id: Q99570 gene_symbol: PIK3R4 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- PIK3R4/VPS15/p150 is the regulatory/scaffolding subunit of human class III PI3K complexes. In PI3KC3-C1 with PIK3C3/VPS34, BECN1, and ATG14, it organizes the autophagy-initiation complex and contributes to complex-level PI3P production required for autophagosome assembly and macroautophagy. In PI3KC3-C2/UVRAG-associated contexts it supports endosomal trafficking, receptor catabolism, and autophagosome maturation. Its central function is PI3KC3 complex regulation rather than independent catalytic signaling. existing_annotations: - term: id: GO:0000425 label: pexophagy evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Pexophagy is too cargo-specific for human PIK3R4; the supported process is PI3KC3-C1-dependent autophagosome assembly/macroautophagy. action: MODIFY reason: Modify to autophagosome assembly. The human evidence supports PIK3R4/VPS15 as a PI3KC3-C1 component for canonical bulk and selective autophagy initiation, but does not establish a PIK3R4-specific pexophagy role. proposed_replacement_terms: - &id032 id: GO:0000045 label: autophagosome assembly additional_reference_ids: - PMID:25490155 - PMID:40442316 - PMID:10625637 supported_by: - &id002 reference_id: PMID:40442316 supporting_text: All forms of canonical autophagy, bulk and selective, are initiated upon the recruitment and activation ... PI3KC3-C1 - &id001 reference_id: PMID:25490155 supporting_text: PI3KC3-C1 ... consists of the lipid kinase VPS34, the scaffolding protein VPS15, the tumor suppressor BECN1, and the autophagy-specific subunit ATG14 - &id014 reference_id: PMID:10625637 supporting_text: overexpressing the p150 adaptor, stimulates macroautophagy - term: id: GO:0034271 label: phosphatidylinositol 3-kinase complex, class III, type I evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: part_of review: summary: PIK3R4/VPS15 is a core subunit of ATG14-containing class III PI3K complex I. action: ACCEPT reason: Accept as core PN-relevant complex membership. PIK3R4/VPS15 organizes PI3KC3-C1 and bridges VPS34 to the ATG14:BECN1 subcomplex in autophagy initiation. additional_reference_ids: - PMID:8999962 - PMID:19270696 - PMID:20643123 - PMID:25490155 - PMID:40442316 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: - *id001 - &id019 reference_id: PMID:25490155 supporting_text: VPS15 organizes the complex and serves as a bridge between VPS34 and the ATG14:BECN1 subcomplex - *id002 - &id003 reference_id: file:human/PIK3R4/PIK3R4-uniprot.txt supporting_text: Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex - term: id: GO:0034272 label: phosphatidylinositol 3-kinase complex, class III, type II evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: part_of review: summary: PIK3R4/VPS15 is also part of UVRAG-containing class III PI3K complex II. action: ACCEPT reason: Accept as core secondary complex membership. PIK3R4 is in the shared VPS34/BECN1 core and participates in UVRAG-containing endosomal/autophagosome-maturation contexts. additional_reference_ids: - PMID:8999962 - PMID:19270696 - PMID:20643123 - PMID:25490155 - PMID:40442316 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: - &id016 reference_id: PMID:19270696 supporting_text: the Beclin 1-hVps34 complex functions in two different steps of autophagy by altering the subunit composition - &id029 reference_id: PMID:20643123 supporting_text: a specific sub-complex containing VPS15, VPS34, Beclin 1, UVRAG and BIF-1 regulates both receptor degradation and cytokinesis - &id004 reference_id: file:human/PIK3R4/PIK3R4-uniprot.txt supporting_text: As component of the PI3K complex II localized predominantly to endosomes - *id003 - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: protein serine/threonine kinase activity is retained as a non-core PIK3R4 molecular function because curated sources support kinase-domain/autophosphorylation biology but recent structures call VPS15 a pseudokinase. action: KEEP_AS_NON_CORE reason: Keep as non-core rather than making it the main functional claim. The dominant biological role of PIK3R4 is regulatory/scaffolding contribution to PI3KC3 complex lipid kinase activity; the protein-kinase annotation remains secondary and mechanistically debated. additional_reference_ids: - PMID:8999962 - PMID:40442316 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: &id008 - &id009 reference_id: file:human/PIK3R4/PIK3R4-uniprot.txt supporting_text: Probably autophosphorylated - &id010 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 - &id018 reference_id: PMID:8999962 supporting_text: Recombinant p150 associated with PtdIns 3-kinase in vitro in a stable manner - &id025 reference_id: PMID:8999962 supporting_text: resulting in a 2-fold increase in lipid kinase activity - term: id: GO:0005770 label: late endosome evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Late-endosome localization/activity context is supported for PIK3R4-containing PI3KC3-C2/endosomal trafficking complexes. action: ACCEPT reason: Accept as supported location/context. Human VPS34/p150 colocalizes with Rab7 on late endosomes, and UniProt places the PI3KC3-C2 form predominantly at endosomes. additional_reference_ids: - PMID:14617358 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: - &id005 reference_id: PMID:14617358 supporting_text: The hVPS34/p150 complex colocalized with rab7 on late endosomes - &id006 reference_id: PMID:14617358 supporting_text: link rab7 to the regulation of phosphatidylinositol 3'-kinase cycling between early and late endosomes - *id004 - term: id: GO:0006623 label: protein targeting to vacuole evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: The yeast/vacuole targeting row should be translated to the human lysosomal targeting/endolysosomal context. action: MODIFY reason: Modify to protein targeting to lysosome. PIK3R4/VPS15 conserves Vps34-linked trafficking biology, but human reviews and GOA should not use a vacuole-specific process when lysosomal/endolysosomal terms are available. proposed_replacement_terms: - id: GO:0006622 label: protein targeting to lysosome additional_reference_ids: - PMID:8999962 - PMID:16467569 supported_by: - &id021 reference_id: PMID:8999962 supporting_text: Vps15p.Vps34p complex has been conserved from yeast to man - &id007 reference_id: PMID:16467569 supporting_text: class III PI 3-kinases mainly mediate receptor-independent trafficking events - term: id: GO:0045324 label: late endosome to vacuole transport evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Late endosome to vacuole transport is a yeast/vacuole phrasing of a supported human endolysosomal trafficking role. action: MODIFY reason: Modify to early endosome to late endosome transport. Human evidence supports Rab7-linked hVPS34/p150 cycling between early and late endosomes rather than a vacuole-specific transport step. proposed_replacement_terms: - &id015 id: GO:0045022 label: early endosome to late endosome transport additional_reference_ids: - PMID:14617358 - PMID:16467569 supported_by: - *id005 - *id006 - *id007 - term: id: GO:0071561 label: nucleus-vacuole junction evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Nucleus-vacuole junction is a yeast-specific cellular component and is not appropriate for human PIK3R4. action: REMOVE reason: Remove. The human protein functions in PI3KC3 complexes at autophagosome/endosomal/membrane contexts; the nucleus-vacuole junction term reflects yeast IBA transfer and has no human organelle equivalent. additional_reference_ids: - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: - &id011 reference_id: file:human/PIK3R4/PIK3R4-uniprot.txt supporting_text: As component of the PI3K complex I localized to pre-autophagosome structures - *id004 - term: id: GO:0004672 label: protein kinase activity evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: protein kinase activity is retained as a non-core PIK3R4 molecular function because curated sources support kinase-domain/autophosphorylation biology but recent structures call VPS15 a pseudokinase. action: KEEP_AS_NON_CORE reason: Keep as non-core rather than making it the main functional claim. The dominant biological role of PIK3R4 is regulatory/scaffolding contribution to PI3KC3 complex lipid kinase activity; the protein-kinase annotation remains secondary and mechanistically debated. additional_reference_ids: - PMID:8999962 - PMID:40442316 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: *id008 - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: protein serine/threonine kinase activity is retained as a non-core PIK3R4 molecular function because curated sources support kinase-domain/autophosphorylation biology but recent structures call VPS15 a pseudokinase. action: KEEP_AS_NON_CORE reason: Keep as non-core rather than making it the main functional claim. The dominant biological role of PIK3R4 is regulatory/scaffolding contribution to PI3KC3 complex lipid kinase activity; the protein-kinase annotation remains secondary and mechanistically debated. additional_reference_ids: - PMID:8999962 - PMID:40442316 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: *id008 - term: id: GO:0005524 label: ATP binding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: ATP binding is plausible from the curated protein-kinase catalytic annotations but is not the main PIK3R4 functional claim. action: KEEP_AS_NON_CORE reason: Keep as non-core. ATP binding follows from the kinase-domain/protein-kinase annotation, whereas the central gene function is scaffolding/regulatory contribution to PI3KC3 lipid kinase complexes. additional_reference_ids: - PMID:40442316 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: - *id009 - *id010 - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: located_in review: summary: cytoplasm is a supported broad location for PIK3R4-containing PI3KC3 complexes. action: ACCEPT reason: Accept as supported location/context. PIK3R4-containing PI3KC3 complexes are cytosolic/peripheral membrane assemblies that localize to autophagosome/pre-autophagosome and endosomal membranes depending on subcomplex composition. additional_reference_ids: - PMID:14617358 - PMID:25490155 - Reactome:R-HSA-5672012 - Reactome:R-HSA-6798174 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: &id012 - *id003 - *id011 - *id004 - reference_id: file:human/PIK3R4/PIK3R4-uniprot.txt supporting_text: Membrane; Lipid-anchor - term: id: GO:0005770 label: late endosome evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Late-endosome localization/activity context is supported for PIK3R4-containing PI3KC3-C2/endosomal trafficking complexes. action: ACCEPT reason: Accept as supported location/context. Human VPS34/p150 colocalizes with Rab7 on late endosomes, and UniProt places the PI3KC3-C2 form predominantly at endosomes. additional_reference_ids: - PMID:14617358 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: - *id005 - *id006 - *id004 - term: id: GO:0005776 label: autophagosome evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: autophagosome is a supported broad location for PIK3R4-containing PI3KC3 complexes. action: ACCEPT reason: Accept as supported location/context. PIK3R4-containing PI3KC3 complexes are cytosolic/peripheral membrane assemblies that localize to autophagosome/pre-autophagosome and endosomal membranes depending on subcomplex composition. additional_reference_ids: - PMID:14617358 - PMID:25490155 - Reactome:R-HSA-5672012 - Reactome:R-HSA-6798174 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: *id012 - term: id: GO:0005856 label: cytoskeleton evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: located_in review: summary: cytoskeleton is retained as non-core localization context, mostly from automated or by-similarity sources. action: KEEP_AS_NON_CORE reason: Keep as non-core. UniProt notes ciliary axoneme puncta by similarity, but the accessible human functional evidence centers on PI3KC3 autophagy/endosomal membrane complexes. additional_reference_ids: - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: - &id013 reference_id: file:human/PIK3R4/PIK3R4-uniprot.txt supporting_text: Localizes also to discrete punctae along the ciliary axoneme - *id003 - term: id: GO:0005929 label: cilium evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: located_in review: summary: cilium is retained as non-core localization context, mostly from automated or by-similarity sources. action: KEEP_AS_NON_CORE reason: Keep as non-core. UniProt notes ciliary axoneme puncta by similarity, but the accessible human functional evidence centers on PI3KC3 autophagy/endosomal membrane complexes. additional_reference_ids: - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: - *id013 - *id003 - term: id: GO:0016020 label: membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: membrane is a supported broad location for PIK3R4-containing PI3KC3 complexes. action: ACCEPT reason: Accept as supported location/context. PIK3R4-containing PI3KC3 complexes are cytosolic/peripheral membrane assemblies that localize to autophagosome/pre-autophagosome and endosomal membranes depending on subcomplex composition. additional_reference_ids: - PMID:14617358 - PMID:25490155 - Reactome:R-HSA-5672012 - Reactome:R-HSA-6798174 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: *id012 - term: id: GO:0016236 label: macroautophagy evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: Macroautophagy is a core process for PIK3R4 through the ATG14-containing PI3KC3-C1 complex. action: ACCEPT reason: Accept as core process. PIK3R4/VPS15 is a PI3KC3-C1 component; class III PI3K activity and the Vps34/Vps15/ATG14/BECN1 complex support canonical autophagy initiation. additional_reference_ids: - PMID:10625637 - PMID:24785657 - PMID:24849286 - PMID:25490155 - PMID:40442316 supported_by: - *id014 - &id022 reference_id: PMID:10625637 supporting_text: specific class III PI3K antisense oligonucleotide greatly inhibited the rate of macroautophagy - *id001 - *id002 - &id020 reference_id: PMID:24849286 supporting_text: assembly of the specific Atg14L-Beclin 1-Vps34-Vps15 complex for autophagy induction - term: id: GO:0045324 label: late endosome to vacuole transport evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: Late endosome to vacuole transport is a yeast/vacuole phrasing of a supported human endolysosomal trafficking role. action: MODIFY reason: Modify to early endosome to late endosome transport. Human evidence supports Rab7-linked hVPS34/p150 cycling between early and late endosomes rather than a vacuole-specific transport step. proposed_replacement_terms: - *id015 additional_reference_ids: - PMID:14617358 - PMID:16467569 supported_by: - *id005 - *id006 - *id007 - term: id: GO:0106310 label: protein serine kinase activity evidence_type: IEA original_reference_id: GO_REF:0000116 qualifier: enables review: summary: protein serine kinase activity is retained as a non-core PIK3R4 molecular function because curated sources support kinase-domain/autophosphorylation biology but recent structures call VPS15 a pseudokinase. action: KEEP_AS_NON_CORE reason: Keep as non-core rather than making it the main functional claim. The dominant biological role of PIK3R4 is regulatory/scaffolding contribution to PI3KC3 complex lipid kinase activity; the protein-kinase annotation remains secondary and mechanistically debated. additional_reference_ids: - PMID:8999962 - PMID:40442316 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: *id008 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:24785657 qualifier: enables review: summary: Generic protein binding is not an informative molecular-function annotation for PIK3R4. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3 complex/subcomplex membership or specific regulatory interactions, not as generic protein binding. additional_reference_ids: - PMID:14617358 - PMID:19270696 - PMID:24785657 - PMID:24849286 - PMID:28514442 - PMID:32296183 - PMID:32707033 - PMID:33961781 supported_by: &id017 - reference_id: PMID:24785657 supporting_text: NRBF2 directly interacts with Vps15 - reference_id: PMID:24785657 supporting_text: NRBF2 binds to complexes that include Vps34, Vps15, Beclin-1 and ATG-14L - *id016 - *id005 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:24849286 qualifier: enables review: summary: Generic protein binding is not an informative molecular-function annotation for PIK3R4. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3 complex/subcomplex membership or specific regulatory interactions, not as generic protein binding. additional_reference_ids: - PMID:14617358 - PMID:19270696 - PMID:24785657 - PMID:24849286 - PMID:28514442 - PMID:32296183 - PMID:32707033 - PMID:33961781 supported_by: *id017 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28514442 qualifier: enables review: summary: Generic protein binding is not an informative molecular-function annotation for PIK3R4. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3 complex/subcomplex membership or specific regulatory interactions, not as generic protein binding. additional_reference_ids: - PMID:14617358 - PMID:19270696 - PMID:24785657 - PMID:24849286 - PMID:28514442 - PMID:32296183 - PMID:32707033 - PMID:33961781 supported_by: *id017 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: Generic protein binding is not an informative molecular-function annotation for PIK3R4. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3 complex/subcomplex membership or specific regulatory interactions, not as generic protein binding. additional_reference_ids: - PMID:14617358 - PMID:19270696 - PMID:24785657 - PMID:24849286 - PMID:28514442 - PMID:32296183 - PMID:32707033 - PMID:33961781 supported_by: *id017 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32707033 qualifier: enables review: summary: Generic protein binding is not an informative molecular-function annotation for PIK3R4. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3 complex/subcomplex membership or specific regulatory interactions, not as generic protein binding. additional_reference_ids: - PMID:14617358 - PMID:19270696 - PMID:24785657 - PMID:24849286 - PMID:28514442 - PMID:32296183 - PMID:32707033 - PMID:33961781 supported_by: *id017 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: Generic protein binding is not an informative molecular-function annotation for PIK3R4. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3 complex/subcomplex membership or specific regulatory interactions, not as generic protein binding. additional_reference_ids: - PMID:14617358 - PMID:19270696 - PMID:24785657 - PMID:24849286 - PMID:28514442 - PMID:32296183 - PMID:32707033 - PMID:33961781 supported_by: *id017 - term: id: GO:0005930 label: axoneme evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: axoneme is retained as non-core localization context, mostly from automated or by-similarity sources. action: KEEP_AS_NON_CORE reason: Keep as non-core. UniProt notes ciliary axoneme puncta by similarity, but the accessible human functional evidence centers on PI3KC3 autophagy/endosomal membrane complexes. additional_reference_ids: - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: - *id013 - *id003 - term: id: GO:0035032 label: phosphatidylinositol 3-kinase complex, class III evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: part_of review: summary: PIK3R4 is a core component of class III PI3K complexes. action: ACCEPT reason: Accept as core complex membership. The generic class III PI3K complex row is supported by both PI3KC3-C1 and PI3KC3-C2 evidence. additional_reference_ids: - PMID:8999962 - PMID:19270696 - PMID:20643123 - PMID:25490155 - PMID:40442316 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: &id024 - *id003 - *id018 - *id001 - *id019 - *id010 - term: id: GO:0042149 label: cellular response to glucose starvation evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Cellular response to glucose starvation is supported as context for starvation-induced PI3KC3-C1 autophagy but is not the core function itself. action: KEEP_AS_NON_CORE reason: Keep as non-core. Starvation-induced autophagy depends on the PIK3R4-containing PI3KC3-C1 complex, but the more informative process annotation is macroautophagy/autophagosome assembly. additional_reference_ids: - PMID:24785657 - PMID:24849286 - PMID:40442316 supported_by: - &id031 reference_id: PMID:24785657 supporting_text: specific member of Vps34 Complex I - *id020 - *id002 - term: id: GO:0006622 label: protein targeting to lysosome evidence_type: NAS original_reference_id: PMID:16467569 qualifier: involved_in review: summary: Protein targeting to lysosome is a broad non-core representation of conserved class III PI3K endolysosomal trafficking. action: KEEP_AS_NON_CORE reason: Keep as non-core. The term is plausible as a broad human equivalent of Vps34/Vps15 trafficking biology, but more specific supported PIK3R4 processes are PI3P biosynthesis, endosomal trafficking, and autophagy. additional_reference_ids: - PMID:8999962 - PMID:16467569 supported_by: - *id021 - *id007 - &id028 reference_id: PMID:16467569 supporting_text: endocytic membrane traffic, phagosome maturation and autophagy - term: id: GO:0010506 label: regulation of autophagy evidence_type: IDA original_reference_id: PMID:16799551 qualifier: involved_in review: summary: regulation of autophagy captures autophagy regulation but the underlying evidence supports PIK3R4 participation in macroautophagy itself. action: MODIFY reason: Modify to macroautophagy. The older class III PI3K and Beclin/UVRAG evidence supports a necessary PI3KC3 complex role in macroautophagy rather than only a regulatory relationship. proposed_replacement_terms: - &id023 id: GO:0016236 label: macroautophagy additional_reference_ids: - PMID:10625637 - PMID:16799551 - PMID:19270696 supported_by: - *id014 - *id022 - *id016 - term: id: GO:0016236 label: macroautophagy evidence_type: NAS original_reference_id: PMID:40442316 qualifier: involved_in review: summary: Macroautophagy is a core process for PIK3R4 through the ATG14-containing PI3KC3-C1 complex. action: ACCEPT reason: Accept as core process. PIK3R4/VPS15 is a PI3KC3-C1 component; class III PI3K activity and the Vps34/Vps15/ATG14/BECN1 complex support canonical autophagy initiation. additional_reference_ids: - PMID:10625637 - PMID:24785657 - PMID:24849286 - PMID:25490155 - PMID:40442316 supported_by: - *id014 - *id022 - *id001 - *id002 - *id020 - term: id: GO:0016241 label: regulation of macroautophagy evidence_type: IDA original_reference_id: PMID:10625637 qualifier: involved_in review: summary: regulation of macroautophagy captures autophagy regulation but the underlying evidence supports PIK3R4 participation in macroautophagy itself. action: MODIFY reason: Modify to macroautophagy. The older class III PI3K and Beclin/UVRAG evidence supports a necessary PI3KC3 complex role in macroautophagy rather than only a regulatory relationship. proposed_replacement_terms: - *id023 additional_reference_ids: - PMID:10625637 - PMID:16799551 - PMID:19270696 supported_by: - *id014 - *id022 - *id016 - term: id: GO:0035032 label: phosphatidylinositol 3-kinase complex, class III evidence_type: IPI original_reference_id: PMID:25490155 qualifier: part_of review: summary: PIK3R4 is a core component of class III PI3K complexes. action: ACCEPT reason: Accept as core complex membership. The generic class III PI3K complex row is supported by both PI3KC3-C1 and PI3KC3-C2 evidence. additional_reference_ids: - PMID:8999962 - PMID:19270696 - PMID:20643123 - PMID:25490155 - PMID:40442316 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: *id024 - term: id: GO:0035032 label: phosphatidylinositol 3-kinase complex, class III evidence_type: IPI original_reference_id: PMID:40442316 qualifier: part_of review: summary: PIK3R4 is a core component of class III PI3K complexes. action: ACCEPT reason: Accept as core complex membership. The generic class III PI3K complex row is supported by both PI3KC3-C1 and PI3KC3-C2 evidence. additional_reference_ids: - PMID:8999962 - PMID:19270696 - PMID:20643123 - PMID:25490155 - PMID:40442316 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: *id024 - term: id: GO:0036092 label: phosphatidylinositol-3-phosphate biosynthetic process evidence_type: IDA original_reference_id: PMID:8999962 qualifier: involved_in review: summary: PIK3R4 participates in PI3P biosynthesis as the regulatory/scaffold subunit required for PIK3C3/VPS34 complex activity. action: ACCEPT reason: Accept as core process. PIK3R4 is not the catalytic lipid kinase, but it is necessary for PIK3C3 catalytic activity, localization, and stability in PI3P-producing class III PI3K complexes. additional_reference_ids: - PMID:8999962 - Reactome:R-HSA-5672012 - Reactome:R-HSA-6798174 supported_by: - *id018 - *id025 - &id034 reference_id: Reactome:R-HSA-5672012 supporting_text: PIK3C3 ... phosphorylates phosphatidylinositol (PI) producing phosphatidylinositol 3-phosphate (PI3P) - &id027 reference_id: Reactome:R-HSA-6798174 supporting_text: PIK3R4, Vps150, necessary for catalytic activity, localization and stability - term: id: GO:0045022 label: early endosome to late endosome transport evidence_type: IDA original_reference_id: PMID:14617358 qualifier: involved_in review: summary: PIK3R4-containing hVPS34/p150 complexes participate in Rab7-linked early-to-late endosomal PI3K cycling. action: ACCEPT reason: Accept as supported endosomal trafficking process. The human Rab7 paper directly places hVPS34/p150 on late endosomes and links Rab7 to PI3K cycling between early and late endosomes. additional_reference_ids: - PMID:14617358 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: - *id005 - *id006 - *id004 - term: id: GO:0097352 label: autophagosome maturation evidence_type: IDA original_reference_id: PMID:10625637 qualifier: involved_in review: summary: Autophagosome maturation is supported for the UVRAG/Rubicon-containing PI3KC3-C2 branch. action: ACCEPT reason: Accept as a supported process for PIK3R4-containing class III PI3K complexes. The Beclin/Vps34 subcomplex changes subunits for different autophagy steps, with Rubicon/UVRAG context affecting maturation. additional_reference_ids: - PMID:19270696 - PMID:21062745 supported_by: - *id016 - &id037 reference_id: PMID:19270696 supporting_text: Knockdown of Rubicon caused enhancement of autophagy, especially at the maturation step - &id026 reference_id: PMID:21062745 supporting_text: Rubicon serves as a negative regulator of PI3KC3 and autophagosome maturation - term: id: GO:0043491 label: phosphatidylinositol 3-kinase/protein kinase B signal transduction evidence_type: IDA original_reference_id: PMID:21062745 qualifier: involved_in review: summary: The PI3K/AKT pathway term conflates class III VPS34 biology with class I PI3K/AKT signaling; the cited Rubicon evidence is autophagosome-maturation biology. action: MODIFY reason: Modify to autophagosome maturation. PMID:21062745 concerns Rubicon inhibition of hVps34/PI3KC3 and autophagosome maturation, not protein kinase B/AKT signal transduction. proposed_replacement_terms: - &id036 id: GO:0097352 label: autophagosome maturation additional_reference_ids: - PMID:21062745 - PMID:19270696 supported_by: - *id026 - *id016 - term: id: GO:0030670 label: phagocytic vesicle membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-6798174 qualifier: located_in review: summary: Phagocytic vesicle membrane is plausible PI3P/PIK3C3 complex context but is not a core PIK3R4 function in this review. action: KEEP_AS_NON_CORE reason: Keep as non-core. Reactome places PIK3C3:PIK3R4 in phagosomal PI3P generation, but the main gene-level functions are PI3KC3-C1 autophagy initiation and PI3KC3-C2 endosomal trafficking. additional_reference_ids: - Reactome:R-HSA-6798174 - PMID:16467569 supported_by: - *id027 - *id028 - term: id: GO:0032465 label: regulation of cytokinesis evidence_type: IMP original_reference_id: PMID:20643123 qualifier: involved_in review: summary: Regulation of cytokinesis is directly supported for a UVRAG/BIF-1-containing PI3KC3 subcomplex but is secondary to PIK3R4 core autophagy/endosomal trafficking. action: KEEP_AS_NON_CORE reason: Keep as non-core. VPS15 is part of the subcomplex implicated in cytokinesis, but this is not the proteostasis-network C1 role and is less central than PI3P/autophagy/endosomal trafficking. additional_reference_ids: - PMID:20643123 supported_by: - *id029 - &id030 reference_id: PMID:20643123 supporting_text: ATG14L, a PI3K-III subunit involved in autophagy, is not required - term: id: GO:0032801 label: receptor catabolic process evidence_type: IMP original_reference_id: PMID:20643123 qualifier: involved_in review: summary: Receptor catabolic process is supported for the UVRAG/BIF-1-containing PI3KC3-C2/endocytic branch. action: ACCEPT reason: Accept as supported secondary core process. The VPS15/VPS34/BECN1/UVRAG/BIF-1 subcomplex regulates receptor degradation and degradative endocytic traffic. additional_reference_ids: - PMID:20643123 supported_by: - *id029 - *id030 - term: id: GO:0035032 label: phosphatidylinositol 3-kinase complex, class III evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: part_of review: summary: PIK3R4 is a core component of class III PI3K complexes. action: ACCEPT reason: Accept as core complex membership. The generic class III PI3K complex row is supported by both PI3KC3-C1 and PI3KC3-C2 evidence. additional_reference_ids: - PMID:8999962 - PMID:19270696 - PMID:20643123 - PMID:25490155 - PMID:40442316 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: *id024 - term: id: GO:0042149 label: cellular response to glucose starvation evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Cellular response to glucose starvation is supported as context for starvation-induced PI3KC3-C1 autophagy but is not the core function itself. action: KEEP_AS_NON_CORE reason: Keep as non-core. Starvation-induced autophagy depends on the PIK3R4-containing PI3KC3-C1 complex, but the more informative process annotation is macroautophagy/autophagosome assembly. additional_reference_ids: - PMID:24785657 - PMID:24849286 - PMID:40442316 supported_by: - *id031 - *id020 - *id002 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-109699 qualifier: located_in review: summary: cytosol is a supported broad location for PIK3R4-containing PI3KC3 complexes. action: ACCEPT reason: Accept as supported location/context. PIK3R4-containing PI3KC3 complexes are cytosolic/peripheral membrane assemblies that localize to autophagosome/pre-autophagosome and endosomal membranes depending on subcomplex composition. additional_reference_ids: - PMID:14617358 - PMID:25490155 - Reactome:R-HSA-5672012 - Reactome:R-HSA-6798174 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: *id012 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-1632857 qualifier: located_in review: summary: cytosol is a supported broad location for PIK3R4-containing PI3KC3 complexes. action: ACCEPT reason: Accept as supported location/context. PIK3R4-containing PI3KC3 complexes are cytosolic/peripheral membrane assemblies that localize to autophagosome/pre-autophagosome and endosomal membranes depending on subcomplex composition. additional_reference_ids: - PMID:14617358 - PMID:25490155 - Reactome:R-HSA-5672012 - Reactome:R-HSA-6798174 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: *id012 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-1675939 qualifier: located_in review: summary: cytosol is a supported broad location for PIK3R4-containing PI3KC3 complexes. action: ACCEPT reason: Accept as supported location/context. PIK3R4-containing PI3KC3 complexes are cytosolic/peripheral membrane assemblies that localize to autophagosome/pre-autophagosome and endosomal membranes depending on subcomplex composition. additional_reference_ids: - PMID:14617358 - PMID:25490155 - Reactome:R-HSA-5672012 - Reactome:R-HSA-6798174 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: *id012 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-1675961 qualifier: located_in review: summary: cytosol is a supported broad location for PIK3R4-containing PI3KC3 complexes. action: ACCEPT reason: Accept as supported location/context. PIK3R4-containing PI3KC3 complexes are cytosolic/peripheral membrane assemblies that localize to autophagosome/pre-autophagosome and endosomal membranes depending on subcomplex composition. additional_reference_ids: - PMID:14617358 - PMID:25490155 - Reactome:R-HSA-5672012 - Reactome:R-HSA-6798174 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: *id012 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-1676024 qualifier: located_in review: summary: cytosol is a supported broad location for PIK3R4-containing PI3KC3 complexes. action: ACCEPT reason: Accept as supported location/context. PIK3R4-containing PI3KC3 complexes are cytosolic/peripheral membrane assemblies that localize to autophagosome/pre-autophagosome and endosomal membranes depending on subcomplex composition. additional_reference_ids: - PMID:14617358 - PMID:25490155 - Reactome:R-HSA-5672012 - Reactome:R-HSA-6798174 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: *id012 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-188002 qualifier: located_in review: summary: cytosol is a supported broad location for PIK3R4-containing PI3KC3 complexes. action: ACCEPT reason: Accept as supported location/context. PIK3R4-containing PI3KC3 complexes are cytosolic/peripheral membrane assemblies that localize to autophagosome/pre-autophagosome and endosomal membranes depending on subcomplex composition. additional_reference_ids: - PMID:14617358 - PMID:25490155 - Reactome:R-HSA-5672012 - Reactome:R-HSA-6798174 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: *id012 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-5672012 qualifier: located_in review: summary: cytosol is a supported broad location for PIK3R4-containing PI3KC3 complexes. action: ACCEPT reason: Accept as supported location/context. PIK3R4-containing PI3KC3 complexes are cytosolic/peripheral membrane assemblies that localize to autophagosome/pre-autophagosome and endosomal membranes depending on subcomplex composition. additional_reference_ids: - PMID:14617358 - PMID:25490155 - Reactome:R-HSA-5672012 - Reactome:R-HSA-6798174 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: *id012 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-5678313 qualifier: located_in review: summary: cytosol is a supported broad location for PIK3R4-containing PI3KC3 complexes. action: ACCEPT reason: Accept as supported location/context. PIK3R4-containing PI3KC3 complexes are cytosolic/peripheral membrane assemblies that localize to autophagosome/pre-autophagosome and endosomal membranes depending on subcomplex composition. additional_reference_ids: - PMID:14617358 - PMID:25490155 - Reactome:R-HSA-5672012 - Reactome:R-HSA-6798174 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: *id012 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-5678315 qualifier: located_in review: summary: cytosol is a supported broad location for PIK3R4-containing PI3KC3 complexes. action: ACCEPT reason: Accept as supported location/context. PIK3R4-containing PI3KC3 complexes are cytosolic/peripheral membrane assemblies that localize to autophagosome/pre-autophagosome and endosomal membranes depending on subcomplex composition. additional_reference_ids: - PMID:14617358 - PMID:25490155 - Reactome:R-HSA-5672012 - Reactome:R-HSA-6798174 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: *id012 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-5679205 qualifier: located_in review: summary: cytosol is a supported broad location for PIK3R4-containing PI3KC3 complexes. action: ACCEPT reason: Accept as supported location/context. PIK3R4-containing PI3KC3 complexes are cytosolic/peripheral membrane assemblies that localize to autophagosome/pre-autophagosome and endosomal membranes depending on subcomplex composition. additional_reference_ids: - PMID:14617358 - PMID:25490155 - Reactome:R-HSA-5672012 - Reactome:R-HSA-6798174 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: *id012 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-5679266 qualifier: located_in review: summary: cytosol is a supported broad location for PIK3R4-containing PI3KC3 complexes. action: ACCEPT reason: Accept as supported location/context. PIK3R4-containing PI3KC3 complexes are cytosolic/peripheral membrane assemblies that localize to autophagosome/pre-autophagosome and endosomal membranes depending on subcomplex composition. additional_reference_ids: - PMID:14617358 - PMID:25490155 - Reactome:R-HSA-5672012 - Reactome:R-HSA-6798174 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: *id012 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-5682385 qualifier: located_in review: summary: cytosol is a supported broad location for PIK3R4-containing PI3KC3 complexes. action: ACCEPT reason: Accept as supported location/context. PIK3R4-containing PI3KC3 complexes are cytosolic/peripheral membrane assemblies that localize to autophagosome/pre-autophagosome and endosomal membranes depending on subcomplex composition. additional_reference_ids: - PMID:14617358 - PMID:25490155 - Reactome:R-HSA-5672012 - Reactome:R-HSA-6798174 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: *id012 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9755359 qualifier: located_in review: summary: cytosol is a supported broad location for PIK3R4-containing PI3KC3 complexes. action: ACCEPT reason: Accept as supported location/context. PIK3R4-containing PI3KC3 complexes are cytosolic/peripheral membrane assemblies that localize to autophagosome/pre-autophagosome and endosomal membranes depending on subcomplex composition. additional_reference_ids: - PMID:14617358 - PMID:25490155 - Reactome:R-HSA-5672012 - Reactome:R-HSA-6798174 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: *id012 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9921171 qualifier: located_in review: summary: cytosol is a supported broad location for PIK3R4-containing PI3KC3 complexes. action: ACCEPT reason: Accept as supported location/context. PIK3R4-containing PI3KC3 complexes are cytosolic/peripheral membrane assemblies that localize to autophagosome/pre-autophagosome and endosomal membranes depending on subcomplex composition. additional_reference_ids: - PMID:14617358 - PMID:25490155 - Reactome:R-HSA-5672012 - Reactome:R-HSA-6798174 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: *id012 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23878393 qualifier: enables review: summary: Generic protein binding is not an informative molecular-function annotation for PIK3R4. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3 complex/subcomplex membership or specific regulatory interactions, not as generic protein binding. additional_reference_ids: - PMID:14617358 - PMID:19270696 - PMID:24785657 - PMID:24849286 - PMID:28514442 - PMID:32296183 - PMID:32707033 - PMID:33961781 supported_by: *id017 - term: id: GO:0016020 label: membrane evidence_type: HDA original_reference_id: PMID:19946888 qualifier: located_in review: summary: membrane is a supported broad location for PIK3R4-containing PI3KC3 complexes. action: ACCEPT reason: Accept as supported location/context. PIK3R4-containing PI3KC3 complexes are cytosolic/peripheral membrane assemblies that localize to autophagosome/pre-autophagosome and endosomal membranes depending on subcomplex composition. additional_reference_ids: - PMID:14617358 - PMID:25490155 - Reactome:R-HSA-5672012 - Reactome:R-HSA-6798174 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: *id012 - term: id: GO:0005930 label: axoneme evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: axoneme is retained as non-core localization context, mostly from automated or by-similarity sources. action: KEEP_AS_NON_CORE reason: Keep as non-core. UniProt notes ciliary axoneme puncta by similarity, but the accessible human functional evidence centers on PI3KC3 autophagy/endosomal membrane complexes. additional_reference_ids: - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: - *id013 - *id003 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19270696 qualifier: enables review: summary: Generic protein binding is not an informative molecular-function annotation for PIK3R4. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3 complex/subcomplex membership or specific regulatory interactions, not as generic protein binding. additional_reference_ids: - PMID:14617358 - PMID:19270696 - PMID:24785657 - PMID:24849286 - PMID:28514442 - PMID:32296183 - PMID:32707033 - PMID:33961781 supported_by: *id017 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:14617358 qualifier: enables review: summary: Generic protein binding is not an informative molecular-function annotation for PIK3R4. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The interaction evidence should be represented as PI3KC3 complex/subcomplex membership or specific regulatory interactions, not as generic protein binding. additional_reference_ids: - PMID:14617358 - PMID:19270696 - PMID:24785657 - PMID:24849286 - PMID:28514442 - PMID:32296183 - PMID:32707033 - PMID:33961781 supported_by: *id017 - term: id: GO:0005770 label: late endosome evidence_type: IDA original_reference_id: PMID:14617358 qualifier: located_in review: summary: Late-endosome localization/activity context is supported for PIK3R4-containing PI3KC3-C2/endosomal trafficking complexes. action: ACCEPT reason: Accept as supported location/context. Human VPS34/p150 colocalizes with Rab7 on late endosomes, and UniProt places the PI3KC3-C2 form predominantly at endosomes. additional_reference_ids: - PMID:14617358 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: - *id005 - *id006 - *id004 - term: id: GO:0004672 label: protein kinase activity evidence_type: NAS original_reference_id: PMID:8999962 qualifier: enables review: summary: protein kinase activity is retained as a non-core PIK3R4 molecular function because curated sources support kinase-domain/autophosphorylation biology but recent structures call VPS15 a pseudokinase. action: KEEP_AS_NON_CORE reason: Keep as non-core rather than making it the main functional claim. The dominant biological role of PIK3R4 is regulatory/scaffolding contribution to PI3KC3 complex lipid kinase activity; the protein-kinase annotation remains secondary and mechanistically debated. additional_reference_ids: - PMID:8999962 - PMID:40442316 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: *id008 - term: id: GO:0006468 label: protein phosphorylation evidence_type: NAS original_reference_id: PMID:8999962 qualifier: involved_in review: summary: Protein phosphorylation is retained only as a non-core process linked to curated PIK3R4 kinase/autophosphorylation biology. action: KEEP_AS_NON_CORE reason: Keep as non-core. UniProt supports probable autophosphorylation, but the central gene function is scaffolding/regulation of class III PI3K lipid kinase complexes. additional_reference_ids: - PMID:8999962 - PMID:40442316 - file:human/PIK3R4/PIK3R4-uniprot.txt supported_by: - *id009 - *id010 - term: *id032 evidence_type: IDA original_reference_id: PMID:40442316 qualifier: involved_in review: summary: PIK3R4/VPS15 supports autophagosome assembly as part of ATG14-containing PI3KC3-C1. action: NEW reason: Add as a new, more precise PN-relevant process annotation. The ATG14-containing PI3KC3-C1 complex includes VPS15/PIK3R4 and is positioned at the canonical autophagy initiation step upstream of autophagosome formation. additional_reference_ids: - PMID:25490155 - PMID:40442316 - Reactome:R-HSA-5672012 supported_by: - *id002 - *id001 - *id019 - &id033 reference_id: Reactome:R-HSA-5672012 supporting_text: The Beclin-1 complex (ATG14:PIK3C3:PIK3R4:BECN1) is essential for autophagosome formation 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:0000116 title: Automatic Gene Ontology annotation based on Rhea mapping 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: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: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: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:23878393 title: Role of membrane association and Atg14-dependent phosphorylation in beclin-1-mediated autophagy. 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:25490155 title: Architecture and dynamics of the autophagic phosphatidylinositol 3-kinase complex. findings: [] - id: PMID:28514442 title: Architecture of the human interactome defines protein communities and disease networks. findings: [] - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] - id: PMID:32707033 title: Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases. findings: [] - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: [] - id: PMID:40442316 title: Structure and activation of the human autophagy-initiating ULK1C:PI3KC3-C1 supercomplex. 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-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/PIK3R4/PIK3R4-uniprot.txt title: UniProtKB record for PIK3R4 findings: [] - id: file:human/PIK3R4/PIK3R4-notes.md title: PIK3R4 review notes findings: [] core_functions: - contributes_to_molecular_function: &id035 id: GO:0016303 label: 1-phosphatidylinositol-3-kinase activity in_complex: id: GO:0034271 label: phosphatidylinositol 3-kinase complex, class III, type I description: PIK3R4/VPS15 organizes ATG14-containing PI3KC3-C1 and contributes to PIK3C3/VPS34-dependent PI3P production for autophagosome assembly and macroautophagy. It is the regulatory/scaffold subunit, not the catalytic lipid kinase. directly_involved_in: - id: GO:0036092 label: phosphatidylinositol-3-phosphate biosynthetic process - *id032 - *id023 locations: - id: GO:0005829 label: cytosol - id: GO:0016020 label: membrane - id: GO:0005776 label: autophagosome supported_by: - *id018 - *id025 - *id001 - *id019 - *id002 - *id033 - *id034 - contributes_to_molecular_function: *id035 in_complex: id: GO:0034272 label: phosphatidylinositol 3-kinase complex, class III, type II description: PIK3R4 is also part of UVRAG-containing class III PI3K complexes that regulate endosomal trafficking, receptor catabolism, and later autophagy/autophagosome maturation steps. directly_involved_in: - *id015 - *id036 - id: GO:0032801 label: receptor catabolic process locations: - id: GO:0005770 label: late endosome - id: GO:0005829 label: cytosol - id: GO:0016020 label: membrane supported_by: - *id005 - *id006 - *id016 - *id029 - *id037 proposed_new_terms: [] suggested_questions: - question: Should PIK3R4/VPS15 protein kinase annotations be retained, narrowed, or removed in light of current UniProt catalytic annotation but recent structural descriptions of VPS15 as a pseudokinase? experts: - GO molecular function editors - PI3KC3 structural biology experts - UniProt curators - question: Should vacuole-specific IBA annotations for human PIK3R4 be systematically translated to lysosomal/endosomal terms for metazoan reviews? experts: - GO autophagy editors - GO endomembrane transport editors - PAINT curators - question: Should PIK3R4 be annotated directly to autophagosome assembly based on PI3KC3-C1 membership and ULK1C:PI3KC3-C1 supercomplex evidence, or should this remain modeled only through complex contribution? experts: - GO autophagy editors - Reactome autophagy curators suggested_experiments: - description: Use PIK3R4 depletion and rescue mutants that disrupt VPS34 binding, ATG14/BECN1 bridging, or membrane anchoring to measure PI3P production, WIPI2/DFCP1 recruitment, LC3 lipidation, and starvation-induced autophagic flux. experiment_type: PI3KC3-C1 autophagy initiation rescue assay hypothesis: PIK3R4 supports autophagosome assembly primarily by organizing PI3KC3-C1 and enabling local VPS34-dependent PI3P production. - description: Separate ATG14-containing and UVRAG-containing PIK3R4 complexes by affinity purification or endogenous tagging, then compare lipid kinase activity, endosomal localization, receptor degradation, and autophagosome maturation readouts. experiment_type: subcomplex-specific functional profiling hypothesis: PIK3R4 has separable C1 and C2 roles, with C1 biased toward autophagy initiation and C2 biased toward endosomal trafficking and maturation. - description: Mutate predicted catalytic/ATP-binding residues in the PIK3R4 kinase-like domain while preserving PI3KC3 complex assembly, then assay autophosphorylation, PI3P production, and autophagy/endosomal phenotypes. experiment_type: kinase-domain separation-of-function assay hypothesis: PIK3R4 kinase-domain chemistry, if present in cells, is secondary to its structural/scaffolding role in PI3KC3 complexes.