PIK3C3 encodes VPS34, the catalytic lipid kinase of class III phosphatidylinositol 3-kinase complexes. VPS34 generates phosphatidylinositol 3-phosphate (PI3P) on endomembranes and operates in two main Beclin 1-containing assemblies: PI3KC3-C1 with ATG14 for autophagosome initiation and PI3KC3-C2 with UVRAG for endosomal sorting and later autophagy-associated trafficking. These complexes recruit PI3P-binding effectors to organize autophagic and endosomal membranes. VPS34-dependent membrane trafficking also contributes to cytokinesis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: VPS34 functions on autophagy and endosomal membranes through class III PI3K complexes. Reason: PIK3C3 acts at cytoplasmic endosomal and autophagic membranes. Cytoplasm includes those organelles, so the inherited broad location describes the actual core compartment without claiming a separate soluble cytosolic pool. Supporting Evidence: file:human/PIK3C3/PIK3C3-uniprot.txt Midbody {ECO:0000269|PubMed:20208530}. Late endosome {ECO:0000269|PubMed:14617358}. Cytoplasmic vesicle, autophagosome {ECO:0000305|PubMed:14617358}. file:human/PIK3C3/PIK3C3-uniprot.txt As component of the PI3K complex I localized to pre-autophagosome structures. As component of the PI3K complex II localized predominantly to endosomes (PubMed:14617358). |
| GO:0016020 membrane | IBA GO_REF:0000033 | ACCEPT | Summary: VPS34 functions on autophagy and endosomal membranes through class III PI3K complexes. Reason: PIK3C3 phosphorylates membrane phosphatidylinositol to PI3P through recruitment of PI3KC3 complexes to endosomal and autophagic membranes. Membrane association is part of this defining catalytic mechanism, even though the source location term does not specify the organelle. Supporting Evidence: file:human/PIK3C3/PIK3C3-uniprot.txt Midbody {ECO:0000269|PubMed:20208530}. Late endosome {ECO:0000269|PubMed:14617358}. Cytoplasmic vesicle, autophagosome {ECO:0000305|PubMed:14617358}. file:human/PIK3C3/PIK3C3-uniprot.txt As component of the PI3K complex I localized to pre-autophagosome structures. As component of the PI3K complex II localized predominantly to endosomes (PubMed:14617358). |
| GO:0048015 phosphatidylinositol-mediated signaling | IBA GO_REF:0000033 | ACCEPT | Summary: PI3P synthesis by VPS34 drives phosphoinositide-dependent signaling. Reason: VPS34-generated PI3P recruits effectors for membrane organization and autophagy. The biosynthetic process and phosphoinositide-mediated signaling describe compatible aspects of the same catalytic output; the former does not disprove the broader IBA. Supporting Evidence: file:human/PIK3C3/PIK3C3-deep-research-falcon.md Human **PIK3C3** encodes **VPS34**, the *class III phosphatidylinositol 3-kinase* catalytic subunit that produces **phosphatidylinositol 3-phosphate (PI3P)**. file:human/PIK3C3/PIK3C3-deep-research-falcon.md VPS34 is described as **exclusively catalyzing PI3P production from phosphatidylinositol (PI) in vitro and in vivo** |
| GO:0006897 endocytosis | IBA GO_REF:0000033 | MODIFY | Summary: The cited human VPS34 evidence directly establishes endosomal trafficking rather than the uptake step. Reason: GO:0006897 describes uptake through plasma-membrane invagination (AmiGO definition checked 2026-09-20). PMID:14617358 places hVPS34/p150 with Rab7 on late endosomes and links the enzyme to cycling between early and late endosomes. Refining this annotation to endosome organization/early-to-late transport captures the demonstrated human role. The IBD at PTN000005955 is a genuine VPS34-clade assertion; a second opinion on conserved involvement at the initial uptake step remains useful, and the refinement does not establish loss of all endocytic roles. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000005955 Β· PTN000005955 UNRESOLVED The VPS34-clade endocytosis IBD was recovered. Human evidence assessed here establishes post-uptake endosomal trafficking; conservation of participation in plasma-membrane internalization is not settled by that evidence. Proposed replacements: endosome organization early endosome to late endosome transport Supporting Evidence: PMID:14617358 The hVPS34/p150 complex colocalized with rab7 on late |
| GO:0000425 pexophagy | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PIK3C3 contributes conserved PI3P-producing machinery to pexophagy. Reason: PTN000005955 inherits experimentally supported yeast VPS34 pexophagy. Full PMID:21121900 identifies complex I and PI3P signaling as the executing machinery. The human ortholog preserves catalytic PI3P production and the autophagic complex architecture; no target-specific loss is established. Retain this conditional selective-autophagy role. PI3P production performs membrane-building work, even though VPS34 does not select peroxisomal cargo; a human experiment is not required for every valid phylogenetic inference. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN000005955 Β· PTN000005955 SUPPORTS TRANSFER The yeast VPS34 experiment supports a conserved complex-I catalytic contribution. The recovered report supports the process; its description of catalysis as indirect and its donor-count reservations do not establish a propagation failure. Supporting Evidence: PMID:21121900 This demonstrates that PtdIns3P-mediated signalling is required for pexophagy. |
| GO:0005768 endosome | IBA GO_REF:0000033 | ACCEPT | Summary: VPS34 functions on autophagy and endosomal membranes through class III PI3K complexes. Reason: PIK3C3 generates PI3P for both ATG14-containing PI3KC3-C1 and UVRAG-containing PI3KC3-C2. Endosomal sorting is a conserved direct function of this catalytic subunit, and membrane/cytoplasmic locations remain valid at broader resolution. A project focus on autophagy is not a biological reason to demote the endosomal machinery or to call membrane association an over-annotation. Supporting Evidence: PMID:40442316 The former three subunits are also present in PI3KC3-C2 involved in endosomal sorting and late steps in autophagy, while ATG14 is uniquely involved in autophagy initiation5β7. file:human/PIK3C3/PIK3C3-deep-research-falcon.md VPS34 activity is strongly tied to **endosomal PI3P pools** that define **early endosome identity** and sorting, and PI3P serves as a platform for downstream trafficking and maturation processes. |
| GO:0000045 autophagosome assembly | IBA GO_REF:0000033 | ACCEPT | Summary: Core PN function. VPS34 is required for autophagosome assembly through the autophagy-initiating PI3KC3-C1 complex. Reason: This is the central autophagy-complex biology for PIK3C3. VPS34-derived PI3P is required for autophagosome formation, and human PI3KC3-C1 is now structurally defined as an autophagy core complex. Supporting Evidence: PMID:33637724 This complex catalyzes the production of PI3P and is required for both bulk and selective types of autophagy by controlling both autophagosome formation and maturation file:human/PIK3C3/PIK3C3-deep-research-falcon.md VPS34-generated PI3P promotes recruitment of WIPI/ATG machinery to phagophore membranes, supporting autophagosome initiation and early biogenesis. |
| GO:0016303 1-phosphatidylinositol-3-kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function. PIK3C3/VPS34 is the class III lipid kinase that phosphorylates phosphatidylinositol to generate PI3P. Reason: Direct biochemical work established the substrate specificity of human VPS34, and this specific lipid kinase activity remains the most precise MF term for the gene product. Supporting Evidence: PMID:7628435 PtdIns 3-kinase does not associate with p85 and phosphorylates PtdIns, but not PtdIns4P or PtdIns(4,5)P2. file:human/PIK3C3/PIK3C3-deep-research-falcon.md Human **PIK3C3** encodes **VPS34**, the *class III phosphatidylinositol 3-kinase* catalytic subunit that produces **phosphatidylinositol 3-phosphate (PI3P)**. file:human/PIK3C3/PIK3C3-deep-research-falcon.md VPS34 is described as **exclusively catalyzing PI3P production from phosphatidylinositol (PI) in vitro and in vivo** |
| GO:0036092 phosphatidylinositol-3-phosphate biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Core process output of VPS34 catalytic activity. PIK3C3 generates PI3P for autophagosome biogenesis and related membrane-trafficking pathways. Reason: PI3P synthesis is the direct biochemical consequence of VPS34 activity and is the process-level claim that best captures the shared output of the type I and type II class III PI3K complexes. Supporting Evidence: PMID:33637724 This complex catalyzes the production of PI3P and is required for both bulk and selective types of autophagy by controlling both autophagosome formation and maturation file:human/PIK3C3/PIK3C3-deep-research-falcon.md Human **PIK3C3** encodes **VPS34**, the *class III phosphatidylinositol 3-kinase* catalytic subunit that produces **phosphatidylinositol 3-phosphate (PI3P)**. |
| GO:0034271 phosphatidylinositol 3-kinase complex, class III, type I | IBA GO_REF:0000033 | ACCEPT | Summary: Core PN complex membership. PIK3C3 is the catalytic subunit of PI3KC3-C1, the ATG14-containing class III PI3K complex that initiates autophagy. Reason: The type I complex is the core autophagy-initiation complex for VPS34 and is the key PN-driven complex call that was previously missing locally. Supporting Evidence: PMID:40442316 PI3KC3-C1 contains one copy each of the lipid kinase VPS34, the pseudokinase VPS15 and the regulatory subunits BECN1 and ATG14 file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**. |
| GO:0034272 phosphatidylinositol 3-kinase complex, class III, type II | IBA GO_REF:0000033 | ACCEPT | Summary: VPS34 functions on autophagy and endosomal membranes through class III PI3K complexes. Reason: PIK3C3 is the catalytic subunit of the UVRAG-containing class III PI3K complex II. Its PI3P production supports endosomal sorting; this complex membership is a core molecular context alongside ATG14-containing complex I. Supporting Evidence: PMID:40442316 The former three subunits are also present in PI3KC3-C2 involved in endosomal sorting and late steps in autophagy, while ATG14 is uniquely involved in autophagy initiation5β7. file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking. |
| GO:0000407 phagophore assembly site | IBA GO_REF:0000033 | ACCEPT | Summary: Core localization for the autophagy-initiation role of PIK3C3. VPS34 acts at the phagophore assembly site as part of PI3KC3-C1. Reason: This term is consistent with the type I complex call and captures the localization at which VPS34-derived PI3P seeds early autophagosome biogenesis. Supporting Evidence: PMID:40442316 All forms of canonical autophagy, bulk and selective, are initiated upon the recruitment and activation of the FIP200 protein4 and the class III phosphatidylinositol 3-OH kinase complex I (PI3KC3-C1)5β7. |
| GO:0005777 peroxisome | IBA GO_REF:0000033 | UNDECIDED | Summary: A conserved peroxisome-associated VPS34 pool remains plausible but unresolved for human. Reason: The yeast seed PMID:21121900 actually localizes Vps34 to peroxisomes under biogenesis conditions using biochemical organelle experiments. It is not simply cargo localization inferred from pexophagy. The recovered report provides no target-specific loss or negative human localization assay, and known endosomal/phagophore pools are not exclusive. Retain uncertainty about conservation and conditional recruitment rather than adopting its removal recommendation or treating primary localization as exhaustive. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN000005955 Β· PTN000005955 UNRESOLVED The source peroxisomal association is directly supported, independently of engulfing autophagic membranes. Target conservation remains unresolved; neither a single experimental seed nor other human locations proves failure. Supporting Evidence: PMID:21121900 kinase Vps34p is already associated with peroxisomes during biogenesis. file:human/PIK3C3/PIK3C3-PMID21121900-primary-check.md a significant portion of Vps34 is associated with peroxisomes. |
| GO:0000045 autophagosome assembly | IEA GO_REF:0000120 | ACCEPT | Summary: Duplicate automated annotation for a reviewed core function. VPS34 is required for autophagosome assembly. Reason: The multi-source IEA is consistent with direct human evidence and the reviewed IBA/IDA annotations for the autophagy-initiation complex. Supporting Evidence: PMID:33637724 This complex catalyzes the production of PI3P and is required for both bulk and selective types of autophagy by controlling both autophagosome formation and maturation file:human/PIK3C3/PIK3C3-deep-research-falcon.md VPS34-generated PI3P promotes recruitment of WIPI/ATG machinery to phagophore membranes, supporting autophagosome initiation and early biogenesis. |
| GO:0004672 protein kinase activity | IEA GO_REF:0000107 | REMOVE | Summary: This annotation is categorically wrong. PIK3C3 is a phosphatidylinositol 3-kinase, not a protein kinase. Reason: Direct biochemical evidence shows that VPS34 phosphorylates phosphatidylinositol rather than protein substrates. This is the wrong enzyme class, not a merely imprecise parent term, and the correct molecular function is already captured by accepted 1-phosphatidylinositol-3-kinase activity annotations elsewhere in the review. Supporting Evidence: PMID:7628435 PtdIns 3-kinase does not associate with p85 and phosphorylates PtdIns, but not PtdIns4P or PtdIns(4,5)P2. |
| GO:0007032 endosome organization | IEA GO_REF:0000107 | ACCEPT | Summary: VPS34 functions on autophagy and endosomal membranes through class III PI3K complexes. Reason: PIK3C3 supplies membrane PI3P that recruits endosomal effectors and supports endosome organization and sorting. This is direct lipid-kinase work in the process, separate from its additional autophagic role. Supporting Evidence: file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking. file:human/PIK3C3/PIK3C3-deep-research-falcon.md VPS34 activity is strongly tied to **endosomal PI3P pools** that define **early endosome identity** and sorting, and PI3P serves as a platform for downstream trafficking and maturation processes. |
| GO:0016236 macroautophagy | IEA GO_REF:0000107 | ACCEPT | Summary: Core PN process. VPS34 is required for macroautophagy through PI3KC3-C1 mediated PI3P generation. Reason: Conserved automated transfer is consistent with direct mammalian evidence that class III PI3K activity is required for macroautophagy. Supporting Evidence: PMID:10625637 Transfection of a specific class III PI3K antisense oligonucleotide greatly inhibited the rate of macroautophagy. file:human/PIK3C3/PIK3C3-deep-research-falcon.md VPS34-generated PI3P promotes recruitment of WIPI/ATG machinery to phagophore membranes, supporting autophagosome initiation and early biogenesis. |
| GO:0016485 protein processing | IEA GO_REF:0000107 | MODIFY | Summary: Protein processing is too generic for the supported trafficking role. Reason: Human and review evidence support PI3P-dependent endocytic membrane traffic, phagosome maturation, autophagy, and lysosome-directed trafficking rather than protein processing as a molecularly informative process. Proposed replacements: early endosome to late endosome transport endosome organization Supporting Evidence: PMID:16467569 By contrast, class III PI 3-kinases mainly mediate receptor-independent trafficking events, which mostly are related to endocytic membrane traffic, phagosome maturation and autophagy. |
| GO:0035032 phosphatidylinositol 3-kinase complex, class III | IEA GO_REF:0000107 | MODIFY | Summary: Generic class III complex membership is true but underspecified for human PIK3C3. Reason: Human VPS34 participates in both ATG14-containing PI3KC3-C1 and UVRAG-containing PI3KC3-C2. The type-specific complex terms preserve the autophagy-versus-trafficking split that matters for conservative curation. Proposed replacements: phosphatidylinositol 3-kinase complex, class III, type I phosphatidylinositol 3-kinase complex, class III, type II Supporting Evidence: PMID:40442316 The former three subunits are also present in PI3KC3-C2 involved in endosomal sorting and late steps in autophagy, while ATG14 is uniquely involved in autophagy initiation5β7. |
| GO:0042149 cellular response to glucose starvation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Glucose starvation response is a contextual autophagy input, not the core PIK3C3 function. Reason: Starvation stimulates VPS34-dependent autophagy and PI3P production, but the reviewed core function is the lipid kinase/autophagy-initiation activity rather than the stimulus-response term itself. Proposed replacements: macroautophagy Supporting Evidence: PMID:25327288 PIK-III acutely inhibits autophagy and de novo lipidation of LC3, and leads to the stabilization of autophagy substrates. file:human/PIK3C3/PIK3C3-deep-research-falcon.md VPS34-generated PI3P promotes recruitment of WIPI/ATG machinery to phagophore membranes, supporting autophagosome initiation and early biogenesis. |
| GO:0043201 response to L-leucine | IEA GO_REF:0000107 | UNDECIDED | Summary: The ortholog-derived response to L-leucine assertion remains unresolved. Reason: The GO_REF:0000107 row projects response to L-leucine from an ortholog. The target-focused PI3KC3 composition and phagophore-recruitment summaries do not test this specific claim and are not used as its supporting evidence. The source experiment and conservation of the indicated stimulus-response context still require assessment. Absence from an autophagy summary does not refute the projection. |
| GO:0043491 phosphatidylinositol 3-kinase/protein kinase B signal transduction | IEA GO_REF:0000107 | REMOVE | Summary: PI3K/AKT signal transduction conflates VPS34 with class I PI3K signaling. Reason: PIK3C3/VPS34 is a class III PI3K that produces PI3P from PI and should not be annotated to the class I PI3K/AKT pathway without direct evidence. Supporting Evidence: file:human/PIK3C3/PIK3C3-deep-research-falcon.md Human **PIK3C3** encodes **VPS34**, the *class III phosphatidylinositol 3-kinase* catalytic subunit that produces **phosphatidylinositol 3-phosphate (PI3P)**. file:human/PIK3C3/PIK3C3-deep-research-falcon.md VPS34 is described as **exclusively catalyzing PI3P production from phosphatidylinositol (PI) in vitro and in vivo** |
| GO:0045335 phagocytic vesicle | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Phagocytic vesicle is a supported but non-core trafficking context. Reason: Class III PI3Ks participate in phagosome maturation and endocytic membrane traffic, but this is contextual relative to the core VPS34 lipid kinase/autophagy initiation function. Supporting Evidence: PMID:16467569 By contrast, class III PI 3-kinases mainly mediate receptor-independent trafficking events, which mostly are related to endocytic membrane traffic, phagosome maturation and autophagy. |
| GO:0048488 synaptic vesicle endocytosis | IEA GO_REF:0000107 | UNDECIDED | Summary: The ortholog-derived synaptic vesicle endocytosis assertion remains unresolved. Reason: The GO_REF:0000107 row projects synaptic vesicle endocytosis from an ortholog. The target-focused PI3KC3 composition and phagophore-recruitment summaries do not test this specific claim and are not used as its supporting evidence. The source experiment and conservation of the indicated neuronal process or compartment still require assessment. Absence from an autophagy summary does not refute the projection. |
| GO:0098794 postsynapse | IEA GO_REF:0000107 | UNDECIDED | Summary: The ortholog-derived postsynaptic localization assertion remains unresolved. Reason: The GO_REF:0000107 row projects postsynaptic localization from an ortholog. The target-focused PI3KC3 composition and phagophore-recruitment summaries do not test this specific claim and are not used as its supporting evidence. The source experiment and conservation of the indicated neuronal process or compartment still require assessment. Absence from an autophagy summary does not refute the projection. |
| GO:0098830 presynaptic endosome | IEA GO_REF:0000107 | UNDECIDED | Summary: The ortholog-derived presynaptic endosome localization assertion remains unresolved. Reason: The GO_REF:0000107 row projects presynaptic endosome localization from an ortholog. The target-focused PI3KC3 composition and phagophore-recruitment summaries do not test this specific claim and are not used as its supporting evidence. The source experiment and conservation of the indicated neuronal process or compartment still require assessment. Absence from an autophagy summary does not refute the projection. |
| GO:0098845 postsynaptic endosome | IEA GO_REF:0000107 | UNDECIDED | Summary: The ortholog-derived postsynaptic endosome localization assertion remains unresolved. Reason: The GO_REF:0000107 row projects postsynaptic endosome localization from an ortholog. The target-focused PI3KC3 composition and phagophore-recruitment summaries do not test this specific claim and are not used as its supporting evidence. The source experiment and conservation of the indicated neuronal process or compartment still require assessment. Absence from an autophagy summary does not refute the projection. |
| GO:0098978 glutamatergic synapse | IEA GO_REF:0000107 | UNDECIDED | Summary: The ortholog-derived glutamatergic synapse localization assertion remains unresolved. Reason: The GO_REF:0000107 row projects glutamatergic synapse localization from an ortholog. The target-focused PI3KC3 composition and phagophore-recruitment summaries do not test this specific claim and are not used as its supporting evidence. The source experiment and conservation of the indicated neuronal process or compartment still require assessment. Absence from an autophagy summary does not refute the projection. |
| GO:0098982 GABA-ergic synapse | IEA GO_REF:0000107 | UNDECIDED | Summary: The ortholog-derived GABA-ergic synapse localization assertion remains unresolved. Reason: The GO_REF:0000107 row projects GABA-ergic synapse localization from an ortholog. The target-focused PI3KC3 composition and phagophore-recruitment summaries do not test this specific claim and are not used as its supporting evidence. The source experiment and conservation of the indicated neuronal process or compartment still require assessment. Absence from an autophagy summary does not refute the projection. |
| GO:0005515 protein binding | IPI PMID:19050071 Identification of Barkor as a mammalian autophagy-specific f... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:20142477 The early autophagic pathway is activated by hepatitis B vir... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:20562859 Network organization of the human autophagy system. | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:21062745 The RUN domain of rubicon is important for hVps34 binding, l... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:22493499 Receptor signaling lymphocyte-activation molecule family 1 (... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:23316280 The VMP1-Beclin 1 interaction regulates autophagy induction. | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:23332761 Differential regulation of distinct Vps34 complexes by AMPK ... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:23364696 Identification of a candidate therapeutic autophagy-inducing... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:23954414 Beclin 2 functions in autophagy, degradation of G protein-co... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:24034250 EGFR-mediated Beclin 1 phosphorylation in autophagy suppress... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:24056303 PtdIns(3)P-bound UVRAG coordinates Golgi-ER retrograde and A... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:24472739 Decorin activates AMPK, an energy sensor kinase, to induce a... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:24785657 NRBF2 regulates macroautophagy as a component of Vps34 Compl... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:24849286 NRBF2 regulates autophagy and prevents liver injury by modul... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:25490155 Architecture and dynamics of the autophagic phosphatidylinos... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:25594178 A kinase-independent role for EGF receptor in autophagy init... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:26496610 A human interactome in three quantitative dimensions organiz... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:26783301 Negative regulation of phosphatidylinositol 3-phosphate leve... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:33422265 ORF3a of the COVID-19 virus SARS-CoV-2 blocks HOPS complex-m... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:34386498 ORF3a-Mediated Incomplete Autophagy Facilitates Severe Acute... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:34524948 Global Proximity Interactome of the Human Macroautophagy Pat... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0005770 late endosome | IEA GO_REF:0000044 | ACCEPT | Summary: VPS34 functions on autophagy and endosomal membranes through class III PI3K complexes. Reason: PIK3C3 generates PI3P for both ATG14-containing PI3KC3-C1 and UVRAG-containing PI3KC3-C2. Endosomal sorting is a conserved direct function of this catalytic subunit, and membrane/cytoplasmic locations remain valid at broader resolution. A project focus on autophagy is not a biological reason to demote the endosomal machinery or to call membrane association an over-annotation. Supporting Evidence: file:human/PIK3C3/PIK3C3-uniprot.txt Midbody {ECO:0000269|PubMed:20208530}. Late endosome {ECO:0000269|PubMed:14617358}. Cytoplasmic vesicle, autophagosome {ECO:0000305|PubMed:14617358}. file:human/PIK3C3/PIK3C3-deep-research-falcon.md VPS34 activity is strongly tied to **endosomal PI3P pools** that define **early endosome identity** and sorting, and PI3P serves as a platform for downstream trafficking and maturation processes. |
| GO:0005776 autophagosome | IEA GO_REF:0000044 | ACCEPT | Summary: Autophagosome localization is supported for PIK3C3 autophagy biology. Reason: PIK3C3 acts in autophagosome biogenesis through PI3KC3-C1 and is curated as associated with cytoplasmic vesicle/autophagosome and pre-autophagosome structures. Supporting Evidence: file:human/PIK3C3/PIK3C3-uniprot.txt Midbody {ECO:0000269|PubMed:20208530}. Late endosome {ECO:0000269|PubMed:14617358}. Cytoplasmic vesicle, autophagosome {ECO:0000305|PubMed:14617358}. file:human/PIK3C3/PIK3C3-uniprot.txt As component of the PI3K complex I localized to pre-autophagosome structures. As component of the PI3K complex II localized predominantly to endosomes (PubMed:14617358). file:human/PIK3C3/PIK3C3-deep-research-falcon.md VPS34-generated PI3P promotes recruitment of WIPI/ATG machinery to phagophore membranes, supporting autophagosome initiation and early biogenesis. |
| GO:0016301 kinase activity | IEA GO_REF:0000120 | MODIFY | Summary: Generic kinase activity is too broad here. The reviewed molecular function for PIK3C3 should be the specific class III phosphatidylinositol 3-kinase activity term. Reason: Human VPS34 is a lipid kinase acting on phosphatidylinositol rather than a generic kinase activity in the GO-review sense. The specific MF term is available and better matches the direct biochemistry. Proposed replacements: 1-phosphatidylinositol-3-kinase activity Supporting Evidence: PMID:7628435 PtdIns 3-kinase does not associate with p85 and phosphorylates PtdIns, but not PtdIns4P or PtdIns(4,5)P2. |
| GO:0016303 1-phosphatidylinositol-3-kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated duplicate of the reviewed core molecular function for PIK3C3. VPS34 is the class III phosphatidylinositol 3-kinase. Reason: The automated call is consistent with the direct biochemical literature and with the accepted curated annotations for this gene. Supporting Evidence: PMID:7628435 PtdIns 3-kinase does not associate with p85 and phosphorylates PtdIns, but not PtdIns4P or PtdIns(4,5)P2. file:human/PIK3C3/PIK3C3-deep-research-falcon.md Human **PIK3C3** encodes **VPS34**, the *class III phosphatidylinositol 3-kinase* catalytic subunit that produces **phosphatidylinositol 3-phosphate (PI3P)**. file:human/PIK3C3/PIK3C3-deep-research-falcon.md VPS34 is described as **exclusively catalyzing PI3P production from phosphatidylinositol (PI) in vitro and in vivo** |
| GO:0016773 phosphotransferase activity, alcohol group as acceptor | IEA GO_REF:0000117 | MODIFY | Summary: This broad phosphotransferase term is less informative than the specific class III phosphatidylinositol 3-kinase activity term that is available for PIK3C3. Reason: Human VPS34 has well-defined lipid-substrate specificity, so the specific GO molecular function should replace this high-level transferase term. Proposed replacements: 1-phosphatidylinositol-3-kinase activity Supporting Evidence: PMID:7628435 PtdIns 3-kinase does not associate with p85 and phosphorylates PtdIns, but not PtdIns4P or PtdIns(4,5)P2. |
| GO:0030496 midbody | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Midbody localization is a supported non-core cytokinesis context. Reason: Human PIK3C3 has experimental midbody localization and a PI3P-dependent cytokinesis role, but this is not the main conserved function emphasized for this review. Supporting Evidence: file:human/PIK3C3/PIK3C3-uniprot.txt Midbody {ECO:0000269|PubMed:20208530}. Late endosome {ECO:0000269|PubMed:14617358}. Cytoplasmic vesicle, autophagosome {ECO:0000305|PubMed:14617358}. |
| GO:0036092 phosphatidylinositol-3-phosphate biosynthetic process | IEA GO_REF:0000117 | ACCEPT | Summary: Automated duplicate of a reviewed core process. VPS34-driven PI3P generation is the central biochemical output of PIK3C3. Reason: This specific process term correctly captures the immediate product of VPS34 catalytic activity and is preferable to broader phosphoinositide biosynthesis labels. Supporting Evidence: PMID:33637724 This complex catalyzes the production of PI3P and is required for both bulk and selective types of autophagy by controlling both autophagosome formation and maturation file:human/PIK3C3/PIK3C3-deep-research-falcon.md Human **PIK3C3** encodes **VPS34**, the *class III phosphatidylinositol 3-kinase* catalytic subunit that produces **phosphatidylinositol 3-phosphate (PI3P)**. |
| GO:0046854 phosphatidylinositol phosphate biosynthetic process | IEA GO_REF:0000002 | MODIFY | Summary: The process is directionally correct but too broad. For PIK3C3 the literature supports the specific PI3P biosynthetic process term. Reason: Human VPS34 is specifically responsible for generating phosphatidylinositol 3-phosphate rather than phosphatidylinositol phosphates in general. Proposed replacements: phosphatidylinositol-3-phosphate biosynthetic process Supporting Evidence: PMID:33637724 This complex catalyzes the production of PI3P and is required for both bulk and selective types of autophagy by controlling both autophagosome formation and maturation |
| GO:0006622 protein targeting to lysosome | NAS PMID:16467569 Regulation of membrane traffic by phosphoinositide 3-kinases... | MODIFY | Summary: Protein targeting to lysosome is a contextual trafficking assignment. Reason: The accessible review evidence supports class III PI3K roles in endocytic membrane traffic, phagosome maturation, and autophagy; a more informative term is endosome organization or early-to-late endosome transport. Proposed replacements: endosome organization early endosome to late endosome transport Supporting Evidence: PMID:16467569 By contrast, class III PI 3-kinases mainly mediate receptor-independent trafficking events, which mostly are related to endocytic membrane traffic, phagosome maturation and autophagy. |
| GO:0010506 regulation of autophagy | IDA PMID:16799551 Autophagic and tumour suppressor activity of a novel Beclin1... | MODIFY | Summary: This study supports PIK3C3 participation in macroautophagy, but classifying VPS34 itself as a regulator is too indirect. The gene product is part of the executing PI3KC3 complex. Reason: PIK3C3 is not merely upstream of autophagy in this context; it is a core catalytic component of the autophagy machinery. The process annotation should therefore be macroautophagy rather than regulation of autophagy. Proposed replacements: macroautophagy Supporting Evidence: PMID:10625637 Transfection of a specific class III PI3K antisense oligonucleotide greatly inhibited the rate of macroautophagy. |
| GO:0016236 macroautophagy | NAS PMID:40442316 Structure and activation of the human autophagy-initiating U... | ACCEPT | Summary: Core PN process assignment. Human structural and mechanistic work places PIK3C3 in the autophagy-initiating PI3KC3-C1 complex required for macroautophagy. Reason: The human literature now directly frames PI3KC3-C1 as an autophagy core complex, which supports macroautophagy as a central process annotation for PIK3C3. Supporting Evidence: PMID:40442316 All forms of canonical autophagy, bulk and selective, are initiated upon the recruitment and activation of the FIP200 protein4 and the class III phosphatidylinositol 3-OH kinase complex I (PI3KC3-C1)5β7. file:human/PIK3C3/PIK3C3-deep-research-falcon.md VPS34-generated PI3P promotes recruitment of WIPI/ATG machinery to phagophore membranes, supporting autophagosome initiation and early biogenesis. |
| GO:0016241 regulation of macroautophagy | IDA PMID:10625637 Distinct classes of phosphatidylinositol 3'-kinases are invo... | MODIFY | Summary: The underlying result supports macroautophagy itself rather than a purely regulatory role. PIK3C3 is required for the process. Reason: In this experiment class III PI3K activity is necessary for macroautophagy, so the process term is more appropriate than a regulation term for PIK3C3. Proposed replacements: macroautophagy Supporting Evidence: PMID:10625637 Transfection of a specific class III PI3K antisense oligonucleotide greatly inhibited the rate of macroautophagy. |
| GO:0036092 phosphatidylinositol-3-phosphate biosynthetic process | IDA PMID:8999962 Characterization of p150, an adaptor protein for the human p... | ACCEPT | Summary: Reviewed core process assignment. Human VPS34/p150 complex activity is part of the specific PI3P-producing pathway. Reason: Across the human literature, VPS34 activity is consistently tied to PI3P generation rather than a generic phosphoinositide biosynthetic role. Supporting Evidence: PMID:10625637 an increase in the class III PI3K product (phosphatidylinositol 3-phosphate), either by feeding cells with a synthetic lipid or by overexpressing the p150 adaptor, stimulates macroautophagy. file:human/PIK3C3/PIK3C3-deep-research-falcon.md Human **PIK3C3** encodes **VPS34**, the *class III phosphatidylinositol 3-kinase* catalytic subunit that produces **phosphatidylinositol 3-phosphate (PI3P)**. |
| GO:0045022 early endosome to late endosome transport | IDA PMID:14617358 Human VPS34 and p150 are Rab7 interacting partners. | ACCEPT | Summary: VPS34 functions on autophagy and endosomal membranes through class III PI3K complexes. Reason: PIK3C3 generates PI3P for both ATG14-containing PI3KC3-C1 and UVRAG-containing PI3KC3-C2. Endosomal sorting is a conserved direct function of this catalytic subunit, and membrane/cytoplasmic locations remain valid at broader resolution. A project focus on autophagy is not a biological reason to demote the endosomal machinery or to call membrane association an over-annotation. Supporting Evidence: PMID:14617358 The hVPS34/p150 complex colocalized with rab7 on late endosomes and hVPS34 activity was dependent on nucleotide cycling of rab7. file:human/PIK3C3/PIK3C3-deep-research-falcon.md VPS34 activity is strongly tied to **endosomal PI3P pools** that define **early endosome identity** and sorting, and PI3P serves as a platform for downstream trafficking and maturation processes. |
| GO:0097352 autophagosome maturation | IDA PMID:10625637 Distinct classes of phosphatidylinositol 3'-kinases are invo... | ACCEPT | Summary: Autophagosome maturation is supported as part of the core autophagy role. Reason: Older macroautophagy evidence and newer VPS34 complex evidence support PIK3C3-dependent PI3P production in autophagosome formation and maturation. Supporting Evidence: PMID:10625637 Transfection of a specific class III PI3K antisense oligonucleotide greatly inhibited the rate of macroautophagy. file:human/PIK3C3/PIK3C3-deep-research-falcon.md VPS34-generated PI3P promotes recruitment of WIPI/ATG machinery to phagophore membranes, supporting autophagosome initiation and early biogenesis. |
| GO:0016236 macroautophagy | TAS Reactome:R-HSA-1632852 | ACCEPT | Summary: Macroautophagy is a core PIK3C3 process. Reason: Reactome and literature synthesis support PIK3C3/VPS34 as the catalytic component of the class III PI3K complex needed for early autophagy. Supporting Evidence: file:reactome/R-HSA-5672012.md PIK3C3 (VPS34), the catalytic component of this complex, is a class III phosphatidylinositol 3-kinase that phosphorylates phosphatidylinositol (PI) producing phosphatidylinositol 3-phosphate (PI3P). file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**. file:human/PIK3C3/PIK3C3-deep-research-falcon.md VPS34-generated PI3P promotes recruitment of WIPI/ATG machinery to phagophore membranes, supporting autophagosome initiation and early biogenesis. |
| GO:0016303 1-phosphatidylinositol-3-kinase activity | TAS Reactome:R-HSA-5672012 | ACCEPT | Summary: The Reactome TAS row correctly captures the core VPS34 lipid kinase activity. Reason: PIK3C3/VPS34 is the catalytic class III PI3K that phosphorylates phosphatidylinositol to produce PI3P. Supporting Evidence: file:reactome/R-HSA-5672012.md PIK3C3 (VPS34), the catalytic component of this complex, is a class III phosphatidylinositol 3-kinase that phosphorylates phosphatidylinositol (PI) producing phosphatidylinositol 3-phosphate (PI3P). file:human/PIK3C3/PIK3C3-deep-research-falcon.md Human **PIK3C3** encodes **VPS34**, the *class III phosphatidylinositol 3-kinase* catalytic subunit that produces **phosphatidylinositol 3-phosphate (PI3P)**. file:human/PIK3C3/PIK3C3-deep-research-falcon.md VPS34 is described as **exclusively catalyzing PI3P production from phosphatidylinositol (PI) in vitro and in vivo** |
| GO:0016303 1-phosphatidylinositol-3-kinase activity | TAS Reactome:R-HSA-6798174 | ACCEPT | Summary: The Reactome TAS row correctly captures the core VPS34 lipid kinase activity. Reason: PIK3C3/VPS34 is the catalytic class III PI3K that phosphorylates phosphatidylinositol to produce PI3P. Supporting Evidence: file:human/PIK3C3/PIK3C3-deep-research-falcon.md Human **PIK3C3** encodes **VPS34**, the *class III phosphatidylinositol 3-kinase* catalytic subunit that produces **phosphatidylinositol 3-phosphate (PI3P)**. file:human/PIK3C3/PIK3C3-deep-research-falcon.md VPS34 is described as **exclusively catalyzing PI3P production from phosphatidylinositol (PI) in vitro and in vivo** |
| GO:0005886 plasma membrane | IDA PMID:17307798 CD160-activating NK cell effector functions depend on the ph... | UNDECIDED | Summary: The experimental localization or process claim requires its complete original evidence. Reason: The original publication cache is abstract-only. The abstract does not settle which PI3K subunit or localization experiment supported the curated annotation, so it cannot justify the previous confident rejection. Full-text methods and figures are required to distinguish evidence for PIK3C3 itself from pathway or cargo readouts. Supporting Evidence: PMID:17307798 CD160 engagement induces the recruitment and co-localization of phosphorylated molecules with redistributed, capped CD160 at the cell surface PMID:17307798 engagement of CD160 induces its polarization and co-localization with PI3K file:human/PIK3C3/PIK3C3-uniprot.txt SUBCELLULAR LOCATION: Midbody |
| GO:0045954 positive regulation of natural killer cell mediated cytotoxicity | IMP PMID:17307798 CD160-activating NK cell effector functions depend on the ph... | UNDECIDED | Summary: The experimental localization or process claim requires its complete original evidence. Reason: The original publication cache is abstract-only. The abstract does not settle which PI3K subunit or localization experiment supported the curated annotation, so it cannot justify the previous confident rejection. Full-text methods and figures are required to distinguish evidence for PIK3C3 itself from pathway or cargo readouts. Supporting Evidence: PMID:17307798 pharmacological inhibitors of PI3K abrogate both CD160-mediated cytotoxicity PMID:17307798 CD160 engagement induced marked phosphorylation of Akt file:human/PIK3C3/PIK3C3-uniprot.txt Catalytic subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate |
| GO:0052742 phosphatidylinositol kinase activity | IDA PMID:7628435 A human phosphatidylinositol 3-kinase complex related to the... | MODIFY | Summary: The activity is valid but too general. Human VPS34 should be annotated to the specific 1-phosphatidylinositol-3-kinase activity term. Reason: The original biochemical characterization resolved the substrate and the 3-position specificity, so the narrower MF term is warranted. Proposed replacements: 1-phosphatidylinositol-3-kinase activity Supporting Evidence: PMID:7628435 PtdIns 3-kinase does not associate with p85 and phosphorylates PtdIns, but not PtdIns4P or PtdIns(4,5)P2. |
| GO:0016303 1-phosphatidylinositol-3-kinase activity | IDA PMID:25327288 Selective VPS34 inhibitor blocks autophagy and uncovers a ro... | ACCEPT | Summary: Reviewed core molecular function. Later chemical-genetic work is fully consistent with VPS34 as the relevant class III PI3 kinase. Reason: This term matches the established biochemical function of PIK3C3 and is consistent with selective VPS34 inhibition experiments in human systems. Supporting Evidence: PMID:25327288 PIK-III is a selective inhibitor of VPS34 that binds a unique hydrophobic pocket not present in related kinases such as PI(3)KΞ±. file:human/PIK3C3/PIK3C3-deep-research-falcon.md Human **PIK3C3** encodes **VPS34**, the *class III phosphatidylinositol 3-kinase* catalytic subunit that produces **phosphatidylinositol 3-phosphate (PI3P)**. file:human/PIK3C3/PIK3C3-deep-research-falcon.md VPS34 is described as **exclusively catalyzing PI3P production from phosphatidylinositol (PI) in vitro and in vivo** |
| GO:1903061 positive regulation of protein lipidation | IMP PMID:25327288 Selective VPS34 inhibitor blocks autophagy and uncovers a ro... | KEEP AS NON CORE | Summary: Positive regulation of protein lipidation is supported as a non-core autophagy pathway effect. Reason: Selective VPS34 inhibition blocks de novo LC3 lipidation, supporting an upstream positive role in LC3 lipidation during autophagy, but the direct core function remains PI3P synthesis. Supporting Evidence: PMID:25327288 PIK-III acutely inhibits autophagy and de novo lipidation of LC3, and leads to the stabilization of autophagy substrates. |
| GO:0005515 protein binding | IPI PMID:30767700 Members of the autophagy class III phosphatidylinositol 3-ki... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0044829 host-mediated activation of viral genome replication | IDA PMID:34320401 Inhibitors of VPS34 and fatty-acid metabolism suppress SARS-... | KEEP AS NON CORE | Summary: PIK3C3/VPS34 supports SARS-CoV-2 replication in inhibitor studies, but this is non-core host-pathway context. Reason: Keep as non-core. The cited paper shows that VPS34 inhibitors suppress SARS-CoV-2 replication and viral RNA synthesis, and UniProt explicitly records the microbial-infection function. This virus-specific host factor role should not displace the core VPS34 function in PI3P biosynthesis, autophagy, and endosomal trafficking. Supporting Evidence: PMID:34320401 Our studies determine that compounds targeting VPS34 are potent SARS-CoV-2 inhibitors PMID:34320401 these studies clarify roles for VPS34 and fatty acid metabolism in SARS-CoV-2 replication file:human/PIK3C3/PIK3C3-uniprot.txt Kinase activity is required for SARS coronavirus-2/SARS-CoV-2 replication |
| GO:0000045 autophagosome assembly | IDA PMID:33637724 VPS34 K29/K48 branched ubiquitination governed by UBE3C and ... | ACCEPT | Summary: Direct human evidence for a core PN process. VPS34 abundance and regulation affect autophagosome formation. Reason: This study explicitly ties VPS34-controlled PI3P production to autophagosome formation and maturation, which is central to the reviewed biology of PIK3C3. Supporting Evidence: PMID:33637724 This complex catalyzes the production of PI3P and is required for both bulk and selective types of autophagy by controlling both autophagosome formation and maturation file:human/PIK3C3/PIK3C3-deep-research-falcon.md VPS34-generated PI3P promotes recruitment of WIPI/ATG machinery to phagophore membranes, supporting autophagosome initiation and early biogenesis. |
| GO:0046854 phosphatidylinositol phosphate biosynthetic process | IDA PMID:7628435 A human phosphatidylinositol 3-kinase complex related to the... | MODIFY | Summary: The biochemical direction is correct but the term is too broad. The human enzyme characterized here specifically supports PI3P biosynthesis. Reason: The original paper established the specific phosphatidylinositol 3-kinase activity of human VPS34, which is more precisely captured by the PI3P biosynthetic process term. Proposed replacements: phosphatidylinositol-3-phosphate biosynthetic process Supporting Evidence: PMID:7628435 PtdIns 3-kinase does not associate with p85 and phosphorylates PtdIns, but not PtdIns4P or PtdIns(4,5)P2. |
| GO:0005515 protein binding | IPI PMID:33473107 Endonuclease G promotes autophagy by suppressing mTOR signal... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:28890335 The ER-Localized Transmembrane Protein EPG-3/VMP1 Regulates ... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:31806350 The ER-Localized Transmembrane Protein TMEM39A/SUSR2 Regulat... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0032465 regulation of cytokinesis | IMP PMID:20208530 PtdIns(3)P controls cytokinesis through KIF13A-mediated recr... | KEEP AS NON CORE | Summary: Human PIK3C3 contributes to cytokinesis through a PI3P-dependent midbody pathway. This role is supported but is contextual relative to the core PN autophagy case. Reason: The cytokinesis phenotype is convincing, but it reflects a contextual deployment of VPS34 PI3P biology rather than the primary autophagy-focused role being curated here. Supporting Evidence: PMID:20208530 Depletion of the VPS34 or Beclin 1 subunits of PI(3)K-III causes cytokinesis arrest and an increased number of binucleate and multinucleate cells, in a similar manner to the depletion of FYVE-CENT, KIF13A or TTC19. |
| GO:0005515 protein binding | IPI PMID:28479384 Beclin1 antagonizes LAPTM4B-mediated EGFR overactivation in ... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:22095288 PKD is a kinase of Vps34 that mediates ROS-induced autophagy... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0006914 autophagy | IMP PMID:25327288 Selective VPS34 inhibitor blocks autophagy and uncovers a ro... | MODIFY | Summary: The biology is correct but the process term is too general. For PIK3C3 the literature supports macroautophagy specifically. Reason: VPS34 inhibition in this study blocks the canonical autophagy pathway tracked by LC3 lipidation and autophagy-substrate turnover, which is better captured as macroautophagy. Proposed replacements: macroautophagy Supporting Evidence: PMID:25327288 PIK-III acutely inhibits autophagy and de novo lipidation of LC3, and leads to the stabilization of autophagy substrates. |
| GO:0044754 autolysosome | IDA PMID:25327288 Selective VPS34 inhibitor blocks autophagy and uncovers a ro... | UNDECIDED | Summary: The experimental localization or process claim requires its complete original evidence. Reason: The original publication cache is abstract-only. The abstract does not settle which PI3K subunit or localization experiment supported the curated annotation, so it cannot justify the previous confident rejection. Full-text methods and figures are required to distinguish evidence for PIK3C3 itself from pathway or cargo readouts. Supporting Evidence: PMID:25327288 NCOA4 directly binds ferritin heavy chain-1 (FTH1) to target the iron-binding ferritin complex with a relative molecular mass of 450,000 to autolysosomes following starvation or iron depletion. |
| GO:0030670 phagocytic vesicle membrane | TAS Reactome:R-HSA-6798174 | KEEP AS NON CORE | Summary: Phagocytic vesicle membrane is a supported but non-core trafficking context. Reason: Class III PI3Ks are linked to phagosome maturation and endocytic membrane traffic; this contextual membrane role should not displace the core autophagy-initiation complex function. Supporting Evidence: PMID:16467569 By contrast, class III PI 3-kinases mainly mediate receptor-independent trafficking events, which mostly are related to endocytic membrane traffic, phagosome maturation and autophagy. |
| GO:0032465 regulation of cytokinesis | IMP PMID:20643123 A phosphatidylinositol 3-kinase class III sub-complex contai... | KEEP AS NON CORE | Summary: Supported contextual role for a UVRAG/BIF-1-containing PI3K-III subcomplex in cytokinesis. This remains outside the core PN autophagy framing. Reason: The human data support a real cytokinesis role for a VPS34-containing complex, but the review should keep this separate from the central autophagy-initiation assignment. Supporting Evidence: PMID:20643123 High-content microscopy-based assays combined with siRNA-mediated depletion of individual subunits indicated that a specific sub-complex containing VPS15, VPS34, Beclin 1, UVRAG and BIF-1 regulates both receptor degradation and cytokinesis, whereas ATG14L, a PI3K-III subunit involved in autophagy, is not required. |
| GO:0016236 macroautophagy | ISS GO_REF:0000024 | ACCEPT | Summary: Conservative orthology-supported duplicate of a core process assignment. Macroautophagy is appropriate for human PIK3C3. Reason: This transfer is consistent with direct human evidence for VPS34 in the autophagy-initiating PI3KC3-C1 complex. Supporting Evidence: PMID:40442316 All forms of canonical autophagy, bulk and selective, are initiated upon the recruitment and activation of the FIP200 protein4 and the class III phosphatidylinositol 3-OH kinase complex I (PI3KC3-C1)5β7. file:human/PIK3C3/PIK3C3-deep-research-falcon.md VPS34-generated PI3P promotes recruitment of WIPI/ATG machinery to phagophore membranes, supporting autophagosome initiation and early biogenesis. |
| GO:0035032 phosphatidylinositol 3-kinase complex, class III | ISS GO_REF:0000024 | MODIFY | Summary: The generic class III PI3K complex term is true but underspecified for human PIK3C3. The literature supports explicit type I and type II complex membership. Reason: For this gene, the main curatorial distinction is between the autophagy-initiating PI3KC3-C1/type I complex and the contextual endosomal PI3KC3-C2/type II complex. Proposed replacements: phosphatidylinositol 3-kinase complex, class III, type I phosphatidylinositol 3-kinase complex, class III, type II Supporting Evidence: PMID:40442316 PI3KC3-C1 contains one copy each of the lipid kinase VPS34, the pseudokinase VPS15 and the regulatory subunits BECN1 and ATG14 PMID:40442316 The former three subunits are also present in PI3KC3-C2 involved in endosomal sorting and late steps in autophagy, while ATG14 is uniquely involved in autophagy initiation5β7. |
| GO:0042149 cellular response to glucose starvation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Glucose starvation response is a contextual autophagy input, not the core PIK3C3 function. Reason: Starvation-dependent autophagy is a supported context for VPS34 action, but the direct conserved role is PI3P production in autophagy and endosomal pathways. Proposed replacements: macroautophagy Supporting Evidence: PMID:25327288 PIK-III acutely inhibits autophagy and de novo lipidation of LC3, and leads to the stabilization of autophagy substrates. file:human/PIK3C3/PIK3C3-deep-research-falcon.md VPS34-generated PI3P promotes recruitment of WIPI/ATG machinery to phagophore membranes, supporting autophagosome initiation and early biogenesis. |
| GO:0005515 protein binding | IPI PMID:23878393 Role of membrane association and Atg14-dependent phosphoryla... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | ACCEPT | Summary: VPS34 functions on autophagy and endosomal membranes through class III PI3K complexes. Reason: PIK3C3 phosphorylates membrane phosphatidylinositol to PI3P through recruitment of PI3KC3 complexes to endosomal and autophagic membranes. Membrane association is part of this defining catalytic mechanism, even though the source location term does not specify the organelle. Supporting Evidence: PMID:19946888 The remaining species were largely involved in cellular processes and molecular functions that could be predicted to be transiently associated with membranes. |
| GO:0005930 axoneme | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Axoneme localization is supported only by similarity and is non-core. Reason: UniProt records a ciliary axoneme localization by similarity, but the reviewed human core function is VPS34 lipid kinase activity in autophagy/endosomal complexes. Supporting Evidence: file:human/PIK3C3/PIK3C3-uniprot.txt Also localizes to discrete punctae along the ciliary axoneme and to the base of the ciliary axoneme (By similarity). |
| GO:0005515 protein binding | IPI PMID:19270696 Two Beclin 1-binding proteins, Atg14L and Rubicon, reciproca... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:14617358 Human VPS34 and p150 are Rab7 interacting partners. | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0005770 late endosome | IDA PMID:14617358 Human VPS34 and p150 are Rab7 interacting partners. | ACCEPT | Summary: VPS34 functions on autophagy and endosomal membranes through class III PI3K complexes. Reason: PIK3C3 generates PI3P for both ATG14-containing PI3KC3-C1 and UVRAG-containing PI3KC3-C2. Endosomal sorting is a conserved direct function of this catalytic subunit, and membrane/cytoplasmic locations remain valid at broader resolution. A project focus on autophagy is not a biological reason to demote the endosomal machinery or to call membrane association an over-annotation. Supporting Evidence: PMID:14617358 The hVPS34/p150 complex colocalized with rab7 on late endosomes and hVPS34 activity was dependent on nucleotide cycling of rab7. |
| GO:0045022 early endosome to late endosome transport | IMP PMID:14617358 Human VPS34 and p150 are Rab7 interacting partners. | ACCEPT | Summary: VPS34 functions on autophagy and endosomal membranes through class III PI3K complexes. Reason: PIK3C3 generates PI3P for both ATG14-containing PI3KC3-C1 and UVRAG-containing PI3KC3-C2. Endosomal sorting is a conserved direct function of this catalytic subunit, and membrane/cytoplasmic locations remain valid at broader resolution. A project focus on autophagy is not a biological reason to demote the endosomal machinery or to call membrane association an over-annotation. Supporting Evidence: PMID:14617358 The data identify rab7 as an important regulator of late endosomal hVPS34 function and link rab7 to the regulation of phosphatidylinositol 3'-kinase cycling between early and late endosomes. file:human/PIK3C3/PIK3C3-deep-research-falcon.md VPS34 activity is strongly tied to **endosomal PI3P pools** that define **early endosome identity** and sorting, and PI3P serves as a platform for downstream trafficking and maturation processes. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-109699 | KEEP AS NON CORE | Summary: Cytosol is a broad Reactome component assignment for PIK3C3 pathway events. Reason: PIK3C3 complexes are cytosolic/peripheral membrane assemblies recruited to autophagy and endosomal membranes; the cytosol rows are retained as non-core pathway context rather than precise localization. Proposed replacements: phagophore assembly site endosome Supporting Evidence: file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**. file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1632857 | KEEP AS NON CORE | Summary: Cytosol is a broad Reactome component assignment for PIK3C3 pathway events. Reason: PIK3C3 complexes are cytosolic/peripheral membrane assemblies recruited to autophagy and endosomal membranes; the cytosol rows are retained as non-core pathway context rather than precise localization. Proposed replacements: phagophore assembly site endosome Supporting Evidence: file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**. file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1675939 | KEEP AS NON CORE | Summary: Cytosol is a broad Reactome component assignment for PIK3C3 pathway events. Reason: PIK3C3 complexes are cytosolic/peripheral membrane assemblies recruited to autophagy and endosomal membranes; the cytosol rows are retained as non-core pathway context rather than precise localization. Proposed replacements: phagophore assembly site endosome Supporting Evidence: file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**. file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1675961 | KEEP AS NON CORE | Summary: Cytosol is a broad Reactome component assignment for PIK3C3 pathway events. Reason: PIK3C3 complexes are cytosolic/peripheral membrane assemblies recruited to autophagy and endosomal membranes; the cytosol rows are retained as non-core pathway context rather than precise localization. Proposed replacements: phagophore assembly site endosome Supporting Evidence: file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**. file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1676024 | KEEP AS NON CORE | Summary: Cytosol is a broad Reactome component assignment for PIK3C3 pathway events. Reason: PIK3C3 complexes are cytosolic/peripheral membrane assemblies recruited to autophagy and endosomal membranes; the cytosol rows are retained as non-core pathway context rather than precise localization. Proposed replacements: phagophore assembly site endosome Supporting Evidence: file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**. file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-188002 | KEEP AS NON CORE | Summary: Cytosol is a broad Reactome component assignment for PIK3C3 pathway events. Reason: PIK3C3 complexes are cytosolic/peripheral membrane assemblies recruited to autophagy and endosomal membranes; the cytosol rows are retained as non-core pathway context rather than precise localization. Proposed replacements: phagophore assembly site endosome Supporting Evidence: file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**. file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5672012 | KEEP AS NON CORE | Summary: Cytosol is a broad Reactome component assignment for PIK3C3 pathway events. Reason: PIK3C3 complexes are cytosolic/peripheral membrane assemblies recruited to autophagy and endosomal membranes; the cytosol rows are retained as non-core pathway context rather than precise localization. Proposed replacements: phagophore assembly site endosome Supporting Evidence: file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**. file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5678313 | KEEP AS NON CORE | Summary: Cytosol is a broad Reactome component assignment for PIK3C3 pathway events. Reason: PIK3C3 complexes are cytosolic/peripheral membrane assemblies recruited to autophagy and endosomal membranes; the cytosol rows are retained as non-core pathway context rather than precise localization. Proposed replacements: phagophore assembly site endosome Supporting Evidence: file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**. file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5678315 | KEEP AS NON CORE | Summary: Cytosol is a broad Reactome component assignment for PIK3C3 pathway events. Reason: PIK3C3 complexes are cytosolic/peripheral membrane assemblies recruited to autophagy and endosomal membranes; the cytosol rows are retained as non-core pathway context rather than precise localization. Proposed replacements: phagophore assembly site endosome Supporting Evidence: file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**. file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5679205 | KEEP AS NON CORE | Summary: Cytosol is a broad Reactome component assignment for PIK3C3 pathway events. Reason: PIK3C3 complexes are cytosolic/peripheral membrane assemblies recruited to autophagy and endosomal membranes; the cytosol rows are retained as non-core pathway context rather than precise localization. Proposed replacements: phagophore assembly site endosome Supporting Evidence: file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**. file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5679266 | KEEP AS NON CORE | Summary: Cytosol is a broad Reactome component assignment for PIK3C3 pathway events. Reason: PIK3C3 complexes are cytosolic/peripheral membrane assemblies recruited to autophagy and endosomal membranes; the cytosol rows are retained as non-core pathway context rather than precise localization. Proposed replacements: phagophore assembly site endosome Supporting Evidence: file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**. file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5682385 | KEEP AS NON CORE | Summary: Cytosol is a broad Reactome component assignment for PIK3C3 pathway events. Reason: PIK3C3 complexes are cytosolic/peripheral membrane assemblies recruited to autophagy and endosomal membranes; the cytosol rows are retained as non-core pathway context rather than precise localization. Proposed replacements: phagophore assembly site endosome Supporting Evidence: file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**. file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9755359 | KEEP AS NON CORE | Summary: Cytosol is a broad Reactome component assignment for PIK3C3 pathway events. Reason: PIK3C3 complexes are cytosolic/peripheral membrane assemblies recruited to autophagy and endosomal membranes; the cytosol rows are retained as non-core pathway context rather than precise localization. Proposed replacements: phagophore assembly site endosome Supporting Evidence: file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**. file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9921171 | KEEP AS NON CORE | Summary: Cytosol is a broad Reactome component assignment for PIK3C3 pathway events. Reason: PIK3C3 complexes are cytosolic/peripheral membrane assemblies recruited to autophagy and endosomal membranes; the cytosol rows are retained as non-core pathway context rather than precise localization. Proposed replacements: phagophore assembly site endosome Supporting Evidence: file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**. file:human/PIK3C3/PIK3C3-deep-research-falcon.md **PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking. |
| GO:0016303 1-phosphatidylinositol-3-kinase activity | IMP PMID:20208530 PtdIns(3)P controls cytokinesis through KIF13A-mediated recr... | ACCEPT | Summary: Contextual cytokinesis paper, but the molecular function assignment itself is core and remains correct for PIK3C3. Reason: Even though this paper focuses on cytokinesis, it does so through the catalytic PI3P-generating activity of the class III PI3K complex. Supporting Evidence: PMID:7628435 PtdIns 3-kinase does not associate with p85 and phosphorylates PtdIns, but not PtdIns4P or PtdIns(4,5)P2. file:human/PIK3C3/PIK3C3-deep-research-falcon.md Human **PIK3C3** encodes **VPS34**, the *class III phosphatidylinositol 3-kinase* catalytic subunit that produces **phosphatidylinositol 3-phosphate (PI3P)**. file:human/PIK3C3/PIK3C3-deep-research-falcon.md VPS34 is described as **exclusively catalyzing PI3P production from phosphatidylinositol (PI) in vitro and in vivo** |
| GO:0030496 midbody | IDA PMID:20208530 PtdIns(3)P controls cytokinesis through KIF13A-mediated recr... | KEEP AS NON CORE | Summary: Midbody association is part of a supported cytokinesis-specific context for VPS34 biology and should not be treated as core PN localization. Reason: The cytokinesis paper supports a midbody-linked PI3P pathway, but this is a contextual deployment of VPS34 rather than the primary autophagy localization used for core-function synthesis. Supporting Evidence: PMID:20208530 We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. |
| GO:0005515 protein binding | IPI PMID:16417406 Hem-1 complexes are essential for Rac activation, actin poly... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:7504174 The SH3 domain of p56lck is involved in binding to phosphati... | REMOVE | Summary: The interaction evidence does not make generic protein binding a useful molecular-function annotation. Reason: PIK3C3 interactions inform complex assembly and regulation, but protein binding does not identify the relevant molecular function. Removal follows project policy for this generic term and does not assert that the reported interaction is false. |
| GO:0016303 1-phosphatidylinositol-3-kinase activity | TAS PMID:7628435 A human phosphatidylinositol 3-kinase complex related to the... | ACCEPT | Summary: Literature-traceable duplicate of the reviewed core molecular function. Human VPS34 is the phosphatidylinositol 3-kinase. Reason: This term directly reflects the original biochemical characterization of the human enzyme and should be retained. Supporting Evidence: PMID:7628435 PtdIns 3-kinase does not associate with p85 and phosphorylates PtdIns, but not PtdIns4P or PtdIns(4,5)P2. file:human/PIK3C3/PIK3C3-deep-research-falcon.md Human **PIK3C3** encodes **VPS34**, the *class III phosphatidylinositol 3-kinase* catalytic subunit that produces **phosphatidylinositol 3-phosphate (PI3P)**. file:human/PIK3C3/PIK3C3-deep-research-falcon.md VPS34 is described as **exclusively catalyzing PI3P production from phosphatidylinositol (PI) in vitro and in vivo** |
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