Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0000425 pexophagy	IBA GO_REF:0000033	MODIFY	Summary: Pexophagy is too cargo-specific for human PIK3R4; the supported process is PI3KC3-C1-dependent autophagosome assembly/macroautophagy. 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 replacements: autophagosome assembly Supporting Evidence: PMID:40442316 All forms of canonical autophagy, bulk and selective, are initiated upon the recruitment and activation ... PI3KC3-C1 PMID:25490155 PI3KC3-C1 ... consists of the lipid kinase VPS34, the scaffolding protein VPS15, the tumor suppressor BECN1, and the autophagy-specific subunit ATG14 PMID:10625637 overexpressing the p150 adaptor, stimulates macroautophagy
GO:0034271 phosphatidylinositol 3-kinase complex, class III, type I	IBA GO_REF:0000033	ACCEPT	Summary: PIK3R4/VPS15 is a core subunit of ATG14-containing class III PI3K complex I. Reason: Accept as core PN-relevant complex membership. PIK3R4/VPS15 organizes PI3KC3-C1 and bridges VPS34 to the ATG14:BECN1 subcomplex in autophagy initiation. Supporting Evidence: PMID:25490155 PI3KC3-C1 ... consists of the lipid kinase VPS34, the scaffolding protein VPS15, the tumor suppressor BECN1, and the autophagy-specific subunit ATG14 PMID:25490155 VPS15 organizes the complex and serves as a bridge between VPS34 and the ATG14:BECN1 subcomplex PMID:40442316 All forms of canonical autophagy, bulk and selective, are initiated upon the recruitment and activation ... PI3KC3-C1 file:human/PIK3R4/PIK3R4-uniprot.txt Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex
GO:0034272 phosphatidylinositol 3-kinase complex, class III, type II	IBA GO_REF:0000033	ACCEPT	Summary: PIK3R4/VPS15 is also part of UVRAG-containing class III PI3K complex II. Reason: Accept as core secondary complex membership. PIK3R4 is in the shared VPS34/BECN1 core and participates in UVRAG-containing endosomal/autophagosome-maturation contexts. Supporting Evidence: PMID:19270696 the Beclin 1-hVps34 complex functions in two different steps of autophagy by altering the subunit composition PMID:20643123 a specific sub-complex containing VPS15, VPS34, Beclin 1, UVRAG and BIF-1 regulates both receptor degradation and cytokinesis file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex II localized predominantly to endosomes file:human/PIK3R4/PIK3R4-uniprot.txt Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex
GO:0004674 protein serine/threonine kinase activity	IBA GO_REF:0000033	KEEP AS NON CORE	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. 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. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Probably autophosphorylated PMID:40442316 PI3KC3-C1 contains one copy each of the lipid kinase VPS34, the pseudokinase VPS15 and the regulatory subunits BECN1 and ATG14 PMID:8999962 Recombinant p150 associated with PtdIns 3-kinase in vitro in a stable manner PMID:8999962 resulting in a 2-fold increase in lipid kinase activity
GO:0005770 late endosome	IBA GO_REF:0000033	ACCEPT	Summary: Late-endosome localization/activity context is supported for PIK3R4-containing PI3KC3-C2/endosomal trafficking complexes. 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. Supporting Evidence: PMID:14617358 The hVPS34/p150 complex colocalized with rab7 on late endosomes PMID:14617358 link rab7 to the regulation of phosphatidylinositol 3'-kinase cycling between early and late endosomes file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex II localized predominantly to endosomes
GO:0006623 protein targeting to vacuole	IBA GO_REF:0000033	MODIFY	Summary: The yeast/vacuole targeting row should be translated to the human lysosomal targeting/endolysosomal context. 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 replacements: protein targeting to lysosome Supporting Evidence: PMID:8999962 Vps15p.Vps34p complex has been conserved from yeast to man PMID:16467569 class III PI 3-kinases mainly mediate receptor-independent trafficking events
GO:0045324 late endosome to vacuole transport	IBA GO_REF:0000033	MODIFY	Summary: Late endosome to vacuole transport is a yeast/vacuole phrasing of a supported human endolysosomal trafficking role. 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 replacements: early endosome to late endosome transport Supporting Evidence: PMID:14617358 The hVPS34/p150 complex colocalized with rab7 on late endosomes PMID:14617358 link rab7 to the regulation of phosphatidylinositol 3'-kinase cycling between early and late endosomes PMID:16467569 class III PI 3-kinases mainly mediate receptor-independent trafficking events
GO:0071561 nucleus-vacuole junction	IBA GO_REF:0000033	REMOVE	Summary: Nucleus-vacuole junction is a yeast-specific cellular component and is not appropriate for human PIK3R4. 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. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex I localized to pre-autophagosome structures file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex II localized predominantly to endosomes
GO:0004672 protein kinase activity	IEA GO_REF:0000002	KEEP AS NON CORE	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. 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. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Probably autophosphorylated PMID:40442316 PI3KC3-C1 contains one copy each of the lipid kinase VPS34, the pseudokinase VPS15 and the regulatory subunits BECN1 and ATG14 PMID:8999962 Recombinant p150 associated with PtdIns 3-kinase in vitro in a stable manner PMID:8999962 resulting in a 2-fold increase in lipid kinase activity
GO:0004674 protein serine/threonine kinase activity	IEA GO_REF:0000120	KEEP AS NON CORE	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. 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. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Probably autophosphorylated PMID:40442316 PI3KC3-C1 contains one copy each of the lipid kinase VPS34, the pseudokinase VPS15 and the regulatory subunits BECN1 and ATG14 PMID:8999962 Recombinant p150 associated with PtdIns 3-kinase in vitro in a stable manner PMID:8999962 resulting in a 2-fold increase in lipid kinase activity
GO:0005524 ATP binding	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: ATP binding is plausible from the curated protein-kinase catalytic annotations but is not the main PIK3R4 functional claim. 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. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Probably autophosphorylated PMID:40442316 PI3KC3-C1 contains one copy each of the lipid kinase VPS34, the pseudokinase VPS15 and the regulatory subunits BECN1 and ATG14
GO:0005737 cytoplasm	IEA GO_REF:0000117	ACCEPT	Summary: cytoplasm is a supported broad location for PIK3R4-containing PI3KC3 complexes. 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. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex I localized to pre-autophagosome structures file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex II localized predominantly to endosomes file:human/PIK3R4/PIK3R4-uniprot.txt Membrane; Lipid-anchor
GO:0005770 late endosome	IEA GO_REF:0000044	ACCEPT	Summary: Late-endosome localization/activity context is supported for PIK3R4-containing PI3KC3-C2/endosomal trafficking complexes. 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. Supporting Evidence: PMID:14617358 The hVPS34/p150 complex colocalized with rab7 on late endosomes PMID:14617358 link rab7 to the regulation of phosphatidylinositol 3'-kinase cycling between early and late endosomes file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex II localized predominantly to endosomes
GO:0005776 autophagosome	IEA GO_REF:0000044	ACCEPT	Summary: autophagosome is a supported broad location for PIK3R4-containing PI3KC3 complexes. 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. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex I localized to pre-autophagosome structures file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex II localized predominantly to endosomes file:human/PIK3R4/PIK3R4-uniprot.txt Membrane; Lipid-anchor
GO:0005856 cytoskeleton	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: cytoskeleton is retained as non-core localization context, mostly from automated or by-similarity sources. 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. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Localizes also to discrete punctae along the ciliary axoneme file:human/PIK3R4/PIK3R4-uniprot.txt Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex
GO:0005929 cilium	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: cilium is retained as non-core localization context, mostly from automated or by-similarity sources. 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. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Localizes also to discrete punctae along the ciliary axoneme file:human/PIK3R4/PIK3R4-uniprot.txt Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex
GO:0016020 membrane	IEA GO_REF:0000044	ACCEPT	Summary: membrane is a supported broad location for PIK3R4-containing PI3KC3 complexes. 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. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex I localized to pre-autophagosome structures file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex II localized predominantly to endosomes file:human/PIK3R4/PIK3R4-uniprot.txt Membrane; Lipid-anchor
GO:0016236 macroautophagy	IEA GO_REF:0000002	ACCEPT	Summary: Macroautophagy is a core process for PIK3R4 through the ATG14-containing PI3KC3-C1 complex. 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. Supporting Evidence: PMID:10625637 overexpressing the p150 adaptor, stimulates macroautophagy PMID:10625637 specific class III PI3K antisense oligonucleotide greatly inhibited the rate of macroautophagy PMID:25490155 PI3KC3-C1 ... consists of the lipid kinase VPS34, the scaffolding protein VPS15, the tumor suppressor BECN1, and the autophagy-specific subunit ATG14 PMID:40442316 All forms of canonical autophagy, bulk and selective, are initiated upon the recruitment and activation ... PI3KC3-C1 PMID:24849286 assembly of the specific Atg14L-Beclin 1-Vps34-Vps15 complex for autophagy induction
GO:0045324 late endosome to vacuole transport	IEA GO_REF:0000002	MODIFY	Summary: Late endosome to vacuole transport is a yeast/vacuole phrasing of a supported human endolysosomal trafficking role. 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 replacements: early endosome to late endosome transport Supporting Evidence: PMID:14617358 The hVPS34/p150 complex colocalized with rab7 on late endosomes PMID:14617358 link rab7 to the regulation of phosphatidylinositol 3'-kinase cycling between early and late endosomes PMID:16467569 class III PI 3-kinases mainly mediate receptor-independent trafficking events
GO:0106310 protein serine kinase activity	IEA GO_REF:0000116	KEEP AS NON CORE	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. 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. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Probably autophosphorylated PMID:40442316 PI3KC3-C1 contains one copy each of the lipid kinase VPS34, the pseudokinase VPS15 and the regulatory subunits BECN1 and ATG14 PMID:8999962 Recombinant p150 associated with PtdIns 3-kinase in vitro in a stable manner PMID:8999962 resulting in a 2-fold increase in lipid kinase activity
GO:0005515 protein binding	IPI PMID:24785657 NRBF2 regulates macroautophagy as a component of Vps34 Compl...	MARK AS OVER ANNOTATED	Summary: Generic protein binding is not an informative molecular-function annotation for PIK3R4. 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. Supporting Evidence: PMID:24785657 NRBF2 directly interacts with Vps15 PMID:24785657 NRBF2 binds to complexes that include Vps34, Vps15, Beclin-1 and ATG-14L PMID:19270696 the Beclin 1-hVps34 complex functions in two different steps of autophagy by altering the subunit composition PMID:14617358 The hVPS34/p150 complex colocalized with rab7 on late endosomes
GO:0005515 protein binding	IPI PMID:24849286 NRBF2 regulates autophagy and prevents liver injury by modul...	MARK AS OVER ANNOTATED	Summary: Generic protein binding is not an informative molecular-function annotation for PIK3R4. 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. Supporting Evidence: PMID:24785657 NRBF2 directly interacts with Vps15 PMID:24785657 NRBF2 binds to complexes that include Vps34, Vps15, Beclin-1 and ATG-14L PMID:19270696 the Beclin 1-hVps34 complex functions in two different steps of autophagy by altering the subunit composition PMID:14617358 The hVPS34/p150 complex colocalized with rab7 on late endosomes
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: Generic protein binding is not an informative molecular-function annotation for PIK3R4. 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. Supporting Evidence: PMID:24785657 NRBF2 directly interacts with Vps15 PMID:24785657 NRBF2 binds to complexes that include Vps34, Vps15, Beclin-1 and ATG-14L PMID:19270696 the Beclin 1-hVps34 complex functions in two different steps of autophagy by altering the subunit composition PMID:14617358 The hVPS34/p150 complex colocalized with rab7 on late endosomes
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Generic protein binding is not an informative molecular-function annotation for PIK3R4. 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. Supporting Evidence: PMID:24785657 NRBF2 directly interacts with Vps15 PMID:24785657 NRBF2 binds to complexes that include Vps34, Vps15, Beclin-1 and ATG-14L PMID:19270696 the Beclin 1-hVps34 complex functions in two different steps of autophagy by altering the subunit composition PMID:14617358 The hVPS34/p150 complex colocalized with rab7 on late endosomes
GO:0005515 protein binding	IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro...	MARK AS OVER ANNOTATED	Summary: Generic protein binding is not an informative molecular-function annotation for PIK3R4. 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. Supporting Evidence: PMID:24785657 NRBF2 directly interacts with Vps15 PMID:24785657 NRBF2 binds to complexes that include Vps34, Vps15, Beclin-1 and ATG-14L PMID:19270696 the Beclin 1-hVps34 complex functions in two different steps of autophagy by altering the subunit composition PMID:14617358 The hVPS34/p150 complex colocalized with rab7 on late endosomes
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Generic protein binding is not an informative molecular-function annotation for PIK3R4. 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. Supporting Evidence: PMID:24785657 NRBF2 directly interacts with Vps15 PMID:24785657 NRBF2 binds to complexes that include Vps34, Vps15, Beclin-1 and ATG-14L PMID:19270696 the Beclin 1-hVps34 complex functions in two different steps of autophagy by altering the subunit composition PMID:14617358 The hVPS34/p150 complex colocalized with rab7 on late endosomes
GO:0005930 axoneme	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: axoneme is retained as non-core localization context, mostly from automated or by-similarity sources. 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. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Localizes also to discrete punctae along the ciliary axoneme file:human/PIK3R4/PIK3R4-uniprot.txt Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex
GO:0035032 phosphatidylinositol 3-kinase complex, class III	IEA GO_REF:0000120	ACCEPT	Summary: PIK3R4 is a core component of class III PI3K complexes. Reason: Accept as core complex membership. The generic class III PI3K complex row is supported by both PI3KC3-C1 and PI3KC3-C2 evidence. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex PMID:8999962 Recombinant p150 associated with PtdIns 3-kinase in vitro in a stable manner PMID:25490155 PI3KC3-C1 ... consists of the lipid kinase VPS34, the scaffolding protein VPS15, the tumor suppressor BECN1, and the autophagy-specific subunit ATG14 PMID:25490155 VPS15 organizes the complex and serves as a bridge between VPS34 and the ATG14:BECN1 subcomplex PMID:40442316 PI3KC3-C1 contains one copy each of the lipid kinase VPS34, the pseudokinase VPS15 and the regulatory subunits BECN1 and ATG14
GO:0042149 cellular response to glucose starvation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Cellular response to glucose starvation is supported as context for starvation-induced PI3KC3-C1 autophagy but is not the core function itself. 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. Supporting Evidence: PMID:24785657 specific member of Vps34 Complex I PMID:24849286 assembly of the specific Atg14L-Beclin 1-Vps34-Vps15 complex for autophagy induction PMID:40442316 All forms of canonical autophagy, bulk and selective, are initiated upon the recruitment and activation ... PI3KC3-C1
GO:0006622 protein targeting to lysosome	NAS PMID:16467569 Regulation of membrane traffic by phosphoinositide 3-kinases...	KEEP AS NON CORE	Summary: Protein targeting to lysosome is a broad non-core representation of conserved class III PI3K endolysosomal trafficking. 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. Supporting Evidence: PMID:8999962 Vps15p.Vps34p complex has been conserved from yeast to man PMID:16467569 class III PI 3-kinases mainly mediate receptor-independent trafficking events PMID:16467569 endocytic membrane traffic, phagosome maturation and autophagy
GO:0010506 regulation of autophagy	IDA PMID:16799551 Autophagic and tumour suppressor activity of a novel Beclin1...	MODIFY	Summary: regulation of autophagy captures autophagy regulation but the underlying evidence supports PIK3R4 participation in macroautophagy itself. 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 replacements: macroautophagy Supporting Evidence: PMID:10625637 overexpressing the p150 adaptor, stimulates macroautophagy PMID:10625637 specific class III PI3K antisense oligonucleotide greatly inhibited the rate of macroautophagy PMID:19270696 the Beclin 1-hVps34 complex functions in two different steps of autophagy by altering the subunit composition
GO:0016236 macroautophagy	NAS PMID:40442316 Structure and activation of the human autophagy-initiating U...	ACCEPT	Summary: Macroautophagy is a core process for PIK3R4 through the ATG14-containing PI3KC3-C1 complex. 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. Supporting Evidence: PMID:10625637 overexpressing the p150 adaptor, stimulates macroautophagy PMID:10625637 specific class III PI3K antisense oligonucleotide greatly inhibited the rate of macroautophagy PMID:25490155 PI3KC3-C1 ... consists of the lipid kinase VPS34, the scaffolding protein VPS15, the tumor suppressor BECN1, and the autophagy-specific subunit ATG14 PMID:40442316 All forms of canonical autophagy, bulk and selective, are initiated upon the recruitment and activation ... PI3KC3-C1 PMID:24849286 assembly of the specific Atg14L-Beclin 1-Vps34-Vps15 complex for autophagy induction
GO:0016241 regulation of macroautophagy	IDA PMID:10625637 Distinct classes of phosphatidylinositol 3'-kinases are invo...	MODIFY	Summary: regulation of macroautophagy captures autophagy regulation but the underlying evidence supports PIK3R4 participation in macroautophagy itself. 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 replacements: macroautophagy Supporting Evidence: PMID:10625637 overexpressing the p150 adaptor, stimulates macroautophagy PMID:10625637 specific class III PI3K antisense oligonucleotide greatly inhibited the rate of macroautophagy PMID:19270696 the Beclin 1-hVps34 complex functions in two different steps of autophagy by altering the subunit composition
GO:0035032 phosphatidylinositol 3-kinase complex, class III	IPI PMID:25490155 Architecture and dynamics of the autophagic phosphatidylinos...	ACCEPT	Summary: PIK3R4 is a core component of class III PI3K complexes. Reason: Accept as core complex membership. The generic class III PI3K complex row is supported by both PI3KC3-C1 and PI3KC3-C2 evidence. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex PMID:8999962 Recombinant p150 associated with PtdIns 3-kinase in vitro in a stable manner PMID:25490155 PI3KC3-C1 ... consists of the lipid kinase VPS34, the scaffolding protein VPS15, the tumor suppressor BECN1, and the autophagy-specific subunit ATG14 PMID:25490155 VPS15 organizes the complex and serves as a bridge between VPS34 and the ATG14:BECN1 subcomplex PMID:40442316 PI3KC3-C1 contains one copy each of the lipid kinase VPS34, the pseudokinase VPS15 and the regulatory subunits BECN1 and ATG14
GO:0035032 phosphatidylinositol 3-kinase complex, class III	IPI PMID:40442316 Structure and activation of the human autophagy-initiating U...	ACCEPT	Summary: PIK3R4 is a core component of class III PI3K complexes. Reason: Accept as core complex membership. The generic class III PI3K complex row is supported by both PI3KC3-C1 and PI3KC3-C2 evidence. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex PMID:8999962 Recombinant p150 associated with PtdIns 3-kinase in vitro in a stable manner PMID:25490155 PI3KC3-C1 ... consists of the lipid kinase VPS34, the scaffolding protein VPS15, the tumor suppressor BECN1, and the autophagy-specific subunit ATG14 PMID:25490155 VPS15 organizes the complex and serves as a bridge between VPS34 and the ATG14:BECN1 subcomplex PMID:40442316 PI3KC3-C1 contains one copy each of the lipid kinase VPS34, the pseudokinase VPS15 and the regulatory subunits BECN1 and ATG14
GO:0036092 phosphatidylinositol-3-phosphate biosynthetic process	IDA PMID:8999962 Characterization of p150, an adaptor protein for the human p...	ACCEPT	Summary: PIK3R4 participates in PI3P biosynthesis as the regulatory/scaffold subunit required for PIK3C3/VPS34 complex activity. 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. Supporting Evidence: PMID:8999962 Recombinant p150 associated with PtdIns 3-kinase in vitro in a stable manner PMID:8999962 resulting in a 2-fold increase in lipid kinase activity Reactome:R-HSA-5672012 PIK3C3 ... phosphorylates phosphatidylinositol (PI) producing phosphatidylinositol 3-phosphate (PI3P) Reactome:R-HSA-6798174 PIK3R4, Vps150, necessary for catalytic activity, localization and stability
GO:0045022 early endosome to late endosome transport	IDA PMID:14617358 Human VPS34 and p150 are Rab7 interacting partners.	ACCEPT	Summary: PIK3R4-containing hVPS34/p150 complexes participate in Rab7-linked early-to-late endosomal PI3K cycling. 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. Supporting Evidence: PMID:14617358 The hVPS34/p150 complex colocalized with rab7 on late endosomes PMID:14617358 link rab7 to the regulation of phosphatidylinositol 3'-kinase cycling between early and late endosomes file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex II localized predominantly to endosomes
GO:0097352 autophagosome maturation	IDA PMID:10625637 Distinct classes of phosphatidylinositol 3'-kinases are invo...	ACCEPT	Summary: Autophagosome maturation is supported for the UVRAG/Rubicon-containing PI3KC3-C2 branch. 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. Supporting Evidence: PMID:19270696 the Beclin 1-hVps34 complex functions in two different steps of autophagy by altering the subunit composition PMID:19270696 Knockdown of Rubicon caused enhancement of autophagy, especially at the maturation step PMID:21062745 Rubicon serves as a negative regulator of PI3KC3 and autophagosome maturation
GO:0043491 phosphatidylinositol 3-kinase/protein kinase B signal transduction	IDA PMID:21062745 The RUN domain of rubicon is important for hVps34 binding, l...	MODIFY	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. Reason: Modify to autophagosome maturation. PMID:21062745 concerns Rubicon inhibition of hVps34/PI3KC3 and autophagosome maturation, not protein kinase B/AKT signal transduction. Proposed replacements: autophagosome maturation Supporting Evidence: PMID:21062745 Rubicon serves as a negative regulator of PI3KC3 and autophagosome maturation PMID:19270696 the Beclin 1-hVps34 complex functions in two different steps of autophagy by altering the subunit composition
GO:0030670 phagocytic vesicle membrane	TAS Reactome:R-HSA-6798174	KEEP AS NON CORE	Summary: Phagocytic vesicle membrane is plausible PI3P/PIK3C3 complex context but is not a core PIK3R4 function in this review. 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. Supporting Evidence: Reactome:R-HSA-6798174 PIK3R4, Vps150, necessary for catalytic activity, localization and stability PMID:16467569 endocytic membrane traffic, phagosome maturation and autophagy
GO:0032465 regulation of cytokinesis	IMP PMID:20643123 A phosphatidylinositol 3-kinase class III sub-complex contai...	KEEP AS NON CORE	Summary: Regulation of cytokinesis is directly supported for a UVRAG/BIF-1-containing PI3KC3 subcomplex but is secondary to PIK3R4 core autophagy/endosomal trafficking. 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. Supporting Evidence: PMID:20643123 a specific sub-complex containing VPS15, VPS34, Beclin 1, UVRAG and BIF-1 regulates both receptor degradation and cytokinesis PMID:20643123 ATG14L, a PI3K-III subunit involved in autophagy, is not required
GO:0032801 receptor catabolic process	IMP PMID:20643123 A phosphatidylinositol 3-kinase class III sub-complex contai...	ACCEPT	Summary: Receptor catabolic process is supported for the UVRAG/BIF-1-containing PI3KC3-C2/endocytic branch. Reason: Accept as supported secondary core process. The VPS15/VPS34/BECN1/UVRAG/BIF-1 subcomplex regulates receptor degradation and degradative endocytic traffic. Supporting Evidence: PMID:20643123 a specific sub-complex containing VPS15, VPS34, Beclin 1, UVRAG and BIF-1 regulates both receptor degradation and cytokinesis PMID:20643123 ATG14L, a PI3K-III subunit involved in autophagy, is not required
GO:0035032 phosphatidylinositol 3-kinase complex, class III	ISS GO_REF:0000024	ACCEPT	Summary: PIK3R4 is a core component of class III PI3K complexes. Reason: Accept as core complex membership. The generic class III PI3K complex row is supported by both PI3KC3-C1 and PI3KC3-C2 evidence. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex PMID:8999962 Recombinant p150 associated with PtdIns 3-kinase in vitro in a stable manner PMID:25490155 PI3KC3-C1 ... consists of the lipid kinase VPS34, the scaffolding protein VPS15, the tumor suppressor BECN1, and the autophagy-specific subunit ATG14 PMID:25490155 VPS15 organizes the complex and serves as a bridge between VPS34 and the ATG14:BECN1 subcomplex PMID:40442316 PI3KC3-C1 contains one copy each of the lipid kinase VPS34, the pseudokinase VPS15 and the regulatory subunits BECN1 and ATG14
GO:0042149 cellular response to glucose starvation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Cellular response to glucose starvation is supported as context for starvation-induced PI3KC3-C1 autophagy but is not the core function itself. 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. Supporting Evidence: PMID:24785657 specific member of Vps34 Complex I PMID:24849286 assembly of the specific Atg14L-Beclin 1-Vps34-Vps15 complex for autophagy induction PMID:40442316 All forms of canonical autophagy, bulk and selective, are initiated upon the recruitment and activation ... PI3KC3-C1
GO:0005829 cytosol	TAS Reactome:R-HSA-109699	ACCEPT	Summary: cytosol is a supported broad location for PIK3R4-containing PI3KC3 complexes. 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. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex I localized to pre-autophagosome structures file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex II localized predominantly to endosomes file:human/PIK3R4/PIK3R4-uniprot.txt Membrane; Lipid-anchor
GO:0005829 cytosol	TAS Reactome:R-HSA-1632857	ACCEPT	Summary: cytosol is a supported broad location for PIK3R4-containing PI3KC3 complexes. 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. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex I localized to pre-autophagosome structures file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex II localized predominantly to endosomes file:human/PIK3R4/PIK3R4-uniprot.txt Membrane; Lipid-anchor
GO:0005829 cytosol	TAS Reactome:R-HSA-1675939	ACCEPT	Summary: cytosol is a supported broad location for PIK3R4-containing PI3KC3 complexes. 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. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex I localized to pre-autophagosome structures file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex II localized predominantly to endosomes file:human/PIK3R4/PIK3R4-uniprot.txt Membrane; Lipid-anchor
GO:0005829 cytosol	TAS Reactome:R-HSA-1675961	ACCEPT	Summary: cytosol is a supported broad location for PIK3R4-containing PI3KC3 complexes. 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. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex I localized to pre-autophagosome structures file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex II localized predominantly to endosomes file:human/PIK3R4/PIK3R4-uniprot.txt Membrane; Lipid-anchor
GO:0005829 cytosol	TAS Reactome:R-HSA-1676024	ACCEPT	Summary: cytosol is a supported broad location for PIK3R4-containing PI3KC3 complexes. 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. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex I localized to pre-autophagosome structures file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex II localized predominantly to endosomes file:human/PIK3R4/PIK3R4-uniprot.txt Membrane; Lipid-anchor
GO:0005829 cytosol	TAS Reactome:R-HSA-188002	ACCEPT	Summary: cytosol is a supported broad location for PIK3R4-containing PI3KC3 complexes. 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. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex I localized to pre-autophagosome structures file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex II localized predominantly to endosomes file:human/PIK3R4/PIK3R4-uniprot.txt Membrane; Lipid-anchor
GO:0005829 cytosol	TAS Reactome:R-HSA-5672012	ACCEPT	Summary: cytosol is a supported broad location for PIK3R4-containing PI3KC3 complexes. 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. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex I localized to pre-autophagosome structures file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex II localized predominantly to endosomes file:human/PIK3R4/PIK3R4-uniprot.txt Membrane; Lipid-anchor
GO:0005829 cytosol	TAS Reactome:R-HSA-5678313	ACCEPT	Summary: cytosol is a supported broad location for PIK3R4-containing PI3KC3 complexes. 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. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex I localized to pre-autophagosome structures file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex II localized predominantly to endosomes file:human/PIK3R4/PIK3R4-uniprot.txt Membrane; Lipid-anchor
GO:0005829 cytosol	TAS Reactome:R-HSA-5678315	ACCEPT	Summary: cytosol is a supported broad location for PIK3R4-containing PI3KC3 complexes. 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. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex I localized to pre-autophagosome structures file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex II localized predominantly to endosomes file:human/PIK3R4/PIK3R4-uniprot.txt Membrane; Lipid-anchor
GO:0005829 cytosol	TAS Reactome:R-HSA-5679205	ACCEPT	Summary: cytosol is a supported broad location for PIK3R4-containing PI3KC3 complexes. 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. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex I localized to pre-autophagosome structures file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex II localized predominantly to endosomes file:human/PIK3R4/PIK3R4-uniprot.txt Membrane; Lipid-anchor
GO:0005829 cytosol	TAS Reactome:R-HSA-5679266	ACCEPT	Summary: cytosol is a supported broad location for PIK3R4-containing PI3KC3 complexes. 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. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex I localized to pre-autophagosome structures file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex II localized predominantly to endosomes file:human/PIK3R4/PIK3R4-uniprot.txt Membrane; Lipid-anchor
GO:0005829 cytosol	TAS Reactome:R-HSA-5682385	ACCEPT	Summary: cytosol is a supported broad location for PIK3R4-containing PI3KC3 complexes. 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. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex I localized to pre-autophagosome structures file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex II localized predominantly to endosomes file:human/PIK3R4/PIK3R4-uniprot.txt Membrane; Lipid-anchor
GO:0005829 cytosol	TAS Reactome:R-HSA-9755359	ACCEPT	Summary: cytosol is a supported broad location for PIK3R4-containing PI3KC3 complexes. 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. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex I localized to pre-autophagosome structures file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex II localized predominantly to endosomes file:human/PIK3R4/PIK3R4-uniprot.txt Membrane; Lipid-anchor
GO:0005829 cytosol	TAS Reactome:R-HSA-9921171	ACCEPT	Summary: cytosol is a supported broad location for PIK3R4-containing PI3KC3 complexes. 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. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex I localized to pre-autophagosome structures file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex II localized predominantly to endosomes file:human/PIK3R4/PIK3R4-uniprot.txt Membrane; Lipid-anchor
GO:0005515 protein binding	IPI PMID:23878393 Role of membrane association and Atg14-dependent phosphoryla...	MARK AS OVER ANNOTATED	Summary: Generic protein binding is not an informative molecular-function annotation for PIK3R4. 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. Supporting Evidence: PMID:24785657 NRBF2 directly interacts with Vps15 PMID:24785657 NRBF2 binds to complexes that include Vps34, Vps15, Beclin-1 and ATG-14L PMID:19270696 the Beclin 1-hVps34 complex functions in two different steps of autophagy by altering the subunit composition PMID:14617358 The hVPS34/p150 complex colocalized with rab7 on late endosomes
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	ACCEPT	Summary: membrane is a supported broad location for PIK3R4-containing PI3KC3 complexes. 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. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex I localized to pre-autophagosome structures file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex II localized predominantly to endosomes file:human/PIK3R4/PIK3R4-uniprot.txt Membrane; Lipid-anchor
GO:0005930 axoneme	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: axoneme is retained as non-core localization context, mostly from automated or by-similarity sources. 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. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Localizes also to discrete punctae along the ciliary axoneme file:human/PIK3R4/PIK3R4-uniprot.txt Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex
GO:0005515 protein binding	IPI PMID:19270696 Two Beclin 1-binding proteins, Atg14L and Rubicon, reciproca...	MARK AS OVER ANNOTATED	Summary: Generic protein binding is not an informative molecular-function annotation for PIK3R4. 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. Supporting Evidence: PMID:24785657 NRBF2 directly interacts with Vps15 PMID:24785657 NRBF2 binds to complexes that include Vps34, Vps15, Beclin-1 and ATG-14L PMID:19270696 the Beclin 1-hVps34 complex functions in two different steps of autophagy by altering the subunit composition PMID:14617358 The hVPS34/p150 complex colocalized with rab7 on late endosomes
GO:0005515 protein binding	IPI PMID:14617358 Human VPS34 and p150 are Rab7 interacting partners.	MARK AS OVER ANNOTATED	Summary: Generic protein binding is not an informative molecular-function annotation for PIK3R4. 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. Supporting Evidence: PMID:24785657 NRBF2 directly interacts with Vps15 PMID:24785657 NRBF2 binds to complexes that include Vps34, Vps15, Beclin-1 and ATG-14L PMID:19270696 the Beclin 1-hVps34 complex functions in two different steps of autophagy by altering the subunit composition PMID:14617358 The hVPS34/p150 complex colocalized with rab7 on late endosomes
GO:0005770 late endosome	IDA PMID:14617358 Human VPS34 and p150 are Rab7 interacting partners.	ACCEPT	Summary: Late-endosome localization/activity context is supported for PIK3R4-containing PI3KC3-C2/endosomal trafficking complexes. 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. Supporting Evidence: PMID:14617358 The hVPS34/p150 complex colocalized with rab7 on late endosomes PMID:14617358 link rab7 to the regulation of phosphatidylinositol 3'-kinase cycling between early and late endosomes file:human/PIK3R4/PIK3R4-uniprot.txt As component of the PI3K complex II localized predominantly to endosomes
GO:0004672 protein kinase activity	NAS PMID:8999962 Characterization of p150, an adaptor protein for the human p...	KEEP AS NON CORE	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. 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. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Probably autophosphorylated PMID:40442316 PI3KC3-C1 contains one copy each of the lipid kinase VPS34, the pseudokinase VPS15 and the regulatory subunits BECN1 and ATG14 PMID:8999962 Recombinant p150 associated with PtdIns 3-kinase in vitro in a stable manner PMID:8999962 resulting in a 2-fold increase in lipid kinase activity
GO:0006468 protein phosphorylation	NAS PMID:8999962 Characterization of p150, an adaptor protein for the human p...	KEEP AS NON CORE	Summary: Protein phosphorylation is retained only as a non-core process linked to curated PIK3R4 kinase/autophosphorylation biology. Reason: Keep as non-core. UniProt supports probable autophosphorylation, but the central gene function is scaffolding/regulation of class III PI3K lipid kinase complexes. Supporting Evidence: file:human/PIK3R4/PIK3R4-uniprot.txt Probably autophosphorylated PMID:40442316 PI3KC3-C1 contains one copy each of the lipid kinase VPS34, the pseudokinase VPS15 and the regulatory subunits BECN1 and ATG14
GO:0000045 autophagosome assembly	IDA PMID:40442316 Structure and activation of the human autophagy-initiating U...	NEW	Summary: PIK3R4/VPS15 supports autophagosome assembly as part of ATG14-containing PI3KC3-C1. 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. Supporting Evidence: PMID:40442316 All forms of canonical autophagy, bulk and selective, are initiated upon the recruitment and activation ... PI3KC3-C1 PMID:25490155 PI3KC3-C1 ... consists of the lipid kinase VPS34, the scaffolding protein VPS15, the tumor suppressor BECN1, and the autophagy-specific subunit ATG14 PMID:25490155 VPS15 organizes the complex and serves as a bridge between VPS34 and the ATG14:BECN1 subcomplex Reactome:R-HSA-5672012 The Beclin-1 complex (ATG14:PIK3C3:PIK3R4:BECN1) is essential for autophagosome formation

Core Functions

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:

phosphatidylinositol-3-phosphate biosynthetic process autophagosome assembly macroautophagy

Cellular Locations:

cytosol membrane autophagosome

In Complex:

phosphatidylinositol 3-kinase complex, class III, type I

Supporting Evidence:

PMID:8999962
Recombinant p150 associated with PtdIns 3-kinase in vitro in a stable manner
PMID:8999962
resulting in a 2-fold increase in lipid kinase activity
PMID:25490155
PI3KC3-C1 ... consists of the lipid kinase VPS34, the scaffolding protein VPS15, the tumor suppressor BECN1, and the autophagy-specific subunit ATG14
PMID:25490155
VPS15 organizes the complex and serves as a bridge between VPS34 and the ATG14:BECN1 subcomplex
PMID:40442316
All forms of canonical autophagy, bulk and selective, are initiated upon the recruitment and activation ... PI3KC3-C1
Reactome:R-HSA-5672012
The Beclin-1 complex (ATG14:PIK3C3:PIK3R4:BECN1) is essential for autophagosome formation
Reactome:R-HSA-5672012
PIK3C3 ... phosphorylates phosphatidylinositol (PI) producing phosphatidylinositol 3-phosphate (PI3P)

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:

early endosome to late endosome transport autophagosome maturation receptor catabolic process

Cellular Locations:

late endosome cytosol membrane

In Complex:

phosphatidylinositol 3-kinase complex, class III, type II

Supporting Evidence:

PMID:14617358
The hVPS34/p150 complex colocalized with rab7 on late endosomes
PMID:14617358
link rab7 to the regulation of phosphatidylinositol 3'-kinase cycling between early and late endosomes
PMID:19270696
the Beclin 1-hVps34 complex functions in two different steps of autophagy by altering the subunit composition
PMID:20643123
a specific sub-complex containing VPS15, VPS34, Beclin 1, UVRAG and BIF-1 regulates both receptor degradation and cytokinesis
PMID:19270696
Knockdown of Rubicon caused enhancement of autophagy, especially at the maturation step

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

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

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

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

GO_REF:0000107

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

GO_REF:0000116

Automatic Gene Ontology annotation based on Rhea mapping

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10625637

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

PMID:14617358

Human VPS34 and p150 are Rab7 interacting partners.

PMID:16467569

Regulation of membrane traffic by phosphoinositide 3-kinases.

PMID:16799551

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

PMID:19270696

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

PMID:19946888

Defining the membrane proteome of NK cells.

PMID:20643123

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

PMID:21062745

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

PMID:23878393

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

PMID:24785657

NRBF2 regulates macroautophagy as a component of Vps34 Complex I.

PMID:24849286

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

PMID:25490155

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

PMID:28514442

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

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32707033

Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases.

PMID:33961781

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

PMID:40442316

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

PMID:8999962

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

Reactome:R-HSA-109699

PI3K-containing complexes phosphorylate PIP2 to PIP3

Reactome:R-HSA-1632857

ULK1 phosphorylates AMBRA1:BECN1 complex

Reactome:R-HSA-1675939

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

Reactome:R-HSA-1675961

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

Reactome:R-HSA-1676024

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

Reactome:R-HSA-188002

Rab5-mediated recruitment of class III PI3K to TLR9

Reactome:R-HSA-5672012

Beclin-1 complex phosphorylates PtdIns

Reactome:R-HSA-5678313

AMBRA1:DYNLL1,DYNLL2 binds BECN1 complex

Reactome:R-HSA-5678315

BECN1 complex, p-AMBRA1 dissociate from DYNLL1,DYNLL2

Reactome:R-HSA-5679205

ULK1 phosphorylates Beclin-1

Reactome:R-HSA-5679266

Beclin-1 complex translocates to the ER

Reactome:R-HSA-5682385

The phagophore extends from the PIP3-enriched structure

Reactome:R-HSA-6798174

PIK3C3:PIK3R4 phosphorylates PI to PI3P

Reactome:R-HSA-9755359

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

Reactome:R-HSA-9921171

NS1 binds Beclin-1

file:human/PIK3R4/PIK3R4-uniprot.txt

UniProtKB record for PIK3R4

file:human/PIK3R4/PIK3R4-notes.md

PIK3R4 review notes

Suggested Experiments

Experiment: 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.

Hypothesis: PIK3R4 supports autophagosome assembly primarily by organizing PI3KC3-C1 and enabling local VPS34-dependent PI3P production.

Type: PI3KC3-C1 autophagy initiation rescue assay

Experiment: 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.

Hypothesis: PIK3R4 has separable C1 and C2 roles, with C1 biased toward autophagy initiation and C2 biased toward endosomal trafficking and maturation.

Type: subcomplex-specific functional profiling

Experiment: 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.

Hypothesis: PIK3R4 kinase-domain chemistry, if present in cells, is secondary to its structural/scaffolding role in PI3KC3 complexes.

Type: kinase-domain separation-of-function assay

📚 Additional Documentation

Notes

(PIK3R4-notes.md)

PIK3R4 review notes

Review started from just fetch-gene human PIK3R4. The proteostasis network places PIK3R4 under Autophagy-Lysosome Pathway > Autophagophore initiation and elongation > Class 3 PI3K complex 1, direct > Class 3 PI3K complex 1 component.

Falcon deep research was requested with just deep-research-falcon human PIK3R4, but the provider timed out after 600 seconds and no PIK3R4-deep-research-falcon.md file was produced. I am completing the review using the cached primary literature, UniProt record, GOA seed, Reactome context, and notes below.

PIK3R4/VPS15/p150 is the regulatory/scaffolding subunit of class III PI3K complexes with PIK3C3/VPS34 and BECN1. The original human p150 paper showed that p150 is homologous to yeast Vps15p, stably associates with PtdIns 3-kinase, increases lipid kinase activity, and conserves the Vps15p/Vps34p protein-trafficking complex from yeast to human [PMID:8999962 "Recombinant p150 associated with PtdIns 3-kinase in vitro in a stable manner" and "Vps15p.Vps34p complex has been conserved from yeast to man"].

The PN leaf is the ATG14-containing PI3KC3-C1/autophagy-initiation branch. PI3KC3-C1 consists of VPS34, VPS15, BECN1, and ATG14; VPS15 organizes the complex and bridges VPS34 to the ATG14:BECN1 subcomplex [PMID:25490155 "PI3KC3-C1 ... consists of the lipid kinase VPS34, the scaffolding protein VPS15, the tumor suppressor BECN1, and the autophagy-specific subunit ATG14" and "VPS15 organizes the complex and serves as a bridge"]. A recent structural paper places VPS15/PIK3R4 in the ULK1C:PI3KC3-C1 initiation supercomplex and states that canonical bulk and selective autophagy are initiated by PI3KC3-C1 recruitment/activation [PMID:40442316 "All forms of canonical autophagy, bulk and selective, are initiated upon the recruitment and activation ... PI3KC3-C1" and "PI3KC3-C1 contains one copy each of ... VPS15"].

PIK3R4 should be modeled as contributing to complex-level PI3P production, not as the catalytic phosphatidylinositol kinase. Reactome says the ATG14:PIK3C3:PIK3R4:BECN1 complex phosphorylates phosphatidylinositol to PI3P for autophagosome formation [Reactome:R-HSA-5672012 "The Beclin-1 complex (ATG14:PIK3C3:PIK3R4:BECN1) is essential for autophagosome formation" and "PIK3C3 ... phosphorylates phosphatidylinositol (PI) producing phosphatidylinositol 3-phosphate (PI3P)"]. Reactome also describes PIK3R4 as necessary for PIK3C3 catalytic activity, localization, and stability in PI3P-producing complexes [Reactome:R-HSA-6798174 "PIK3C3, Vps34 ... is found in intracellular membrane complexes with ... PIK3R4, Vps150, necessary for catalytic activity, localization and stability"].

The UVRAG-containing PI3KC3-C2 branch is also real but is secondary to this PN leaf. The Rab7 paper supports late-endosome localization and early/late endosomal PI3K cycling [PMID:14617358 "The hVPS34/p150 complex colocalized with rab7 on late endosomes" and "link rab7 to the regulation of phosphatidylinositol 3'-kinase cycling between early and late endosomes"]. The UVRAG/BIF-1 paper supports receptor degradation and cytokinesis through a VPS15/VPS34/BECN1/UVRAG/BIF-1 subcomplex, while ATG14L is not required for those C2-like functions [PMID:20643123 "a specific sub-complex containing VPS15, VPS34, Beclin 1, UVRAG and BIF-1 regulates both receptor degradation and cytokinesis" and "ATG14L ... is not required"].

Autophagy process rows are supportable at the macroautophagy/autophagosome-assembly level, but cargo-specific pexophagy is too specific for the accessible human PIK3R4 evidence. The class III PI3K macroautophagy paper showed that increasing PI3P by overexpressing p150 stimulates macroautophagy and class III PI3K antisense inhibits macroautophagy [PMID:10625637 "overexpressing the p150 adaptor, stimulates macroautophagy" and "specific class III PI3K antisense oligonucleotide greatly inhibited the rate of macroautophagy"]. NRBF2 studies further support the ATG14-linked Vps34/Vps15 complex in starvation-induced autophagy [PMID:24785657 "NRBF2 binds to complexes that include Vps34, Vps15, Beclin-1 and ATG-14L" and PMID:24849286 "assembly of the specific Atg14L-Beclin 1-Vps34-Vps15 complex for autophagy induction"].

PIK3R4 also carries protein kinase annotations. UniProt currently curates catalytic protein serine/threonine reactions, Mn(2+) cofactor, and probable autophosphorylation, but the recent structural literature describes VPS15 as a pseudokinase [file:human/PIK3R4/PIK3R4-uniprot.txt "Probably autophosphorylated" and PMID:40442316 "the pseudokinase VPS15"]. I am retaining the protein kinase/ATP-binding rows as non-core rather than making them the central functional claim.

Generic protein binding annotations are not useful molecular-function annotations here. NRBF2, ATG14, BECN1, UVRAG, RAB7A, and high-throughput interactome rows should be interpreted as PI3KC3 complex/subcomplex evidence or interaction context, not as a core generic binding function [PMID:19270696 "Atg14L and UVRAG bind to Beclin 1 in a mutually exclusive manner"; PMID:24785657 "NRBF2 directly interacts with Vps15"; PMID:14617358 "hVPS34 and its adaptor protein p150 are rab7 interacting partners"].

Curation stance:
- Core: PI3KC3-C1 and PI3KC3-C2 complex membership, contribution to complex-level 1-phosphatidylinositol-3-kinase activity/PI3P biosynthesis, autophagosome assembly and macroautophagy, autophagosome maturation/endosomal trafficking context, late endosome/autophagosome/membrane/cytosol localization.
- Modify: pexophagy to autophagosome assembly; vacuole terms to human lysosomal/endosomal equivalents; PI3K/AKT signaling to autophagosome maturation.
- Keep as non-core: protein kinase/ATP-binding/protein phosphorylation rows, cilium/axoneme/cytoskeleton context, glucose-starvation response, phagocytic vesicle membrane, cytokinesis.
- Remove: nucleus-vacuole junction as a yeast/vacuole-specific cellular component that does not map to human PIK3R4.
- Mark over-annotated: generic protein binding rows.

Description cleanup note

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

Moved out of the YAML description: the prior wording identified PI3KC3 complex regulation, not independent catalytic signaling, as the central PN function.

Pn Notes

(PIK3R4-pn-notes.md)

PIK3R4 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q99570
AIGR review status: COMPLETE
Review batch: proteostasis-pr-1217 (PR 1217)
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/PIK3R4/PIK3R4-ai-review.yaml
AIGR review HTML: present - genes/human/PIK3R4/PIK3R4-ai-review.html
Gene notes: present - genes/human/PIK3R4/PIK3R4-notes.md
GOA TSV: present - genes/human/PIK3R4/PIK3R4-goa.tsv
UniProt record: present - genes/human/PIK3R4/PIK3R4-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/PIK3R4.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/PIK3R4.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

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/core annotation action counts: ACCEPT: 33; KEEP_AS_NON_CORE: 16; MARK_AS_OVER_ANNOTATED: 9; MODIFY: 7; NEW: 1; REMOVE: 1

PN Consistency Summary

Consistency: Strong. Notes, review YAML, and PN all model PIK3R4/VPS15 as the regulatory/scaffolding subunit of class III PI3K complexes (PI3KC3-C1 and -C2), not the catalytic kinase. Review description and core_functions name both complexes explicitly. No contradictions.
PN story / NEW pressure: Already captured. PN asserts membership in both class III complexes; review ACCEPTs GO:0034271 and GO:0034272 (both already IBA in GOA — PN goa_status already_in_goa_exact). No NEW GO term needed. Verdict: already captured.
Evidence alignment: Partial overlap. PN cites review-style sources (Annual Review; Yang & Klionsky; PMID:19270696 Matsunaga Atg14L/Rubicon Nat Cell Biol). Review uses primary literature: PMID:8999962, 25490155, 40442316 (PI3KC3-C1 structure), 19270696, 20643123, 14617358. PMID:19270696 is shared. Review also flags VPS15 as a pseudokinase (PMID:40442316) and REMOVEs yeast nucleus-vacuole junction, MODIFYs pexophagy→autophagosome assembly — finer than PN.
Verdict: Consistent; PN complex membership fully captured by existing GOA + review ACCEPT. No new GO pressure; mapping grain correct. No edits required.

Full Consistency Review

UniProt: Q99570 · batch: proteostasis-pr-1217 · review status: COMPLETE
PN placement: ALP|Autophagophore initiation and elongation|Class 3 PI3K complex 1, direct|Class 3 PI3K complex 1 component (row 1) and ALP|Autophagosome closure maturation and lysosome fusion|Class 3 PI3K complex 2, direct|Class 3 PI3K complex 2 component (row 2) ; PN-node mapping: both type leaves mapped, ok_for_propagation_to_go → GO:0034271 (C1/type I) and GO:0034272 (C2/type II); group/class/branch ancestors all context_only/no_mapping.
Consistency: Strong. Notes, review YAML, and PN all model PIK3R4/VPS15 as the regulatory/scaffolding subunit of class III PI3K complexes (PI3KC3-C1 and -C2), not the catalytic kinase. Review description and core_functions name both complexes explicitly. No contradictions.
PN story / NEW pressure: Already captured. PN asserts membership in both class III complexes; review ACCEPTs GO:0034271 and GO:0034272 (both already IBA in GOA — PN goa_status already_in_goa_exact). No NEW GO term needed. Verdict: already captured.
Mapping strategy: Correct and unchanged by this gene. The two type-leaf mappings to GO:0034271/GO:0034272 are the right grain; ancestors (GO:0035032 class III PI3K complex; GO:0016236 macroautophagy) are correctly held as too_broad_to_propagate, consistent with the TRAPP-overpropagation precedent. PN-projected terms are neither broader nor narrower than the review — they coincide.
Evidence alignment: Partial overlap. PN cites review-style sources (Annual Review; Yang & Klionsky; PMID:19270696 Matsunaga Atg14L/Rubicon Nat Cell Biol). Review uses primary literature: PMID:8999962, 25490155, 40442316 (PI3KC3-C1 structure), 19270696, 20643123, 14617358. PMID:19270696 is shared. Review also flags VPS15 as a pseudokinase (PMID:40442316) and REMOVEs yeast nucleus-vacuole junction, MODIFYs pexophagy→autophagosome assembly — finer than PN.
Verdict: Consistent; PN complex membership fully captured by existing GOA + review ACCEPT. No new GO pressure; mapping grain correct. No edits required.

PN Dossier Context

review_batch: proteostasis-pr-1217
review_yaml: genes/human/PIK3R4/PIK3R4-ai-review.yaml
PN workbook rows: 2

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

UniProt: Q99570
In branches: ALP
Notes: Member of class III PI3K complex 1 that produces PI(3)P at the site of phagophore nucleation. Member of class III PI3K complex 2 that is involved in endosome and autophagosome maturation and recruits the HOPS complex for lysosome fusion
PN references (titles):
- Mammalian Autophagy: How Does It Work? | Annual Review of Biochemistry (annualreviews.org)
- Full article: Autophagy pathway: Cellular and molecular mechanisms (tandfonline.com)
- Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages | Nature Cell Biology
PN-node mapping records (path + ancestors):
- [type] Autophagy-Lysosome Pathway|Autophagophore initiation and elongation|Class 3 PI3K complex 1, direct|Class 3 PI3K complex 1 component
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0034271 phosphatidylinositol 3-kinase complex, class III, type I]
  rationale: This PN type is a curated component class for the direct autophagy- promoting class III PI3K complex 1. Propagation to the matching GO cellular-component term is appropriate, although the source is a component-role category rather than the complex term itself.
- [group] Autophagy-Lysosome Pathway|Autophagophore initiation and elongation|Class 3 PI3K complex 1, direct
  status=context_only scope=too_broad_to_propagate GO=[GO:0035032 phosphatidylinositol 3-kinase complex, class III]
  rationale: Reviewed as a class-III PI3K complex context or regulator bucket. This node is useful for curator interpretation, but it should not project cellular-component membership; only explicit complex-component leaves propagate to GO complex terms.
- [class] Autophagy-Lysosome Pathway|Autophagophore initiation and elongation
  status=context_only scope=too_broad_to_propagate GO=[GO:0016236 macroautophagy]
  rationale: This class is a real macroautophagy context, but its descendants include core factors, component buckets, upstream modulators, localization roles, and residual categories. Projecting generic macroautophagy from this ancestor creates TRAPP-like overpropagation, so candidate GO annotations must come from narrower curated nodes.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

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

UniProt: Q99570
In branches: ALP
Notes: Member of class III PI3K complex 1 that produces PI(3)P at the site of phagophore nucleation. Member of class III PI3K complex 2 that is involved in endosome and autophagosome maturation and recruits the HOPS complex for lysosome fusion
PN references (titles):
- Mammalian Autophagy: How Does It Work? | Annual Review of Biochemistry (annualreviews.org)
- Full article: Autophagy pathway: Cellular and molecular mechanisms (tandfonline.com)
- Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages | Nature Cell Biology
PN-node mapping records (path + ancestors):
- [type] Autophagy-Lysosome Pathway|Autophagosome closure maturation and lysosome fusion|Class 3 PI3K complex 2, direct|Class 3 PI3K complex 2 component
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0034272 phosphatidylinositol 3-kinase complex, class III, type II]
  rationale: This PN type denotes component membership in the direct class III PI3K complex 2 module used during autophagosome maturation and lysosome fusion. The corresponding GO complex term is the right propagation target.
- [group] Autophagy-Lysosome Pathway|Autophagosome closure maturation and lysosome fusion|Class 3 PI3K complex 2, direct
  status=context_only scope=too_broad_to_propagate GO=[GO:0035032 phosphatidylinositol 3-kinase complex, class III]
  rationale: Reviewed as a class-III PI3K complex context or regulator bucket. This node is useful for curator interpretation, but it should not project cellular-component membership; only explicit complex-component leaves propagate to GO complex terms.
- [class] Autophagy-Lysosome Pathway|Autophagosome closure maturation and lysosome fusion
  status=context_only scope=too_broad_to_propagate GO=[GO:0016236 macroautophagy]
  rationale: This class is a late macroautophagy context, but the subtree mixes docking, fusion, localization, membrane-composition, and unknown late-stage roles. The class-level relation is useful for display while propagation is restricted to narrower mechanism nodes.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

Projected GO annotations (2)

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

Note

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

📄 View Raw YAML

id: 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.

PIK3R4

Gene Description

Existing Annotations Review

Core Functions

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.

PIK3R4 is also part of UVRAG-containing class III PI3K complexes that regulate endosomal trafficking, receptor catabolism, and later autophagy/autophagosome maturation steps.

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Notes

PIK3R4 review notes

Description cleanup note

Pn Notes

PIK3R4 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

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

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

Projected GO annotations (2)

Note

📄 View Raw YAML