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.