinase Vps34 by a G protein alpha subunit at the endosome. Cell 188 16839886
2015 Cul3-KLHL20 Ubiquitin Ligase Governs the Turnover of ULK1 and VPS34 Complexes to Control Autophagy Termination. Molecular cell 186 26687681
2013 Acetylated hsp70 and KAP1-mediated Vps34 SUMOylation is required for autophagosome creation in autophagy. Proceedings of the National Academy of Sciences of the United States of America 171 23569248
2002 Role of Rab5 in the recruitment of hVps34/p150 to the early endosome. Traffic (Copenhagen, Denmark) 160 12010460
2015 SAR405, a PIK3C3/Vps34 inhibitor that prevents autophagy and synergizes with MTOR inhibition in tumor cells. Autophagy 148 25905679
2010 Negative regulation of Vps34 by Cdk mediated phosphorylation. Molecular cell 142 20513426
1998 Distinct roles for the p110alpha and hVPS34 phosphatidylinositol 3'-kinases in vesicular trafficking, regulation of the actin cytoskeleton, and mitogenesis. The Journal of cell biology 142 9852157
2020 Lipopolysaccharide induces neuroinflammation in microglia by activating the MTOR pathway and downregulating Vps34 to inhibit autophagosome formation. Journal of neuroinflammation 140 31926553
2003 Human VPS34 and p150 are Rab7 interacting partners. Traffic (Copenhagen, Denmark) 140 14617358
2011 Rab5 and class III phosphoinositide 3-kinase Vps34 are involved in hepatitis C virus NS4B-induced autophagy. Journal of virology 137 21835792
2015 MTOR, PIK3C3, and autophagy: Signaling the beginning from the end. Autophagy 135 26565689
2015 mTOR activates the VPS34-UVRAG complex to regulate autolysosomal tubulation and cell survival. The EMBO journal 127 26139536
2010 The RUN domain of rubicon is important for hVps34 binding, lipid kinase inhibition, and autophagy suppression. The Journal of biological chemistry 114 21062745
2018 VPS34 complexes from a structural perspective. Journal of lipid research 112 30397185
2011 PKD is a kinase of Vps34 that mediates ROS-induced autophagy downstream of DAPk. Cell death and differentiation 108 22095288
2021 SRSF1 inhibits autophagy through regulating Bcl-x splicing and interacting with PIK3C3 in lung cancer. Signal transduction and targeted therapy 97 33664238
2021 Structural basis for VPS34 kinase activation by Rab1 and Rab5 on membranes. Nature communications 94 33692360
2021 Inhibitors of VPS34 and fatty-acid metabolism suppress SARS-CoV-2 replication. Cell reports 94 34320401
2007 Resveratrol-induced apoptosis depends on the lipid kinase activity of Vps34 and on the formation of autophagolysosomes. Carcinogenesis 94 18048384
2017 Vps34 Kinase Domain Dynamics Regulate the Autophagic PI 3-Kinase Complex. Molecular cell 93 28757208
2006 Gene silencing reveals a specific function of hVps34 phosphatidylinositol 3-kinase in late versus early endosomes. Journal of cell science 92 16522686
2012 Mouse skeletal muscle fiber-type-specific macroautophagy and muscle wasting are regulated by a Fyn/STAT3/Vps34 signaling pathway. Cell reports 85 22745922
2009 hVps15, but not Ca2+/CaM, is required for the activity and regulation of hVps34 in mammalian cells. The Biochemical journal 83 18957027
2002 Novel PtdIns(3)P-binding protein Etf1 functions as an effector of the Vps34 PtdIns 3-kinase in autophagy. The Journal of cell biology 82 12186856
2011 The mammalian class 3 PI3K (PIK3C3) is required for early embryogenesis and cell proliferation. PloS one 79 21283715
2011 The class III kinase Vps34 promotes T lymphocyte survival through regulating IL-7Rα surface expression. Journal of immunology (Baltimore, Md. : 1950) 77 22021616
2014 A PIK3C3-ankyrin-B-dynactin pathway promotes axonal growth and multiorganelle transport. The Journal of cell biology 74 25533844
2021 VPS34 K29/K48 branched ubiquitination governed by UBE3C and TRABID regulates autophagy, proteostasis and liver metabolism. Nature communications 72 33637724
2018 ULK1 O-GlcNAcylation Is Crucial for Activating VPS34 via ATG14L during Autophagy Initiation. Cell reports 72 30517873
2016 Leucyl-tRNA Synthetase Activates Vps34 in Amino Acid-Sensing mTORC1 Signaling. Cell reports 72 27477288
2007 Myotubularin lipid phosphatase binds the hVPS15/hVPS34 lipid kinase complex on endosomes. Traffic (Copenhagen, Denmark) 71 17651088
2017 Vps34 PI 3-kinase inactivation enhances insulin sensitivity through reprogramming of mitochondrial metabolism. Nature communications 67 29180704
2016 Vps34 regulates Rab7 and late endocytic trafficking through recruitment of the GTPase-activating protein Armus. Journal of cell science 67 27793976
2015 FBXL20-mediated Vps34 ubiquitination as a p53 controlled checkpoint in regulating autophagy and receptor degradation. Genes & development 67 25593308
2014 NRBF2 regulates macroautophagy as a component of Vps34 Complex I. The Biochemical journal 67 24785657
2016 The hVps34-SGK3 pathway alleviates sustained PI3K/Akt inhibition by stimulating mTORC1 and tumour growth. The EMBO journal 66 27481935
2020 Autophagy-related protein PIK3C3/VPS34 controls T cell metabolism and function. Autophagy 65 32268825
2017 Autophagy-related protein Vps34 controls the homeostasis and function of antigen cross-presenting CD8α+ dendritic cells. Proceedings of the National Academy of Sciences of the United States of America 65 28716903
2021 Macrophage SR-BI modulates autophagy via VPS34 complex and PPARα transcription of Tfeb in atherosclerosis. The Journal of clinical investigation 64 33661763
2020 PI3KC2α-dependent and VPS34-independent generation of PI3P controls primary cilium-mediated autophagy in response to shear stress. Nature communications 62 31941925
2014 Dapper1 promotes autophagy by enhancing the Beclin1-Vps34-Atg14L complex formation. Cell research 62 24980960
2020 Auto-ubiquitination of NEDD4-1 Recruits USP13 to Facilitate Autophagy through Deubiquitinating VPS34. Cell reports 60 32101753
2006 TbVps34, the trypanosome orthologue of Vps34, is required for Golgi complex segregation. The Journal of biological chemistry 60 16835237
2016 Characterization of Atg38 and NRBF2, a fifth subunit of the autophagic Vps34/PIK3C3 complex. Autophagy 53 27630019
2020 Arsenic induces dysfunctional autophagy via dual regulation of mTOR pathway and Beclin1-Vps34/PI3K complex in MLTC-1 cells. Journal of hazardous materials 52 32044640
2021 Phosphoproteomic identification of ULK substrates reveals VPS15-dependent ULK/VPS34 interplay in the regulation of autophagy. The EMBO journal 51 34121209
2020 Beclin 1-ATG14L Protein-Protein Interaction Inhibitor Selectively Inhibits Autophagy through Disruption of VPS34 Complex I. Journal of the American Chemical Society 51 32320221
2019 Recruitment of Vps34 PI3K and enrichment of PI3P phosphoinositide in the viral replication compartment is crucial for replication of a positive-strand RNA virus. PLoS pathogens 51 30625229
2015 BECLIN 1-VPS34 COMPLEX ARCHITECTURE: UNDERSTANDING THE NUTS AND BOLTS OF THERAPEUTIC TARGETS. Frontiers in biology 51 26692106
2017 Phenotypic Identification of a Novel Autophagy Inhibitor Chemotype Targeting Lipid Kinase VPS34. Angewandte Chemie (International ed. in English) 48 28544137
2007 Phosphoinositide-regulated retrograde transport of ricin: crosstalk between hVps34 and sorting nexins. Traffic (Copenhagen, Denmark) 47 17319803
2017 Dual Inhibition of PIK3C3 and FGFR as a New Therapeutic Approach to Treat Bladder Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 46 29222162
2022 Lipid kinases VPS34 and PIKfyve coordinate a phosphoinositide cascade to regulate retriever-mediated recycling on endosomes. eLife 43 35040777
2021 Activation Mechanisms of the VPS34 Complexes. Cells 43 34831348
2010 Pik3c3 deletion in pyramidal neurons results in loss of synapses, extensive gliosis and progressive neurodegeneration. Neuroscience 43 20955765
2019 SUMOylation of Vps34 by SUMO1 promotes phenotypic switching of vascular smooth muscle cells by activating autophagy in pulmonary arterial hypertension. Pulmonary pharmacology & therapeutics 37 30703554
2020 Antileukemic activity of the VPS34-IN1 inhibitor in acute myeloid leukemia. Oncogenesis 36 33093450
2020 Membrane characteristics tune activities of endosomal and autophagic human VPS34 complexes. eLife 35 32602837
2017 A dual role for the class III PI3K, Vps34, in platelet production and thrombus growth. Blood 34 28903944
2017 Ubiquitination of the PI3-kinase VPS-34 promotes VPS-34 stability and phagosome maturation. The Journal of cell biology 33 29092895
2024 Dietary pro-oxidant therapy by a vitamin K precursor targets PI 3-kinase VPS34 function. Science (New York, N.Y.) 31 39446948
2020 Lighting up the fire in cold tumors to improve cancer immunotherapy by blocking the activity of the autophagy-related protein PIK3C3/VPS34. Autophagy 31 32892693
2019 Binding of Avibirnavirus VP3 to the PIK3C3-PDPK1 complex inhibits autophagy by activating the AKT-MTOR pathway. Autophagy 31 31885313
2017 HMGB1 Mediates Autophagy Dysfunction via Perturbing Beclin1-Vps34 Complex in Dopaminergic Cell Model. Frontiers in molecular neuroscience 31 28197072
2021 Adaptor SH3BGRL drives autophagy-mediated chemoresistance through promoting PIK3C3 translation and ATG12 stability in breast cancers. Autophagy 30 34870550
2014 Conditional knockout of pik3c3 causes a murine muscular dystrophy. The American journal of pathology 30 24726497
2013 Class III phosphoinositide 3-kinase/VPS34 and dynamin are critical for apical endocytic recycling. Traffic (Copenhagen, Denmark) 30 23621784
2020 Firing up the cold tumors by targeting Vps34. Oncoimmunology 29 32939326
2015 Nuclear trafficking of EGFR by Vps34 represses Arf expression to promote lung tumor cell survival. Oncogene 29 26686095
2013 AMPK connects energy stress to PIK3C3/VPS34 regulation. Autophagy 29 23669030
2020 Inhibitors of VPS34 and lipid metabolism suppress SARS-CoV-2 replication. bioRxiv : the preprint server for biology 28 32743584
2021 AHCYL1 senses SAH to inhibit autophagy through interaction with PIK3C3 in an MTORC1-independent manner. Autophagy 27 33993848
2022 Corynoxine B derivative CB6 prevents Parkinsonian toxicity in mice by inducing PIK3C3 complex-dependent autophagy. Acta pharmacologica Sinica 26 35217810
2020 PDPK1 regulates autophagosome biogenesis by binding to PIK3C3. Autophagy 26 32876514
2019 Group A Streptococcus modulates RAB1- and PIK3C3 complex-dependent autophagy. Autophagy 26 31177902
2016 VPS34 regulates TSC1/TSC2 heterodimer to mediate RheB and mTORC1/S6K1 activation and cellular transformation. Oncotarget 25 27409169
2015 GADD45A inhibits autophagy by regulating the interaction between BECN1 and PIK3C3. Autophagy 25 26636486
2015 Ironing out VPS34 inhibition. Nature cell biology 24 25679028
2019 Aurone derivatives as Vps34 inhibitors that modulate autophagy. Acta pharmaceutica Sinica. B 23 31193773
2022 VPS34-dependent control of apical membrane function of proximal tubule cells and nutrient recovery by the kidney. Science signaling 22 36445937
2020 The NEDD4-USP13 axis facilitates autophagy via deubiquitinating PIK3C3. Autophagy 22 32174250
2017 FoxO1-AMPK-ULK1 Regulates Ethanol-Induced Autophagy in Muscle by Enhanced ATG14 Association with the BECN1-PIK3C3 Complex. Alcoholism, clinical and experimental research 22 28299793
2010 Promoter variant of PIK3C3 is associated with autoimmunity against Ro and Sm epitopes in African-American lupus patients. Journal of biomedicine & biotechnology 22 20671926
2022 Lipid kinase PIK3C3 maintains healthy brown and white adipose tissues to prevent metabolic diseases. Proceedings of the National Academy of Sciences of the United States of America 21 36574710
2016 Simultaneous inhibition of Vps34 kinase would enhance PI3Kδ inhibitor cytotoxicity in the B-cell malignancies. Oncotarget 21 27447747