Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005737 cytoplasm	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Cytoplasm is a broad but directionally compatible localization for a cytoplasmic vesicle-associated lipid kinase. Reason: PIK3C3 is best localized to specific autophagy and endosomal membranes/complexes; cytoplasm is retained only as a broad contextual cellular-component annotation. Proposed replacements: phagophore assembly site endosome 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	MARK AS OVER ANNOTATED	Summary: Membrane is too broad for PIK3C3 localization. Reason: The evidence supports specific endomembrane contexts, especially phagophore/autophagosome and endosomal membranes, rather than a generic membrane annotation. Proposed replacements: phagophore assembly site endosome 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	MODIFY	Summary: Phosphatidylinositol-mediated signaling is directionally related but too broad for VPS34. Reason: The direct process output of PIK3C3 is PI3P biosynthesis, with downstream effects in autophagosome formation and endosomal organization; the signaling parent term blurs that specificity. Proposed replacements: phosphatidylinositol-3-phosphate biosynthetic process 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: Endocytosis is supported only as a contextual trafficking role. Reason: PIK3C3 participates in endosomal PI3P-dependent trafficking and maturation, but endocytosis itself is too broad; endosome organization or early-to-late endosome transport better captures the supported role. Proposed replacements: endosome organization early endosome to late endosome transport 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:0000425 pexophagy	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: Pexophagy is a selective-autophagy overextension for PIK3C3. Reason: PIK3C3 is core for canonical autophagy initiation and can support selective autophagy generally, but this row does not provide human evidence for a specific pexophagy role. Proposed replacements: macroautophagy 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 VPS34-generated PI3P promotes recruitment of WIPI/ATG machinery to phagophore membranes, supporting autophagosome initiation and early biogenesis.
GO:0005768 endosome	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: PIK3C3 is active on endosomal membranes as part of the UVRAG-containing PI3KC3-C2 complex. This localization is well supported but is contextual relative to the core PN autophagy-initiation case. Reason: Human VPS34 participates in a type II class III PI3K complex dedicated to endosomal sorting and later autophagy-associated trafficking. That role is real, but it is not the central PN framing for this gene. 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 initiation5–7. 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	KEEP AS NON CORE	Summary: PIK3C3 also participates in PI3KC3-C2, the UVRAG-containing class III PI3K complex linked to endosomal sorting and later autophagy-associated trafficking. This is supported but is contextual relative to the core PN autophagy-initiation case. Reason: Type II complex membership is well established, but the primary PN-focused role for PIK3C3 is the autophagy-initiation complex PI3KC3-C1 rather than the broader trafficking context. 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 initiation5–7. 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)5–7.
GO:0005777 peroxisome	IBA GO_REF:0000033	REMOVE	Summary: Peroxisome localization is not supported for PIK3C3. Reason: A pexophagy-related inference does not justify localizing PIK3C3 to the peroxisome; curated locations place VPS34 at midbody, late endosome, cytoplasmic vesicle/autophagosome, and pre-autophagosome/endosome contexts. 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: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	KEEP AS NON CORE	Summary: Endosome organization is a supported non-core PIK3C3 process. Reason: PIK3C3-derived PI3P helps define endosomal identity and trafficking, especially in the UVRAG-containing type II complex, but the central reviewed function remains class III PI3K activity in autophagy initiation. 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 initiation5–7.
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	MARK AS OVER ANNOTATED	Summary: Response to L-leucine is a nutrient-response overextension for PIK3C3. Reason: PIK3C3 participates in nutrient-sensitive autophagy pathways, but this specific amino-acid response is not the direct activity or best-supported process for the gene product. Proposed replacements: macroautophagy 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 VPS34-generated PI3P promotes recruitment of WIPI/ATG machinery to phagophore membranes, supporting autophagosome initiation and early biogenesis.
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	MARK AS OVER ANNOTATED	Summary: Synaptic vesicle endocytosis is an over-specific inference from a general endosomal role. Reason: PIK3C3 supports endosomal PI3P-dependent trafficking, but the reviewed evidence here does not establish a synaptic-vesicle-specific function. Proposed replacements: endosome organization 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:0098794 postsynapse	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Postsynapse localization is not established as a reviewed PIK3C3 localization. Reason: The available human/Falcon evidence supports endosomal, autophagic, and midbody contexts; synapse-specific localization is not part of the core or well-supported contextual function. Proposed replacements: endosome 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:0098830 presynaptic endosome	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Presynaptic endosome is too specific for the evidence used here. Reason: Endosomal PI3P biology is supported, but this annotation narrows the localization to a neuronal presynaptic compartment without direct evidence in the reviewed record. Proposed replacements: endosome 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:0098845 postsynaptic endosome	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Postsynaptic endosome is too specific for the evidence used here. Reason: Endosomal PI3P biology is supported, but this annotation narrows the localization to a neuronal postsynaptic compartment without direct evidence in the reviewed record. Proposed replacements: endosome 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:0098978 glutamatergic synapse	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Glutamatergic synapse localization is an unsupported specialization. Reason: PIK3C3 has supported endosomal and autophagy-related localizations; the reviewed evidence does not establish a glutamatergic synapse location. Proposed replacements: endosome 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:0098982 GABA-ergic synapse	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: GABA-ergic synapse localization is an unsupported specialization. Reason: PIK3C3 has supported endosomal and autophagy-related localizations; the reviewed evidence does not establish a GABA-ergic synapse location. Proposed replacements: endosome 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:0005515 protein binding	IPI PMID:19050071 Identification of Barkor as a mammalian autophagy-specific f...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
GO:0005515 protein binding	IPI PMID:20142477 The early autophagic pathway is activated by hepatitis B vir...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
GO:0005515 protein binding	IPI PMID:20562859 Network organization of the human autophagy system.	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
GO:0005515 protein binding	IPI PMID:21062745 The RUN domain of rubicon is important for hVps34 binding, l...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
GO:0005515 protein binding	IPI PMID:22493499 Receptor signaling lymphocyte-activation molecule family 1 (...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
GO:0005515 protein binding	IPI PMID:23316280 The VMP1-Beclin 1 interaction regulates autophagy induction.	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
GO:0005515 protein binding	IPI PMID:23332761 Differential regulation of distinct Vps34 complexes by AMPK ...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
GO:0005515 protein binding	IPI PMID:23364696 Identification of a candidate therapeutic autophagy-inducing...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
GO:0005515 protein binding	IPI PMID:23954414 Beclin 2 functions in autophagy, degradation of G protein-co...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
GO:0005515 protein binding	IPI PMID:24034250 EGFR-mediated Beclin 1 phosphorylation in autophagy suppress...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
GO:0005515 protein binding	IPI PMID:24056303 PtdIns(3)P-bound UVRAG coordinates Golgi-ER retrograde and A...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
GO:0005515 protein binding	IPI PMID:24472739 Decorin activates AMPK, an energy sensor kinase, to induce a...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
GO:0005515 protein binding	IPI PMID:24785657 NRBF2 regulates macroautophagy as a component of Vps34 Compl...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
GO:0005515 protein binding	IPI PMID:24849286 NRBF2 regulates autophagy and prevents liver injury by modul...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
GO:0005515 protein binding	IPI PMID:25490155 Architecture and dynamics of the autophagic phosphatidylinos...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
GO:0005515 protein binding	IPI PMID:25594178 A kinase-independent role for EGF receptor in autophagy init...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
GO:0005515 protein binding	IPI PMID:26496610 A human interactome in three quantitative dimensions organiz...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
GO:0005515 protein binding	IPI PMID:26783301 Negative regulation of phosphatidylinositol 3-phosphate leve...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
GO:0005515 protein binding	IPI PMID:33422265 ORF3a of the COVID-19 virus SARS-CoV-2 blocks HOPS complex-m...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
GO:0005515 protein binding	IPI PMID:34386498 ORF3a-Mediated Incomplete Autophagy Facilitates Severe Acute...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
GO:0005515 protein binding	IPI PMID:34524948 Global Proximity Interactome of the Human Macroautophagy Pat...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
GO:0005770 late endosome	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Late endosome is a supported contextual localization for PIK3C3. Reason: Late-endosome localization and endosomal trafficking are supported, especially through the type II complex, but are contextual relative to the core autophagy-initiation function. 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)5–7. 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.	KEEP AS NON CORE	Summary: Human VPS34/p150 participates in Rab7-linked endosomal trafficking. This is supported but is contextual relative to the core PN autophagy role. Reason: The late-endosomal transport function is directly supported in human cells, but it should be kept distinct from the autophagy-initiation complex that defines the core PN case for PIK3C3. 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...	REMOVE	Summary: Plasma membrane localization should not be retained for PIK3C3 from the CD160/NK-cell paper. Reason: Remove. PMID:17307798 shows recruitment of a PI3K signaling molecule to CD160 at the NK-cell surface and downstream Akt signaling, but it does not establish that the class III PI3K catalytic subunit PIK3C3/VPS34 is a plasma-membrane protein. UniProt-supported PIK3C3 locations are endosomal, autophagic, midbody, and related cytoplasmic membrane contexts. 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...	REMOVE	Summary: Natural killer cell cytotoxicity is not supported as a PIK3C3-specific process. Reason: Remove. The CD160 study demonstrates a requirement for pharmacologically defined PI3K signaling in NK-cell effector functions, with Akt/ERK/Syk signaling, but it does not assign the phenotype to class III PI3K/VPS34 rather than class I PI3K signaling. 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)Kα. 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...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
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...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
GO:0005515 protein binding	IPI PMID:28890335 The ER-Localized Transmembrane Protein EPG-3/VMP1 Regulates ...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
GO:0005515 protein binding	IPI PMID:31806350 The ER-Localized Transmembrane Protein TMEM39A/SUSR2 Regulat...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
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 ...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
GO:0005515 protein binding	IPI PMID:22095288 PKD is a kinase of Vps34 that mediates ROS-induced autophagy...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
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...	MARK AS OVER ANNOTATED	Summary: Autolysosome localization is over-annotated from an inhibitor/substrate study. Reason: The cited inhibitor study supports VPS34-dependent autophagy and NCOA4/ferritin delivery to autolysosomes, but it does not directly place PIK3C3 itself in the autolysosome. Proposed replacements: autophagosome macroautophagy 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)5–7. 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 initiation5–7.
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...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	MARK AS OVER ANNOTATED	Summary: Broad membrane association from large-scale proteomics is weak and uninformative for PIK3C3. Reason: PIK3C3 is a cytosolic/peripheral lipid kinase recruited to autophagy and endosomal membranes, so generic membrane association is not entirely wrong, but this broad HDA row is not specific enough for the reviewed function. 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...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
GO:0005515 protein binding	IPI PMID:14617358 Human VPS34 and p150 are Rab7 interacting partners.	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
GO:0005770 late endosome	IDA PMID:14617358 Human VPS34 and p150 are Rab7 interacting partners.	KEEP AS NON CORE	Summary: Supported contextual localization. Human VPS34/p150 colocalizes with Rab7 on late endosomes. Reason: The localization is directly supported in human cells, but it belongs to the contextual endosomal-trafficking side of PIK3C3 biology rather than the core PN autophagy claim. 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.	KEEP AS NON CORE	Summary: Contextual trafficking role supported by human Rab7/VPS34 data. Appropriate to retain as non-core. Reason: This transport function is part of the broader endosomal deployment of VPS34 PI3P signaling and should remain separate from the core macroautophagy-focused curation. 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...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
GO:0005515 protein binding	IPI PMID:7504174 The SH3 domain of p56lck is involved in binding to phosphati...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to serve as an informative molecular-function annotation for PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or process terms. Reason: Per project convention, `protein binding` should not be retained when it does not convey a specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual pathway roles rather than a standalone MF annotation.
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

Core Functions

PIK3C3/VPS34 is the catalytic lipid kinase of the ATG14-containing class III PI3K complex that generates PI3P at early autophagy membranes to drive phagophore formation and autophagosome assembly during macroautophagy.

Molecular Function:

1-phosphatidylinositol-3-kinase activity

Directly Involved In:

phosphatidylinositol-3-phosphate biosynthetic process autophagosome assembly macroautophagy autophagosome maturation

Cellular Locations:

phagophore assembly site autophagosome

In Complex:

phosphatidylinositol 3-kinase complex, class III, type I

Supporting Evidence:

PMID:7628435
PtdIns 3-kinase does not associate with p85 and phosphorylates PtdIns, but not PtdIns4P or PtdIns(4,5)P2.
PMID:40442316
PI3KC3-C1 contains one copy each of the lipid kinase VPS34, the pseudokinase VPS15 and the regulatory subunits BECN1 and ATG14
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)**.
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.

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10625637

Distinct classes of phosphatidylinositol 3'-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells.

PMID:14617358

Human VPS34 and p150 are Rab7 interacting partners.

PMID:16417406

Hem-1 complexes are essential for Rac activation, actin polymerization, and myosin regulation during neutrophil chemotaxis.

PMID:16467569

Regulation of membrane traffic by phosphoinositide 3-kinases.

PMID:16799551

Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG.

PMID:17307798

CD160-activating NK cell effector functions depend on the phosphatidylinositol 3-kinase recruitment.

PMID:19050071

Identification of Barkor as a mammalian autophagy-specific factor for Beclin 1 and class III phosphatidylinositol 3-kinase.

PMID:19270696

Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages.

PMID:19946888

Defining the membrane proteome of NK cells.

PMID:20142477

The early autophagic pathway is activated by hepatitis B virus and required for viral DNA replication.

PMID:20208530

PtdIns(3)P controls cytokinesis through KIF13A-mediated recruitment of FYVE-CENT to the midbody.

PMID:20562859

Network organization of the human autophagy system.

PMID:20643123

A phosphatidylinositol 3-kinase class III sub-complex containing VPS15, VPS34, Beclin 1, UVRAG and BIF-1 regulates cytokinesis and degradative endocytic traffic.

PMID:21062745

The RUN domain of rubicon is important for hVps34 binding, lipid kinase inhibition, and autophagy suppression.

PMID:22095288

PKD is a kinase of Vps34 that mediates ROS-induced autophagy downstream of DAPk.

PMID:22493499

Receptor signaling lymphocyte-activation molecule family 1 (Slamf1) regulates membrane fusion and NADPH oxidase 2 (NOX2) activity by recruiting a Beclin-1/Vps34/ultraviolet radiation resistance-associated gene (UVRAG) complex.

PMID:23316280

The VMP1-Beclin 1 interaction regulates autophagy induction.

PMID:23332761

Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy.

PMID:23364696

Identification of a candidate therapeutic autophagy-inducing peptide.

PMID:23878393

Role of membrane association and Atg14-dependent phosphorylation in beclin-1-mediated autophagy.

PMID:23954414

Beclin 2 functions in autophagy, degradation of G protein-coupled receptors, and metabolism.

PMID:24034250

EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance.

PMID:24056303

PtdIns(3)P-bound UVRAG coordinates Golgi-ER retrograde and Atg9 transport by differential interactions with the ER tether and the beclin 1 complex.

PMID:24472739

Decorin activates AMPK, an energy sensor kinase, to induce autophagy in endothelial cells.

PMID:24785657

NRBF2 regulates macroautophagy as a component of Vps34 Complex I.

PMID:24849286

NRBF2 regulates autophagy and prevents liver injury by modulating Atg14L-linked phosphatidylinositol-3 kinase III activity.

PMID:25327288

Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo.

PMID:25490155

Architecture and dynamics of the autophagic phosphatidylinositol 3-kinase complex.

PMID:25594178

A kinase-independent role for EGF receptor in autophagy initiation.

PMID:26496610

A human interactome in three quantitative dimensions organized by stoichiometries and abundances.

PMID:26783301

Negative regulation of phosphatidylinositol 3-phosphate levels in early-to-late endosome conversion.

PMID:28479384

Beclin1 antagonizes LAPTM4B-mediated EGFR overactivation in gastric cancer cells.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:28890335

The ER-Localized Transmembrane Protein EPG-3/VMP1 Regulates SERCA Activity to Control ER-Isolation Membrane Contacts for Autophagosome Formation.

PMID:30767700

Members of the autophagy class III phosphatidylinositol 3-kinase complex I interact with GABARAP and GABARAPL1 via LIR motifs.

PMID:31806350

The ER-Localized Transmembrane Protein TMEM39A/SUSR2 Regulates Autophagy by Controlling the Trafficking of the PtdIns(4)P Phosphatase SAC1.

PMID:33422265

ORF3a of the COVID-19 virus SARS-CoV-2 blocks HOPS complex-mediated assembly of the SNARE complex required for autolysosome formation.

PMID:33473107

Endonuclease G promotes autophagy by suppressing mTOR signaling and activating the DNA damage response.

PMID:33637724

VPS34 K29/K48 branched ubiquitination governed by UBE3C and TRABID regulates autophagy, proteostasis and liver metabolism.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:34320401

Inhibitors of VPS34 and fatty-acid metabolism suppress SARS-CoV-2 replication.

PMID:34386498

ORF3a-Mediated Incomplete Autophagy Facilitates Severe Acute Respiratory Syndrome Coronavirus-2 Replication.

PMID:34524948

Global Proximity Interactome of the Human Macroautophagy Pathway.

PMID:35271311

OpenCell: Endogenous tagging for the cartography of human cellular organization.

PMID:40442316

Structure and activation of the human autophagy-initiating ULK1C:PI3KC3-C1 supercomplex.

PMID:7504174

The SH3 domain of p56lck is involved in binding to phosphatidylinositol 3'-kinase from T lymphocytes.

PMID:7628435

A human phosphatidylinositol 3-kinase complex related to the yeast Vps34p-Vps15p protein sorting system.

PMID:8999962

Characterization of p150, an adaptor protein for the human phosphatidylinositol (PtdIns) 3-kinase. Substrate presentation by phosphatidylinositol transfer protein to the p150.Ptdins 3-kinase complex.

Reactome:R-HSA-109699

PI3K-containing complexes phosphorylate PIP2 to PIP3

Reactome:R-HSA-1632852

Macroautophagy

Reactome:R-HSA-1632857

ULK1 phosphorylates AMBRA1:BECN1 complex

Reactome:R-HSA-1675939

PI is phosphorylated to PI3P by PIK3C2A/3 at the early endosome membrane

Reactome:R-HSA-1675961

PI is phosphorylated to PI3P by PIK3C2A/3 at the Golgi membrane

Reactome:R-HSA-1676024

PI is phosphorylated to PI3P by PIK3C2A/3 at the late endosome membrane

Reactome:R-HSA-188002

Rab5-mediated recruitment of class III PI3K to TLR9

Reactome:R-HSA-5672012

Beclin-1 complex phosphorylates PtdIns

Reactome:R-HSA-5678313

AMBRA1:DYNLL1,DYNLL2 binds BECN1 complex

Reactome:R-HSA-5678315

BECN1 complex, p-AMBRA1 dissociate from DYNLL1,DYNLL2

Reactome:R-HSA-5679205

ULK1 phosphorylates Beclin-1

Reactome:R-HSA-5679266

Beclin-1 complex translocates to the ER

Reactome:R-HSA-5682385

The phagophore extends from the PIP3-enriched structure

Reactome:R-HSA-6798174

PIK3C3:PIK3R4 phosphorylates PI to PI3P

Reactome:R-HSA-9755359

SARS-CoV-2 8:class I MHC binds BECN1

Reactome:R-HSA-9921171

NS1 binds Beclin-1

file:human/PIK3C3/PIK3C3-deep-research-falcon.md

Falcon deep research synthesis for PIK3C3

file:human/PIK3C3/PIK3C3-uniprot.txt

UniProt record for human PIK3C3

file:reactome/R-HSA-5672012.md

Reactome autophagy initiation event containing PIK3C3

file:human/PIK3C3/PIK3C3-notes.md

PIK3C3 review notes

Deep Research

Falcon

(PIK3C3-deep-research-falcon.md)

Question: You are an expert researcher providing comprehensive, well-cited information. Falcon Edison Scientific Literature 28 citations 2026-05-12T07:27:33.020845

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Perform concise GO-focused deep research on the human PIK3C3 gene (UniProt Q8NEB9; phosphatidylinositol 3-kinase catalytic subunit type 3/Vps34). Summarize the core molecular function, major biological processes, cellular locations, key experimental evidence, and any GO annotation caveats. Include PMID or DOI citations where available, and keep the report focused for gene annotation review.

GO-focused gene annotation research report: human PIK3C3 (VPS34) (UniProt Q8NEB9)

1) Key concepts and definitions (current understanding)

Gene/protein: Human PIK3C3 encodes VPS34, the class III phosphatidylinositol 3-kinase catalytic subunit that produces phosphatidylinositol 3-phosphate (PI3P). In the most authoritative recent pharmacology-focused synthesis, VPS34 is described as exclusively catalyzing PI3P production from phosphatidylinositol (PI) in vitro and in vivo—a key point for GO molecular function specificity (i.e., not generating PIP3 from PI(4,5)P2 as class I PI3Ks do). (burke2023beyondpi3kstargeting pages 22-23)

GO-relevant biochemical reaction (MF + BP):
- Substrate/product specificity for curation: PI → PI3P (phosphatidylinositol 3-phosphate biosynthesis) as the defining catalytic activity of VPS34. (burke2023beyondpi3kstargeting pages 22-23, lee2024regulatorymechanismsgoverning pages 1-2)

Complex architecture and nomenclature (GO CC + context for BP): VPS34 functions as a subunit of two distinct tetrameric complexes:
- PI3KC3 Complex I (PI3KC3-C1): VPS34 (PIK3C3) + VPS15 (PIK3R4) + BECN1 + ATG14. This complex is classically associated with autophagy initiation/autophagosome nucleation. (burke2023beyondpi3kstargeting pages 22-23, lee2024regulatorymechanismsgoverning pages 1-2, chau2024thecellularadaptor pages 1-2)
- PI3KC3 Complex II (PI3KC3-C2): VPS34 (PIK3C3) + VPS15 (PIK3R4) + BECN1 + UVRAG, classically associated with endocytic sorting/endosome maturation and related trafficking. (burke2023beyondpi3kstargeting pages 22-23, lee2024regulatorymechanismsgoverning pages 1-2)

Key regulators frequently relevant to annotation context:
- NRBF2: described as an activator of Complex I (and thus relevant when annotating autophagy-initiation-linked PI3P production). (burke2023beyondpi3kstargeting pages 22-23, lee2024regulatorymechanismsgoverning pages 12-12)
- Rubicon (RUBCN): described as a Complex-II-associated regulator that can modulate autophagy stages and endocytic roles in a context-dependent manner; it contributes to why Complex I vs II should be separated in annotation where possible. (lee2024regulatorymechanismsgoverning pages 12-12)

2) Core GO Molecular Function (MF): what VPS34 does

Core MF statement for PIK3C3: VPS34 is the catalytic subunit of class III PI3K and produces PI3P from PI, with major sources emphasizing the exclusivity of this reaction for VPS34 in vivo/in vitro among class III PI3Ks. (burke2023beyondpi3kstargeting pages 22-23, lee2024regulatorymechanismsgoverning pages 1-2)

Complex requirement for activity: VPS34 activity depends on its complex context; notably VPS15/PIK3R4 is described as required for VPS34 activity, reinforcing that MF evidence often comes from complex-level biochemistry/structural studies rather than isolated VPS34. (lee2024regulatorymechanismsgoverning pages 1-2)

3) Major GO Biological Processes (BP): autophagy and endocytosis-centered roles

3.1 Autophagy initiation / autophagosome nucleation (canonical macroautophagy)

Multiple sources converge on the model that Complex I (ATG14-containing) is the autophagy initiation VPS34 complex, generating PI3P to recruit downstream PI3P-binding effectors (including WIPI proteins) to early autophagic membranes. (lee2024regulatorymechanismsgoverning pages 1-2, lee2024regulatorymechanismsgoverning pages 12-12)
In an experimentally grounded signaling study (STING/autophagy), PI3P is described as a key product that recruits ATG12–ATG5–ATG16L1 via WIPI2 to target LC3 to the phagophore, consistent with a canonical pathway in which VPS34-derived PI3P supports phagophore maturation steps. (wan2023stingdirectlyrecruits pages 1-2)

3.2 Endocytic trafficking, endosomal identity, and endolysosomal maturation

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. (thibault2023targetingclassiiiiii pages 8-10, swamynathan2024dietaryprooxidanttherapy pages 8-9)
A recent 2024 Science study provides direct phenotype-level support consistent with an endosomal identity role: both a selective VPS34 inhibitor (VPS34-IN1) and an oxidative intervention (MSB) produce endosomal defects alongside a reduction in PI3P-reporter puncta (GFP-2xFYVE), and CRISPR targeting of VPS34 phenocopies these effects. This supports annotating VPS34 to PI3P-dependent endosomal organization/trafficking processes. (swamynathan2024dietaryprooxidanttherapy pages 8-9)

4) GO Cellular Component (CC): where VPS34 acts

Complex-level CC annotations (high confidence):
- PI3KC3-C1 (Complex I) and PI3KC3-C2 (Complex II) as distinct cellular components/complexes are directly supported by recent authoritative reviews describing their tetrameric composition and functional distinctness. (burke2023beyondpi3kstargeting pages 22-23, lee2024regulatorymechanismsgoverning pages 1-2)

Membrane compartments (context-dependent localization):
- ER-linked autophagy initiation sites / phagophore assembly sites: Evidence that Complex I is functionally tied to ER-associated initiation emerges from work showing that factors can promote ATG14 targeting to the ER and enhance PI3KC3-C1 activity, supporting ER/phagophore-associated CC assignments for the autophagy-initiation complex. (chau2024thecellularadaptor pages 1-2)
- Early endosomes: A recent Science study reports that VPS34 perturbation reduces PI3P reporter puncta and yields vacuoles retaining early-endosome markers (e.g., Rab5 association) while lacking lysosomal marker LAMP1 in the tested context, consistent with a key VPS34 role at early endosomal membranes. (swamynathan2024dietaryprooxidanttherapy pages 8-9)
- Endosomes and endosome–lysosome interface: Complex composition is described as directing VPS34 to endosome-linked vs phagophore-linked functions, and VPS34-dependent PI3P is connected to later fusion/maturation events involving late endosomes/lysosomes in trafficking-centric models. (wible2024unexpectedinhibitionof pages 1-3, thibault2023targetingclassiiiiii pages 8-10)

5) Key experimental evidence (selected, GO-curation-relevant)

5.1 PI3P reporter depletion and endosomal phenotypes (2024)

Swamynathan et al., Science (Oct 2024; DOI: 10.1126/science.adk9167; URL: https://doi.org/10.1126/science.adk9167): Demonstrates that an oxidative agent (MSB) functionally antagonizes VPS34 and phenocopies VPS34 inhibition, sharply reducing PI3P reporter puncta (GFP-2xFYVE) and producing endosome identity defects; NAC reverses MSB effects consistent with oxidative inactivation rather than simple competitive inhibition. This is strong support for PI3P biosynthesis and endosomal organization functions at the cellular level. (swamynathan2024dietaryprooxidanttherapy pages 8-9, swamynathan2024dietaryprooxidanttherapy pages 1-3)

5.2 Genetic + inhibitor evidence tying VPS34 to endosomal trafficking during viral entry (2024; quantitative)

Gong et al., PLoS Pathogens (Aug 2024; DOI: 10.1371/journal.ppat.1012444; URL: https://doi.org/10.1371/journal.ppat.1012444): Shows VPS34/PIK3C3 is required for Ebola virus entry via endocytic trafficking. Quantitatively, VPS34-IN-1 inhibits EBOV infection with IC50 = 371 nM (EBOVΔVP30-EGFP model) and IC50 = 405 nM (authentic EBOV), and a kinase-dead PIK3C3 D761A does not complement PIK3C3 KO. These results link VPS34 kinase activity to endosomal maturation/trafficking to NPC1-positive endolysosomal compartments. (gong2024genomewidecrisprcas9screen pages 7-10)

5.3 Autophagy-independent PI3P-dependent membrane phenotypes (2024)

Wible et al., Cell Death & Disease (Jan 2024; DOI: 10.1038/s41419-024-06423-0; URL: https://doi.org/10.1038/s41419-024-06423-0): Reports that a vacuolation phenotype can rely on the PIK3C3 complex and PI(3)P production but not on autophagy per se, supporting VPS34 assignment to endolysosomal organization/volume control processes that are distinct from canonical macroautophagy readouts. (wible2024unexpectedinhibitionof pages 1-3)

5.4 Noncanonical autophagy route bypassing PIK3C3 (2023; caveat)

Wan et al., EMBO Journal (Mar 2023; DOI: 10.15252/embj.2022112387; URL: https://doi.org/10.15252/embj.2022112387): Shows STING-induced autophagy requires WIPI2 but not the PIK3C3 complex, an important warning against blanket annotation of PIK3C3 as required for all forms of autophagosome formation/LC3 lipidation. (wan2023stingdirectlyrecruits pages 1-2)

6) GO annotation caveats and curation guidance (for review)

Avoid class I PI3K conflation: VPS34 produces PI3P from PI, not PIP3 from PI(4,5)P2; MF terms should reflect PI3P biosynthesis rather than PI(3,4,5)P3-linked signaling. (burke2023beyondpi3kstargeting pages 22-23)
Complex-specific annotation is preferred: When evidence indicates autophagy initiation, it is most consistent with Complex I (ATG14; NRBF2-activated); when evidence indicates endocytic sorting/viral entry/early endosome identity, it is most consistent with Complex II (UVRAG) and shared core subunits. Consider annotating to both BP terms only when evidence supports both, or qualifying via complex context. (burke2023beyondpi3kstargeting pages 22-23, lee2024regulatorymechanismsgoverning pages 1-2, thibault2023targetingclassiiiiii pages 8-10)
Noncanonical autophagy can be VPS34-independent: STING-induced autophagy provides a clear example that autophagy-related phenotypes can occur without PIK3C3 dependency; phenotype-only studies should not automatically imply direct PIK3C3 participation in all autophagy initiation contexts. (wan2023stingdirectlyrecruits pages 1-2)
Endosomal PI3P roles can masquerade as ‘autophagy’ phenotypes: PI3P-dependent vacuolation and endolysosomal swelling can depend on PIK3C3 but be autophagy-independent, affecting inference of BP terms from morphology alone. (wible2024unexpectedinhibitionof pages 1-3)
Phenotype interpretation (KO vs kinase-dead; compensatory PI3P): A synthesis focused on PI3K targeting highlights that VPS34 has roles that can be complicated by scaffolding/complex-level effects, differences between genetic knockout and catalytic inactivation, and potential compensatory PI3P sources in specific contexts; this argues for prioritizing direct biochemical/kinase-activity evidence (IDAs/IMP with catalytic mutants) for MF/BP assertions. (thibault2023targetingclassiiiiii pages 8-10)

7) Recent developments and real-world applications (2023–2024)

Therapeutic targeting/redox pharmacology: A high-impact 2024 Science paper identifies an oxidative dietary compound (MSB) as functionally antagonizing VPS34 by oxidation of key cysteines, tying VPS34 to endosomal identity/sorting and suggesting redox-sensitive control points relevant to drug development and disease models. (Oct 2024; https://doi.org/10.1126/science.adk9167). (swamynathan2024dietaryprooxidanttherapy pages 1-3, swamynathan2024dietaryprooxidanttherapy pages 8-9)
Antiviral host-factor targeting: A 2024 PLOS Pathogens study provides quantitative inhibitor potency (sub-micromolar IC50s) and genetic validation of kinase activity requirement for EBOV entry, supporting VPS34 as a potential host-directed antiviral target specifically through endocytic/endolysosomal trafficking mechanisms. (Aug 2024; https://doi.org/10.1371/journal.ppat.1012444). (gong2024genomewidecrisprcas9screen pages 7-10)
Expert synthesis of complex biology and druggability: A widely cited 2023 Nature Reviews Drug Discovery review emphasizes VPS34’s catalytic specificity and clear complex partitioning (C1 vs C2), supporting precise GO MF/CC curation and motivating use of complex-aware annotations. (Nov 2023; https://doi.org/10.1038/s41573-022-00582-5). (burke2023beyondpi3kstargeting pages 22-23)

8) GO-focused evidence summary table

GO aspect	Proposed GO concept / term label	Evidence summary	Key complex context	Representative experimental evidence types	Citations
MF	Phosphatidylinositol 3-kinase activity; phosphatidylinositol-3-phosphate biosynthetic process	Human VPS34/PIK3C3 is the class III PI3K catalytic subunit that converts phosphatidylinositol (PI) to PI3P, with recent reviews emphasizing this as its defining enzymatic activity and distinguishing it from class I PI3Ks.	Shared catalytic core in both Complex I and II with VPS15/PIK3R4 and BECN1; VPS15 is required for full VPS34 activity.	Biochemical/structural studies; kinase inhibition; PI3P-effector recruitment analyses.	Burke et al., Nat Rev Drug Discov (Nov 2023), DOI: 10.1038/s41573-022-00582-5, https://doi.org/10.1038/s41573-022-00582-5 (burke2023beyondpi3kstargeting pages 22-23, lee2024regulatorymechanismsgoverning pages 1-2)
BP	Macroautophagy initiation / autophagosome nucleation	VPS34-generated PI3P promotes recruitment of WIPI/ATG machinery to phagophore membranes, supporting autophagosome initiation and early biogenesis.	Complex I: PIK3C3-VPS15-BECN1-ATG14; activated by NRBF2 and regulated by ULK1-linked inputs.	Complex reconstitution/structural studies; localization of ATG14 puncta; PI3P-dependent effector recruitment.	Lee et al., Biomol Ther (Oct 2024), DOI: 10.4062/biomolther.2024.094, https://doi.org/10.4062/biomolther.2024.094 (lee2024regulatorymechanismsgoverning pages 12-12, lee2024regulatorymechanismsgoverning pages 6-7)
CC	PI3KC3-C1 autophagy initiation complex; ER/phagophore assembly site / omegasome-associated membrane	PI3KC3-C1 is targeted to ER-linked autophagy initiation sites, and ATG14-directed ER localization promotes autophagic vacuole formation.	Complex I with ATG14 as specifying subunit; GULP1 can enhance ATG14 targeting to ER and stimulate PI3KC3-C1 activity.	ER localization microscopy; autophagic vacuole analysis; modulation of ATG14 targeting.	Chau et al., Cell Mol Life Sci (Jul 2024), DOI: 10.1007/s00018-024-05351-8, https://doi.org/10.1007/s00018-024-05351-8 (chau2024thecellularadaptor pages 1-2)
BP	Endocytic trafficking / early endosome organization	VPS34 activity is required to maintain PI3P-positive early endosome identity, and oxidative or pharmacologic VPS34 inhibition depletes PI3P and disrupts endosomal sorting.	Most consistent with endosomal VPS34 complexes, especially Complex II-linked endocytic function; shared VPS34-VPS15-BECN1 core.	GFP-2xFYVE PI3P reporter loss; CRISPR targeting; VPS34-IN1; live-cell vacuolization imaging.	Swamynathan et al., Science (Oct 2024), DOI: 10.1126/science.adk9167, https://doi.org/10.1126/science.adk9167 (swamynathan2024dietaryprooxidanttherapy pages 8-9, swamynathan2024dietaryprooxidanttherapy pages 1-3)
CC	Early endosome	PI3P reporter depletion, Rab5-associated vacuoles, and loss of normal endosomal identity after VPS34 perturbation support localization/function at early endosomal membranes.	Endosomal VPS34 complexes; Rab5-dependent recruitment of hVPS34/p150 noted in review-level mechanistic summaries.	PI3P reporter imaging; Rab5 colocalization; inhibitor phenocopy; CRISPR knockout.	Swamynathan et al., Science (Oct 2024), DOI: 10.1126/science.adk9167, https://doi.org/10.1126/science.adk9167; Lee et al., Biomol Ther (Oct 2024), DOI: 10.4062/biomolther.2024.094, https://doi.org/10.4062/biomolther.2024.094 (swamynathan2024dietaryprooxidanttherapy pages 8-9, lee2024regulatorymechanismsgoverning pages 12-12)
BP	Endosome maturation / endolysosomal trafficking	VPS34 kinase activity is necessary for trafficking cargo/virions into NPC1-positive endolysosomal compartments, supporting a role in endosomal maturation and membrane traffic beyond canonical autophagy.	Functional emphasis on endocytic VPS34 activity; Complex II is the main endocytic sorting complex in current models.	KO/rescue with kinase-dead mutant; selective inhibitor; confocal colocalization with NPC1; viral entry assays.	Gong et al., PLoS Pathog (Aug 2024), DOI: 10.1371/journal.ppat.1012444, https://doi.org/10.1371/journal.ppat.1012444; VPS34-IN-1 IC50 = 371 nM for EBOVΔVP30-EGFP and 405 nM for authentic EBOV (gong2024genomewidecrisprcas9screen pages 7-10)
BP	Regulation of autophagy-independent endolysosomal membrane organization	Some VPS34-dependent PI3P phenotypes reflect endolysosomal control rather than autophagy itself, since vacuolation can require the PIK3C3 complex and PI3P but occur independently of autophagy per se.	Shared VPS34 complex with context-dependent adaptor usage; not uniquely attributable to Complex I.	Pharmacologic perturbation; PI3P dependence tests; endolysosomal morphology assays.	Wible et al., Cell Death & Disease (Jan 2024), DOI: 10.1038/s41419-024-06423-0, https://doi.org/10.1038/s41419-024-06423-0 (wible2024unexpectedinhibitionof pages 1-3)
CC	Endosome/lysosome fusion pathway; autophagosome-endolysosome interface	VPS34 participates in pathways linking PI3P-positive autophagic/endosomal membranes to later Rab7-dependent fusion with late endosomes and lysosomes.	Complex composition helps determine whether VPS34 acts at phagophore-associated or endosomal membranes; UVRAG/Rubicon-linked contexts are especially relevant downstream.	Membrane-trafficking studies; inhibitor phenotypes; pathway reconstruction from imaging and genetics.	Wible et al., Cell Death & Disease (Jan 2024), DOI: 10.1038/s41419-024-06423-0, https://doi.org/10.1038/s41419-024-06423-0; Thibault et al., Cancers (Jan 2023), DOI: 10.3390/cancers15030784, https://doi.org/10.3390/cancers15030784 (wible2024unexpectedinhibitionof pages 1-3, thibault2023targetingclassiiiiii pages 8-10)
CC/BP caveat	Context-specific: not all LC3 lipidation/autophagosome formation is VPS34-dependent	STING-induced autophagy can require WIPI2 but not the PIK3C3 complex, so annotations for autophagosome formation should avoid overgeneralizing VPS34 dependence to all noncanonical autophagy pathways.	Canonical autophagy uses Complex I; this caveat applies to noncanonical STING-driven LC3 lipidation/autophagosome formation.	Genetic pathway dissection; VPS34 inhibitor insensitivity in STING context; WIPI2 dependency tests.	Wan et al., EMBO J (Mar 2023), DOI: 10.15252/embj.2022112387, https://doi.org/10.15252/embj.2022112387 (wan2023stingdirectlyrecruits pages 1-2)

Table: This table summarizes GO-relevant molecular function, biological process, and cellular component evidence for human PIK3C3/VPS34, with emphasis on complex-specific context and annotation caveats. It also includes the key quantitative antiviral statistic from Gong 2024 for VPS34-IN-1.

References

(burke2023beyondpi3kstargeting pages 22-23): John E Burke, Joanna Catherine Caprio Triscott, Brooke M Emerling, and Gerald R V Hammond. Beyond pi3ks: targeting phosphoinositide kinases in disease. Nature Reviews. Drug Discovery, 22:357-386, Nov 2023. URL: https://doi.org/10.1038/s41573-022-00582-5, doi:10.1038/s41573-022-00582-5. This article has 157 citations.
(lee2024regulatorymechanismsgoverning pages 1-2): Yongook Lee, Nguyen Minh Tuan, Gi Jeong Lee, Boram Kim, Jung Ho Park, and Chang Hoon Lee. Regulatory mechanisms governing the autophagy-initiating vps34 complex and its inhibitors. Biomolecules & Therapeutics, 32:723-735, Oct 2024. URL: https://doi.org/10.4062/biomolther.2024.094, doi:10.4062/biomolther.2024.094. This article has 16 citations and is from a peer-reviewed journal.
(chau2024thecellularadaptor pages 1-2): Dennis Dik-Long Chau, Zhicheng Yu, Wai Wa Ray Chan, Zhai Yuqi, Raymond Chuen Chung Chang, Jacky Chi Ki Ngo, Ho Yin Edwin Chan, and Kwok-Fai Lau. The cellular adaptor gulp1 interacts with atg14 to potentiate autophagy and app processing. Cellular and Molecular Life Sciences: CMLS, Jul 2024. URL: https://doi.org/10.1007/s00018-024-05351-8, doi:10.1007/s00018-024-05351-8. This article has 6 citations.
(lee2024regulatorymechanismsgoverning pages 12-12): Yongook Lee, Nguyen Minh Tuan, Gi Jeong Lee, Boram Kim, Jung Ho Park, and Chang Hoon Lee. Regulatory mechanisms governing the autophagy-initiating vps34 complex and its inhibitors. Biomolecules & Therapeutics, 32:723-735, Oct 2024. URL: https://doi.org/10.4062/biomolther.2024.094, doi:10.4062/biomolther.2024.094. This article has 16 citations and is from a peer-reviewed journal.
(wan2023stingdirectlyrecruits pages 1-2): Wei Wan, Chuying Qian, Qian Wang, Jin Li, Hongtao Zhang, Lei Wang, Maomao Pu, Yewei Huang, Zhengfu He, Tianhua Zhou, Han‐Ming Shen, and Wei Liu. Sting directly recruits wipi2 for autophagosome formation during sting‐induced autophagy. The EMBO Journal, Mar 2023. URL: https://doi.org/10.15252/embj.2022112387, doi:10.15252/embj.2022112387. This article has 71 citations.
(thibault2023targetingclassiiiiii pages 8-10): Benoît Thibault, Fernanda Ramos-Delgado, and Julie Guillermet-Guibert. Targeting class i-ii-iii pi3ks in cancer therapy: recent advances in tumor biology and preclinical research. Cancers, 15:784, Jan 2023. URL: https://doi.org/10.3390/cancers15030784, doi:10.3390/cancers15030784. This article has 36 citations.
(swamynathan2024dietaryprooxidanttherapy pages 8-9): Manojit M. Swamynathan, Shan Kuang, Kaitlin E. Watrud, Mary R. Doherty, Charlotte Gineste, Grinu Mathew, Grace Q. Gong, Hilary Cox, Eileen Cheng, David Reiss, Jude Kendall, Diya Ghosh, Colleen R. Reczek, Xiang Zhao, Tali Herzka, Saulė Špokaitė, Antoine N. Dessus, Seung Tea Kim, Olaf Klingbeil, Juan Liu, Dawid G. Nowak, Habeeb Alsudani, Tse-Luen Wee, Youngkyu Park, Francesca Minicozzi, Keith Rivera, Ana S. Almeida, Kenneth Chang, Ram P. Chakrabarty, John E. Wilkinson, Phyllis A. Gimotty, Sarah D. Diermeier, Mikala Egeblad, Christopher R. Vakoc, Jason W. Locasale, Navdeep S. Chandel, Tobias Janowitz, James B. Hicks, Michael Wigler, Darryl J. Pappin, Roger L. Williams, Paolo Cifani, David A. Tuveson, Jocelyn Laporte, and Lloyd C. Trotman. Dietary pro-oxidant therapy by a vitamin k precursor targets pi 3-kinase vps34 function. Science, Oct 2024. URL: https://doi.org/10.1126/science.adk9167, doi:10.1126/science.adk9167. This article has 41 citations and is from a highest quality peer-reviewed journal.
(wible2024unexpectedinhibitionof pages 1-3): Daric J. Wible, Zalak Parikh, Eun Jeong Cho, Miao-Der Chen, Collene R. Jeter, Somshuvra Mukhopadhyay, Kevin N. Dalby, Shankar Varadarajan, and Shawn B. Bratton. Unexpected inhibition of the lipid kinase pikfyve reveals an epistatic role for p38 mapks in endolysosomal fission and volume control. Cell Death & Disease, Jan 2024. URL: https://doi.org/10.1038/s41419-024-06423-0, doi:10.1038/s41419-024-06423-0. This article has 19 citations and is from a peer-reviewed journal.
(swamynathan2024dietaryprooxidanttherapy pages 1-3): Manojit M. Swamynathan, Shan Kuang, Kaitlin E. Watrud, Mary R. Doherty, Charlotte Gineste, Grinu Mathew, Grace Q. Gong, Hilary Cox, Eileen Cheng, David Reiss, Jude Kendall, Diya Ghosh, Colleen R. Reczek, Xiang Zhao, Tali Herzka, Saulė Špokaitė, Antoine N. Dessus, Seung Tea Kim, Olaf Klingbeil, Juan Liu, Dawid G. Nowak, Habeeb Alsudani, Tse-Luen Wee, Youngkyu Park, Francesca Minicozzi, Keith Rivera, Ana S. Almeida, Kenneth Chang, Ram P. Chakrabarty, John E. Wilkinson, Phyllis A. Gimotty, Sarah D. Diermeier, Mikala Egeblad, Christopher R. Vakoc, Jason W. Locasale, Navdeep S. Chandel, Tobias Janowitz, James B. Hicks, Michael Wigler, Darryl J. Pappin, Roger L. Williams, Paolo Cifani, David A. Tuveson, Jocelyn Laporte, and Lloyd C. Trotman. Dietary pro-oxidant therapy by a vitamin k precursor targets pi 3-kinase vps34 function. Science, Oct 2024. URL: https://doi.org/10.1126/science.adk9167, doi:10.1126/science.adk9167. This article has 41 citations and is from a highest quality peer-reviewed journal.
(gong2024genomewidecrisprcas9screen pages 7-10): Mingli Gong, Cheng Peng, Chen Yang, Zhenhua Wang, Hongwu Qian, Xue Hu, Peng Zhou, Chao Shan, and Qiang Ding. Genome-wide crispr/cas9 screen identifies slc39a9 and pik3c3 as crucial entry factors for ebola virus infection. PLOS Pathogens, 20:e1012444, Aug 2024. URL: https://doi.org/10.1371/journal.ppat.1012444, doi:10.1371/journal.ppat.1012444. This article has 12 citations and is from a highest quality peer-reviewed journal.
(lee2024regulatorymechanismsgoverning pages 6-7): Yongook Lee, Nguyen Minh Tuan, Gi Jeong Lee, Boram Kim, Jung Ho Park, and Chang Hoon Lee. Regulatory mechanisms governing the autophagy-initiating vps34 complex and its inhibitors. Biomolecules & Therapeutics, 32:723-735, Oct 2024. URL: https://doi.org/10.4062/biomolther.2024.094, doi:10.4062/biomolther.2024.094. This article has 16 citations and is from a peer-reviewed journal.

Citations

lee2024regulatorymechanismsgoverning pages 12-12
lee2024regulatorymechanismsgoverning pages 1-2
wan2023stingdirectlyrecruits pages 1-2
swamynathan2024dietaryprooxidanttherapy pages 8-9
chau2024thecellularadaptor pages 1-2
wible2024unexpectedinhibitionof pages 1-3
thibault2023targetingclassiiiiii pages 8-10
swamynathan2024dietaryprooxidanttherapy pages 1-3
lee2024regulatorymechanismsgoverning pages 6-7
https://doi.org/10.1126/science.adk9167
https://doi.org/10.1371/journal.ppat.1012444
https://doi.org/10.1038/s41419-024-06423-0
https://doi.org/10.15252/embj.2022112387
https://doi.org/10.1038/s41573-022-00582-5
https://doi.org/10.4062/biomolther.2024.094
https://doi.org/10.1007/s00018-024-05351-8
https://doi.org/10.1126/science.adk9167;
https://doi.org/10.1371/journal.ppat.1012444;
https://doi.org/10.1038/s41419-024-06423-0;
https://doi.org/10.3390/cancers15030784
https://doi.org/10.1038/s41573-022-00582-5,
https://doi.org/10.4062/biomolther.2024.094,
https://doi.org/10.1007/s00018-024-05351-8,
https://doi.org/10.15252/embj.2022112387,
https://doi.org/10.3390/cancers15030784,
https://doi.org/10.1126/science.adk9167,
https://doi.org/10.1038/s41419-024-06423-0,
https://doi.org/10.1371/journal.ppat.1012444,

📚 Additional Documentation

Notes

(PIK3C3-notes.md)

PIK3C3 notes

PIK3C3 encodes VPS34, the catalytic lipid kinase of the human class III PI3K system, and the core molecular-function claim should stay at specific phosphatidylinositol 3-kinase activity rather than generic kinase terms [PMID:7628435 A human phosphatidylinositol 3-kinase complex related to the yeast Vps34p-Vps15p protein sorting system., "PtdIns 3-kinase does not associate with p85 and phosphorylates PtdIns, but not PtdIns4P or PtdIns(4,5)P2."].
The strongest PN-supported core case is macroautophagy initiation through PI3KC3-C1/type I, which contains VPS34 with VPS15, BECN1, and ATG14 and acts at the earliest autophagy stages [PMID:40442316 Structure and activation of the human autophagy-initiating ULK1C:PI3KC3-C1 supercomplex., "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)5–7."] [PMID:40442316 Structure and activation of the human autophagy-initiating ULK1C:PI3KC3-C1 supercomplex., "PI3KC3-C1 contains one copy each of the lipid kinase VPS34, the pseudokinase VPS15 and the regulatory subunits BECN1 and ATG14."].
PI3P production is the key process-level output shared across VPS34 deployments and directly underpins autophagosome formation and maturation, which makes GO:0036092 a better process term than broad phosphatidylinositol-phosphate biosynthesis [PMID:33637724 VPS34 K29/K48 branched ubiquitination governed by UBE3C and TRABID regulates autophagy, proteostasis and liver metabolism., "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."].
Human data also support a UVRAG-containing PI3KC3-C2/type II complex linked to endosomal sorting and later autophagy-associated trafficking, but this should be kept contextual rather than core in the PN framing [PMID:40442316 Structure and activation of the human autophagy-initiating ULK1C:PI3KC3-C1 supercomplex., "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 initiation."].
Endosomal trafficking and cytokinesis are supported human roles for VPS34 complexes, but they should remain non-core relative to the autophagy-initiation case [PMID:14617358 Human VPS34 and p150 are Rab7 interacting partners., "The hVPS34/p150 complex colocalized with rab7 on late endosomes and hVPS34 activity was dependent on nucleotide cycling of rab7."] [PMID:20208530 PtdIns(3)P controls cytokinesis through KIF13A-mediated recruitment of FYVE-CENT to the midbody., "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."] [PMID:20643123 A phosphatidylinositol 3-kinase class III sub-complex containing VPS15, VPS34, Beclin 1, UVRAG and BIF-1 regulates cytokinesis and degradative endocytic traffic., "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."].
Broad membrane proteomics is too weak to retain as a meaningful PIK3C3 localization assertion in the review [PMID:19946888 Defining the membrane proteome of NK cells., "The remaining species were largely involved in cellular processes and molecular functions that could be predicted to be transiently associated with membranes."].

Description cleanup note

The YAML description field was revised to keep it as a standalone biological summary. Project-specific curation framing moved here instead.

Moved out of the YAML description: the Proteostasis Network context emphasized the autophagy-initiation complex and macroautophagy as central core claims, with endosomal trafficking and cytokinesis as supported contextual extensions.

Pn Notes

(PIK3C3-pn-notes.md)

PIK3C3 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q8NEB9
AIGR review status: COMPLETE
Review batch: proteostasis-pr-1217 (PR 1217)
Batch change status: modified

Source Files Checked

AIGR review YAML: present - genes/human/PIK3C3/PIK3C3-ai-review.yaml
AIGR review HTML: present - genes/human/PIK3C3/PIK3C3-ai-review.html
Gene notes: present - genes/human/PIK3C3/PIK3C3-notes.md
GOA TSV: present - genes/human/PIK3C3/PIK3C3-goa.tsv
UniProt record: present - genes/human/PIK3C3/PIK3C3-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/PIK3C3.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/PIK3C3.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/PIK3C3/PIK3C3-deep-research-falcon.md

AIGR Review Snapshot

Description: 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. Autophagy initiation and macroautophagy are major VPS34 roles, whereas endosomal trafficking and cytokinesis are contextual extensions of the same PI3P-generating biology.
Existing/core annotation action counts: ACCEPT: 21; KEEP_AS_NON_CORE: 33; MARK_AS_OVER_ANNOTATED: 46; MODIFY: 14; REMOVE: 5

PN Consistency Summary

Consistency: Fully consistent. PN notes (VPS34 in PI3KC3-C1 making PI3P at nucleation; PI3KC3-C2 in endosome/autophagosome maturation + HOPS recruitment) match the review and deep research (falcon). Both projected complex terms are present: GO:0034271 ACCEPT (core, PI3KC3-C1) and GO:0034272 KEEP_AS_NON_CORE (PI3KC3-C2). The PN type-I = core / type-II = trafficking split mirrors the review's core-vs-non-core split exactly.
PN story / NEW pressure: No new pressure — PN's complex memberships are already in GOA and the review. Both type-specific complex terms (GO:0034271/GO:0034272) verified real via the review's annotations; GO:0097352 autophagosome maturation (used in core_functions) verified real via OLS. The review additionally REMOVEs miscalls (GO:0004672 protein kinase, GO:0043491 PI3K/AKT) consistent with VPS34 being a class III lipid kinase. Conclusion: already captured; PN adds no over-reach.
Evidence alignment: PN cites PI3KC3-C1/C2 reviews + Matsunaga (ATG14L/Rubicon) Nat Cell Biol; review anchors the same complex biology to PMID:40442316 (PI3KC3-C1 structure), PMID:33637724, PMID:7628435 (substrate specificity). Substantive overlap on complex composition and PI3P output.
Verdict: Fully consistent and well-scoped; PN complex projections already captured, type-I/type-II split correctly preserved. No edits required.

Full Consistency Review

UniProt: Q8NEB9 · batch: proteostasis-pr-1217 · review status: COMPLETE
PN placement: ALP|Autophagophore initiation and elongation|Class 3 PI3K complex 1, direct|Class 3 PI3K complex 1 component and ALP|Autophagosome closure maturation and lysosome fusion|Class 3 PI3K complex 2, direct|Class 3 PI3K complex 2 component ; PN-node mapping: type leaves mapped / ok_for_propagation to GO:0034271 (C-III type I) and GO:0034272 (C-III type II); group nodes context_only / GO:0035032; class context_only / GO:0016236. Both projected terms already_in_goa_exact.
Consistency: Fully consistent. PN notes (VPS34 in PI3KC3-C1 making PI3P at nucleation; PI3KC3-C2 in endosome/autophagosome maturation + HOPS recruitment) match the review and deep research (falcon). Both projected complex terms are present: GO:0034271 ACCEPT (core, PI3KC3-C1) and GO:0034272 KEEP_AS_NON_CORE (PI3KC3-C2). The PN type-I = core / type-II = trafficking split mirrors the review's core-vs-non-core split exactly.
PN story / NEW pressure: No new pressure — PN's complex memberships are already in GOA and the review. Both type-specific complex terms (GO:0034271/GO:0034272) verified real via the review's annotations; GO:0097352 autophagosome maturation (used in core_functions) verified real via OLS. The review additionally REMOVEs miscalls (GO:0004672 protein kinase, GO:0043491 PI3K/AKT) consistent with VPS34 being a class III lipid kinase. Conclusion: already captured; PN adds no over-reach.
Mapping strategy: No change. The two mapped component leaves are correctly the only propagating nodes; the group/class nodes are correctly context_only (generic GO:0035032 / GO:0016236 not propagated). This is the model case for "only explicit complex-component leaves propagate to GO complex terms."
Evidence alignment: PN cites PI3KC3-C1/C2 reviews + Matsunaga (ATG14L/Rubicon) Nat Cell Biol; review anchors the same complex biology to PMID:40442316 (PI3KC3-C1 structure), PMID:33637724, PMID:7628435 (substrate specificity). Substantive overlap on complex composition and PI3P output.
Verdict: Fully consistent and well-scoped; PN complex projections already captured, type-I/type-II split correctly preserved. No edits required.

PN Dossier Context

review_batch: proteostasis-pr-1217
review_yaml: genes/human/PIK3C3/PIK3C3-ai-review.yaml
PN workbook rows: 2

PN row 1: Autophagy-Lysosome Pathway | Autophagophore initiation and elongation | Class 3 PI3K complex 1, direct | Class 3 PI3K complex 1 component

UniProt: Q8NEB9
In branches: ALP
Notes: Member of class III PI3K complex 1 that produces PI(3)P at the site of phagophore nucleation. Member of class III PI3K complex 2 that is involved in endosome and autophagosome maturation and recruits the HOPS complex for lysosome fusion
PN references (titles):
- Mammalian Autophagy: How Does It Work? | Annual Review of Biochemistry (annualreviews.org)
- Full article: Autophagy pathway: Cellular and molecular mechanisms (tandfonline.com)
- Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages | Nature Cell Biology
PN-node mapping records (path + ancestors):
- [type] Autophagy-Lysosome Pathway|Autophagophore initiation and elongation|Class 3 PI3K complex 1, direct|Class 3 PI3K complex 1 component
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0034271 phosphatidylinositol 3-kinase complex, class III, type I]
  rationale: This PN type is a curated component class for the direct autophagy- promoting class III PI3K complex 1. Propagation to the matching GO cellular-component term is appropriate, although the source is a component-role category rather than the complex term itself.
- [group] Autophagy-Lysosome Pathway|Autophagophore initiation and elongation|Class 3 PI3K complex 1, direct
  status=context_only scope=too_broad_to_propagate GO=[GO:0035032 phosphatidylinositol 3-kinase complex, class III]
  rationale: Reviewed as a class-III PI3K complex context or regulator bucket. This node is useful for curator interpretation, but it should not project cellular-component membership; only explicit complex-component leaves propagate to GO complex terms.
- [class] Autophagy-Lysosome Pathway|Autophagophore initiation and elongation
  status=context_only scope=too_broad_to_propagate GO=[GO:0016236 macroautophagy]
  rationale: This class is a real macroautophagy context, but its descendants include core factors, component buckets, upstream modulators, localization roles, and residual categories. Projecting generic macroautophagy from this ancestor creates TRAPP-like overpropagation, so candidate GO annotations must come from narrower curated nodes.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

PN row 2: Autophagy-Lysosome Pathway | Autophagosome closure maturation and lysosome fusion | Class 3 PI3K complex 2, direct | Class 3 PI3K complex 2 component

UniProt: Q8NEB9
In branches: ALP
Notes: Member of class III PI3K complex 1 that produces PI(3)P at the site of phagophore nucleation. Member of class III PI3K complex 2 that is involved in endosome and autophagosome maturation and recruits the HOPS complex for lysosome fusion
PN references (titles):
- Mammalian Autophagy: How Does It Work? | Annual Review of Biochemistry (annualreviews.org)
- Full article: Autophagy pathway: Cellular and molecular mechanisms (tandfonline.com)
- Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages | Nature Cell Biology
PN-node mapping records (path + ancestors):
- [type] Autophagy-Lysosome Pathway|Autophagosome closure maturation and lysosome fusion|Class 3 PI3K complex 2, direct|Class 3 PI3K complex 2 component
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0034272 phosphatidylinositol 3-kinase complex, class III, type II]
  rationale: This PN type denotes component membership in the direct class III PI3K complex 2 module used during autophagosome maturation and lysosome fusion. The corresponding GO complex term is the right propagation target.
- [group] Autophagy-Lysosome Pathway|Autophagosome closure maturation and lysosome fusion|Class 3 PI3K complex 2, direct
  status=context_only scope=too_broad_to_propagate GO=[GO:0035032 phosphatidylinositol 3-kinase complex, class III]
  rationale: Reviewed as a class-III PI3K complex context or regulator bucket. This node is useful for curator interpretation, but it should not project cellular-component membership; only explicit complex-component leaves propagate to GO complex terms.
- [class] Autophagy-Lysosome Pathway|Autophagosome closure maturation and lysosome fusion
  status=context_only scope=too_broad_to_propagate GO=[GO:0016236 macroautophagy]
  rationale: This class is a late macroautophagy context, but the subtree mixes docking, fusion, localization, membrane-composition, and unknown late-stage roles. The class-level relation is useful for display while propagation is restricted to narrower mechanism nodes.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

Projected GO annotations (2)

GO:0034271 phosphatidylinositol 3-kinase complex, class III, type I | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Autophagy-Lysosome Pathway|Autophagophore initiation and elongation|Class 3 PI3K complex 1, direct|Class 3 PI3K complex 1 component
GO:0034272 phosphatidylinositol 3-kinase complex, class III, type II | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Autophagy-Lysosome Pathway|Autophagosome closure maturation and lysosome fusion|Class 3 PI3K complex 2, direct|Class 3 PI3K complex 2 component

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

id: Q8NEB9
gene_symbol: PIK3C3
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  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. Autophagy
  initiation and macroautophagy are major VPS34 roles, whereas endosomal trafficking and cytokinesis
  are contextual extensions of the same PI3P-generating biology.
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Cytoplasm is a broad but directionally compatible localization for a cytoplasmic 
      vesicle-associated lipid kinase.
    action: KEEP_AS_NON_CORE
    reason: PIK3C3 is best localized to specific autophagy and endosomal membranes/complexes; cytoplasm is 
      retained only as a broad contextual cellular-component annotation.
    proposed_replacement_terms:
    - id: GO:0000407
      label: phagophore assembly site
    - id: GO:0005768
      label: endosome
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-uniprot.txt
      supporting_text: Midbody {ECO:0000269|PubMed:20208530}. Late endosome {ECO:0000269|PubMed:14617358}. 
        Cytoplasmic vesicle, autophagosome {ECO:0000305|PubMed:14617358}.
    - reference_id: file:human/PIK3C3/PIK3C3-uniprot.txt
      supporting_text: 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).
  qualifier: is_active_in
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Membrane is too broad for PIK3C3 localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: The evidence supports specific endomembrane contexts, especially phagophore/autophagosome and 
      endosomal membranes, rather than a generic membrane annotation.
    proposed_replacement_terms:
    - id: GO:0000407
      label: phagophore assembly site
    - id: GO:0005768
      label: endosome
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-uniprot.txt
      supporting_text: Midbody {ECO:0000269|PubMed:20208530}. Late endosome {ECO:0000269|PubMed:14617358}. 
        Cytoplasmic vesicle, autophagosome {ECO:0000305|PubMed:14617358}.
    - reference_id: file:human/PIK3C3/PIK3C3-uniprot.txt
      supporting_text: 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).
  qualifier: is_active_in
- term:
    id: GO:0048015
    label: phosphatidylinositol-mediated signaling
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Phosphatidylinositol-mediated signaling is directionally related but too broad for VPS34.
    action: MODIFY
    reason: The direct process output of PIK3C3 is PI3P biosynthesis, with downstream effects in autophagosome
      formation and endosomal organization; the signaling parent term blurs that specificity.
    proposed_replacement_terms:
    - id: GO:0036092
      label: phosphatidylinositol-3-phosphate biosynthetic process
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: Human **PIK3C3** encodes **VPS34**, the *class III phosphatidylinositol 3-kinase* 
        catalytic subunit that produces **phosphatidylinositol 3-phosphate (PI3P)**.
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: VPS34 is described as **exclusively catalyzing PI3P production from 
        phosphatidylinositol (PI) in vitro and in vivo**
  qualifier: involved_in
- term:
    id: GO:0006897
    label: endocytosis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Endocytosis is supported only as a contextual trafficking role.
    action: MODIFY
    reason: PIK3C3 participates in endosomal PI3P-dependent trafficking and maturation, but endocytosis itself
      is too broad; endosome organization or early-to-late endosome transport better captures the supported 
      role.
    proposed_replacement_terms:
    - id: GO:0007032
      label: endosome organization
    - id: GO:0045022
      label: early endosome to late endosome transport
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking.'
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: 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.
  qualifier: involved_in
- term:
    id: GO:0000425
    label: pexophagy
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Pexophagy is a selective-autophagy overextension for PIK3C3.
    action: MARK_AS_OVER_ANNOTATED
    reason: PIK3C3 is core for canonical autophagy initiation and can support selective autophagy generally, 
      but this row does not provide human evidence for a specific pexophagy role.
    proposed_replacement_terms:
    - id: GO:0016236
      label: macroautophagy
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**.'
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: VPS34-generated PI3P promotes recruitment of WIPI/ATG machinery to phagophore 
        membranes, supporting autophagosome initiation and early biogenesis.
  qualifier: involved_in
- term:
    id: GO:0005768
    label: endosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: PIK3C3 is active on endosomal membranes as part of the UVRAG-containing PI3KC3-C2 complex. This 
      localization is well supported but is contextual relative to the core PN autophagy-initiation case.
    action: KEEP_AS_NON_CORE
    reason: Human VPS34 participates in a type II class III PI3K complex dedicated to endosomal sorting and 
      later autophagy-associated trafficking. That role is real, but it is not the central PN framing for this
      gene.
    supported_by:
    - reference_id: PMID:40442316
      supporting_text: 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 initiation5–7.
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: 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.
  qualifier: is_active_in
- term:
    id: GO:0000045
    label: autophagosome assembly
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Core PN function. VPS34 is required for autophagosome assembly through the autophagy-initiating 
      PI3KC3-C1 complex.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:33637724
      supporting_text: 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
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: VPS34-generated PI3P promotes recruitment of WIPI/ATG machinery to phagophore 
        membranes, supporting autophagosome initiation and early biogenesis.
  qualifier: involved_in
- term:
    id: GO:0016303
    label: 1-phosphatidylinositol-3-kinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Core molecular function. PIK3C3/VPS34 is the class III lipid kinase that phosphorylates 
      phosphatidylinositol to generate PI3P.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:7628435
      supporting_text: PtdIns 3-kinase does not associate with p85 and phosphorylates PtdIns, but not PtdIns4P
        or PtdIns(4,5)P2.
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: Human **PIK3C3** encodes **VPS34**, the *class III phosphatidylinositol 3-kinase* 
        catalytic subunit that produces **phosphatidylinositol 3-phosphate (PI3P)**.
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: VPS34 is described as **exclusively catalyzing PI3P production from 
        phosphatidylinositol (PI) in vitro and in vivo**
  qualifier: enables
- term:
    id: GO:0036092
    label: phosphatidylinositol-3-phosphate biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Core process output of VPS34 catalytic activity. PIK3C3 generates PI3P for autophagosome 
      biogenesis and related membrane-trafficking pathways.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:33637724
      supporting_text: 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
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: Human **PIK3C3** encodes **VPS34**, the *class III phosphatidylinositol 3-kinase* 
        catalytic subunit that produces **phosphatidylinositol 3-phosphate (PI3P)**.
  qualifier: involved_in
- term:
    id: GO:0034271
    label: phosphatidylinositol 3-kinase complex, class III, type I
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Core PN complex membership. PIK3C3 is the catalytic subunit of PI3KC3-C1, the ATG14-containing 
      class III PI3K complex that initiates autophagy.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:40442316
      supporting_text: PI3KC3-C1 contains one copy each of the lipid kinase VPS34, the pseudokinase VPS15 and 
        the regulatory subunits BECN1 and ATG14
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**.'
  qualifier: part_of
- term:
    id: GO:0034272
    label: phosphatidylinositol 3-kinase complex, class III, type II
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: PIK3C3 also participates in PI3KC3-C2, the UVRAG-containing class III PI3K complex linked to 
      endosomal sorting and later autophagy-associated trafficking. This is supported but is contextual 
      relative to the core PN autophagy-initiation case.
    action: KEEP_AS_NON_CORE
    reason: Type II complex membership is well established, but the primary PN-focused role for PIK3C3 is the 
      autophagy-initiation complex PI3KC3-C1 rather than the broader trafficking context.
    supported_by:
    - reference_id: PMID:40442316
      supporting_text: 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 initiation5–7.
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking.'
  qualifier: part_of
- term:
    id: GO:0000407
    label: phagophore assembly site
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Core localization for the autophagy-initiation role of PIK3C3. VPS34 acts at the phagophore 
      assembly site as part of PI3KC3-C1.
    action: ACCEPT
    reason: This term is consistent with the type I complex call and captures the localization at which 
      VPS34-derived PI3P seeds early autophagosome biogenesis.
    supported_by:
    - reference_id: PMID:40442316
      supporting_text: 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)5–7.
  qualifier: is_active_in
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Peroxisome localization is not supported for PIK3C3.
    action: REMOVE
    reason: A pexophagy-related inference does not justify localizing PIK3C3 to the peroxisome; curated 
      locations place VPS34 at midbody, late endosome, cytoplasmic vesicle/autophagosome, and 
      pre-autophagosome/endosome contexts.
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-uniprot.txt
      supporting_text: Midbody {ECO:0000269|PubMed:20208530}. Late endosome {ECO:0000269|PubMed:14617358}. 
        Cytoplasmic vesicle, autophagosome {ECO:0000305|PubMed:14617358}.
    - reference_id: file:human/PIK3C3/PIK3C3-uniprot.txt
      supporting_text: 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).
  qualifier: is_active_in
- term:
    id: GO:0000045
    label: autophagosome assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Duplicate automated annotation for a reviewed core function. VPS34 is required for autophagosome 
      assembly.
    action: ACCEPT
    reason: The multi-source IEA is consistent with direct human evidence and the reviewed IBA/IDA annotations
      for the autophagy-initiation complex.
    supported_by:
    - reference_id: PMID:33637724
      supporting_text: 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
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: VPS34-generated PI3P promotes recruitment of WIPI/ATG machinery to phagophore 
        membranes, supporting autophagosome initiation and early biogenesis.
  qualifier: involved_in
- term:
    id: GO:0004672
    label: protein kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: This annotation is categorically wrong. PIK3C3 is a phosphatidylinositol 3-kinase, not a protein 
      kinase.
    action: REMOVE
    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.
    supported_by:
    - reference_id: PMID:7628435
      supporting_text: PtdIns 3-kinase does not associate with p85 and phosphorylates PtdIns, but not PtdIns4P
        or PtdIns(4,5)P2.
  qualifier: enables
- term:
    id: GO:0007032
    label: endosome organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Endosome organization is a supported non-core PIK3C3 process.
    action: KEEP_AS_NON_CORE
    reason: PIK3C3-derived PI3P helps define endosomal identity and trafficking, especially in the 
      UVRAG-containing type II complex, but the central reviewed function remains class III PI3K activity in 
      autophagy initiation.
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking.'
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: 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.
  qualifier: involved_in
- term:
    id: GO:0016236
    label: macroautophagy
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Core PN process. VPS34 is required for macroautophagy through PI3KC3-C1 mediated PI3P generation.
    action: ACCEPT
    reason: Conserved automated transfer is consistent with direct mammalian evidence that class III PI3K 
      activity is required for macroautophagy.
    supported_by:
    - reference_id: PMID:10625637
      supporting_text: Transfection of a specific class III PI3K antisense oligonucleotide greatly inhibited 
        the rate of macroautophagy.
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: VPS34-generated PI3P promotes recruitment of WIPI/ATG machinery to phagophore 
        membranes, supporting autophagosome initiation and early biogenesis.
  qualifier: involved_in
- term:
    id: GO:0016485
    label: protein processing
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Protein processing is too generic for the supported trafficking role.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0045022
      label: early endosome to late endosome transport
    - id: GO:0007032
      label: endosome organization
    supported_by:
    - reference_id: PMID:16467569
      supporting_text: 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.
  qualifier: involved_in
- term:
    id: GO:0035032
    label: phosphatidylinositol 3-kinase complex, class III
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Generic class III complex membership is true but underspecified for human PIK3C3.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0034271
      label: phosphatidylinositol 3-kinase complex, class III, type I
    - id: GO:0034272
      label: phosphatidylinositol 3-kinase complex, class III, type II
    supported_by:
    - reference_id: PMID:40442316
      supporting_text: 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 initiation5–7.
  qualifier: part_of
- term:
    id: GO:0042149
    label: cellular response to glucose starvation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Glucose starvation response is a contextual autophagy input, not the core PIK3C3 function.
    action: KEEP_AS_NON_CORE
    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_replacement_terms:
    - id: GO:0016236
      label: macroautophagy
    supported_by:
    - reference_id: PMID:25327288
      supporting_text: PIK-III acutely inhibits autophagy and de novo lipidation of LC3, and leads to the 
        stabilization of autophagy substrates.
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: VPS34-generated PI3P promotes recruitment of WIPI/ATG machinery to phagophore 
        membranes, supporting autophagosome initiation and early biogenesis.
  qualifier: involved_in
- term:
    id: GO:0043201
    label: response to L-leucine
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Response to L-leucine is a nutrient-response overextension for PIK3C3.
    action: MARK_AS_OVER_ANNOTATED
    reason: PIK3C3 participates in nutrient-sensitive autophagy pathways, but this specific amino-acid 
      response is not the direct activity or best-supported process for the gene product.
    proposed_replacement_terms:
    - id: GO:0016236
      label: macroautophagy
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**.'
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: VPS34-generated PI3P promotes recruitment of WIPI/ATG machinery to phagophore 
        membranes, supporting autophagosome initiation and early biogenesis.
  qualifier: involved_in
- term:
    id: GO:0043491
    label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: PI3K/AKT signal transduction conflates VPS34 with class I PI3K signaling.
    action: REMOVE
    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.
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: Human **PIK3C3** encodes **VPS34**, the *class III phosphatidylinositol 3-kinase* 
        catalytic subunit that produces **phosphatidylinositol 3-phosphate (PI3P)**.
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: VPS34 is described as **exclusively catalyzing PI3P production from 
        phosphatidylinositol (PI) in vitro and in vivo**
  qualifier: involved_in
- term:
    id: GO:0045335
    label: phagocytic vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Phagocytic vesicle is a supported but non-core trafficking context.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:16467569
      supporting_text: 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.
  qualifier: located_in
- term:
    id: GO:0048488
    label: synaptic vesicle endocytosis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Synaptic vesicle endocytosis is an over-specific inference from a general endosomal role.
    action: MARK_AS_OVER_ANNOTATED
    reason: PIK3C3 supports endosomal PI3P-dependent trafficking, but the reviewed evidence here does not 
      establish a synaptic-vesicle-specific function.
    proposed_replacement_terms:
    - id: GO:0007032
      label: endosome organization
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking.'
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: 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.
  qualifier: involved_in
- term:
    id: GO:0098794
    label: postsynapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Postsynapse localization is not established as a reviewed PIK3C3 localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: The available human/Falcon evidence supports endosomal, autophagic, and midbody contexts; 
      synapse-specific localization is not part of the core or well-supported contextual function.
    proposed_replacement_terms:
    - id: GO:0005768
      label: endosome
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-uniprot.txt
      supporting_text: Midbody {ECO:0000269|PubMed:20208530}. Late endosome {ECO:0000269|PubMed:14617358}. 
        Cytoplasmic vesicle, autophagosome {ECO:0000305|PubMed:14617358}.
    - reference_id: file:human/PIK3C3/PIK3C3-uniprot.txt
      supporting_text: 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).
  qualifier: is_active_in
- term:
    id: GO:0098830
    label: presynaptic endosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Presynaptic endosome is too specific for the evidence used here.
    action: MARK_AS_OVER_ANNOTATED
    reason: Endosomal PI3P biology is supported, but this annotation narrows the localization to a neuronal 
      presynaptic compartment without direct evidence in the reviewed record.
    proposed_replacement_terms:
    - id: GO:0005768
      label: endosome
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking.'
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: 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.
  qualifier: is_active_in
- term:
    id: GO:0098845
    label: postsynaptic endosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Postsynaptic endosome is too specific for the evidence used here.
    action: MARK_AS_OVER_ANNOTATED
    reason: Endosomal PI3P biology is supported, but this annotation narrows the localization to a neuronal 
      postsynaptic compartment without direct evidence in the reviewed record.
    proposed_replacement_terms:
    - id: GO:0005768
      label: endosome
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking.'
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: 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.
  qualifier: is_active_in
- term:
    id: GO:0098978
    label: glutamatergic synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Glutamatergic synapse localization is an unsupported specialization.
    action: MARK_AS_OVER_ANNOTATED
    reason: PIK3C3 has supported endosomal and autophagy-related localizations; the reviewed evidence does not
      establish a glutamatergic synapse location.
    proposed_replacement_terms:
    - id: GO:0005768
      label: endosome
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-uniprot.txt
      supporting_text: Midbody {ECO:0000269|PubMed:20208530}. Late endosome {ECO:0000269|PubMed:14617358}. 
        Cytoplasmic vesicle, autophagosome {ECO:0000305|PubMed:14617358}.
    - reference_id: file:human/PIK3C3/PIK3C3-uniprot.txt
      supporting_text: 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).
  qualifier: is_active_in
- term:
    id: GO:0098982
    label: GABA-ergic synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: GABA-ergic synapse localization is an unsupported specialization.
    action: MARK_AS_OVER_ANNOTATED
    reason: PIK3C3 has supported endosomal and autophagy-related localizations; the reviewed evidence does not
      establish a GABA-ergic synapse location.
    proposed_replacement_terms:
    - id: GO:0005768
      label: endosome
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-uniprot.txt
      supporting_text: Midbody {ECO:0000269|PubMed:20208530}. Late endosome {ECO:0000269|PubMed:14617358}. 
        Cytoplasmic vesicle, autophagosome {ECO:0000305|PubMed:14617358}.
    - reference_id: file:human/PIK3C3/PIK3C3-uniprot.txt
      supporting_text: 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).
  qualifier: is_active_in
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19050071
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20142477
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20562859
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21062745
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22493499
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23316280
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23332761
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23364696
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23954414
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24034250
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24056303
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24472739
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24785657
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24849286
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25490155
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25594178
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26496610
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26783301
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33422265
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34386498
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34524948
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0005770
    label: late endosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Late endosome is a supported contextual localization for PIK3C3.
    action: KEEP_AS_NON_CORE
    reason: Late-endosome localization and endosomal trafficking are supported, especially through the type II
      complex, but are contextual relative to the core autophagy-initiation function.
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-uniprot.txt
      supporting_text: Midbody {ECO:0000269|PubMed:20208530}. Late endosome {ECO:0000269|PubMed:14617358}. 
        Cytoplasmic vesicle, autophagosome {ECO:0000305|PubMed:14617358}.
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: 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.
  qualifier: located_in
- term:
    id: GO:0005776
    label: autophagosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Autophagosome localization is supported for PIK3C3 autophagy biology.
    action: ACCEPT
    reason: PIK3C3 acts in autophagosome biogenesis through PI3KC3-C1 and is curated as associated with 
      cytoplasmic vesicle/autophagosome and pre-autophagosome structures.
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-uniprot.txt
      supporting_text: Midbody {ECO:0000269|PubMed:20208530}. Late endosome {ECO:0000269|PubMed:14617358}. 
        Cytoplasmic vesicle, autophagosome {ECO:0000305|PubMed:14617358}.
    - reference_id: file:human/PIK3C3/PIK3C3-uniprot.txt
      supporting_text: 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).
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: VPS34-generated PI3P promotes recruitment of WIPI/ATG machinery to phagophore 
        membranes, supporting autophagosome initiation and early biogenesis.
  qualifier: located_in
- term:
    id: GO:0016301
    label: kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    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.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0016303
      label: 1-phosphatidylinositol-3-kinase activity
    supported_by:
    - reference_id: PMID:7628435
      supporting_text: PtdIns 3-kinase does not associate with p85 and phosphorylates PtdIns, but not PtdIns4P
        or PtdIns(4,5)P2.
  qualifier: enables
- term:
    id: GO:0016303
    label: 1-phosphatidylinositol-3-kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Automated duplicate of the reviewed core molecular function for PIK3C3. VPS34 is the class III 
      phosphatidylinositol 3-kinase.
    action: ACCEPT
    reason: The automated call is consistent with the direct biochemical literature and with the accepted 
      curated annotations for this gene.
    supported_by:
    - reference_id: PMID:7628435
      supporting_text: PtdIns 3-kinase does not associate with p85 and phosphorylates PtdIns, but not PtdIns4P
        or PtdIns(4,5)P2.
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: Human **PIK3C3** encodes **VPS34**, the *class III phosphatidylinositol 3-kinase* 
        catalytic subunit that produces **phosphatidylinositol 3-phosphate (PI3P)**.
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: VPS34 is described as **exclusively catalyzing PI3P production from 
        phosphatidylinositol (PI) in vitro and in vivo**
  qualifier: enables
- term:
    id: GO:0016773
    label: phosphotransferase activity, alcohol group as acceptor
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: This broad phosphotransferase term is less informative than the specific class III 
      phosphatidylinositol 3-kinase activity term that is available for PIK3C3.
    action: MODIFY
    reason: Human VPS34 has well-defined lipid-substrate specificity, so the specific GO molecular function 
      should replace this high-level transferase term.
    proposed_replacement_terms:
    - id: GO:0016303
      label: 1-phosphatidylinositol-3-kinase activity
    supported_by:
    - reference_id: PMID:7628435
      supporting_text: PtdIns 3-kinase does not associate with p85 and phosphorylates PtdIns, but not PtdIns4P
        or PtdIns(4,5)P2.
  qualifier: enables
- term:
    id: GO:0030496
    label: midbody
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Midbody localization is a supported non-core cytokinesis context.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-uniprot.txt
      supporting_text: Midbody {ECO:0000269|PubMed:20208530}. Late endosome {ECO:0000269|PubMed:14617358}. 
        Cytoplasmic vesicle, autophagosome {ECO:0000305|PubMed:14617358}.
  qualifier: located_in
- term:
    id: GO:0036092
    label: phosphatidylinositol-3-phosphate biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Automated duplicate of a reviewed core process. VPS34-driven PI3P generation is the central 
      biochemical output of PIK3C3.
    action: ACCEPT
    reason: This specific process term correctly captures the immediate product of VPS34 catalytic activity 
      and is preferable to broader phosphoinositide biosynthesis labels.
    supported_by:
    - reference_id: PMID:33637724
      supporting_text: 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
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: Human **PIK3C3** encodes **VPS34**, the *class III phosphatidylinositol 3-kinase* 
        catalytic subunit that produces **phosphatidylinositol 3-phosphate (PI3P)**.
  qualifier: involved_in
- term:
    id: GO:0046854
    label: phosphatidylinositol phosphate biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: The process is directionally correct but too broad. For PIK3C3 the literature supports the 
      specific PI3P biosynthetic process term.
    action: MODIFY
    reason: Human VPS34 is specifically responsible for generating phosphatidylinositol 3-phosphate rather 
      than phosphatidylinositol phosphates in general.
    proposed_replacement_terms:
    - id: GO:0036092
      label: phosphatidylinositol-3-phosphate biosynthetic process
    supported_by:
    - reference_id: PMID:33637724
      supporting_text: 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
  qualifier: involved_in
- term:
    id: GO:0006622
    label: protein targeting to lysosome
  evidence_type: NAS
  original_reference_id: PMID:16467569
  review:
    summary: Protein targeting to lysosome is a contextual trafficking assignment.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0007032
      label: endosome organization
    - id: GO:0045022
      label: early endosome to late endosome transport
    supported_by:
    - reference_id: PMID:16467569
      supporting_text: 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.
  qualifier: involved_in
- term:
    id: GO:0010506
    label: regulation of autophagy
  evidence_type: IDA
  original_reference_id: PMID:16799551
  review:
    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.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0016236
      label: macroautophagy
    supported_by:
    - reference_id: PMID:10625637
      supporting_text: Transfection of a specific class III PI3K antisense oligonucleotide greatly inhibited 
        the rate of macroautophagy.
  qualifier: involved_in
- term:
    id: GO:0016236
    label: macroautophagy
  evidence_type: NAS
  original_reference_id: PMID:40442316
  review:
    summary: Core PN process assignment. Human structural and mechanistic work places PIK3C3 in the 
      autophagy-initiating PI3KC3-C1 complex required for macroautophagy.
    action: ACCEPT
    reason: The human literature now directly frames PI3KC3-C1 as an autophagy core complex, which supports 
      macroautophagy as a central process annotation for PIK3C3.
    supported_by:
    - reference_id: PMID:40442316
      supporting_text: 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)5–7.
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: VPS34-generated PI3P promotes recruitment of WIPI/ATG machinery to phagophore 
        membranes, supporting autophagosome initiation and early biogenesis.
  qualifier: involved_in
- term:
    id: GO:0016241
    label: regulation of macroautophagy
  evidence_type: IDA
  original_reference_id: PMID:10625637
  review:
    summary: The underlying result supports macroautophagy itself rather than a purely regulatory role. PIK3C3
      is required for the process.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0016236
      label: macroautophagy
    supported_by:
    - reference_id: PMID:10625637
      supporting_text: Transfection of a specific class III PI3K antisense oligonucleotide greatly inhibited 
        the rate of macroautophagy.
  qualifier: involved_in
- term:
    id: GO:0036092
    label: phosphatidylinositol-3-phosphate biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:8999962
  review:
    summary: Reviewed core process assignment. Human VPS34/p150 complex activity is part of the specific 
      PI3P-producing pathway.
    action: ACCEPT
    reason: Across the human literature, VPS34 activity is consistently tied to PI3P generation rather than a 
      generic phosphoinositide biosynthetic role.
    supported_by:
    - reference_id: PMID:10625637
      supporting_text: 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.
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: Human **PIK3C3** encodes **VPS34**, the *class III phosphatidylinositol 3-kinase* 
        catalytic subunit that produces **phosphatidylinositol 3-phosphate (PI3P)**.
  qualifier: involved_in
- term:
    id: GO:0045022
    label: early endosome to late endosome transport
  evidence_type: IDA
  original_reference_id: PMID:14617358
  review:
    summary: Human VPS34/p150 participates in Rab7-linked endosomal trafficking. This is supported but is 
      contextual relative to the core PN autophagy role.
    action: KEEP_AS_NON_CORE
    reason: The late-endosomal transport function is directly supported in human cells, but it should be kept 
      distinct from the autophagy-initiation complex that defines the core PN case for PIK3C3.
    supported_by:
    - reference_id: PMID:14617358
      supporting_text: The hVPS34/p150 complex colocalized with rab7 on late endosomes and hVPS34 activity was
        dependent on nucleotide cycling of rab7.
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: 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.
  qualifier: involved_in
- term:
    id: GO:0097352
    label: autophagosome maturation
  evidence_type: IDA
  original_reference_id: PMID:10625637
  review:
    summary: Autophagosome maturation is supported as part of the core autophagy role.
    action: ACCEPT
    reason: Older macroautophagy evidence and newer VPS34 complex evidence support PIK3C3-dependent PI3P 
      production in autophagosome formation and maturation.
    supported_by:
    - reference_id: PMID:10625637
      supporting_text: Transfection of a specific class III PI3K antisense oligonucleotide greatly inhibited 
        the rate of macroautophagy.
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: VPS34-generated PI3P promotes recruitment of WIPI/ATG machinery to phagophore 
        membranes, supporting autophagosome initiation and early biogenesis.
  qualifier: involved_in
- term:
    id: GO:0016236
    label: macroautophagy
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1632852
  review:
    summary: Macroautophagy is a core PIK3C3 process.
    action: ACCEPT
    reason: Reactome and literature synthesis support PIK3C3/VPS34 as the catalytic component of the class III
      PI3K complex needed for early autophagy.
    supported_by:
    - reference_id: file:reactome/R-HSA-5672012.md
      supporting_text: PIK3C3 (VPS34), the catalytic component of this complex, is a class III 
        phosphatidylinositol 3-kinase that phosphorylates phosphatidylinositol (PI) producing 
        phosphatidylinositol 3-phosphate (PI3P).
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**.'
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: VPS34-generated PI3P promotes recruitment of WIPI/ATG machinery to phagophore 
        membranes, supporting autophagosome initiation and early biogenesis.
  qualifier: involved_in
- term:
    id: GO:0016303
    label: 1-phosphatidylinositol-3-kinase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5672012
  review:
    summary: The Reactome TAS row correctly captures the core VPS34 lipid kinase activity.
    action: ACCEPT
    reason: PIK3C3/VPS34 is the catalytic class III PI3K that phosphorylates phosphatidylinositol to produce 
      PI3P.
    supported_by:
    - reference_id: file:reactome/R-HSA-5672012.md
      supporting_text: PIK3C3 (VPS34), the catalytic component of this complex, is a class III 
        phosphatidylinositol 3-kinase that phosphorylates phosphatidylinositol (PI) producing 
        phosphatidylinositol 3-phosphate (PI3P).
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: Human **PIK3C3** encodes **VPS34**, the *class III phosphatidylinositol 3-kinase* 
        catalytic subunit that produces **phosphatidylinositol 3-phosphate (PI3P)**.
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: VPS34 is described as **exclusively catalyzing PI3P production from 
        phosphatidylinositol (PI) in vitro and in vivo**
  qualifier: enables
- term:
    id: GO:0016303
    label: 1-phosphatidylinositol-3-kinase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798174
  review:
    summary: The Reactome TAS row correctly captures the core VPS34 lipid kinase activity.
    action: ACCEPT
    reason: PIK3C3/VPS34 is the catalytic class III PI3K that phosphorylates phosphatidylinositol to produce 
      PI3P.
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: Human **PIK3C3** encodes **VPS34**, the *class III phosphatidylinositol 3-kinase* 
        catalytic subunit that produces **phosphatidylinositol 3-phosphate (PI3P)**.
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: VPS34 is described as **exclusively catalyzing PI3P production from 
        phosphatidylinositol (PI) in vitro and in vivo**
  qualifier: enables
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:17307798
  review:
    summary: Plasma membrane localization should not be retained for PIK3C3 from the CD160/NK-cell paper.
    action: REMOVE
    reason: Remove. PMID:17307798 shows recruitment of a PI3K signaling molecule to CD160 at the NK-cell 
      surface and downstream Akt signaling, but it does not establish that the class III PI3K catalytic 
      subunit PIK3C3/VPS34 is a plasma-membrane protein. UniProt-supported PIK3C3 locations are endosomal, 
      autophagic, midbody, and related cytoplasmic membrane contexts.
    additional_reference_ids:
    - PMID:17307798
    - file:human/PIK3C3/PIK3C3-uniprot.txt
    supported_by:
    - reference_id: PMID:17307798
      supporting_text: CD160 engagement induces the recruitment and co-localization of phosphorylated 
        molecules with redistributed, capped CD160 at the cell surface
    - reference_id: PMID:17307798
      supporting_text: engagement of CD160 induces its polarization and co-localization with PI3K
    - reference_id: file:human/PIK3C3/PIK3C3-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Midbody'
  qualifier: is_active_in
- term:
    id: GO:0045954
    label: positive regulation of natural killer cell mediated cytotoxicity
  evidence_type: IMP
  original_reference_id: PMID:17307798
  review:
    summary: Natural killer cell cytotoxicity is not supported as a PIK3C3-specific process.
    action: REMOVE
    reason: Remove. The CD160 study demonstrates a requirement for pharmacologically defined PI3K signaling in
      NK-cell effector functions, with Akt/ERK/Syk signaling, but it does not assign the phenotype to class 
      III PI3K/VPS34 rather than class I PI3K signaling.
    additional_reference_ids:
    - PMID:17307798
    - file:human/PIK3C3/PIK3C3-uniprot.txt
    supported_by:
    - reference_id: PMID:17307798
      supporting_text: pharmacological inhibitors of PI3K abrogate both CD160-mediated cytotoxicity
    - reference_id: PMID:17307798
      supporting_text: CD160 engagement induced marked phosphorylation of Akt
    - reference_id: file:human/PIK3C3/PIK3C3-uniprot.txt
      supporting_text: Catalytic subunit of the PI3K complex that mediates formation of phosphatidylinositol 
        3-phosphate
  qualifier: involved_in
- term:
    id: GO:0052742
    label: phosphatidylinositol kinase activity
  evidence_type: IDA
  original_reference_id: PMID:7628435
  review:
    summary: The activity is valid but too general. Human VPS34 should be annotated to the specific 
      1-phosphatidylinositol-3-kinase activity term.
    action: MODIFY
    reason: The original biochemical characterization resolved the substrate and the 3-position specificity, 
      so the narrower MF term is warranted.
    proposed_replacement_terms:
    - id: GO:0016303
      label: 1-phosphatidylinositol-3-kinase activity
    supported_by:
    - reference_id: PMID:7628435
      supporting_text: PtdIns 3-kinase does not associate with p85 and phosphorylates PtdIns, but not PtdIns4P
        or PtdIns(4,5)P2.
  qualifier: enables
- term:
    id: GO:0016303
    label: 1-phosphatidylinositol-3-kinase activity
  evidence_type: IDA
  original_reference_id: PMID:25327288
  review:
    summary: Reviewed core molecular function. Later chemical-genetic work is fully consistent with VPS34 as 
      the relevant class III PI3 kinase.
    action: ACCEPT
    reason: This term matches the established biochemical function of PIK3C3 and is consistent with selective 
      VPS34 inhibition experiments in human systems.
    supported_by:
    - reference_id: PMID:25327288
      supporting_text: PIK-III is a selective inhibitor of VPS34 that binds a unique hydrophobic pocket not 
        present in related kinases such as PI(3)Kα.
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: Human **PIK3C3** encodes **VPS34**, the *class III phosphatidylinositol 3-kinase* 
        catalytic subunit that produces **phosphatidylinositol 3-phosphate (PI3P)**.
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: VPS34 is described as **exclusively catalyzing PI3P production from 
        phosphatidylinositol (PI) in vitro and in vivo**
  qualifier: enables
- term:
    id: GO:1903061
    label: positive regulation of protein lipidation
  evidence_type: IMP
  original_reference_id: PMID:25327288
  review:
    summary: Positive regulation of protein lipidation is supported as a non-core autophagy pathway effect.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:25327288
      supporting_text: PIK-III acutely inhibits autophagy and de novo lipidation of LC3, and leads to the 
        stabilization of autophagy substrates.
  qualifier: acts_upstream_of_or_within
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30767700
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0044829
    label: host-mediated activation of viral genome replication
  evidence_type: IDA
  original_reference_id: PMID:34320401
  review:
    summary: PIK3C3/VPS34 supports SARS-CoV-2 replication in inhibitor studies, but this is non-core 
      host-pathway context.
    action: KEEP_AS_NON_CORE
    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.
    additional_reference_ids:
    - PMID:34320401
    - file:human/PIK3C3/PIK3C3-uniprot.txt
    - file:human/PIK3C3/PIK3C3-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:34320401
      supporting_text: Our studies determine that compounds targeting VPS34 are potent SARS-CoV-2 inhibitors
    - reference_id: PMID:34320401
      supporting_text: these studies clarify roles for VPS34 and fatty acid metabolism in SARS-CoV-2 
        replication
    - reference_id: file:human/PIK3C3/PIK3C3-uniprot.txt
      supporting_text: Kinase activity is required for SARS coronavirus-2/SARS-CoV-2 replication
  qualifier: involved_in
- term:
    id: GO:0000045
    label: autophagosome assembly
  evidence_type: IDA
  original_reference_id: PMID:33637724
  review:
    summary: Direct human evidence for a core PN process. VPS34 abundance and regulation affect autophagosome 
      formation.
    action: ACCEPT
    reason: This study explicitly ties VPS34-controlled PI3P production to autophagosome formation and 
      maturation, which is central to the reviewed biology of PIK3C3.
    supported_by:
    - reference_id: PMID:33637724
      supporting_text: 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
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: VPS34-generated PI3P promotes recruitment of WIPI/ATG machinery to phagophore 
        membranes, supporting autophagosome initiation and early biogenesis.
  qualifier: involved_in
- term:
    id: GO:0046854
    label: phosphatidylinositol phosphate biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:7628435
  review:
    summary: The biochemical direction is correct but the term is too broad. The human enzyme characterized 
      here specifically supports PI3P biosynthesis.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0036092
      label: phosphatidylinositol-3-phosphate biosynthetic process
    supported_by:
    - reference_id: PMID:7628435
      supporting_text: PtdIns 3-kinase does not associate with p85 and phosphorylates PtdIns, but not PtdIns4P
        or PtdIns(4,5)P2.
  qualifier: involved_in
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33473107
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28890335
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31806350
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0032465
    label: regulation of cytokinesis
  evidence_type: IMP
  original_reference_id: PMID:20208530
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:20208530
      supporting_text: 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.
  qualifier: involved_in
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28479384
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22095288
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0006914
    label: autophagy
  evidence_type: IMP
  original_reference_id: PMID:25327288
  review:
    summary: The biology is correct but the process term is too general. For PIK3C3 the literature supports 
      macroautophagy specifically.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0016236
      label: macroautophagy
    supported_by:
    - reference_id: PMID:25327288
      supporting_text: PIK-III acutely inhibits autophagy and de novo lipidation of LC3, and leads to the 
        stabilization of autophagy substrates.
  qualifier: acts_upstream_of_or_within
- term:
    id: GO:0044754
    label: autolysosome
  evidence_type: IDA
  original_reference_id: PMID:25327288
  review:
    summary: Autolysosome localization is over-annotated from an inhibitor/substrate study.
    action: MARK_AS_OVER_ANNOTATED
    reason: The cited inhibitor study supports VPS34-dependent autophagy and NCOA4/ferritin delivery to 
      autolysosomes, but it does not directly place PIK3C3 itself in the autolysosome.
    proposed_replacement_terms:
    - id: GO:0005776
      label: autophagosome
    - id: GO:0016236
      label: macroautophagy
    supported_by:
    - reference_id: PMID:25327288
      supporting_text: 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.
  qualifier: located_in
- term:
    id: GO:0030670
    label: phagocytic vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798174
  review:
    summary: Phagocytic vesicle membrane is a supported but non-core trafficking context.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:16467569
      supporting_text: 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.
  qualifier: located_in
- term:
    id: GO:0032465
    label: regulation of cytokinesis
  evidence_type: IMP
  original_reference_id: PMID:20643123
  review:
    summary: Supported contextual role for a UVRAG/BIF-1-containing PI3K-III subcomplex in cytokinesis. This 
      remains outside the core PN autophagy framing.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:20643123
      supporting_text: 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.
  qualifier: involved_in
- term:
    id: GO:0016236
    label: macroautophagy
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Conservative orthology-supported duplicate of a core process assignment. Macroautophagy is 
      appropriate for human PIK3C3.
    action: ACCEPT
    reason: This transfer is consistent with direct human evidence for VPS34 in the autophagy-initiating 
      PI3KC3-C1 complex.
    supported_by:
    - reference_id: PMID:40442316
      supporting_text: 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)5–7.
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: VPS34-generated PI3P promotes recruitment of WIPI/ATG machinery to phagophore 
        membranes, supporting autophagosome initiation and early biogenesis.
  qualifier: involved_in
- term:
    id: GO:0035032
    label: phosphatidylinositol 3-kinase complex, class III
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    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.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0034271
      label: phosphatidylinositol 3-kinase complex, class III, type I
    - id: GO:0034272
      label: phosphatidylinositol 3-kinase complex, class III, type II
    supported_by:
    - reference_id: PMID:40442316
      supporting_text: PI3KC3-C1 contains one copy each of the lipid kinase VPS34, the pseudokinase VPS15 and 
        the regulatory subunits BECN1 and ATG14
    - reference_id: PMID:40442316
      supporting_text: 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 initiation5–7.
  qualifier: part_of
- term:
    id: GO:0042149
    label: cellular response to glucose starvation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Glucose starvation response is a contextual autophagy input, not the core PIK3C3 function.
    action: KEEP_AS_NON_CORE
    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_replacement_terms:
    - id: GO:0016236
      label: macroautophagy
    supported_by:
    - reference_id: PMID:25327288
      supporting_text: PIK-III acutely inhibits autophagy and de novo lipidation of LC3, and leads to the 
        stabilization of autophagy substrates.
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: VPS34-generated PI3P promotes recruitment of WIPI/ATG machinery to phagophore 
        membranes, supporting autophagosome initiation and early biogenesis.
  qualifier: involved_in
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23878393
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  review:
    summary: Broad membrane association from large-scale proteomics is weak and uninformative for PIK3C3.
    action: MARK_AS_OVER_ANNOTATED
    reason: PIK3C3 is a cytosolic/peripheral lipid kinase recruited to autophagy and endosomal membranes, so 
      generic membrane association is not entirely wrong, but this broad HDA row is not specific enough for 
      the reviewed function.
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: The remaining species were largely involved in cellular processes and molecular 
        functions that could be predicted to be transiently associated with membranes.
  qualifier: located_in
- term:
    id: GO:0005930
    label: axoneme
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Axoneme localization is supported only by similarity and is non-core.
    action: KEEP_AS_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.
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-uniprot.txt
      supporting_text: Also localizes to discrete punctae along the ciliary axoneme and to the base of the 
        ciliary axoneme (By similarity).
  qualifier: located_in
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19270696
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14617358
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0005770
    label: late endosome
  evidence_type: IDA
  original_reference_id: PMID:14617358
  review:
    summary: Supported contextual localization. Human VPS34/p150 colocalizes with Rab7 on late endosomes.
    action: KEEP_AS_NON_CORE
    reason: The localization is directly supported in human cells, but it belongs to the contextual 
      endosomal-trafficking side of PIK3C3 biology rather than the core PN autophagy claim.
    supported_by:
    - reference_id: PMID:14617358
      supporting_text: The hVPS34/p150 complex colocalized with rab7 on late endosomes and hVPS34 activity was
        dependent on nucleotide cycling of rab7.
  qualifier: located_in
- term:
    id: GO:0045022
    label: early endosome to late endosome transport
  evidence_type: IMP
  original_reference_id: PMID:14617358
  review:
    summary: Contextual trafficking role supported by human Rab7/VPS34 data. Appropriate to retain as 
      non-core.
    action: KEEP_AS_NON_CORE
    reason: This transport function is part of the broader endosomal deployment of VPS34 PI3P signaling and 
      should remain separate from the core macroautophagy-focused curation.
    supported_by:
    - reference_id: PMID:14617358
      supporting_text: 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.
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: 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.
  qualifier: involved_in
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-109699
  review:
    summary: Cytosol is a broad Reactome component assignment for PIK3C3 pathway events.
    action: KEEP_AS_NON_CORE
    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_replacement_terms:
    - id: GO:0000407
      label: phagophore assembly site
    - id: GO:0005768
      label: endosome
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**.'
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking.'
  qualifier: located_in
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1632857
  review:
    summary: Cytosol is a broad Reactome component assignment for PIK3C3 pathway events.
    action: KEEP_AS_NON_CORE
    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_replacement_terms:
    - id: GO:0000407
      label: phagophore assembly site
    - id: GO:0005768
      label: endosome
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**.'
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking.'
  qualifier: located_in
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1675939
  review:
    summary: Cytosol is a broad Reactome component assignment for PIK3C3 pathway events.
    action: KEEP_AS_NON_CORE
    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_replacement_terms:
    - id: GO:0000407
      label: phagophore assembly site
    - id: GO:0005768
      label: endosome
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**.'
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking.'
  qualifier: located_in
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1675961
  review:
    summary: Cytosol is a broad Reactome component assignment for PIK3C3 pathway events.
    action: KEEP_AS_NON_CORE
    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_replacement_terms:
    - id: GO:0000407
      label: phagophore assembly site
    - id: GO:0005768
      label: endosome
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**.'
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking.'
  qualifier: located_in
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1676024
  review:
    summary: Cytosol is a broad Reactome component assignment for PIK3C3 pathway events.
    action: KEEP_AS_NON_CORE
    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_replacement_terms:
    - id: GO:0000407
      label: phagophore assembly site
    - id: GO:0005768
      label: endosome
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**.'
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking.'
  qualifier: located_in
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-188002
  review:
    summary: Cytosol is a broad Reactome component assignment for PIK3C3 pathway events.
    action: KEEP_AS_NON_CORE
    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_replacement_terms:
    - id: GO:0000407
      label: phagophore assembly site
    - id: GO:0005768
      label: endosome
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**.'
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking.'
  qualifier: located_in
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5672012
  review:
    summary: Cytosol is a broad Reactome component assignment for PIK3C3 pathway events.
    action: KEEP_AS_NON_CORE
    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_replacement_terms:
    - id: GO:0000407
      label: phagophore assembly site
    - id: GO:0005768
      label: endosome
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**.'
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking.'
  qualifier: located_in
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5678313
  review:
    summary: Cytosol is a broad Reactome component assignment for PIK3C3 pathway events.
    action: KEEP_AS_NON_CORE
    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_replacement_terms:
    - id: GO:0000407
      label: phagophore assembly site
    - id: GO:0005768
      label: endosome
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**.'
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking.'
  qualifier: located_in
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5678315
  review:
    summary: Cytosol is a broad Reactome component assignment for PIK3C3 pathway events.
    action: KEEP_AS_NON_CORE
    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_replacement_terms:
    - id: GO:0000407
      label: phagophore assembly site
    - id: GO:0005768
      label: endosome
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**.'
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking.'
  qualifier: located_in
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5679205
  review:
    summary: Cytosol is a broad Reactome component assignment for PIK3C3 pathway events.
    action: KEEP_AS_NON_CORE
    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_replacement_terms:
    - id: GO:0000407
      label: phagophore assembly site
    - id: GO:0005768
      label: endosome
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**.'
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking.'
  qualifier: located_in
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5679266
  review:
    summary: Cytosol is a broad Reactome component assignment for PIK3C3 pathway events.
    action: KEEP_AS_NON_CORE
    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_replacement_terms:
    - id: GO:0000407
      label: phagophore assembly site
    - id: GO:0005768
      label: endosome
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**.'
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking.'
  qualifier: located_in
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5682385
  review:
    summary: Cytosol is a broad Reactome component assignment for PIK3C3 pathway events.
    action: KEEP_AS_NON_CORE
    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_replacement_terms:
    - id: GO:0000407
      label: phagophore assembly site
    - id: GO:0005768
      label: endosome
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**.'
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking.'
  qualifier: located_in
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9755359
  review:
    summary: Cytosol is a broad Reactome component assignment for PIK3C3 pathway events.
    action: KEEP_AS_NON_CORE
    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_replacement_terms:
    - id: GO:0000407
      label: phagophore assembly site
    - id: GO:0005768
      label: endosome
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**.'
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking.'
  qualifier: located_in
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9921171
  review:
    summary: Cytosol is a broad Reactome component assignment for PIK3C3 pathway events.
    action: KEEP_AS_NON_CORE
    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_replacement_terms:
    - id: GO:0000407
      label: phagophore assembly site
    - id: GO:0005768
      label: endosome
    supported_by:
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **ATG14**. This complex is classically associated with **autophagy initiation/autophagosome nucleation**.'
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: '**PI3KC3 Complex II (PI3KC3-C2)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** +
        **UVRAG**, classically associated with **endocytic sorting/endosome maturation** and related trafficking.'
  qualifier: located_in
- term:
    id: GO:0016303
    label: 1-phosphatidylinositol-3-kinase activity
  evidence_type: IMP
  original_reference_id: PMID:20208530
  review:
    summary: Contextual cytokinesis paper, but the molecular function assignment itself is core and remains 
      correct for PIK3C3.
    action: ACCEPT
    reason: Even though this paper focuses on cytokinesis, it does so through the catalytic PI3P-generating 
      activity of the class III PI3K complex.
    supported_by:
    - reference_id: PMID:7628435
      supporting_text: PtdIns 3-kinase does not associate with p85 and phosphorylates PtdIns, but not PtdIns4P
        or PtdIns(4,5)P2.
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: Human **PIK3C3** encodes **VPS34**, the *class III phosphatidylinositol 3-kinase* 
        catalytic subunit that produces **phosphatidylinositol 3-phosphate (PI3P)**.
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: VPS34 is described as **exclusively catalyzing PI3P production from 
        phosphatidylinositol (PI) in vitro and in vivo**
  qualifier: enables
- term:
    id: GO:0030496
    label: midbody
  evidence_type: IDA
  original_reference_id: PMID:20208530
  review:
    summary: Midbody association is part of a supported cytokinesis-specific context for VPS34 biology and 
      should not be treated as core PN localization.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:20208530
      supporting_text: 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.
  qualifier: located_in
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16417406
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:7504174
  review:
    summary: Protein binding is too generic to serve as an informative molecular-function annotation for 
      PIK3C3. Interaction-derived biology is captured elsewhere through specific complex, localization, or 
      process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project convention, `protein binding` should not be retained when it does not convey a 
      specific molecular function. For PIK3C3, these interaction data inform complex membership and contextual
      pathway roles rather than a standalone MF annotation.
  qualifier: enables
- term:
    id: GO:0016303
    label: 1-phosphatidylinositol-3-kinase activity
  evidence_type: TAS
  original_reference_id: PMID:7628435
  review:
    summary: Literature-traceable duplicate of the reviewed core molecular function. Human VPS34 is the 
      phosphatidylinositol 3-kinase.
    action: ACCEPT
    reason: This term directly reflects the original biochemical characterization of the human enzyme and 
      should be retained.
    supported_by:
    - reference_id: PMID:7628435
      supporting_text: PtdIns 3-kinase does not associate with p85 and phosphorylates PtdIns, but not PtdIns4P
        or PtdIns(4,5)P2.
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: Human **PIK3C3** encodes **VPS34**, the *class III phosphatidylinositol 3-kinase* 
        catalytic subunit that produces **phosphatidylinositol 3-phosphate (PI3P)**.
    - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
      supporting_text: VPS34 is described as **exclusively catalyzing PI3P production from 
        phosphatidylinositol (PI) in vitro and in vivo**
  qualifier: enables
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment
    of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: 'Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied
    by conservative changes to GO terms applied by UniProt'
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl 
    Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10625637
  title: Distinct classes of phosphatidylinositol 3'-kinases are involved in signaling pathways that control 
    macroautophagy in HT-29 cells.
  findings: []
- id: PMID:14617358
  title: Human VPS34 and p150 are Rab7 interacting partners.
  findings: []
- id: PMID:16417406
  title: 'Hem-1 complexes are essential for Rac activation, actin polymerization, and myosin regulation during neutrophil
    chemotaxis.'
  findings: []
- id: PMID:16467569
  title: 'Regulation of membrane traffic by phosphoinositide 3-kinases.'
  findings: []
- id: PMID:16799551
  title: Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG.
  findings: []
- id: PMID:17307798
  title: 'CD160-activating NK cell effector functions depend on the phosphatidylinositol 3-kinase recruitment.'
  findings: []
- id: PMID:19050071
  title: 'Identification of Barkor as a mammalian autophagy-specific factor for Beclin 1 and class III phosphatidylinositol
    3-kinase.'
  findings: []
- id: PMID:19270696
  title: 'Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages.'
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:20142477
  title: 'The early autophagic pathway is activated by hepatitis B virus and required for viral DNA replication.'
  findings: []
- id: PMID:20208530
  title: PtdIns(3)P controls cytokinesis through KIF13A-mediated recruitment of FYVE-CENT to the midbody.
  findings: []
- id: PMID:20562859
  title: 'Network organization of the human autophagy system.'
  findings: []
- id: PMID:20643123
  title: A phosphatidylinositol 3-kinase class III sub-complex containing VPS15, VPS34, Beclin 1, UVRAG and 
    BIF-1 regulates cytokinesis and degradative endocytic traffic.
  findings: []
- id: PMID:21062745
  title: 'The RUN domain of rubicon is important for hVps34 binding, lipid kinase inhibition, and autophagy suppression.'
  findings: []
- id: PMID:22095288
  title: 'PKD is a kinase of Vps34 that mediates ROS-induced autophagy downstream of DAPk.'
  findings: []
- id: PMID:22493499
  title: 'Receptor signaling lymphocyte-activation molecule family 1 (Slamf1) regulates membrane fusion and NADPH
    oxidase 2 (NOX2) activity by recruiting a Beclin-1/Vps34/ultraviolet radiation resistance-associated gene (UVRAG)
    complex.'
  findings: []
- id: PMID:23316280
  title: 'The VMP1-Beclin 1 interaction regulates autophagy induction.'
  findings: []
- id: PMID:23332761
  title: 'Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy.'
  findings: []
- id: PMID:23364696
  title: 'Identification of a candidate therapeutic autophagy-inducing peptide.'
  findings: []
- id: PMID:23878393
  title: 'Role of membrane association and Atg14-dependent phosphorylation in beclin-1-mediated autophagy.'
  findings: []
- id: PMID:23954414
  title: 'Beclin 2 functions in autophagy, degradation of G protein-coupled receptors, and metabolism.'
  findings: []
- id: PMID:24034250
  title: 'EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance.'
  findings: []
- id: PMID:24056303
  title: 'PtdIns(3)P-bound UVRAG coordinates Golgi-ER retrograde and Atg9 transport by differential interactions
    with the ER tether and the beclin 1 complex.'
  findings: []
- id: PMID:24472739
  title: 'Decorin activates AMPK, an energy sensor kinase, to induce autophagy in endothelial cells.'
  findings: []
- id: PMID:24785657
  title: 'NRBF2 regulates macroautophagy as a component of Vps34 Complex I.'
  findings: []
- id: PMID:24849286
  title: 'NRBF2 regulates autophagy and prevents liver injury by modulating Atg14L-linked phosphatidylinositol-3
    kinase III activity.'
  findings: []
- id: PMID:25327288
  title: Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and 
    iron homeostasis in vivo.
  findings: []
- id: PMID:25490155
  title: 'Architecture and dynamics of the autophagic phosphatidylinositol 3-kinase complex.'
  findings: []
- id: PMID:25594178
  title: 'A kinase-independent role for EGF receptor in autophagy initiation.'
  findings: []
- id: PMID:26496610
  title: 'A human interactome in three quantitative dimensions organized by stoichiometries and abundances.'
  findings: []
- id: PMID:26783301
  title: 'Negative regulation of phosphatidylinositol 3-phosphate levels in early-to-late endosome conversion.'
  findings: []
- id: PMID:28479384
  title: 'Beclin1 antagonizes LAPTM4B-mediated EGFR overactivation in gastric cancer cells.'
  findings: []
- id: PMID:28514442
  title: 'Architecture of the human interactome defines protein communities and disease networks.'
  findings: []
- id: PMID:28890335
  title: 'The ER-Localized Transmembrane Protein EPG-3/VMP1 Regulates SERCA Activity to Control ER-Isolation Membrane
    Contacts for Autophagosome Formation.'
  findings: []
- id: PMID:30767700
  title: 'Members of the autophagy class III phosphatidylinositol 3-kinase complex I interact with GABARAP and GABARAPL1
    via LIR motifs.'
  findings: []
- id: PMID:31806350
  title: 'The ER-Localized Transmembrane Protein TMEM39A/SUSR2 Regulates Autophagy by Controlling the Trafficking
    of the PtdIns(4)P Phosphatase SAC1.'
  findings: []
- id: PMID:33422265
  title: 'ORF3a of the COVID-19 virus SARS-CoV-2 blocks HOPS complex-mediated assembly of the SNARE complex required
    for autolysosome formation.'
  findings: []
- id: PMID:33473107
  title: 'Endonuclease G promotes autophagy by suppressing mTOR signaling and activating the DNA damage response.'
  findings: []
- id: PMID:33637724
  title: VPS34 K29/K48 branched ubiquitination governed by UBE3C and TRABID regulates autophagy, proteostasis 
    and liver metabolism.
  findings: []
- id: PMID:33961781
  title: 'Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.'
  findings: []
- id: PMID:34320401
  title: 'Inhibitors of VPS34 and fatty-acid metabolism suppress SARS-CoV-2 replication.'
  findings: []
- id: PMID:34386498
  title: 'ORF3a-Mediated Incomplete Autophagy Facilitates Severe Acute Respiratory Syndrome Coronavirus-2 Replication.'
  findings: []
- id: PMID:34524948
  title: 'Global Proximity Interactome of the Human Macroautophagy Pathway.'
  findings: []
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
- id: PMID:40442316
  title: Structure and activation of the human autophagy-initiating ULK1C:PI3KC3-C1 supercomplex.
  findings: []
- id: PMID:7504174
  title: 'The SH3 domain of p56lck is involved in binding to phosphatidylinositol 3''-kinase from T lymphocytes.'
  findings: []
- id: PMID:7628435
  title: A human phosphatidylinositol 3-kinase complex related to the yeast Vps34p-Vps15p protein sorting 
    system.
  findings: []
- id: PMID:8999962
  title: Characterization of p150, an adaptor protein for the human phosphatidylinositol (PtdIns) 3-kinase. 
    Substrate presentation by phosphatidylinositol transfer protein to the p150.Ptdins 3-kinase complex.
  findings: []
- id: Reactome:R-HSA-109699
  title: 'PI3K-containing complexes phosphorylate PIP2 to PIP3'
  findings: []
- id: Reactome:R-HSA-1632852
  title: Macroautophagy
  findings: []
- id: Reactome:R-HSA-1632857
  title: 'ULK1 phosphorylates AMBRA1:BECN1 complex'
  findings: []
- id: Reactome:R-HSA-1675939
  title: 'PI is phosphorylated to PI3P by PIK3C2A/3 at the early endosome membrane'
  findings: []
- id: Reactome:R-HSA-1675961
  title: 'PI is phosphorylated to PI3P by PIK3C2A/3 at the Golgi membrane'
  findings: []
- id: Reactome:R-HSA-1676024
  title: 'PI is phosphorylated to PI3P by PIK3C2A/3 at the late endosome membrane'
  findings: []
- id: Reactome:R-HSA-188002
  title: 'Rab5-mediated recruitment of class III PI3K to TLR9'
  findings: []
- id: Reactome:R-HSA-5672012
  title: Beclin-1 complex phosphorylates PtdIns
  findings: []
- id: Reactome:R-HSA-5678313
  title: 'AMBRA1:DYNLL1,DYNLL2 binds BECN1 complex'
  findings: []
- id: Reactome:R-HSA-5678315
  title: 'BECN1 complex, p-AMBRA1 dissociate from DYNLL1,DYNLL2'
  findings: []
- id: Reactome:R-HSA-5679205
  title: 'ULK1 phosphorylates Beclin-1'
  findings: []
- id: Reactome:R-HSA-5679266
  title: 'Beclin-1 complex translocates to the ER'
  findings: []
- id: Reactome:R-HSA-5682385
  title: 'The phagophore extends from the PIP3-enriched structure'
  findings: []
- id: Reactome:R-HSA-6798174
  title: 'PIK3C3:PIK3R4 phosphorylates PI to PI3P'
  findings: []
- id: Reactome:R-HSA-9755359
  title: 'SARS-CoV-2 8:class I MHC binds BECN1'
  findings: []
- id: Reactome:R-HSA-9921171
  title: 'NS1 binds Beclin-1'
  findings: []
- id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
  title: Falcon deep research synthesis for PIK3C3
  findings: []
- id: file:human/PIK3C3/PIK3C3-uniprot.txt
  title: UniProt record for human PIK3C3
  findings: []
- id: file:reactome/R-HSA-5672012.md
  title: Reactome autophagy initiation event containing PIK3C3
  findings: []
- id: file:human/PIK3C3/PIK3C3-notes.md
  title: PIK3C3 review notes
  findings: []
core_functions:
- molecular_function:
    id: GO:0016303
    label: 1-phosphatidylinositol-3-kinase activity
  description: PIK3C3/VPS34 is the catalytic lipid kinase of the ATG14-containing class III PI3K complex that 
    generates PI3P at early autophagy membranes to drive phagophore formation and autophagosome assembly 
    during macroautophagy.
  directly_involved_in:
  - id: GO:0036092
    label: phosphatidylinositol-3-phosphate biosynthetic process
  - id: GO:0000045
    label: autophagosome assembly
  - id: GO:0016236
    label: macroautophagy
  - id: GO:0097352
    label: autophagosome maturation
  locations:
  - id: GO:0000407
    label: phagophore assembly site
  - id: GO:0005776
    label: autophagosome
  in_complex:
    id: GO:0034271
    label: phosphatidylinositol 3-kinase complex, class III, type I
  supported_by:
  - reference_id: PMID:7628435
    supporting_text: PtdIns 3-kinase does not associate with p85 and phosphorylates PtdIns, but not PtdIns4P 
      or PtdIns(4,5)P2.
  - reference_id: PMID:40442316
    supporting_text: PI3KC3-C1 contains one copy each of the lipid kinase VPS34, the pseudokinase VPS15 and 
      the regulatory subunits BECN1 and ATG14
  - reference_id: PMID:33637724
    supporting_text: 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
  - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
    supporting_text: Human **PIK3C3** encodes **VPS34**, the *class III phosphatidylinositol 3-kinase* 
      catalytic subunit that produces **phosphatidylinositol 3-phosphate (PI3P)**.
  - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
    supporting_text: '**PI3KC3 Complex I (PI3KC3-C1)**: VPS34 (**PIK3C3**) + **VPS15 (PIK3R4)** + **BECN1** + **ATG14**.
      This complex is classically associated with **autophagy initiation/autophagosome nucleation**.'
  - reference_id: file:human/PIK3C3/PIK3C3-deep-research-falcon.md
    supporting_text: VPS34-generated PI3P promotes recruitment of WIPI/ATG machinery to phagophore membranes, 
      supporting autophagosome initiation and early biogenesis.

PIK3C3

Gene Description

Existing Annotations Review

Core Functions

PIK3C3/VPS34 is the catalytic lipid kinase of the ATG14-containing class III PI3K complex that generates PI3P at early autophagy membranes to drive phagophore formation and autophagosome assembly during macroautophagy.

References

Deep Research

Falcon

GO-focused gene annotation research report: human PIK3C3 (VPS34) (UniProt Q8NEB9)

1) Key concepts and definitions (current understanding)

2) Core GO Molecular Function (MF): what VPS34 does

3) Major GO Biological Processes (BP): autophagy and endocytosis-centered roles

3.1 Autophagy initiation / autophagosome nucleation (canonical macroautophagy)

3.2 Endocytic trafficking, endosomal identity, and endolysosomal maturation

4) GO Cellular Component (CC): where VPS34 acts

5) Key experimental evidence (selected, GO-curation-relevant)

5.1 PI3P reporter depletion and endosomal phenotypes (2024)

5.2 Genetic + inhibitor evidence tying VPS34 to endosomal trafficking during viral entry (2024; quantitative)

5.3 Autophagy-independent PI3P-dependent membrane phenotypes (2024)

5.4 Noncanonical autophagy route bypassing PIK3C3 (2023; caveat)

6) GO annotation caveats and curation guidance (for review)

7) Recent developments and real-world applications (2023–2024)

8) GO-focused evidence summary table

Citations

📚 Additional Documentation

Notes

PIK3C3 notes

Description cleanup note

Pn Notes

PIK3C3 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Autophagy-Lysosome Pathway | Autophagophore initiation and elongation | Class 3 PI3K complex 1, direct | Class 3 PI3K complex 1 component

PN row 2: Autophagy-Lysosome Pathway | Autophagosome closure maturation and lysosome fusion | Class 3 PI3K complex 2, direct | Class 3 PI3K complex 2 component

Projected GO annotations (2)

Note

📄 View Raw YAML