PIK3R4 encodes VPS15/p150, the regulatory scaffold of class III phosphatidylinositol 3-kinase complexes. Its GTP-binding pseudokinase domain and N-terminal myristate control membrane engagement and the conformation of the catalytic VPS34 subunit. VPS15 supports PI3P production in ATG14-containing complex I for autophagosome formation and in UVRAG-containing complex II for endosomal trafficking, receptor degradation and later autophagy-associated events. A cis-Golgi pool interacts with GM130 and contributes to IFT20-dependent trafficking toward the primary cilium.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000425 pexophagy | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: VPS15 contributes the conserved PI3KC3 execution complex to pexophagy. Reason: The VPS15-node PTN000426471 assertion is supported by yeast experiments. Full PMID:21121900 Fig. 4B directly tests VPS15 deletion alongside VPS30, ATG14 and VPS38, linking complex I to peroxisome degradation. Human VPS15 preserves complex organization and membrane-coupled VPS34 activation (PMID:39913640), providing the required cofactor/scaffold work. Retain the conditional inherited process without requiring cargo-recognition activity or an independent human experiment for each conserved context. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN000426471 · PTN000426471 SUPPORTS TRANSFER Direct yeast VPS15 loss blocks pexophagy in the tested complex-I-dependent route. Conserved human scaffold/allosteric function supports transfer; no loss or incompatible mechanism has been demonstrated. Supporting Evidence: file:human/PIK3C3/PIK3C3-PMID21121900-primary-check.md Loss of the first three blocks peroxisomal thiolase degradation; VPS38 deletion does not. PMID:39913640 GTP binding functions in concert with the N-myristate to dock PI3KC3-C1 onto membranes and orient and activate VPS34KD for PI3P production. |
| 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 | REMOVE | Summary: Human VPS15 has a GTP-binding regulatory pseudokinase domain rather than the asserted protein-kinase activity. Reason: PMID:39913640 combines human PI3KC3-C1 structures with HPLC and mass spectrometry: bound GTP is detected, ATP/ADP are not, and the phosphate geometry plus altered P-loop prevent transfer to an external protein phosphoacceptor. This is direct target-specific mechanistic evidence against the legacy catalytic inference, not a rejection because scaffolding is the better-known function. The demonstrated allosteric control of VPS34 is retained. Propagation Review Root cause: PROPAGATION BAD Failure modes: PSEUDO OR SUBACTIVITY LOSS Sources checked: PANTHER:PTN000426471 · PTN000426471 SUPPORTS SOURCE BUT NOT TARGET Actual PTHR17583 v19 root PTN000426471 is ancestral to exact Q99570 leaf PTN002497817, and its kinase IBD uses experimentally grounded yeast VPS15. No loss is present in the cached PAINT path. Independent human PMID:39913640 structural/nucleotide evidence argues against the retained catalytic assertion for this target; the phylogenetic review proposes a catalytic-function correction without denying conserved scaffolding or every possible noncatalytic process role. Supporting Evidence: PMID:39913640 This structure rules out that VPS15 is a GTP-dependent protein kinase. PMID:39913640 This directly confirmed that the dominant nucleotide present was GTP, with no detectable ATP or ADP. |
| 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 | ACCEPT | Summary: PIK3R4 contributes to protein delivery through the endolysosomal system. Reason: The class III PI3K complex organizes membrane traffic that delivers proteins for lysosomal degradation. PMID:20643123 directly implicates the VPS15-containing UVRAG complex in receptor degradation. GO vacuole is a broad eukaryotic compartment and includes the lytic vacuole/lysosome lineage, so human lysosomes do not create a taxon contradiction. This broad core trafficking claim does not imply that PIK3R4 is a cargo-recognition receptor. Supporting Evidence: PMID:20643123 a specific sub-complex containing VPS15, VPS34, Beclin 1, UVRAG and BIF-1 regulates both receptor degradation and cytokinesis |
| GO:0045324 late endosome to vacuole transport | IBA GO_REF:0000033 | ACCEPT | Summary: PIK3R4 supports late endosomal delivery toward the degradative vacuole/lysosome. Reason: The late-endosome-to-vacuole term is compatible with endolysosomal degradative traffic; vacuole is not restricted to yeast. Human VPS15 acts in the UVRAG complex controlling receptor degradation (PMID:20643123), while PMID:14617358 places VPS34/p150 on late endosomes. The previous early-to-late-endosome replacement changed the transport stage and did not correct a demonstrated biological error. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000426471 · PTN000426471 SUPPORTS TRANSFER The conserved late degradative trafficking role is consistent with human VPS15-containing endosomal complexes. Neither the word vacuole nor the target organism establishes a propagation failure. Supporting Evidence: PMID:20643123 a specific sub-complex containing VPS15, VPS34, Beclin 1, UVRAG and BIF-1 regulates both receptor degradation and cytokinesis PMID:14617358 The hVPS34/p150 complex colocalized with rab7 on late endosomes |
| GO:0071561 nucleus-vacuole junction | IBA GO_REF:0000033 | UNDECIDED | Summary: Focused adjudication confirms the yeast source but does not settle human contact-site localization. Reason: Actual PTHR17583 version19 topology places human Q99570 leaf PTN002497817 below the GO:0071561 IBD at root PTN000426471; no loss event was recovered on this path. Source PMID:23335340 observes a fraction of yeast Vps15-GFP near nuclear pores at NVJ edges. This grounds the ancestral inference, while conservation of the specific human contact remains unresolved. The focused report supplies no target loss or exclusion assay. Its assertion that humans lack vacuoles conflicts with GO:0005764 lysosome is_a GO:0000323 lytic vacuole; the yeast Vac8/Nvj1 example in GO:0071561 is not a universal scaffold requirement. Neither predominant endosomal localization nor absent PIK3C3 annotation refutes this inherited conditional site. Retain uncertainty after adjudication, without adding a NOT assertion. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN000426471 UNRESOLVED The real v19 root-to-Q99570 path and literal root IBD were inspected, not inferred from donor count. SGD:S000000301 has independent IDA PMID:23335340. The provider did not reconstruct the tree or demonstrate human loss; human contact-site conservation remains unresolved. Supporting Evidence: PMID:23335340 colocalization of a fraction of Vps15-GFP and Vps34-GFP with nuclear pores at nucleus-vacuole (NV) junctions in live cells. file:human/PIK3R4/PIK3R4-hypotheses/nucleus-vacuole-junction-and-nuclear-lysosomal-contacts/openscientist.md absence of a curated human NVJ annotation is not absolute proof that human class III PI3K never visits a nuclear-envelope contact site |
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | REMOVE | Summary: Human VPS15 has a GTP-binding regulatory pseudokinase domain rather than the asserted protein-kinase activity. Reason: PMID:39913640 combines human PI3KC3-C1 structures with HPLC and mass spectrometry: bound GTP is detected, ATP/ADP are not, and the phosphate geometry plus altered P-loop prevent transfer to an external protein phosphoacceptor. This is direct target-specific mechanistic evidence against the legacy catalytic inference, not a rejection because scaffolding is the better-known function. The demonstrated allosteric control of VPS34 is retained. Supporting Evidence: PMID:39913640 This structure rules out that VPS15 is a GTP-dependent protein kinase. PMID:39913640 This directly confirmed that the dominant nucleotide present was GTP, with no detectable ATP or ADP. |
| GO:0004674 protein serine/threonine kinase activity | IEA GO_REF:0000120 | REMOVE | Summary: Human VPS15 has a GTP-binding regulatory pseudokinase domain rather than the asserted protein-kinase activity. Reason: PMID:39913640 combines human PI3KC3-C1 structures with HPLC and mass spectrometry: bound GTP is detected, ATP/ADP are not, and the phosphate geometry plus altered P-loop prevent transfer to an external protein phosphoacceptor. This is direct target-specific mechanistic evidence against the legacy catalytic inference, not a rejection because scaffolding is the better-known function. The demonstrated allosteric control of VPS34 is retained. Supporting Evidence: PMID:39913640 This structure rules out that VPS15 is a GTP-dependent protein kinase. PMID:39913640 This directly confirmed that the dominant nucleotide present was GTP, with no detectable ATP or ADP. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | MODIFY | Summary: The VPS15 pseudokinase domain binds GTP. Reason: Human-complex cryo-EM, HPLC and mass spectrometry in PMID:39913640 directly identify GTP in the VPS15 nucleotide pocket, with no detectable ATP or ADP. Arg103 confers guanine specificity and couples nucleotide occupancy to myristate-dependent regulation of VPS34. Replace the legacy ATP-binding inference with the experimentally demonstrated nucleotide. Proposed replacements: GTP binding Supporting Evidence: PMID:39913640 VPS15PKD is an unusual pseudokinase that binds GTP instead of ATP. |
| 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: A conditional ciliary pool is supported by the directly localized mouse ortholog. Reason: Mouse donor Q8VD65 has IDA PMID:24089209: Fig3/Video1 place VPS15 on axonemes of serum-starved kidney epithelial cells. The negative human fibroblast result PMID:27882921 tests a different cell context and does not establish lineage-wide loss. Retain the ortholog-inferred location as noncore with that limitation. |
| GO:0005929 cilium | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: A conditional ciliary pool is supported by the directly localized mouse ortholog. Reason: Mouse donor Q8VD65 has IDA PMID:24089209: Fig3/Video1 place VPS15 on axonemes of serum-starved kidney epithelial cells. The negative human fibroblast result PMID:27882921 tests a different cell context and does not establish lineage-wide loss. Retain the ortholog-inferred location as noncore with that limitation. |
| 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 | ACCEPT | Summary: PIK3R4 supports late endosomal delivery toward the degradative vacuole/lysosome. Reason: The late-endosome-to-vacuole term is compatible with endolysosomal degradative traffic; vacuole is not restricted to yeast. Human VPS15 acts in the UVRAG complex controlling receptor degradation (PMID:20643123), while PMID:14617358 places VPS34/p150 on late endosomes. The previous early-to-late-endosome replacement changed the transport stage and did not correct a demonstrated biological error. Supporting Evidence: PMID:20643123 a specific sub-complex containing VPS15, VPS34, Beclin 1, UVRAG and BIF-1 regulates both receptor degradation and cytokinesis PMID:14617358 The hVPS34/p150 complex colocalized with rab7 on late endosomes |
| GO:0106310 protein serine kinase activity | IEA GO_REF:0000116 | REMOVE | Summary: Human VPS15 has a GTP-binding regulatory pseudokinase domain rather than the asserted protein-kinase activity. Reason: PMID:39913640 combines human PI3KC3-C1 structures with HPLC and mass spectrometry: bound GTP is detected, ATP/ADP are not, and the phosphate geometry plus altered P-loop prevent transfer to an external protein phosphoacceptor. This is direct target-specific mechanistic evidence against the legacy catalytic inference, not a rejection because scaffolding is the better-known function. The demonstrated allosteric control of VPS34 is retained. Supporting Evidence: PMID:39913640 This structure rules out that VPS15 is a GTP-dependent protein kinase. PMID:39913640 This directly confirmed that the dominant nucleotide present was GTP, with no detectable ATP or ADP. |
| GO:0005515 protein binding | IPI PMID:24785657 NRBF2 regulates macroautophagy as a component of Vps34 Compl... | REMOVE | Summary: The reported interaction is retained as evidence, but generic protein binding is uninformative. Reason: The cited interaction evidence can inform complex membership or a demonstrated regulatory/adaptor mechanism. Generic protein binding does not identify that function; removing this annotation does not reject the measured interaction or assign an untested mechanism to every interactor. 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... | REMOVE | Summary: The reported interaction is retained as evidence, but generic protein binding is uninformative. Reason: The cited interaction evidence can inform complex membership or a demonstrated regulatory/adaptor mechanism. Generic protein binding does not identify that function; removing this annotation does not reject the measured interaction or assign an untested mechanism to every interactor. 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... | REMOVE | Summary: The reported interaction is retained as evidence, but generic protein binding is uninformative. Reason: The cited interaction evidence can inform complex membership or a demonstrated regulatory/adaptor mechanism. Generic protein binding does not identify that function; removing this annotation does not reject the measured interaction or assign an untested mechanism to every interactor. 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. | REMOVE | Summary: The reported interaction is retained as evidence, but generic protein binding is uninformative. Reason: The cited interaction evidence can inform complex membership or a demonstrated regulatory/adaptor mechanism. Generic protein binding does not identify that function; removing this annotation does not reject the measured interaction or assign an untested mechanism to every interactor. 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... | REMOVE | Summary: The reported interaction is retained as evidence, but generic protein binding is uninformative. Reason: The cited interaction evidence can inform complex membership or a demonstrated regulatory/adaptor mechanism. Generic protein binding does not identify that function; removing this annotation does not reject the measured interaction or assign an untested mechanism to every interactor. 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... | REMOVE | Summary: The reported interaction is retained as evidence, but generic protein binding is uninformative. Reason: The cited interaction evidence can inform complex membership or a demonstrated regulatory/adaptor mechanism. Generic protein binding does not identify that function; removing this annotation does not reject the measured interaction or assign an untested mechanism to every interactor. 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: A conditional ciliary pool is supported by the directly localized mouse ortholog. Reason: Mouse donor Q8VD65 has IDA PMID:24089209: Fig3/Video1 place VPS15 on axonemes of serum-starved kidney epithelial cells. The negative human fibroblast result PMID:27882921 tests a different cell context and does not establish lineage-wide loss. Retain the ortholog-inferred location as noncore with that limitation. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q8VD65 SUPPORTS TRANSFER Exact donor IDA PMID:24089209 independently verified. Positive mouse kidney-cell imaging and negative human fibroblast imaging are not matched tissue/context experiments. |
| 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... | ACCEPT | Summary: PIK3R4 contributes to protein delivery through the endolysosomal system. Reason: The class III PI3K complex organizes membrane traffic that delivers proteins for lysosomal degradation. PMID:20643123 directly implicates the VPS15-containing UVRAG complex in receptor degradation. GO vacuole is a broad eukaryotic compartment and includes the lytic vacuole/lysosome lineage, so human lysosomes do not create a taxon contradiction. This broad core trafficking claim does not imply that PIK3R4 is a cargo-recognition receptor. Supporting Evidence: PMID:20643123 a specific sub-complex containing VPS15, VPS34, Beclin 1, UVRAG and BIF-1 regulates both receptor degradation and cytokinesis |
| GO:0010506 regulation of autophagy | IDA PMID:16799551 Autophagic and tumour suppressor activity of a novel Beclin1... | ACCEPT | Summary: PIK3R4 regulates autophagy through class III PI3K complex activation. Reason: A structural complex subunit can directly regulate a pathway. PMID:39913640 shows that the VPS15 nucleotide pocket and myristate control membrane docking and VPS34 activation, with combined mutations strongly reducing autophagic flux. Thus participation in autophagy does not displace the separately supported regulatory relationship. Supporting Evidence: PMID:39913640 GTP binding functions in concert with the N-myristate to dock PI3KC3-C1 onto membranes and orient and activate VPS34KD for PI3P production. |
| 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... | ACCEPT | Summary: PIK3R4 regulates autophagy through class III PI3K complex activation. Reason: A structural complex subunit can directly regulate a pathway. PMID:39913640 shows that the VPS15 nucleotide pocket and myristate control membrane docking and VPS34 activation, with combined mutations strongly reducing autophagic flux. Thus participation in autophagy does not displace the separately supported regulatory relationship. Supporting Evidence: PMID:39913640 GTP binding functions in concert with the N-myristate to dock PI3KC3-C1 onto membranes and orient and activate VPS34KD for PI3P production. |
| 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 source supports the PI3KC3 system producing PI3P, without establishing the AKT endpoint. Reason: Full PMID:21062745 identifies p150/VPS15 in the Rubicon-containing class III PI3K complex and assays VPS34 lipid kinase regulation. It does not present a p150-specific PDK1/AKT readout. Refine this source-specific annotation to the demonstrated PI3P-producing complex contribution, also established by PMID:8999962; this is not a claim that PIK3R4 can never influence AKT signaling. Proposed replacements: phosphatidylinositol-3-phosphate biosynthetic process Supporting Evidence: PMID:8999962 resulting in a 2-fold increase in lipid kinase activity |
| 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: The VPS15/VPS34/BECN1/UVRAG/BIF-1 subcomplex is implicated experimentally in cytokinesis (PMID:20643123). This contextual cellular role is retained alongside the central lipid-kinase regulatory and degradative-trafficking functions. 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... | REMOVE | Summary: The reported interaction is retained as evidence, but generic protein binding is uninformative. Reason: The cited interaction evidence can inform complex membership or a demonstrated regulatory/adaptor mechanism. Generic protein binding does not identify that function; removing this annotation does not reject the measured interaction or assign an untested mechanism to every interactor. 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: A conditional ciliary pool is supported by the directly localized mouse ortholog. Reason: Mouse donor Q8VD65 has IDA PMID:24089209: Fig3/Video1 place VPS15 on axonemes of serum-starved kidney epithelial cells. The negative human fibroblast result PMID:27882921 tests a different cell context and does not establish lineage-wide loss. Retain the ortholog-inferred location as noncore with that limitation. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q8VD65 SUPPORTS TRANSFER Exact donor IDA PMID:24089209 independently verified. Positive mouse kidney-cell imaging and negative human fibroblast imaging are not matched tissue/context experiments. Supporting Evidence: PMID:24089209 Vps15) localized as discrete puncta along the ciliary axoneme |
| GO:0005515 protein binding | IPI PMID:19270696 Two Beclin 1-binding proteins, Atg14L and Rubicon, reciproca... | REMOVE | Summary: The reported interaction is retained as evidence, but generic protein binding is uninformative. Reason: The cited interaction evidence can inform complex membership or a demonstrated regulatory/adaptor mechanism. Generic protein binding does not identify that function; removing this annotation does not reject the measured interaction or assign an untested mechanism to every interactor. 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. | REMOVE | Summary: The reported interaction is retained as evidence, but generic protein binding is uninformative. Reason: The cited interaction evidence can inform complex membership or a demonstrated regulatory/adaptor mechanism. Generic protein binding does not identify that function; removing this annotation does not reject the measured interaction or assign an untested mechanism to every interactor. 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... | REMOVE | Summary: Human VPS15 has a GTP-binding regulatory pseudokinase domain rather than the asserted protein-kinase activity. Reason: PMID:39913640 combines human PI3KC3-C1 structures with HPLC and mass spectrometry: bound GTP is detected, ATP/ADP are not, and the phosphate geometry plus altered P-loop prevent transfer to an external protein phosphoacceptor. This is direct target-specific mechanistic evidence against the legacy catalytic inference, not a rejection because scaffolding is the better-known function. The demonstrated allosteric control of VPS34 is retained. Supporting Evidence: PMID:39913640 This structure rules out that VPS15 is a GTP-dependent protein kinase. PMID:39913640 This directly confirmed that the dominant nucleotide present was GTP, with no detectable ATP or ADP. |
| GO:0006468 protein phosphorylation | NAS PMID:8999962 Characterization of p150, an adaptor protein for the human p... | UNDECIDED | Summary: The focused report leaves VPS15 contribution to protein phosphorylation unresolved. Reason: Full PMID:8999962 Table I establishes peptide/protein phosphorylation by an Sf9-produced affinity-purified GST-p150/VPS34 preparation; this is distinct from p150 being phosphorylated in Fig4 and from its stimulation of lipid kinase in Fig5. The catalyst and a required VPS15 structural contribution were not isolated. Full PMID:39913640 strongly disfavors intrinsic VPS15 phosphotransfer, while PMID:34121209 establishes VPS15 as a ULK substrate regulating VPS34 lipid output. Neither result excludes all noncatalytic participation in a protein-kinase reaction. Full PMID:40442316 supports physical FIP200/VPS15 contacts but does not show VPS15-specific phosphorylation activation; adding PI3KC3-C1 did not enhance the 2:2:2 fraction in matched solution assays. The focused report admits key full-text gaps, supplies no new subunit-resolved test, and its REMOVE/noncore alternatives are therefore not adopted automatically. Retain UNDECIDED after adjudication; a substrate-only observation is insufficient for involvement, but an active scaffold contribution could qualify if demonstrated. Supporting Evidence: PMID:39913640 This structure rules out that VPS15 is a GTP-dependent protein kinase. PMID:34121209 VPS15 is phosphorylated at six sites by ULK and mutation of these residues inhibits autophagy in cells and VPS34 lipid kinase activity in vitro. PMID:40442316 Addition of PI3KC3-C1 did not lead to a further enhancement of the 2:2:2-to-2:1:1 ratio in solution file:human/PIK3R4/PIK3R4-hypotheses/protein-phosphorylation-complex-contribution/openscientist.md Checked: abstract + seed description; unresolved. |
Loading supporting content…
Download this section (compressed HTML)Q: Does endogenous human VPS15 occupy nuclear-envelope/lysosome contact sites corresponding to the ancestral nucleus-vacuole junction assertion?
Q: Which selective-autophagy cargo contexts require VPS15-dependent PI3P production, including pexophagy, and which operate through alternative membrane-building routes?
Q: Which tissues or conditions support the inferred axonemal VPS15 pool, given its demonstrated cis-Golgi localization in human fibroblasts?
Q: Which protein catalyzes the historical GST-p150/VPS34 preparation protein-substrate reaction, and does disrupting VPS15 scaffold contacts while retaining VPS34 integrity selectively alter that reaction?
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
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)