Affinage

Showing PIKFYVE — PIP5K is a alias.

PIKFYVE

1-phosphatidylinositol 3-phosphate 5-kinase · UniProt Q9Y2I7

Length
2098 aa
Mass
237.1 kDa
Annotated
2026-06-10
100 papers in source corpus 50 papers cited in narrative 48 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PIKfyve is a dual-specificity lipid/protein kinase that generates the low-abundance phosphoinositides PtdIns(3,5)P2 and PtdIns5P on endolysosomal membranes, thereby governing endosomal membrane homeostasis, retrograde and recycling trafficking, lysosome reformation, autophagy, and immune-cell function (PMID:10419465, PMID:11285266, PMID:11714711, PMID:23047693). It phosphorylates PtdIns to PtdIns(3,5)P2 and is responsible for essentially the entire cellular PtdIns(3,5)P2 pool and nearly all PtdIns5P in vivo, with PtdIns5P arising from PtdIns(3,5)P2 (PMID:23047693). PIKfyve also harbors an intrinsic serine protein kinase activity, and its autophosphorylation downregulates its own lipid kinase output, establishing a self-limiting feedback mechanism (PMID:11123925). Membrane targeting to the late endocytic pathway requires its FYVE domain binding PtdIns3P generated by PI3-kinase (PMID:11706043). PIKfyve operates within the trimeric PAS complex with the scaffold Vac14/ArPIKfyve and the PtdIns(3,5)P2 phosphatase Fig4/Sac3, in which five copies of Vac14 organize one PIKfyve and one Fig4; Fig4 acts both as a lipid phosphatase and as a protein phosphatase that reactivates PIKfyve, coupling synthesis and turnover (PMID:15542851, PMID:17556371, PMID:33098764). Its activity is integrated into signaling by upstream kinases AKT (Ser318), AMPK (Ser307), and ULK1 (Ser1548), linking it to insulin/RTK trafficking, contraction-stimulated glucose uptake, and glucose-starvation autophagy respectively (PMID:15546921, PMID:23905686, PMID:34107300). Functionally, PIKfyve-generated PtdIns(3,5)P2 controls endolysosomal fission/fusion balance and lysosome reformation, retrograde endosome-to-TGN transport, phagosome/phagolysosome maturation, receptor degradation, and TFEB nuclear translocation via the mTORC1-PP2A axis (PMID:11285266, PMID:11714711, PMID:16954148, PMID:19582903, PMID:25041080, PMID:29661845, PMID:28857423, PMID:35020443), while PtdIns5P mediates insulin-induced actin remodeling and Rac1-dependent cell migration and chemotaxis (PMID:22621786, PMID:23154468, PMID:28779020). PIKfyve activity is required for viral entry through late endosomes and for insulin-regulated glucose metabolism in muscle, and its inhibition has been linked to enhanced anti-tumor immunity and to amelioration of ALS pathology (PMID:32764148, PMID:23673157, PMID:34738088, PMID:36754049).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 1999 High

    Established the founding biochemical identity of PIKfyve as a phosphoinositide kinase, answering what reaction it catalyzes.

    Evidence In vitro lipid kinase assay with HPLC product identification and deletion-mutant analysis in COS cells

    PMID:10419465

    Open questions at the time
    • Did not establish cellular product or physiological role
    • Substrate specificity defined only in vitro
  2. 2000 High

    Revealed that PIKfyve has an intrinsic protein kinase activity whose autophosphorylation downregulates its own lipid kinase output, defining a self-regulatory feedback mechanism.

    Evidence In vitro kinase assays on PIKfyve purified from multiple sources with phosphatase reversal and kinase-dead controls

    PMID:11123925

    Open questions at the time
    • Autophosphorylation sites not mapped
    • Counteracting phosphatase not identified at the time
  3. 2001 High

    Defined how PIKfyve is targeted to membranes and that its PtdIns(3,5)P2-producing activity, specifically, is required for endosomal membrane homeostasis.

    Evidence FYVE-domain liposome binding with wortmannin sensitivity, plus kinase-dead/activation-loop mutants and PtdIns(3,5)P2 microinjection rescue in COS cells

    PMID:11285266 PMID:11706043 PMID:11714711

    Open questions at the time
    • Did not separate PtdIns5P functions from PtdIns(3,5)P2
    • Endosomal targeting receptor beyond PtdIns3P not defined
  4. 2002 High

    Showed PIKfyve generates the cellular PtdIns5P pool and links this product to osmotic-response signaling, broadening its product repertoire in vivo.

    Evidence 32P-labeling with HPLC and type II PIP kinase conversion assay across multiple cell types with dominant-negative expression

    PMID:12270933

    Open questions at the time
    • Route of PtdIns5P synthesis (direct vs via PtdIns(3,5)P2) unresolved
    • Downstream effectors of PtdIns5P unknown
  5. 2004 High

    Identified Vac14/ArPIKfyve as a positive regulator physically associated with PIKfyve, beginning assembly of the regulatory complex concept.

    Evidence Co-IP, co-fractionation, siRNA knockdown and overexpression with lipid kinase assay

    PMID:15542851

    Open questions at the time
    • Stoichiometry and architecture of complex unresolved
    • Mechanism of activation by Vac14 unknown
  6. 2004 High

    Connected PIKfyve to insulin signaling by showing AKT phosphorylates Ser318 to stimulate lipid kinase activity and regulate GLUT4 trafficking.

    Evidence In vitro PKB kinase assay, intact-cell phospho-detection, and S318A mutant GLUT4 translocation assay in 3T3-L1 adipocytes

    PMID:15546921

    Open questions at the time
    • Whether Ser318 phosphorylation alters localization vs catalysis not fully dissected
    • Physiological relevance in vivo not yet tested here
  7. 2007 High

    Defined the PAS complex with Fig4/Sac3 as a PtdIns(3,5)P2 phosphatase that paradoxically associates with the kinase, establishing that synthesis and turnover are physically coupled.

    Evidence Co-IP of endogenous proteins, in vitro phosphatase assay, siRNA knockdown, and in vitro vesicle-formation reconstitution

    PMID:17556371 PMID:19840946

    Open questions at the time
    • Mechanistic basis for coupling kinase and phosphatase not resolved at the time
    • Domain map of complex assembly incomplete
  8. 2008 High

    Mapped ArPIKfyve as the homomeric organizer of the PAS complex and showed complex integrity is required for PIKfyve activity and GLUT4 trafficking.

    Evidence Co-IP with varied protein combinations, in vitro lipid kinase assay, and dominant-interfering C-terminal peptide in adipocytes

    PMID:18950639

    Open questions at the time
    • Quantitative stoichiometry not determined
    • Structural basis of scaffolding unresolved
  9. 2006 High

    Established PIKfyve's cell-biological role in endosome-to-TGN retrograde transport, distinguishing it from receptor degradative/recycling sorting.

    Evidence siRNA knockdown with live imaging and specific cargo trafficking assays (CI-M6PR, EGFR, transferrin)

    PMID:16954148

    Open questions at the time
    • Effector linking PtdIns(3,5)P2 to retrograde transport not identified here
    • Relationship to motor machinery unknown
  10. 2007 High

    Identified molecular effectors (p40/Rab9 effector and the kinesin adapter JLP) that mechanistically connect PIKfyve to microtubule-dependent endosome-to-TGN transport.

    Evidence Y2H, GST pulldown, co-IP, in vitro kinase assay, and cargo trafficking assays with siRNA rescue and peptide interference

    PMID:14530284 PMID:19056739

    Open questions at the time
    • Whether p40 phosphorylation is direct in cells not fully resolved
    • How lipid product and protein-kinase functions cooperate here unclear
  11. 2009 High

    Extended PIKfyve to cargo degradation and autophagy, showing its inhibition traps receptors in swollen endosomes and accumulates LC3 autophagosomes.

    Evidence siRNA knockdown, pharmacological inhibition, and EGFR/Met degradation and GFP-LC3 assays

    PMID:19582903

    Open questions at the time
    • Threshold of PtdIns(3,5)P2 for distinct cargoes not quantified
    • Direct fusion machinery target unknown
  12. 2011 High

    Demonstrated that PIKfyve is essential for development and cell division, with complete loss causing early embryonic lethality and impaired DNA synthesis.

    Evidence Cre-loxP conditional knockout mice, embryo culture, and DNA synthesis assay with biochemical lipid quantification

    PMID:21349843

    Open questions at the time
    • Mechanism linking PIKfyve to DNA synthesis unresolved
    • Nonlinear lipid-dosage relationship not mechanistically explained
  13. 2012 High

    Showed in vivo that PIKfyve produces essentially all cellular PtdIns(3,5)P2 and PtdIns5P, with PtdIns5P arising from PtdIns(3,5)P2, settling the in vivo product hierarchy.

    Evidence Pikfyve gene-trap hypomorph mouse with shRNA silencing and 32P-lipid labeling/HPLC

    PMID:23047693

    Open questions at the time
    • Identity of the 3'-phosphatase generating PtdIns5P not pinned down
    • Tissue-specific lipid pools not fully profiled
  14. 2012 High

    Functionally separated PIKfyve's two lipid products, attributing insulin-induced actin remodeling and cell migration to PtdIns5P rather than PtdIns(3,5)P2.

    Evidence Differential-dose YM201636 with HPLC lipid quantification, actin and GLUT4 assays, plus MTMR3 cooperation and exogenous PtdIns5P rescue

    PMID:22621786 PMID:23154468

    Open questions at the time
    • Direct PtdIns5P effectors in actin/migration not all identified
    • How dose-dependence reflects spatial pools unclear
  15. 2013 High

    Embedded PIKfyve in growth-factor and energy-sensing signaling, showing AKT and AMPK phosphorylate it to drive receptor degradation and contraction-stimulated glucose uptake.

    Evidence Kinase inhibition, knockdown/overexpression, in vitro and intact-cell phosphorylation with Ser307 mutant, and RTK trafficking and glucose-uptake assays

    PMID:23673157 PMID:23757022 PMID:23905686

    Open questions at the time
    • Cross-talk between AKT and AMPK inputs on PIKfyve unresolved
    • How phosphorylation alters recruitment vs catalysis incompletely defined
  16. 2013 High

    Validated PIKfyve as a direct drug target and connected it to innate immune cytokine signaling.

    Evidence Apilimod affinity approach with in vitro kinase assay and siRNA validation in TLR-stimulated cells

    PMID:23890009

    Open questions at the time
    • Binding site of apilimod not structurally defined here
    • Downstream lipid effector of TLR signaling not specified
  17. 2016 Medium

    Linked PIKfyve to lysosome fusion, exosome/MVB biology, and nutrient recovery, expanding its role in degradative and secretory membrane dynamics.

    Evidence Apilimod/siRNA with quantitative EM, mass spectrometry, degradation assays, and TRPML1 manipulation

    PMID:27438886 PMID:27623384

    Open questions at the time
    • TRPML1 as obligatory effector only partially established
    • Distinction between fusion vs fission contributions not fully resolved here
  18. 2017 High

    Resolved the basis of lysosome enlargement upon PIKfyve loss as fusion/fission imbalance and ultrastructurally implicated PIKfyve in lysosome reformation.

    Evidence Pharmacological inhibition with TFEB/TFE3/MITF reporters, fusion-blocking conditions, live-cell imaging, and electron tomography

    PMID:28857423 PMID:29661845

    Open questions at the time
    • Membrane-remodeling effectors downstream of PtdIns(3,5)P2 not identified
    • Role of transcriptional response in chronic loss unclear
  19. 2018 High

    Connected PIKfyve to immune effector functions, showing its activity is required for phagosome maturation, neutrophil chemotaxis/ROS via Rac, and MHC class II antigen presentation.

    Evidence PIKfyve inhibition in macrophages and neutrophils with marker, cathepsin, Rac activation, and T-cell presentation assays plus ionophore/TRPML1 rescue

    PMID:25041080 PMID:28779020 PMID:30612035

    Open questions at the time
    • Direct molecular link between PtdIns5P and Rac not reconstituted
    • Whether PtdIns(3,5)P2 acts solely through TRPML1 not settled
  20. 2020 High

    Determined the architecture and bidirectional enzymatic logic of the PIKfyve complex, explaining why an antagonistic phosphatase is required for maximal lipid synthesis.

    Evidence Structural/biochemical analysis with stoichiometry, in vitro lipid and protein phosphatase assays, kinase assays, and mutagenesis

    PMID:33098764

    Open questions at the time
    • Dynamic conformational cycling on membranes not directly visualized
    • How upstream kinase inputs feed into the structural cycle unresolved
  21. 2020 High

    Established PIKfyve as essential for late-endosomal viral entry, providing a therapeutic rationale against enveloped viruses.

    Evidence Chimeric VSV and authentic SARS-CoV-2 infection assays with apilimod and vacuolin-1 inhibition and live-cell trafficking imaging

    PMID:32764148

    Open questions at the time
    • Whether viral block is purely trafficking vs lipid-signaling not dissected
    • Breadth across virus families not exhaustively defined
  22. 2021 High

    Defined a ULK1-PIKfyve axis in which Ser1548 phosphorylation selectively boosts PtdIns5P to drive starvation-induced autophagy, and identified palmitoylation as a stability control point.

    Evidence In vitro ULK1 kinase assay, phospho-mutants, PI5P and LC3 flux assays; plus zDHHC9/21 acylation assays and stability/rescue experiments

    PMID:34107300 PMID:34291577

    Open questions at the time
    • How a single phosphosite selectively tunes one lipid product unclear
    • In vivo relevance of acylation control beyond prion models untested
  23. 2022 High

    Mechanistically linked PIKfyve to lysosomal biogenesis signaling, showing PtdIns(3,5)P2 enables mTORC1 access to TFEB so that PIKfyve loss triggers PP2A-mediated TFEB activation, and to retriever-mediated cargo recycling.

    Evidence PIKfyve inhibition with TFEB Ser-211 phospho-analysis, mTORC1-TFEB co-IP, PP2A/calcineurin inhibitors; plus integrin recycling and co-localization with SNX17/Retriever/WASH/CCC

    PMID:35020443 PMID:35040777

    Open questions at the time
    • How a lipid signal selectively gates one mTORC1 substrate not fully resolved
    • Direct effector reading PtdIns species for recycling not identified
  24. 2023 High

    Distinguished PIKfyve recruitment from its catalytic activity on phagosomes/macropinosomes and revealed a self-limiting dissociation mechanism, refining spatiotemporal control.

    Evidence Validated PI(3,5)P2 reporter (GFP-SnxA) with live-cell imaging in Dictyostelium and mammalian cells

    PMID:37382666

    Open questions at the time
    • Molecular trigger for activity-driven dissociation undefined
    • Pathway-specific retention determinants not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PIKfyve achieves selective production and spatial deployment of PtdIns(3,5)P2 versus PtdIns5P to specify distinct downstream outputs, and the direct effectors reading each lipid, remain incompletely defined.
  • No unified model of how single phosphosites bias one lipid product
  • Direct PtdIns5P effectors for Rac/actin not reconstituted
  • Spatial control of complex assembly on different organelles unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 4 GO:0140096 catalytic activity, acting on a protein 3 GO:0008289 lipid binding 1 GO:0140657 ATP-dependent activity 1
Localization
GO:0005764 lysosome 3 GO:0005768 endosome 3 GO:0005794 Golgi apparatus 1 GO:0005829 cytosol 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-9612973 Autophagy 3 R-HSA-1430728 Metabolism 2
Partners
AKT1AMPKAPPFIG4JIP4MTMR3ULK1VAC14
Complex memberships
PAS complex (PIKfyve-Vac14/ArPIKfyve-Fig4/Sac3)

Evidence

Reading pass · 48 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 PIKfyve (p235) is a phosphoinositide 5-kinase that phosphorylates PtdIns to generate PtdIns 5-P and PtdIns 3,5-P2 in vitro; recombinant PIKfyve expressed in COS cells showed striking substrate specificity for PtdIns over other PI substrates, and deletion mutant analysis showed that regions beyond the catalytic domain are critical for enzymatic activity. In vitro lipid kinase assay with HPLC product identification, COS cell expression of deletion mutants The Journal of biological chemistry High 10419465
2000 PIKfyve possesses an intrinsic protein kinase (serine kinase) activity inseparable from its lipid kinase activity; PIKfyve autophosphorylation on serine residues downregulates its lipid product formation by ~70%, which is reversed by phosphatase treatment, establishing a self-regulatory feedback mechanism. In vitro kinase assay with immunopurified and affinity-purified PIKfyve from COS cells, Sf9 cells, and native adipocytes; phosphatase treatment reversal; lipid kinase dead mutants as controls Biochemistry High 11123925
2001 PIKfyve FYVE domain specifically and with high affinity binds PtdIns 3-P-containing liposomes; this interaction requires the conserved core of basic residues in the FYVE finger and is absolutely necessary for PIKfyve targeting to late endocytic pathway membranes. Wortmannin treatment dissociates endosome-bound PIKfyve, confirming PI 3-kinase-dependent membrane targeting. Liposome binding assay with recombinant FYVE domain peptide, wortmannin treatment, fluorescence microscopy of localization mutants The Journal of biological chemistry High 11706043
2001 PIKfyve enzymatic activity is required for endosomal membrane homeostasis in mammalian cells; a kinase-dead point mutant (K1831E) causes dominant-negative swollen vacuolation of late endocytic structures. Functional dissection using double mutants (K1999E/K2000E) established that it is specifically the PtdIns 3,5-P2-producing lipid kinase activity (not protein kinase or PtdIns 5-P synthesis) that is critical, as microinjection of PtdIns 3,5-P2 selectively rescued the endomembrane defects. Transient transfection of kinase-dead and activation-loop mutants in COS cells; phosphoinositide microinjection rescue experiments; dominant-negative morphological assay The Journal of biological chemistry High 11285266 11714711
2002 PIKfyve is responsible for intracellular PtdIns 5-P production in cells; overexpression of PIKfyve(WT) increased PtdIns 5-P levels by 20-50% while dominant-negative PIKfyve(K1831E) decreased them by 60%. PtdIns 5-P levels decrease profoundly upon hypo-osmotic shock, implicating PIKfyve-produced PtdIns 5-P in osmotic response pathways. 32P-labeling of multiple cell types (Sf9, 3T3-L1, HEK293) with HPLC head group analysis; type II PIP kinase-directed conversion assay for PtdIns 5-P quantification; kinase-dead dominant-negative expression The Journal of biological chemistry High 12270933
2003 PIKfyve physically interacts with p40 (a Rab9 effector for endosome-to-TGN transport) via its chaperonin domain; PIKfyve enzymatic activity is required for membrane attachment of p40, and PIKfyve phosphorylates p40 on serine residues in vitro. Kinase-dead PIKfyve expression markedly depletes p40 from membrane fractions, suggesting PIKfyve-catalyzed p40 phosphorylation anchors p40 to facilitate late endosome-to-TGN transport. Yeast two-hybrid, GST pulldown, co-immunoprecipitation in HEK293 cells, differential centrifugation fractionation, in vitro kinase assay, liposome binding assay The Journal of biological chemistry High 14530284
2004 PKB/Akt phosphorylates PIKfyve at Ser318 in a PI3-kinase-dependent manner in response to insulin, stimulating its PtdIns 3-P 5-kinase activity. A PIKfyve S318A phosphorylation-deficient mutant enhances insulin-stimulated IRAP/GLUT4 vesicle translocation to the plasma membrane in 3T3-L1 adipocytes, demonstrating that PKB-dependent phosphorylation of PIKfyve regulates GLUT4 trafficking. In vitro PKB kinase assay, phospho-specific detection in intact cells, 3T3-L1 adipocyte GLUT4 translocation assay with phosphorylation-deficient mutant, PIKfyve-IRAP/GLUT4 co-localization by fluorescence microscopy Journal of cell science High 15546921
2004 Human Vac14 (ArPIKfyve/hVac14) is a positive regulator of PIKfyve enzymatic activity; it physically associates with PIKfyve, co-localizes on intracellular membranes, and its siRNA-mediated depletion reduces PIKfyve lipid kinase activity and PtdIns 3,5-P2 production while inducing vacuolar morphology. Ectopic hVac14 expression increases PIKfyve activity and PtdIns 3,5-P2 synthesis. Co-immunoprecipitation, co-fractionation, siRNA knockdown with lipid kinase assay and 32P-labeling, morphological vacuolation assay, ectopic overexpression Molecular and cellular biology High 15542851
2006 PIKfyve is predominantly associated with dynamic tubular/vesicular elements of the early endosomal compartment; siRNA suppression of PIKfyve induces swollen endosomes and causes a specific defect in endosome-to-TGN retrograde transport without perturbing EGF receptor or transferrin receptor sorting. Fixed and live-cell fluorescence imaging, siRNA knockdown, receptor trafficking assays (EGFR degradation, transferrin recycling, CI-M6PR retrograde trafficking) Journal of cell science High 16954148
2007 Sac3 (mammalian Fig4) is a PtdIns 3,5-P2-specific phosphatase that forms a stable ternary complex with ArPIKfyve and PIKfyve (the PAS complex); Sac3 preferentially hydrolyzes PtdIns 3,5-P2 in vitro; siRNA ablation of Sac3 elevated PtdIns 3,5-P2 levels; in vitro reconstitution of vesicle formation from early endosomes showed gain of function upon Sac3 loss and loss of function upon PIKfyve/ArPIKfyve depletion, demonstrating that PtdIns 3,5-P2 synthesis and turnover are coupled through this physical complex. Co-immunoprecipitation of endogenous proteins, co-fractionation, co-localization, in vitro phosphatase assay, 32P-labeling with HPLC, siRNA knockdown, in vitro vesicle formation reconstitution The Journal of biological chemistry High 17556371
2007 PIKfyve physically interacts with kinesin adapter JLP (a splice variant of Jip4) via the PIKfyve cpn60_TCP1 domain; both PIKfyve and JLP siRNA knockdown profoundly delays microtubule-based transport of furin cargo from endosomes to the TGN, but not the microtubule-independent TGN38 trafficking pathway, indicating PIKfyve-JLP interaction is specifically required for microtubule-dependent endosome-to-TGN transport. Yeast two-hybrid, GST pulldown, co-immunoprecipitation, siRNA knockdown with Tac-furin and Tac-TGN38 trafficking assays, peptide microinjection, rescue with siRNA-resistant constructs The Journal of biological chemistry High 19056739
2007 PIKfyve mediates HB-EGF-stimulated EGFR nuclear trafficking; RNA silencing of PIKfyve blocks EGFR transit to the nucleus, EGFR binding to the cyclin D1 promoter, and cell cycle progression in bladder cancer cells. PIKfyve was identified as a component of EGFR immune complexes by mass spectrometry. Mass spectrometry of EGFR immune complexes, RNA silencing, nuclear fractionation, ChIP assay, cell cycle analysis Cancer research Medium 17909029
2007 PIKfyve localizes to a subpopulation of secretory granules in chromaffin and PC12 cells; PIKfyve activity negatively regulates regulated exocytosis. PIKfyve inhibition or knockdown potentiates secretory granule exocytosis, while PIKfyve overexpression or its yeast ortholog Fab1p overexpression inhibits it. A catalytically inactive PIKfyve mutant had no effect, indicating the lipid kinase activity is required for this inhibitory role. Live-cell imaging (PIKfyve-EGFP recruitment), siRNA knockdown, pharmacological inhibition (YM-201636), secretion assay in PC12 cells, overexpression of active and inactive mutants The Journal of biological chemistry High 18039667
2008 ArPIKfyve organizes the PAS (PIKfyve-ArPIKfyve-Sac3) complex through homomeric interactions mediated by its conserved C-terminal domain; ArPIKfyve interacts with both PIKfyve and Sac3, while Sac3 is permissive for maximal PIKfyve-ArPIKfyve association. Introduction of the ArPIKfyve C-terminal peptide fragment disassembles the PAS complex, reduces PIKfyve lipid kinase activity in vitro, and inhibits GLUT4 surface accumulation in 3T3-L1 adipocytes. Co-immunoprecipitation in transfected mammalian cells with varied protein combinations, in vitro lipid kinase assay, GLUT4 translocation assay, dominant-interfering peptide Journal of molecular biology High 18950639
2008 PIKfyve inhibition by YM201636 disrupts endosomal sorting and causes accumulation of a late endosomal compartment, blocking retroviral (HIV) exit. The specificity of PIKfyve inhibition was confirmed by siRNA knockdown and by rescue with the drug-resistant yeast ortholog Fab1. Pharmacological inhibition (YM201636), siRNA knockdown, rescue with drug-resistant yeast Fab1, 32P-labeling of phosphoinositides, electron microscopy, retroviral budding assay EMBO reports High 18188180
2009 PIKfyve inhibition blocks lysosomal degradation of activated EGFR and Met receptors (trapping them in swollen endosomes) and causes accumulation of lipidated GFP-LC3 autophagosomes; combined siRNA knockdown of PIKfyve and its activator Vac14 is required to block EGFR degradation, suggesting a low threshold of PtdIns 3,5-P2 is sufficient for this pathway. siRNA knockdown, pharmacological inhibition (PIKfyve-specific compound), immunofluorescence, EGF/Met receptor degradation assay, GFP-LC3 autophagosome assay Traffic High 19582903
2009 PIKfyve phosphorylates Ser318 on PIKfyve in a SGK consensus sequence; PIKfyve expression increases EAAT2 (glutamate transporter) current and protein abundance at the cell membrane in Xenopus oocytes; the S318A PIKfyve mutant lacking the SGK phosphorylation site abolishes PIKfyve's stimulatory effect on EAAT2. Xenopus oocyte expression system, dual-electrode voltage clamp, confocal microscopy of membrane protein abundance, kinase-dead and phosphorylation-site mutants Cellular physiology and biochemistry Medium 19910676
2009 PIKfyve regulates degradation of the voltage-gated calcium channel CaV1.2; NMDA receptor activation recruits PIKfyve to CaV1.2 channels and increases cellular PtdIns(3,5)P2, promoting CaV1.2 targeting to lysosomes. PIKfyve knockdown prevents CaV1.2 degradation and increases neuronal susceptibility to excitotoxicity. Co-immunoprecipitation, PIKfyve knockdown (shRNA), lipid mass measurement, CaV1.2 internalization and degradation assays, excitotoxicity assay in neurons The Journal of cell biology High 19841139
2009 PIKfyve Sac3 (assembled in the PAS complex) retains active PtdIns 3,5-P2 phosphatase activity; the Cpn60_TCP1 domain of PIKfyve is the major determinant for associating the ArPIKfyve-Sac3 subcomplex; phosphatase-dead Sac3(D488A) co-expressed with ArPIKfyve mitigates vacuolation caused by kinase-dead PIKfyve(K1831E), confirming that Sac3 activity within the complex turns over PtdIns 3,5-P2 at endosomes. Co-immunoprecipitation with truncation and point mutants, morphological vacuolation assay in triple-transfected COS cells The Journal of biological chemistry High 19840946
2012 In vivo, Pikfyve generates all of the cellular PI(3,5)P2 pool and nearly all of the PI5P pool; PI5P is generated directly from PI(3,5)P2 likely via 3'-phosphatase activity. shRNA silencing of residual Pikfyve in hypomorphic fibroblasts demonstrated Pikfyve is required for the entire PI(3,5)P2 pool. Pikfyve gene-trap mouse hypomorph, shRNA silencing of residual Pikfyve transcript, 32P-lipid labeling with HPLC from fibroblasts and tissues Proceedings of the National Academy of Sciences High 23047693
2012 PIKfyve-synthesized PtdIns 5-P (not PtdIns 3,5-P2) mediates insulin-induced actin stress fiber disassembly; low-dose YM201636 preferentially inhibits PtdIns 5-P synthesis over PtdIns 3,5-P2 synthesis and blocks actin disassembly but not GLUT4 translocation, providing first experimental separation of the two PIKfyve lipid products' cellular functions. Differential dose-response with PIKfyve inhibitor YM201636, 32P-labeling and HPLC lipid quantification, actin stress fiber assay, GLUT4 translocation assay in 3T3-L1 adipocytes and CHO-T cells American journal of physiology. Cell physiology High 22621786
2012 PIKfyve and MTMR3 together produce PtdIns 5-P via a phosphoinositide loop (PtdIns → PtdIns 3-P → PtdIns(3,5)P2 → PtdIns 5-P) that promotes cell migration; direct addition of exogenous PtdIns 5-P or a PtdIns 5-P-producing bacterial enzyme stimulates migration, and PIKfyve knockdown reduces cell migration in fibroblasts. siRNA knockdown, exogenous PtdIns 5-P delivery, bacterial enzyme-driven PtdIns 5-P production, Drosophila in vivo model, cell migration screen EMBO reports High 23154468
2013 AKT phosphorylates and activates PIKfyve upon EGF stimulation, promoting EGFR endocytic trafficking to lysosomes and degradation; AKT-impaired cells accumulate EGFR in early endosomes and show prolonged ERK/RSK signaling. This AKT→PIKfyve→vesicle trafficking axis was also observed for PDGFR, indicating a common RTK feedback mechanism. AKT inhibition, PIKfyve knockdown/overexpression, EGFR trafficking and degradation assays, co-immunoprecipitation, kinase assay, early endosome immunofluorescence, PDGFR validation Science signaling High 23757022
2013 Apilimod binds directly to PIKfyve and blocks its phosphotransferase activity; pharmacological or genetic inactivation of PIKfyve is necessary and sufficient for suppression of TLR-induced IL-12/IL-23p40 expression, establishing PIKfyve as a critical player in TLR signaling. Chemical genetic affinity approach (apilimod as affinity tool), in vitro kinase assay, siRNA knockdown of PIKfyve, TLR stimulation assays, cytokine measurement Chemistry & biology High 23890009
2013 AMPK phosphorylates PIKfyve at Ser307 both in vitro and in intact cells; contraction/AMPK activation increases PtdIns(3,5)P2 levels and PIKfyve phosphorylation in skeletal muscle; wild-type but not S307A PIKfyve is recruited to endosomal vesicles upon AMPK activation; PIKfyve inhibition reduces contraction- and AMPK-stimulated glucose uptake, positioning PIKfyve as an AMPK substrate linking contraction to GLUT4 translocation. In vitro AMPK kinase assay, intact cell phosphorylation, subcellular fractionation, siRNA knockdown in C2C12, PIKfyve inhibitor in rat muscles, S307A phosphorylation-site mutant The Biochemical journal High 23905686
2014 PIKfyve inhibition in macrophages hinders phagosome maturation by delaying removal of PtdIns 3-P from phagosomes and reducing acquisition of LAMP1 and cathepsin D (lysosomal markers), reducing phagosomal degradative capacity; lysosomal trafficking and degradative capacity were also reduced, consistent with PIKfyve/PtdIns 3,5-P2 synthesis being required for phagolysosome maturation. FcγR-mediated phagocytosis assay in macrophages, pharmacological PIKfyve inhibition, immunofluorescence for PI3P, LAMP1, cathepsin D, degradation assays Traffic High 25041080
2015 APP (Amyloid Precursor Protein) intracellular domain directly binds purified Vac14 (a PIKfyve complex scaffolding protein); APP associates with the PIKfyve complex (Vac14/PIKfyve/Fig4) and drives formation of PI(3,5)P2-positive vesicles. APP family members are required for PIKfyve function and the PIKfyve complex is required for APP trafficking, establishing a feedback loop. Proteo-liposome interactome assay, direct binding with purified Vac14, co-immunoprecipitation of APP with complex members, PI(3,5)P2 vesicle formation assay, C. elegans genetic epistasis Cellular and molecular life sciences High 26125944 26216398
2016 PIKfyve inhibition increases exosome secretion and induces secretory autophagy; apilimod treatment or siRNA depletion of PIKfyve increased MVBs per cell and intraluminal vesicles per MVB; autophagy-related proteins (NBR1, p62, LC3, WIPI2) are enriched in exosomal fractions from PIKfyve-inhibited cells; both EGF and long-lived protein degradation were reduced. These data indicate PIKfyve is required for lysosome fusion with MVBs and autophagosomes. Apilimod treatment, siRNA knockdown, quantitative electron microscopy, mass spectrometry, immunoblotting, density gradients, EGF degradation assay, long-lived protein degradation assay Cellular and molecular life sciences High 27438886
2016 PIKfyve regulates vacuole maturation and nutrient recovery during macropinocytosis, entosis, and phagocytosis partly through its downstream effector TRPML1 (a cationic transporter); PIKfyve activity promotes recovery of nutrients from vacuoles and protects nutrient-depleted Ras-mutant cells from starvation-induced cell death. PIKfyve inhibition, TRPML1 agonists/antagonists, vacuole maturation assay, nutrient recovery assay, cell death assay under starvation Developmental cell Medium 27623384
2017 PIKfyve inhibition leads to lysosome enlargement through lysosome coalescence (fusion over fission imbalance) rather than through biosynthesis; PIKfyve inhibition activates TFEB/TFE3/MITF but this transcriptional response does not augment lysosomal protein levels during acute inhibition and deletion of TFEB/related proteins did not impair lysosome swelling; conditions reducing fusion curtailed lysosome swelling. Pharmacological PIKfyve inhibition, TFEB/TFE3/MITF reporter assays, lysosomal protein immunoblotting, live-cell imaging of lysosome dynamics, fusion-inhibiting conditions Journal of cell science High 29661845
2017 PIKfyve activity is required for terminal lysosome reformation from endolysosomes; live-cell imaging and electron tomography show PIKfyve activity regulates extensive membrane remodeling that initiates lysosome reformation from acidic, hydrolase-active endolysosomes. Live-cell imaging, electron tomography, PIKfyve inhibition Traffic High 28857423
2017 PIKfyve inhibition in neutrophils blocks phagosome-lysosome fusion (rescuable with Ca2+ ionophores or TRPML1 agonists), and inhibits chemotaxis and reactive oxygen species (ROS) production through failure to activate Rac GTPases; PtdIns 5-P (not PtdIns 3,5-P2) is proposed to control Rac and thus chemotaxis/ROS, while PtdIns 3,5-P2 activates TRPML1 to regulate phagosome maturation. Human and mouse neutrophil PIKfyve inhibition, granule morphology assay, degranulation assay, phagosome-lysosome fusion assay, Ca2+ ionophore rescue, TRPML1 agonist rescue, chemotaxis assay, ROS assay, Rac activation assay Journal of immunology High 28779020
2018 PIKfyve inhibition blocks phago/lysosome maturation and acidification, elevates ROS, reduces cathepsin S and B activity (but not cathepsin X), impairs invariant chain processing, and disrupts MHC class II antigen presentation to CD4+ T cells. PIKfyve inhibitor treatment, phagosome acidification assay, ROS measurement, cathepsin activity assay, universal MHC class II presentation assay with bio-orthogonal antigen, T cell activation assay iScience High 30612035
2019 PIKfyve activity regulates early melanosome homeostasis; PIKfyve activity controls membrane remodeling of stage I melanosomes regulating PMEL protein abundance and processing, controls kiss-and-run interactions with lysosomes required for PMEL amyloidogenesis, and promotes formation and release of membrane tubules from melanosomes by modulating endosomal actin branching. PIKfyve inhibition in melanocytes, live-cell imaging, immunofluorescence, Western blotting for PMEL processing, actin regulation assays Journal of cell science Medium 30709920
2020 PIKfyve kinase activity is required for SARS-CoV-2 and Zaire ebolavirus (ZEBOV) endosomal content release and infection; apilimod (PIKfyve inhibitor) potently inhibits infection by VSV-ZEBOV, VSV-SARS-CoV-2 chimeras and authentic SARS-CoV-2, establishing PIKfyve-mediated endosomal trafficking as essential for viral entry through late endosomes. Chimeric VSV viral infection assays, authentic SARS-CoV-2 infection assay, apilimod pharmacological inhibition, Vacuolin-1 inhibition, live-cell imaging of viral trafficking Proceedings of the National Academy of Sciences High 32764148
2020 The PIKfyve complex comprises five copies of the scaffolding protein Vac14 and one copy each of PIKfyve and Fig4 (by structural analysis); Fig4 is active as a lipid phosphatase within the complex; PIKfyve autophosphorylation represses its lipid kinase activity and stimulates Fig4 lipid phosphatase activity; Fig4 is also a protein phosphatase acting on PIKfyve to stimulate PIKfyve lipid kinase activity, explaining why catalytically active Fig4 is required for maximal PI(3,5)P2 production. Structural-biochemical analysis (cryo-EM/structural characterization), in vitro lipid phosphatase assays, in vitro kinase assays, mutagenesis, stoichiometry determination Molecular cell High 33098764
2021 ULK1, activated by AMPK during glucose starvation, phosphorylates PIKfyve at S1548, increasing PIKfyve activity and PtdIns 5-P synthesis without changing PtdIns 3,5-P2 levels; ULK1-mediated PIKfyve activation enhances PI(5)P-containing autophagosome formation and autophagy flux; phospho-mimic PIKfyve S1548D drives autophagy upregulation. In vitro ULK1 kinase assay on PIKfyve, phospho-specific detection in cells, PI5P measurement, LC3 autophagy flux assay, phospho-mimic and phospho-dead PIKfyve mutants, AMPK-ULK1 inhibition Developmental cell High 34107300
2021 PIKfyve is acylated by acyltransferases zDHHC9 and zDHHC21; prion infection or prolonged UPR disturbs the juxtavesicular topology of these acyltransferases, causing PIKfyve deacylation and rapid degradation, resulting in endolysosomal hypertrophy. Overexpression of zDHHC9/zDHHC21 or PI(3,5)P2 supplementation suppressed prion-induced vacuolation. Acylation assay, zDHHC9/21 overexpression and knockdown, PIKfyve protein stability measurement in prion-infected cells and brain, PI(3,5)P2 supplementation rescue, UPR induction experiments EMBO molecular medicine High 34291577
2021 PIKfyve inhibition activates an unconventional protein clearance mechanism involving exocytosis of aggregation-prone proteins (rather than macroautophagy or the ubiquitin-proteasome system); reducing PIKfyve activity ameliorates ALS pathology in animal models and patient-derived motor neurons representing diverse ALS forms (C9ORF72, TARDBP, FUS, sporadic). PIKfyve inhibitor treatment, genetic knockdown in animal models, patient-derived motor neuron culture, exocytosis assay for aggregation-prone proteins, ALS pathology markers Cell High 36754049
2021 PIKfyve inhibition impairs autophagic flux, causing accumulation of MHC-I at the cancer cell surface through reduced autophagic degradation; genetic depletion or pharmacological inhibition of PIKfyve elevated tumor-specific MHC-I surface expression and increased intratumoral functional CD8+ T cells; the effect was CD8+ T cell- and MHC-I-dependent. PIKfyve knockdown and pharmacological inhibition, MHC-I surface expression by flow cytometry, autophagy flux assays, CD8+ T cell depletion, B2m knockout, syngeneic mouse tumor models Nature cancer High 34738088
2022 PIKfyve and its upstream PI3-kinase VPS34 coordinate a phosphoinositide cascade to regulate retriever-mediated recycling of cargo (including integrins) from endosomes to the plasma membrane; endogenous PIKfyve co-localizes with SNX17, Retriever, WASH, and CCC complexes on endosomes; PIKfyve inhibition displaces Retriever and CCC from endosomes. PIKfyve and VPS34 inhibition, integrin recycling assay, co-localization by immunofluorescence, fractionation, endosome displacement assay eLife High 35040777
2022 PIKfyve inhibition selectively impairs mTORC1 interaction with TFEB (not other mTORC1 substrates), leading to TFEB dephosphorylation at Ser-211 by PP2A (not calcineurin) and TFEB nuclear translocation; this establishes that PI(3,5)P2 promotes TFEB phosphorylation by facilitating mTORC1 access to TFEB. PIKfyve inhibition, TFEB phosphorylation assay (Ser-211), mTORC1 activity toward multiple substrates, co-immunoprecipitation of TFEB-mTORC1, PP2A and calcineurin inhibitors, nuclear TFEB localization Molecular biology of the cell High 35020443
2023 PIKfyve recruitment and activity on phagosomes/macropinosomes are separable events; PI(3,5)P2 accumulates on Dictyostelium phagosomes and macropinosomes ~3 min after engulfment but is retained differently on the two pathways, indicating pathway-specific regulation; PIKfyve activation stimulates its own dissociation from membranes (self-limiting mechanism). Novel PI(3,5)P2 reporter (GFP-SnxA, validated by PI(3,5)P2 selectivity assay), live-cell imaging of PIKfyve and PI(3,5)P2 dynamics in Dictyostelium and mammalian cells The Journal of cell biology High 37382666
2011 PIKfyve KO/KO mouse embryos die before the 32-64-cell stage; kultured PIKfyve-null fibroblasts show severely reduced DNA synthesis, consistent with impaired cell division causing lethality; PIKfyve heterozygous mice are viable with 50-55% reduced PIKfyve protein and enzymatic activity but only 35-40% reduced PtdIns 3,5-P2/PtdIns 5-P, indicating nonlinear regulation of lipid product levels. Cre-loxP conditional knockout mice, embryo culture, DNA synthesis assay in Cre-treated floxed fibroblasts, 32P lipid labeling, in vitro PIKfyve kinase assay The Journal of biological chemistry High 21349843
2000 PIKfyve localizes predominantly to cytosol (~76%), with ~20% on low-density microsomal (LDM) fraction coinciding with trans-Golgi network/multivesicular body markers (not recycling endosomes or GLUT4 storage compartment) in 3T3-L1 adipocytes; insulin stimulation recruits cytosolic PIKfyve to LDM membranes with concomitant increase in PIKfyve lipid kinase activity and electrophoretic mobility shift. Subcellular fractionation, density gradient sedimentation, immunoadsorption, fluorescence microscopy, immunoreactive PIKfyve measurement, in vitro lipid kinase assay The Journal of biological chemistry High 11112776
2011 NPM-ALK oncogene interacts with PIKfyve (via the 181-300 region of NPM-ALK) and the tyrosine kinase activity of NPM-ALK controls PIKfyve lipid kinase activity (independent of complex formation); PIKfyve silencing or inhibition has no effect on proliferation or migration but strongly reduces invasive capacity of NPM-ALK cells and impairs MMP9 surface localization and maturation. Co-immunoprecipitation, siRNA knockdown, YM201636 inhibition, invasion assay, MMP9 localization by immunofluorescence, in vitro lipid kinase assay The Journal of biological chemistry Medium 21737449
2015 TLR9 trafficking to LAMP1+ compartments required for type I IFN induction requires PIKfyve activity; PIKfyve inhibition preferentially blocks TLR9 signaling for type I IFN (not cytokine) induction in FLT3L-derived DCs; confocal analysis shows PIKfyve inhibition blocks TLR9 and CpG trafficking to LAMP1+ endosomes while VAMP3+ trafficking remains intact; AP-3 recruitment to TLR9 endosomes is impaired by PIKfyve inhibition. PIKfyve pharmacological inhibition, FLT3L-derived DC stimulation, type I IFN measurement, confocal microscopy of TLR9/CpG trafficking, AP-3 recruitment assay International immunology High 25925170
2013 Muscle-specific Pikfyve gene disruption causes glucose intolerance, insulin resistance, and severely blunted insulin-stimulated glucose uptake and GLUT4 surface translocation in skeletal muscle, with premature attenuation of Akt phosphorylation in vivo, establishing PIKfyve as essential for insulin-regulated glucose metabolism in skeletal muscle. Muscle-specific Pikfyve conditional knockout mouse, glucose tolerance test, insulin tolerance test, ex vivo glucose uptake assay, GLUT4 surface translocation assay, Akt phosphorylation by Western blot American journal of physiology. Endocrinology and metabolism High 23673157

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 PIP5K-driven PtdIns(4,5)P2 synthesis: regulation and cellular functions. Journal of cell science 271 19889969
2008 A selective PIKfyve inhibitor blocks PtdIns(3,5)P(2) production and disrupts endomembrane transport and retroviral budding. EMBO reports 252 18188180
1985 Identification of two proteins (actin-binding protein and P235) that are hydrolyzed by endogenous Ca2+-dependent protease during platelet aggregation. The Journal of biological chemistry 230 2981831
1999 PIKfyve, a mammalian ortholog of yeast Fab1p lipid kinase, synthesizes 5-phosphoinositides. Effect of insulin. The Journal of biological chemistry 223 10419465
2016 PIKfyve inhibition increases exosome release and induces secretory autophagy. Cellular and molecular life sciences : CMLS 221 27438886
2006 The mammalian phosphatidylinositol 3-phosphate 5-kinase (PIKfyve) regulates endosome-to-TGN retrograde transport. Journal of cell science 221 16954148
2001 Mammalian cell morphology and endocytic membrane homeostasis require enzymatically active phosphoinositide 5-kinase PIKfyve. The Journal of biological chemistry 207 11285266
2012 In vivo, Pikfyve generates PI(3,5)P2, which serves as both a signaling lipid and the major precursor for PI5P. Proceedings of the National Academy of Sciences of the United States of America 196 23047693
2009 PIKfyve regulation of endosome-linked pathways. Traffic (Copenhagen, Denmark) 187 19582903
2020 Inhibition of PIKfyve kinase prevents infection by Zaire ebolavirus and SARS-CoV-2. Proceedings of the National Academy of Sciences of the United States of America 170 32764148
2013 PIKfyve, a class III PI kinase, is the target of the small molecular IL-12/IL-23 inhibitor apilimod and a player in Toll-like receptor signaling. Chemistry & biology 170 23890009
2017 Identification of apilimod as a first-in-class PIKfyve kinase inhibitor for treatment of B-cell non-Hodgkin lymphoma. Blood 169 28104689
2009 Phosphatidylinositol 3,5-bisphosphate and Fab1p/PIKfyve underPPIn endo-lysosome function. The Biochemical journal 163 19272020
2007 Core protein machinery for mammalian phosphatidylinositol 3,5-bisphosphate synthesis and turnover that regulates the progression of endosomal transport. Novel Sac phosphatase joins the ArPIKfyve-PIKfyve complex. The Journal of biological chemistry 160 17556371
2008 PIKfyve: Partners, significance, debates and paradoxes. Cell biology international 146 18304842
2011 The phosphoinositide kinase PIKfyve is vital in early embryonic development: preimplantation lethality of PIKfyve-/- embryos but normality of PIKfyve+/- mice. The Journal of biological chemistry 127 21349843
2018 Lysosome enlargement during inhibition of the lipid kinase PIKfyve proceeds through lysosome coalescence. Journal of cell science 116 29661845
2004 Protein kinase B phosphorylation of PIKfyve regulates the trafficking of GLUT4 vesicles. Journal of cell science 114 15546921
2006 The phosphoinositide kinase PIKfyve/Fab1p regulates terminal lysosome maturation in Caenorhabditis elegans. Molecular biology of the cell 111 16801682
2019 A family of PIKFYVE inhibitors with therapeutic potential against autophagy-dependent cancer cells disrupt multiple events in lysosome homeostasis. Autophagy 104 30806145
2016 PIKfyve Regulates Vacuole Maturation and Nutrient Recovery following Engulfment. Developmental cell 104 27623384
2002 Phosphatidylinositol 5-phosphate biosynthesis is linked to PIKfyve and is involved in osmotic response pathway in mammalian cells. The Journal of biological chemistry 104 12270933
2001 Functional dissection of lipid and protein kinase signals of PIKfyve reveals the role of PtdIns 3,5-P2 production for endomembrane integrity. The Journal of biological chemistry 102 11714711
2017 PIKfyve activity regulates reformation of terminal storage lysosomes from endolysosomes. Traffic (Copenhagen, Denmark) 99 28857423
2001 Phosphatidylinositol 3-phosphate-interacting domains in PIKfyve. Binding specificity and role in PIKfyve. Endomenbrane localization. The Journal of biological chemistry 97 11706043
2014 PIKfyve inhibition interferes with phagosome and endosome maturation in macrophages. Traffic (Copenhagen, Denmark) 92 25041080
2021 Autophagy Inhibition by Targeting PIKfyve Potentiates Response to Immune Checkpoint Blockade in Prostate Cancer. Nature cancer 90 34738088
1982 Purification and properties of human platelet P235. A high molecular weight protein substrate of endogenous calcium-activated protease(s). The Journal of biological chemistry 90 6177689
2013 AKT facilitates EGFR trafficking and degradation by phosphorylating and activating PIKfyve. Science signaling 87 23757022
2023 PIKFYVE inhibition mitigates disease in models of diverse forms of ALS. Cell 85 36754049
2009 Essential and unique roles of PIP5K-gamma and -alpha in Fcgamma receptor-mediated phagocytosis. The Journal of cell biology 82 19153220
2022 Roles of PIKfyve in multiple cellular pathways. Current opinion in cell biology 76 35584589
1986 Demonstration of a relationship between talin and P235, a major substrate of the calcium-dependent protease in platelets. Journal of cellular biochemistry 72 3009504
2021 Glucose starvation induces autophagy via ULK1-mediated activation of PIKfyve in an AMPK-dependent manner. Developmental cell 70 34107300
2020 Insights into Lysosomal PI(3,5)P2 Homeostasis from a Structural-Biochemical Analysis of the PIKfyve Lipid Kinase Complex. Molecular cell 69 33098764
2002 Requirement for PIKfyve enzymatic activity in acute and long-term insulin cellular effects. Endocrinology 68 12446602
2000 Localization and insulin-regulated relocation of phosphoinositide 5-kinase PIKfyve in 3T3-L1 adipocytes. The Journal of biological chemistry 68 11112776
2015 Daam2-PIP5K is a regulatory pathway for Wnt signaling and therapeutic target for remyelination in the CNS. Neuron 67 25754822
2012 Functional dissociation between PIKfyve-synthesized PtdIns5P and PtdIns(3,5)P2 by means of the PIKfyve inhibitor YM201636. American journal of physiology. Cell physiology 67 22621786
2012 NMDA receptor-mediated PIP5K activation to produce PI(4,5)P₂ is essential for AMPA receptor endocytosis during LTD. Neuron 63 22243752
2012 Production of phosphatidylinositol 5-phosphate via PIKfyve and MTMR3 regulates cell migration. EMBO reports 63 23154468
2008 ArPIKfyve homomeric and heteromeric interactions scaffold PIKfyve and Sac3 in a complex to promote PIKfyve activity and functionality. Journal of molecular biology 62 18950639
2000 PIKfyve lipid kinase is a protein kinase: downregulation of 5'-phosphoinositide product formation by autophosphorylation. Biochemistry 57 11123925
2011 Regulation of PIP5K activity by Arf6 and its physiological significance. Journal of cellular physiology 56 20945365
2007 The phosphoinositide kinase PIKfyve mediates epidermal growth factor receptor trafficking to the nucleus. Cancer research 56 17909029
2003 Active PIKfyve associates with and promotes the membrane attachment of the late endosome-to-trans-Golgi network transport factor Rab9 effector p40. The Journal of biological chemistry 56 14530284
2019 Small molecule PIKfyve inhibitors as cancer therapeutics: Translational promises and limitations. Toxicology and applied pharmacology 55 31628917
2009 PIKfyve-ArPIKfyve-Sac3 core complex: contact sites and their consequence for Sac3 phosphatase activity and endocytic membrane homeostasis. The Journal of biological chemistry 55 19840946
2015 APP controls the formation of PI(3,5)P(2) vesicles through its binding of the PIKfyve complex. Cellular and molecular life sciences : CMLS 54 26216398
2013 Phosphatidylinositol 3-phosphate 5-kinase (PIKfyve) is an AMPK target participating in contraction-stimulated glucose uptake in skeletal muscle. The Biochemical journal 54 23905686
2006 Cloning and subcellular localization of a human phosphatidylinositol 3-phosphate 5-kinase, PIKfyve/Fab1. Gene 54 16448788
2008 PIP5K-dependent production of PIP2 sustains microtubule organization to establish polarized transport in the Drosophila oocyte. Development (Cambridge, England) 53 18948416
2004 A mammalian ortholog of Saccharomyces cerevisiae Vac14 that associates with and up-regulates PIKfyve phosphoinositide 5-kinase activity. Molecular and cellular biology 53 15542851
2009 PIKfyve regulates CaV1.2 degradation and prevents excitotoxic cell death. The Journal of cell biology 52 19841139
2009 Regulation of the glutamate transporter EAAT2 by PIKfyve. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 49 19910676
2007 PIKfyve in the SGK1 mediated regulation of the creatine transporter SLC6A8. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 49 17982255
2018 The Phosphoinositide Kinase PIKfyve Promotes Cathepsin-S-Mediated Major Histocompatibility Complex Class II Antigen Presentation. iScience 48 30612035
2007 ArPIKfyve-PIKfyve interaction and role in insulin-regulated GLUT4 translocation and glucose transport in 3T3-L1 adipocytes. Experimental cell research 48 17475247
2012 PIKfyve and its Lipid products in health and in sickness. Current topics in microbiology and immunology 47 23086417
2007 PIKfyve negatively regulates exocytosis in neurosecretory cells. The Journal of biological chemistry 45 18039667
2022 Lipid kinases VPS34 and PIKfyve coordinate a phosphoinositide cascade to regulate retriever-mediated recycling on endosomes. eLife 44 35040777
2013 PIKfyve sensitivity of hERG channels. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 44 23735862
2023 A PI(3,5)P2 reporter reveals PIKfyve activity and dynamics on macropinosomes and phagosomes. The Journal of cell biology 41 37382666
2016 Active vacuolar H+ ATPase and functional cycle of Rab5 are required for the vacuolation defect triggered by PtdIns(3,5)P2 loss under PIKfyve or Vps34 deficiency. American journal of physiology. Cell physiology 41 27335171
2010 Rac controls PIP5K localisation and PtdIns(4,5)P₂ synthesis, which modulates vinculin localisation and neurite dynamics. Journal of cell science 41 20841379
2009 The beta- and gamma-isoforms of type I PIP5K regulate distinct stages of Ca2+ signaling in mast cells. Journal of cell science 41 19549683
2021 Synergistic Block of SARS-CoV-2 Infection by Combined Drug Inhibition of the Host Entry Factors PIKfyve Kinase and TMPRSS2 Protease. Journal of virology 40 34406858
2018 Inhibition of PIKfyve using YM201636 suppresses the growth of liver cancer via the induction of autophagy. Oncology reports 40 30569119
2014 PIKfyve, MTMR3 and their product PtdIns5P regulate cancer cell migration and invasion through activation of Rac1. The Biochemical journal 40 24840251
2021 Loss of PIKfyve drives the spongiform degeneration in prion diseases. EMBO molecular medicine 39 34291577
2019 Biogenesis of lysosome-related organelles complex-1 (BORC) regulates late endosomal/lysosomal size through PIKfyve-dependent phosphatidylinositol-3,5-bisphosphate. Traffic (Copenhagen, Denmark) 37 31314175
2019 PIKfyve/Fab1 is required for efficient V-ATPase and hydrolase delivery to phagosomes, phagosomal killing, and restriction of Legionella infection. PLoS pathogens 35 30730983
2012 Up-regulation of amino acid transporter SLC6A19 activity and surface protein abundance by PKB/Akt and PIKfyve. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 35 23234856
2019 Identification of PIKfyve kinase as a target in multiple myeloma. Haematologica 34 31582538
2025 Targeting PIKfyve-driven lipid metabolism in pancreatic cancer. Nature 33 40269157
2017 Inhibition of PIKfyve prevents myocardial apoptosis and hypertrophy through activation of SIRT3 in obese mice. EMBO molecular medicine 33 28396567
2017 The Lipid Kinase PIKfyve Coordinates the Neutrophil Immune Response through the Activation of the Rac GTPase. Journal of immunology (Baltimore, Md. : 1950) 33 28779020
2018 Indolyl-Pyridinyl-Propenone-Induced Methuosis through the Inhibition of PIKFYVE. ACS omega 32 30221232
2023 Targeting the lipid kinase PIKfyve upregulates surface expression of MHC class I to augment cancer immunotherapy. Proceedings of the National Academy of Sciences of the United States of America 31 38011559
2022 PP2A-dependent TFEB activation is blocked by PIKfyve-induced mTORC1 activity. Molecular biology of the cell 31 35020443
2021 PIKfyve activity is required for lysosomal trafficking of tau aggregates and tau seeding. The Journal of biological chemistry 31 33831417
2008 Kinesin adapter JLP links PIKfyve to microtubule-based endosome-to-trans-Golgi network traffic of furin. The Journal of biological chemistry 31 19056739
2013 Muscle-specific Pikfyve gene disruption causes glucose intolerance, insulin resistance, adiposity, and hyperinsulinemia but not muscle fiber-type switching. American journal of physiology. Endocrinology and metabolism 29 23673157
2007 The phosphoinositide kinase PIP5K that produces the versatile signaling phospholipid PI4,5P(2). Biological & pharmaceutical bulletin 29 17827707
2021 Combined Inhibition of p38MAPK and PIKfyve Synergistically Disrupts Autophagy to Selectively Target Cancer Cells. Cancer research 28 33685990
2022 Disruption of PIKFYVE causes congenital cataract in human and zebrafish. eLife 27 35023829
2019 The PIKfyve complex regulates the early melanosome homeostasis required for physiological amyloid formation. Journal of cell science 27 30709920
2017 Deletion of PIKfyve alters alveolar macrophage populations and exacerbates allergic inflammation in mice. The EMBO journal 26 28533230
2016 The activation loop of PIP5K functions as a membrane sensor essential for lipid substrate processing. Science advances 26 28138522
2012 Up-regulation of the inwardly rectifying K⁺ channel Kir2.1 (KCNJ2) by protein kinase B (PKB/Akt) and PIKfyve. The Journal of membrane biology 26 23188060
2015 Toll-like receptor 9 trafficking and signaling for type I interferons requires PIKfyve activity. International immunology 25 25925170
2002 PIKfyve Kinase and SKD1 AAA ATPase define distinct endocytic compartments. Only PIKfyve expression inhibits the cell-vacoulating activity of Helicobacter pylori VacA toxin. The Journal of biological chemistry 25 12213828
2017 Identification of a conserved 8 aa insert in the PIP5K protein in the Saccharomycetaceae family of fungi and the molecular dynamics simulations and structural analysis to investigate its potential functional role. Proteins 24 28407364
2022 Membrane-mediated dimerization potentiates PIP5K lipid kinase activity. eLife 23 35976097
2023 PI4KA and PIKfyve: Essential phosphoinositide signaling enzymes involved in myriad human diseases. Current opinion in cell biology 21 37453227
2011 The nucleophosmin-anaplastic lymphoma kinase oncogene interacts, activates, and uses the kinase PIKfyve to increase invasiveness. The Journal of biological chemistry 21 21737449
2015 Shlnc-EC6 regulates murine erythroid enucleation by Rac1-PIP5K pathway. Development, growth & differentiation 20 26098172
2015 The Amyloid Precursor Protein Controls PIKfyve Function. PloS one 20 26125944
2020 Inhibition of PIKfyve kinase prevents infection by Zaire ebolavirus and SARS-CoV-2. bioRxiv : the preprint server for biology 19 32511398
2019 Snx10 and PIKfyve are required for lysosome formation in osteoclasts. Journal of cellular biochemistry 19 31692073

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