INPP5E (inositol polyphosphate-5-phosphatase E, type IV 5-phosphatase) is a lipid phosphatase that removes the 5-phosphate from phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate, with the highest affinity for PI(3,4,5)P3 among the 5-phosphatases. It is C-terminally farnesylated and is carried to the primary cilium by the prenyl-binding protein PDE6D, with release mediated by ARL3 and ciliary retention supported by ARL13B. In the cilium INPP5E concentrates along the axoneme/ciliary membrane, where it converts PI(4,5)P2 to PI(4)P, keeping PI(4,5)P2 restricted to the ciliary base. This lipid identity limits ciliary entry of PI(4,5)P2-binding TULP3 and its cargo GPR161, permitting Hedgehog signalling, and dampens ciliary PI3K signalling to maintain stability of pre-formed cilia. A pool is also associated with Golgi membranes. Mutations that impair the phosphatase cause Joubert syndrome and MORM syndrome.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000139 Golgi membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Golgi membrane transferred from mouse Inpp5e. Reason: INPP5E is a peripheral protein of Golgi stacks (HPA main location is also Golgi), but its characterized function is in the ciliary membrane. Supporting Evidence: file:human/INPP5E/INPP5E-uniprot.txt Note=Peripheral membrane protein associated with Golgi stacks. |
| GO:0001726 ruffle | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Ruffle localization transferred from rat. Reason: Based on the rat ortholog only; not examined for human INPP5E and peripheral to its ciliary role. Supporting Evidence: file:human/INPP5E/INPP5E-uniprot.txt Cell projection, ruffle |
| GO:0004439 phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity | EXP PMID:10764818 The isolation and characterization of a cDNA encoding phosph... | ACCEPT | Summary: Cloned type IV 5-phosphatase hydrolyzes PI(4,5)P2. Reason: Direct enzymology with recombinant human enzyme; core catalytic activity. Supporting Evidence: PMID:10764818 This enzyme hydrolyzes only lipid substrates, phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 4,5-bisphosphate. |
| GO:0004439 phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity | EXP PMID:19668216 Mutations in INPP5E, encoding inositol polyphosphate-5-phosp... | ACCEPT | Summary: Joubert syndrome mutations impair INPP5E 5-phosphatase activity. Reason: Direct assay of wild-type and mutant enzyme; core activity. Supporting Evidence: PMID:19668216 Mutations clustered in the phosphatase domain and impaired 5-phosphatase activity, resulting in altered cellular PtdIns ratios. |
| GO:0004439 phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: PI(4,5)P2 5-phosphatase activity. Reason: Consistent with direct enzymology. Supporting Evidence: PMID:10764818 This enzyme hydrolyzes only lipid substrates, phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 4,5-bisphosphate. |
| GO:0004439 phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Rhea/EC-based annotation (EC 3.1.3.36). Reason: Consistent with direct enzymology. Supporting Evidence: PMID:10764818 This enzyme hydrolyzes only lipid substrates, phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 4,5-bisphosphate. |
| GO:0004439 phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity | TAS Reactome:R-HSA-1675824 | ACCEPT | Summary: Reactome: INPP5E hydrolyzes PI(4,5)P2. Reason: Consistent with direct enzymology. Supporting Evidence: PMID:10764818 This enzyme hydrolyzes only lipid substrates, phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 4,5-bisphosphate. |
| GO:0004445 inositol-polyphosphate 5-phosphatase activity | IEA GO_REF:0000120 | MODIFY | Summary: InterPro/ortholog mapping to inositol-polyphosphate 5-phosphatase activity. Reason: GO:0004445 is a compound grouping term for soluble inositol phosphate substrates. Human INPP5E was originally characterized as hydrolyzing only lipid substrates; the specific lipid activities are the informative terms. Proposed replacements: phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity Supporting Evidence: PMID:10764818 This enzyme hydrolyzes only lipid substrates, phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 4,5-bisphosphate. |
| GO:0004445 inositol-polyphosphate 5-phosphatase activity | TAS PMID:10764818 The isolation and characterization of a cDNA encoding phosph... | MODIFY | Summary: TAS from the cloning paper. Reason: The cited paper explicitly distinguishes INPP5E from family members that hydrolyze soluble inositol phosphates; it supports the lipid-specific 5-phosphatase activities instead. Proposed replacements: phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity Supporting Evidence: PMID:10764818 This enzyme hydrolyzes only lipid substrates, phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 4,5-bisphosphate. PMID:10764818 All previously described members hydrolyze water soluble inositol phosphates. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: Interaction with 14-3-3 eta (YWHAH) from BioPlex. Reason: Generic protein binding from interactome/14-3-3 screens is uninformative; no specific, functionally characterized activity of INPP5E toward YWHAH can be assigned from these data. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Interaction with YWHAH from a proteome-scale network. Reason: Generic protein binding from interactome/14-3-3 screens is uninformative; no specific, functionally characterized activity of INPP5E toward YWHAH can be assigned from these data. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | REMOVE | Summary: Interaction with YWHAH from OpenCell. Reason: Generic protein binding from interactome/14-3-3 screens is uninformative; no specific, functionally characterized activity of INPP5E toward YWHAH can be assigned from these data. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c... | REMOVE | Summary: Interaction with YWHAH from a 14-3-3 interactome study. Reason: Generic protein binding from interactome/14-3-3 screens is uninformative; no specific, functionally characterized activity of INPP5E toward YWHAH can be assigned from these data. Removal does not imply the interaction is false. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA: nucleus. Reason: Nuclear localization rests on mouse data (UniProt "by similarity"); there is no evidence that INPP5E acts in the nucleus in human cells. Retained as non-core pending direct data. Supporting Evidence: file:human/INPP5E/INPP5E-uniprot.txt Nucleus {ECO:0000250|UniProtKB:Q9JII1}. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic nucleus annotation from mouse. Reason: As for the IBA nucleus row. Supporting Evidence: file:human/INPP5E/INPP5E-uniprot.txt Nucleus {ECO:0000250|UniProtKB:Q9JII1}. |
| GO:0005634 nucleus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS nucleus from mouse. Reason: As for the IBA nucleus row. Supporting Evidence: file:human/INPP5E/INPP5E-uniprot.txt Nucleus {ECO:0000250|UniProtKB:Q9JII1}. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Cytoplasm (UniProt subcellular location). Reason: Correct broad location for a peripheral membrane protein. Supporting Evidence: file:human/INPP5E/INPP5E-uniprot.txt Note=Peripheral membrane protein associated with Golgi stacks. |
| GO:0005794 Golgi apparatus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA: Golgi apparatus. Reason: Golgi pool is documented but secondary to the ciliary role. Supporting Evidence: file:human/INPP5E/INPP5E-uniprot.txt Note=Peripheral membrane protein associated with Golgi stacks. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1675824 | KEEP AS NON CORE | Summary: Reactome PI metabolism: cytosol. Reason: INPP5E acts on membrane lipids as a peripheral membrane protein; a soluble cytosolic pool (e.g., PDE6D-bound in transit) is plausible but not its site of action. Supporting Evidence: PMID:24166846 Altogether, these results indicate that PDE6D is required for INPP5E ciliary targeting and suggest a broader role for PDE6D in targeting other prenylated proteins to the cilia. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5624954 | KEEP AS NON CORE | Summary: Reactome ciliary targeting: cytosol. Reason: Transit pool bound to PDE6D before ciliary release. Supporting Evidence: PMID:24166846 Altogether, these results indicate that PDE6D is required for INPP5E ciliary targeting and suggest a broader role for PDE6D in targeting other prenylated proteins to the cilia. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5624956 | KEEP AS NON CORE | Summary: Reactome ciliary targeting: cytosol. Reason: Transit pool bound to PDE6D before ciliary release. Supporting Evidence: PMID:24166846 Altogether, these results indicate that PDE6D is required for INPP5E ciliary targeting and suggest a broader role for PDE6D in targeting other prenylated proteins to the cilia. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Plasma membrane (UniProt, by similarity to rat). Reason: The ciliary membrane is a specialized domain of the plasma membrane where INPP5E acts. Supporting Evidence: PMID:26305592 Thus, Inpp5e limits ciliary PI(4,5)P2 and generates ciliary PI(4)P, consistent with a role in converting PI(4,5)P2 to PI(4)P within cilia. |
| GO:0005929 cilium | IEA GO_REF:0000107 | ACCEPT | Summary: Cilium, transferred from mouse. Reason: Supported by direct ciliary localization of human INPP5E. Supporting Evidence: PMID:19668216 INPP5E localized to cilia in major organs affected by Joubert syndrome, and mutations promoted premature destabilization of cilia in response to stimulation. |
| GO:0005929 cilium | TAS Reactome:R-HSA-5624953 | ACCEPT | Summary: Reactome: INPP5E in cilium. Reason: Supported by direct localization. Supporting Evidence: PMID:19668216 INPP5E localized to cilia in major organs affected by Joubert syndrome, and mutations promoted premature destabilization of cilia in response to stimulation. |
| GO:0005929 cilium | TAS Reactome:R-HSA-5624954 | ACCEPT | Summary: Reactome: ARL3-mediated release of INPP5E in cilium. Reason: Supported by direct localization. Supporting Evidence: PMID:24166846 Altogether, these results indicate that PDE6D is required for INPP5E ciliary targeting and suggest a broader role for PDE6D in targeting other prenylated proteins to the cilia. |
| GO:0005929 cilium | TAS Reactome:R-HSA-5638012 | ACCEPT | Summary: Reactome: INPP5E in cilium. Reason: Supported by direct localization. Supporting Evidence: PMID:19668216 INPP5E localized to cilia in major organs affected by Joubert syndrome, and mutations promoted premature destabilization of cilia in response to stimulation. |
| GO:0005930 axoneme | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: axoneme. Reason: Consistent with direct axonemal localization. Supporting Evidence: PMID:19668215 In ciliated mouse embryonic fibroblasts, Inpp5e is concentrated in the axoneme of the primary cilium. |
| GO:0005930 axoneme | IDA PMID:19668215 INPP5E mutations cause primary cilium signaling defects, cil... | ACCEPT | Summary: Inpp5e concentrated in the primary cilium axoneme. Reason: Direct localization (abstract-only cache; consistent with UniProt and later work). INPP5E acts on the ciliary membrane overlying the axoneme; ciliary membrane (GO:0060170) is used in core_functions as the site of activity. Supporting Evidence: PMID:19668215 In ciliated mouse embryonic fibroblasts, Inpp5e is concentrated in the axoneme of the primary cilium. |
| GO:0005930 axoneme | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic axoneme annotation. Reason: Consistent with direct localization. Supporting Evidence: PMID:19668215 In ciliated mouse embryonic fibroblasts, Inpp5e is concentrated in the axoneme of the primary cilium. |
| GO:0006661 phosphatidylinositol biosynthetic process | TAS Reactome:R-HSA-1660514 | MODIFY | Summary: Reactome: phosphatidylinositol biosynthetic process. Reason: INPP5E removes a 5-phosphate from phosphoinositides; it does not synthesize phosphatidylinositol itself. The appropriate process is phosphatidylinositol dephosphorylation. Proposed replacements: phosphatidylinositol dephosphorylation Supporting Evidence: PMID:26305592 Thus, Inpp5e limits ciliary PI(4,5)P2 and generates ciliary PI(4)P, consistent with a role in converting PI(4,5)P2 to PI(4)P within cilia. |
| GO:0016314 phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity | IEA GO_REF:0000107 | REMOVE | Summary: PI(3,4,5)P3 3-phosphatase activity transferred from rat. Reason: INPP5E is a 5-phosphatase that converts PI(3,4,5)P3 to PI(3,4)P2; there is no evidence it removes the 3-phosphate (the PTEN reaction). This electronic transfer is inconsistent with the enzyme specificity. Supporting Evidence: PMID:10764818 This enzyme hydrolyzes only lipid substrates, phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 4,5-bisphosphate. |
| GO:0016791 phosphatase activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro: phosphatase activity. Reason: Correct but general. Supporting Evidence: PMID:10764818 This enzyme hydrolyzes only lipid substrates, phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 4,5-bisphosphate. |
| GO:0017148 negative regulation of translation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Negative regulation of translation (IEA), transferred from rat Inpp5e (pharbin), whose over-expression reduces IGF-1-stimulated protein synthesis by dampening PI3K/Akt signalling (PMID:21436142). Reason: The row is transferred from rat Inpp5e (pharbin), annotated by direct assay in a study showing that pharbin expression suppresses IGF-1-induced Akt activation, inhibits phosphorylation of p70 S6 kinase and 4E-BP1, and reduces the protein synthesis that follows IGF-1 treatment (PMID:21436142). The claim therefore has an experimental basis and is not unrelated to the lipid phosphatase function. The reduced protein synthesis is, however, a downstream consequence of dampened PI3K/Akt signalling in cells over-expressing the enzyme, not evidence that INPP5E acts in translational control itself. The term over-reads the result and is marked as an over-annotation rather than removed. |
| GO:0019637 organophosphate metabolic process | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA: organophosphate metabolic process. Reason: Very broad but correct for a phosphoinositide phosphatase. Supporting Evidence: PMID:10764818 This enzyme hydrolyzes only lipid substrates, phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 4,5-bisphosphate. |
| GO:0032580 Golgi cisterna membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Golgi cisterna membrane (UniProt, by similarity). Reason: Golgi pool, secondary. Supporting Evidence: file:human/INPP5E/INPP5E-uniprot.txt Note=Peripheral membrane protein associated with Golgi stacks. |
| GO:0034485 phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity | EXP PMID:10764818 The isolation and characterization of a cDNA encoding phosph... | ACCEPT | Summary: Cloned enzyme hydrolyzes PI(3,4,5)P3 with high affinity (Km 0.65 uM). Reason: Direct enzymology; core catalytic activity alongside PI(4,5)P2 hydrolysis. Supporting Evidence: PMID:10764818 This enzyme hydrolyzes only lipid substrates, phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 4,5-bisphosphate. PMID:10764818 It is a highly basic protein (pI = 8.8) and has the greatest affinity toward phosphatidylinositol 3,4,5-trisphosphate of known 5-phosphatases. |
| GO:0034485 phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Rhea/EC-based annotation (EC 3.1.3.86). Reason: Consistent with direct enzymology. Supporting Evidence: PMID:10764818 This enzyme hydrolyzes only lipid substrates, phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 4,5-bisphosphate. |
| GO:0034594 phosphatidylinositol trisphosphate phosphatase activity | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA: phosphatidylinositol trisphosphate phosphatase activity. Reason: Correct parent of the PI(3,4,5)P3 5-phosphatase activity. Supporting Evidence: PMID:10764818 This enzyme hydrolyzes only lipid substrates, phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 4,5-bisphosphate. |
| GO:0036092 phosphatidylinositol-3-phosphate biosynthetic process | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Inferred PI3P biosynthetic process from PI(3,5)P2 5-phosphatase activity. Reason: A mechanical inference from the PI(3,5)P2 5-phosphatase activity. Cellular evidence for PI(3,5)P2 to PI3P conversion exists only for a lysosomal INPP5E pool in neurons (autophagosome-lysosome fusion), so this is retained as a context-specific, non-core process. Supporting Evidence: file:human/INPP5E/INPP5E-uniprot.txt (PtdIns(3,5)P2) (By similarity) (PubMed:10764818). file:human/INPP5E/INPP5E-deep-research-falcon.md In neuronal lysosomes, experimental evidence supports a third reaction |
| GO:0043813 phosphatidylinositol-3,5-bisphosphate 5-phosphatase activity | IEA GO_REF:0000116 | KEEP AS NON CORE | Summary: PI(3,5)P2 5-phosphatase activity (Rhea). Reason: Activity reported for the rodent ortholog with cell-free assays that disagree; cellular support is limited to a neuronal lysosomal pool. Non-core. Supporting Evidence: file:human/INPP5E/INPP5E-uniprot.txt (PtdIns(3,5)P2) (By similarity) (PubMed:10764818). file:human/INPP5E/INPP5E-deep-research-falcon.md In neuronal lysosomes, experimental evidence supports a third reaction |
| GO:0043813 phosphatidylinositol-3,5-bisphosphate 5-phosphatase activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: PI(3,5)P2 5-phosphatase activity (ISS from mouse). Reason: As above. Supporting Evidence: file:human/INPP5E/INPP5E-uniprot.txt (PtdIns(3,5)P2) (By similarity) (PubMed:10764818). |
| GO:0046856 phosphatidylinositol dephosphorylation | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: phosphatidylinositol dephosphorylation. Reason: Core process. Supporting Evidence: PMID:10764818 This enzyme hydrolyzes only lipid substrates, phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 4,5-bisphosphate. PMID:26305592 Thus, Inpp5e limits ciliary PI(4,5)P2 and generates ciliary PI(4)P, consistent with a role in converting PI(4,5)P2 to PI(4)P within cilia. |
| GO:0046856 phosphatidylinositol dephosphorylation | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro: phosphatidylinositol dephosphorylation. Reason: Core process. Supporting Evidence: PMID:10764818 This enzyme hydrolyzes only lipid substrates, phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 4,5-bisphosphate. |
| GO:0051898 negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Negative regulation of PI3K/AKT signalling transferred from rat. Reason: Hydrolysis of PI(3,4,5)P3 can dampen PI3K signalling, and Inpp5e controls ciliary PI3K signalling in mouse cells; plausible but secondary to the ciliary lipid-identity role. Supporting Evidence: PMID:19668215 Together, our results show that INPP5E plays an essential role in the primary cilium by controlling ciliary growth factor and PI3K signaling and stability, and highlight the consequences of INPP5E dysfunction. |
| GO:0052658 inositol-1,4,5-trisphosphate 5-phosphatase activity | IEA GO_REF:0000116 | KEEP AS NON CORE | Summary: Ins(1,4,5)P3 5-phosphatase activity (Rhea). Reason: UniProt cites a recent report of Ins(1,4,5)P3 hydrolysis with low affinity (Km 29 uM), whereas the original characterization found INPP5E specific for lipid substrates. A minor activity of uncertain physiological relevance. Supporting Evidence: file:human/INPP5E/INPP5E-uniprot.txt Can also remove the 5-phosphate from 1D-myo-inositol PMID:10764818 This enzyme hydrolyzes only lipid substrates, phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 4,5-bisphosphate. |
| GO:0106019 phosphatidylinositol-4,5-bisphosphate phosphatase activity | IEA GO_REF:0000107 | ACCEPT | Summary: PI(4,5)P2 phosphatase activity transferred from rat. Reason: Correct parent of the core activity. Supporting Evidence: PMID:10764818 This enzyme hydrolyzes only lipid substrates, phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 4,5-bisphosphate. |
| GO:0120025 plasma membrane bounded cell projection | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA: plasma membrane bounded cell projection. Reason: Correct broad parent of cilium. Supporting Evidence: PMID:19668216 INPP5E localized to cilia in major organs affected by Joubert syndrome, and mutations promoted premature destabilization of cilia in response to stimulation. |
| GO:0060170 ciliary membrane | ISS PMID:26305592 Phosphoinositides Regulate Ciliary Protein Trafficking to Mo... | NEW | Summary: Proposed NEW annotation. INPP5E acts on the lipids of the ciliary membrane, converting PI(4,5)P2 to PI(4)P along the ciliary membrane (shown for the mouse ortholog in fibroblasts and neural stem cells). Reason: INPP5E is a farnesylated peripheral membrane enzyme delivered to cilia by PDE6D; loss of Inpp5e redistributes PI(4,5)P2 along the entire ciliary membrane, demonstrating that the enzyme is active there. Existing annotations capture cilium and axoneme but not the membrane on which the enzyme acts. Evidence is from the mouse ortholog, hence ISS. Supporting Evidence: PMID:26305592 Thus, Inpp5e limits ciliary PI(4,5)P2 and generates ciliary PI(4)P, consistent with a role in converting PI(4,5)P2 to PI(4)P within cilia. PMID:26190144 Upon INPP5E inactivation, PI(4,5)P2 accumulates at the ciliary tip whereas PI4P is depleted. |
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Download this section (compressed HTML)Q: Is PI(3,4,5)P3 or PI(4,5)P2 the physiologically dominant INPP5E substrate in the ciliary membrane, and does this differ between cell types?
Q: Should the ciliary-membrane location (GO:0060170) be annotated directly for INPP5E, given that it acts on ciliary membrane lipids while being described as axonemal?
Q: Does INPP5E have any function in the Golgi or nucleus, or are these pools transit/storage?
Experiment: Replace endogenous INPP5E with a cilium-targeted heterologous 5-phosphatase (or catalytic-dead INPP5E) in INPP5E-null human cells and quantify ciliary PI(4,5)P2, TULP3 and GPR161.
Hypothesis: Ciliary PI(4)P generation by INPP5E is sufficient to exclude TULP3 and GPR161 from cilia.
Type: Targeted enzyme replacement
Experiment: Lipidomics of isolated cilia from wild-type and INPP5E-null cells to quantify PI(4,5)P2, PI(3,4,5)P3 and PI(3,4)P2.
Hypothesis: INPP5E substrate preference in vivo differs from in vitro kinetics.
Type: Ciliary lipidomics
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