Affinage

INPP5E

Phosphatidylinositol polyphosphate 5-phosphatase type IV · UniProt Q9NRR6

Length
644 aa
Mass
70.2 kDa
Annotated
2026-06-10
56 papers in source corpus 33 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

INPP5E is an inositol polyphosphate 5-phosphatase that hydrolyzes the 5-phosphate of PtdIns(4,5)P2 and PtdIns(3,4,5)P3, thereby controlling phosphoinositide composition at the primary cilium and other membranes; loss-of-function mutations cluster in its catalytic domain and cause Joubert syndrome (PMID:19668216, PMID:10405344). Within the cilium it is the enzyme that maintains a PI4P-enriched, PI(4,5)P2-excluded membrane, and its loss redistributes PI(4,5)P2 along the ciliary length while abolishing ciliary PI4P (PMID:38514901). This lipid control governs cilium stability and signaling: INPP5E restricts a cilia-compartmentalized PI3K/AKT axis whose hyperactivation destabilizes cilia and, in renal epithelium, drives mTORC1-dependent polycystic kidney disease (PMID:19668215, PMID:27056978, PMID:28650469), and it acts upstream of Gli3 repressor and Smoothened to shape Hedgehog output, including by sustaining transition-zone integrity through clearance of PI(4,5)P2/PI(3,4,5)P3 (PMID:27998989, PMID:31964774, PMID:32840212). Ciliary targeting of INPP5E is a multi-signal process built on its C-terminal CaaX-farnesyl moiety, which is methylated by ICMT and bound by the prenyl carrier PDE6D for delivery and ARL3-GTP-mediated release, facilitated by ARL13B, TULP3/IFT-A, RPGR, CEP164, and ARL16-dependent Golgi-to-cilium transport (PMID:23150559, PMID:24166846, PMID:27063844, PMID:28172980, PMID:30583862, PMID:36063381, PMID:35196065, PMID:42127111). Beyond cilia, INPP5E promotes autophagosome–lysosome fusion by lowering lysosomal PI(3,5)P2 to relieve cortactin-dependent actin stabilization, maintains photoreceptor outer-segment disc morphogenesis and IFT trafficking, and supports mitotic genomic stability (PMID:27340123, PMID:33711342, PMID:39871753, PMID:28031327).

Mechanistic history

Synthesis pass · year-by-year structured walk · 29 steps
  1. 1999 Medium

    Established the founding biochemical identity of INPP5E (pharbin) as an inositol polyphosphate 5-phosphatase with a CaaX-driven membrane association and cell-shape effects, defining the enzyme before its ciliary role was known.

    Evidence Enzymatic activity assay and CaaX mutagenesis in transfected COS-7 cells and fibroblasts

    PMID:10405344

    Open questions at the time
    • In vitro substrate panel did not establish the physiological membrane substrate
    • No link to cilia or disease at this stage
  2. 2009 High

    Defined INPP5E as a Joubert syndrome gene by showing disease mutations impair 5-phosphatase activity and ciliary localization while destabilizing pre-formed cilia, linking phosphoinositide turnover to cilium maintenance rather than assembly.

    Evidence Enzymatic assays on patient mutations, cellular phosphoinositide measurements, ciliary immunofluorescence, knockout mouse with PI3K-inhibitor rescue

    PMID:19668215 PMID:19668216

    Open questions at the time
    • Did not resolve the precise ciliary lipid substrate in vivo
    • Mechanism linking PI3K signaling to cilium destabilization unspecified
  3. 2011 Medium

    Showed INPP5E negatively regulates the IGF-1/PI3K/Akt/mTOR translational axis, providing the signaling logic later invoked for cilium destabilization and renal disease.

    Evidence Gain- and loss-of-function with Akt/S6K/4E-BP1 phospho-immunoblots after IGF-1 stimulation

    PMID:21436142

    Open questions at the time
    • Not connected to a ciliary compartment
    • Direct lipid substrate driving the effect not demonstrated
  4. 2012 High

    Identified the ciliary targeting machinery, showing a C-terminal motif plus PDE6D and ARL13B route INPP5E to cilia and that Joubert ARL13B mutations break the ARL13B–INPP5E interaction.

    Evidence Reciprocal Co-IP/pulldown, ARL13B mutation analysis, ciliary targeting assays with mutant constructs

    PMID:23150559

    Open questions at the time
    • Hierarchy among PDE6D, ARL13B and CEP164 not resolved
    • Structural basis of the sorting signal undefined
  5. 2014 High

    Mechanized prenyl-cargo delivery by establishing PDE6D as the farnesyl-binding carrier for INPP5E and ARL3-GTP as the ciliary release factor, explaining how a farnesylated phosphatase reaches the cilium.

    Evidence Proteomics, biochemical binding with mutant PDE6D, patient fibroblast IF, zebrafish rescue

    PMID:24166846

    Open questions at the time
    • Selectivity for cilia versus other PDE6D cargoes not yet structurally explained
    • Spatial site of ARL3-mediated release unresolved
  6. 2014 Medium

    Revealed an AURKA–INPP5E feedback loop in which AURKA phosphorylation boosts INPP5E activity that in turn downregulates AURKA via AKT, coupling the phosphatase to cilium-disassembly control.

    Evidence Co-IP, in vitro kinase and phosphatase assays, AKT pathway and cilia-stability readouts

    PMID:25395580

    Open questions at the time
    • Phosphosite on INPP5E not mapped
    • Feedback demonstrated in a single lab without in vivo confirmation
  7. 2014 Medium

    Extended INPP5E function to phagosome maturation by showing it cooperates with Rab20/Rab5 to control phagosomal PtdIns3P and acidification kinetics in macrophages.

    Evidence shRNA knockdown in RAW264.7, phagosomal fractionation, lipid measurements, Rab rescue experiments

    PMID:25269936

    Open questions at the time
    • Direct physical INPP5E–Rab interaction not established
    • Relevance to ciliopathy phenotypes unclear
  8. 2015 Medium

    Placed INPP5E within a transition-zone regulatory pathway by showing MKS1 controls ciliary INPP5E levels through ARL13B, connecting transition-zone integrity to ciliary lipid content.

    Evidence Patient fibroblast IF and 3D spheroid rescue with MKS1 alleles

    PMID:26490104

    Open questions at the time
    • Molecular step by which MKS1 affects ARL13B not defined
    • Epistasis inferred rather than biochemically reconstituted
  9. 2016 High

    Demonstrated INPP5E is the catalytic convergence point linking Hedgehog and phosphoinositide signaling at the transition zone, clearing PI(4,5)P2/PI(3,4,5)P3 to permit Smoothened accumulation.

    Evidence Knockout mouse genetics, transition-zone phosphoinositide IF, Smoothened-M2 and catalytic-dead INPP5E rescues

    PMID:27998989

    Open questions at the time
    • How lipid changes mechanically recruit TZ scaffolds unresolved
    • Effector reading the lipid signal not identified
  10. 2016 Medium

    Showed INPP5E and PIPKIγ antagonistically tune basal-body PtdIns(4)P to regulate TTBK2/CEP164-dependent ciliogenesis initiation, revealing a pre-ciliary role at the centrosome.

    Evidence Phosphoinositide binding, Co-IP, centrosome localization and ciliogenesis assays

    PMID:26916822

    Open questions at the time
    • Reconciliation with the maintenance-not-assembly model needed
    • Single-lab functional data
  11. 2016 High

    Provided the structural basis for cilia-exclusive sorting, showing PDE6δ recognizes residues at the -1/-3 positions of the farnesylated cysteine and that ARL3 (not ARL2) selectively releases cargo into cilia.

    Evidence Crystal structures of PDE6δ/cargo complexes, affinity measurements, structure-guided mutants, ARL2/ARL3 release assays

    PMID:27063844

    Open questions at the time
    • Does not explain spatial restriction of ARL3-GTP to cilia
    • Other CaaX cargoes share the motif, raising specificity questions
  12. 2016 High

    Connected INPP5E loss to PI3K/Akt/mTORC1 hyperactivation as the driver of polycystic kidney disease, with mTORC1 inhibition rescuing kidney function independently of cilia number.

    Evidence Kidney-specific conditional knockout, mTORC1-inhibitor treatment, signaling immunoblots, cilia measurement

    PMID:27056978

    Open questions at the time
    • Ciliary versus non-ciliary site of the regulated lipid pool not separated
    • Cell-type-specific effectors unmapped
  13. 2016 High

    Established a lysosomal, cilia-independent function: INPP5E lowers lysosomal PI(3,5)P2 to relieve cortactin-driven actin stabilization required for autophagosome–lysosome fusion in neurons.

    Evidence Knockdown in neuronal cells, autophagy flux, lysosomal fractionation, PI(3,5)P2 and actin/cortactin assays, patient mutations

    PMID:27340123

    Open questions at the time
    • Mechanism of INPP5E lysosomal targeting not defined
    • Link between autophagy defect and ciliopathy phenotypes unclear
  14. 2016 Medium

    Showed INPP5E directs apical basal-body docking in renal epithelia by segregating PI(4,5)P2/PI(3,4,5)P3 and acting upstream of an PI3K-PtdIns(3,4,5)P3-Ezrin-F-actin axis.

    Evidence Zebrafish knockdown/knockout with PI3K-inhibitor and ezrin-overexpression rescues, phosphoinositide and F-actin IF

    PMID:27401686

    Open questions at the time
    • Direct INPP5E–ezrin relationship not biochemically shown
    • Generality beyond renal epithelium untested
  15. 2016 Medium

    Defined a PDE6δ–RPGR–INPP5E trafficking cascade, with RPGR ciliary localization required for INPP5E delivery, integrating a retinal disease gene into INPP5E transport.

    Evidence Proteomics, Co-IP, domain mapping, ciliary localization assays

    PMID:28172980

    Open questions at the time
    • Temporal order relative to ARL13B/TULP3 inputs unresolved
    • In vivo requirement in photoreceptors not directly tested here
  16. 2016 High

    Showed ARL13B's regulation of IFT-A retrograde trafficking requires its interaction with INPP5E, linking ciliary lipid control to GPR161 exit and IFT dynamics.

    Evidence Visible IP, ARL13B-KO cells, IFT and GPR161 exit assays, rescue with INPP5E-binding-defective ARL13B

    PMID:27927754

    Open questions at the time
    • Whether INPP5E catalysis or scaffolding mediates IFT effect unresolved
    • Direct lipid dependence of IFT-A turnaround not shown
  17. 2017 Medium

    Revealed an unexpected mitotic role, with INPP5E required for spindle-assembly checkpoint function, centrosome/spindle integrity and chromosomal stability, and cell-cycle-regulated localization to mitotic structures.

    Evidence Knockdown/KO in human and murine cells, SAC and chromosome integrity assays, mitotic localization imaging

    PMID:28031327

    Open questions at the time
    • Lipid substrate underlying the mitotic role unidentified
    • Relationship to ciliary functions unclear
  18. 2018 Medium

    Dissected ciliary entry versus intraflagellar movement, showing PDE6δ/dynein mediate sorting and entry while IFT independently governs intra-ciliary transport, and that farnesylation creates an affinity trap overcome by PDE6δ.

    Evidence Live imaging, FRAP, dynein and IFT inhibition, PDE6δ-deficient and farnesylation-mutant constructs

    PMID:29140789

    Open questions at the time
    • Molecular identity of the centriolar affinity trap unknown
    • Quantitative flux model not established
  19. 2018 Medium

    Showed TULP3 targets INPP5E (and ARL13B) to cilia through IFT-A binding, adding an IFT-A-dependent arm to the targeting network.

    Evidence TULP3-KO RPE1 cells with wild-type and IFT-A-binding-deficient rescue

    PMID:30583862

    Open questions at the time
    • Interplay between TULP3/IFT-A and PDE6D routes not integrated
    • Direct TULP3–INPP5E contact not mapped
  20. 2020 Medium

    Placed Inpp5e upstream of Gli3 repressor and Smoothened in Hedgehog-dependent neural-tube and cortical neurogenesis, showing both positive and negative pathway roles dependent on cilia.

    Evidence Forward-genetic and mutant mouse models, neural-tube and cortical analyses, Gli3 and Smoothened epistasis

    PMID:31964774 PMID:32840212

    Open questions at the time
    • Lipid-level basis of the Gli3 repressor effect undefined
    • Context-dependence of positive versus negative roles unresolved
  21. 2021 High

    Demonstrated cell-type-specific ciliary lipid zoning, with Inpp5e confining PI(4,5)P2 to the proximal olfactory cilium segment and shaping odor adaptation kinetics, rescued by gene replacement.

    Evidence Conditional KO in olfactory sensory neurons, phosphoinositide IF, electrophysiology, adenoviral rescue

    PMID:33771931

    Open questions at the time
    • Downstream odor-channel effectors of the lipid change not pinpointed
    • Mechanism establishing proximal-segment boundary unknown
  22. 2021 High

    Established INPP5E as essential for photoreceptor axoneme and disc morphogenesis, with its loss trapping IFT-A/IFT-B particles at connecting-cilia tips despite normal outer-segment protein delivery.

    Evidence Retina-specific conditional KO, electron microscopy, IFT and outer-segment protein localization

    PMID:33711342

    Open questions at the time
    • Whether IFT defect is direct lipid consequence not proven
    • Link to non-syndromic retinal degeneration genotypes not addressed
  23. 2021 Medium

    Identified ATG16L1 as an INPP5E partner whose ATG16L1/IFT20 complex controls ciliary INPP5E trafficking, tying an autophagy factor to ciliary lipid composition.

    Evidence Co-IP, ATG16L1-deficient cell IF, phosphoinositide biosensor imaging

    PMID:33910006

    Open questions at the time
    • Direct binding interface not mapped here
    • Mechanistic overlap with autophagy role unresolved
  24. 2022 High

    Provided a unified targeting code by mapping four ciliary localization signals on INPP5E and assigning specific partners (PDE6D, RPGR, ARL13B, TULP3, CEP164, ATG16L1) to each, with some Joubert mutations disrupting targeting.

    Evidence Systematic CLS mutagenesis, interaction mapping, ciliary targeting and patient-mutation assays

    PMID:36063381

    Open questions at the time
    • Temporal order of multi-signal engagement not resolved
    • Quantitative contribution of each CLS in vivo untested
  25. 2022 Medium

    Identified ARL16 as a regulator of a specific Golgi-to-cilium route for INPP5E and IFT140, since ARL16 loss strands both at the Golgi.

    Evidence ARL16-KO MEFs with ciliary versus Golgi localization analysis

    PMID:35196065

    Open questions at the time
    • Whether ARL16 acts on INPP5E directly unknown
    • Relation to PDE6D and IFT-A routes not integrated
  26. 2023 Medium

    Extended INPP5E function to the immune synapse, where it complexes with CD3ζ/ZAP-70/Lck and clears central PI(4,5)P2 to support TCR-proximal phosphorylation and IL-2 output.

    Evidence Immune-synapse IF, Co-IP, siRNA knockdown, PI(4,5)P2 imaging, phospho-immunoblot, IL-2 ELISA in Jurkat cells

    PMID:37670137

    Open questions at the time
    • Direct versus indirect complex membership not separated
    • Physiological relevance in primary T cells untested
  27. 2024 Medium

    Provided direct biosensor evidence that INPP5E is the enzyme defining the ciliary PI4P-enriched, PI(4,5)P2-excluded membrane, since its KO redistributes PI(4,5)P2 and erases ciliary PI4P.

    Evidence CRISPR INPP5E-KO RPE1 cells with fluorescent PI4P and PI(4,5)P2 biosensors

    PMID:38514901

    Open questions at the time
    • Source of ciliary PI4P production not identified
    • Spatial dynamics of the lipid boundary not quantified
  28. 2025 High

    Resolved the cellular basis of retinal disease by showing inducible Inpp5e loss disrupts disc morphogenesis, rhodopsin localization, Golgi structure and the actin network at disc-forming sites.

    Evidence Conditional and inducible KO mice, electron microscopy, rhodopsin and actin IF, Golgi analysis

    PMID:39871753

    Open questions at the time
    • Causal lipid species at disc-morphogenesis sites not defined
    • Whether actin defect is downstream of lysosomal-type or ciliary lipid control unresolved
  29. 2026 Medium

    Connected post-prenylation processing to INPP5E membrane function by identifying it as an ICMT methylation substrate whose displacement upon ICMT inhibition raises PI(4,5)P2 and contributes to melanoma growth phenotypes.

    Evidence Genetic/pharmacologic ICMT inhibition, methylation assay, membrane fractionation, PI(4,5)P2 measurement, forced-membrane-targeting rescue in BRAFV600E melanoma

    PMID:42127111

    Open questions at the time
    • Direct role of methylation in ciliary targeting not tested
    • Tumor relevance beyond a single melanoma context unestablished

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single phosphatase coordinates its distinct ciliary, lysosomal, mitotic, immune-synapse and tumor functions—and which lipid effectors translate INPP5E lipid changes into each cellular outcome—remains unresolved.
  • Effectors reading INPP5E-generated lipid changes are largely unidentified
  • Integration of the multi-signal ciliary targeting code in vivo is incomplete
  • Spatial control restricting ARL3-GTP-mediated release to cilia is unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 5 GO:0008289 lipid binding 4 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005929 cilium 4 GO:0005815 microtubule organizing center 3 GO:0005794 Golgi apparatus 2 GO:0005886 plasma membrane 2 GO:0005764 lysosome 1
Pathway
R-HSA-9609507 Protein localization 5 R-HSA-162582 Signal Transduction 4 R-HSA-9709957 Sensory Perception 3 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-1640170 Cell Cycle 1 R-HSA-9612973 Autophagy 1
Partners
ARL13BARL3ATG16L1AURKACEP164PDE6DRPGRTULP3

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 INPP5E hydrolyzes the 5-phosphate of PtdIns(3,4,5)P3 and PtdIns(4,5)P2; Joubert syndrome mutations cluster in the phosphatase domain and impair 5-phosphatase activity, resulting in altered cellular PtdIns ratios. INPP5E localizes to cilia in major organs affected by Joubert syndrome, and mutations promote premature destabilization of cilia in response to stimulation. Enzymatic activity assay on patient-mutation constructs; cellular phosphoinositide ratio measurements; immunofluorescence localization; cilia stability assay with stimulation Nature genetics High 19668216
2009 Inpp5e concentrates in the axoneme of the primary cilium in ciliated mouse embryonic fibroblasts. Inpp5e inactivation does not impair ciliary assembly but alters stability of pre-established cilia after serum addition. Blocking PI3K activity or ciliary PDGFRα signaling restores ciliary stability in Inpp5e-null cells. A human INPP5E mutation affecting ciliary localization also impairs cilium stability. Inpp5e knockout mouse model; immunofluorescence of axonemal localization; cilia stability assay with serum; PI3K inhibitor rescue; patient mutation analysis Nature genetics High 19668215
1999 Pharbin (INPP5E) has inositol polyphosphate 5-phosphatase activity, hydrolyzing inositol 1,4,5-trisphosphate, inositol 1,3,4,5-tetrakisphosphate, and phosphatidylinositol 4,5-bisphosphate. It localizes to plasma membrane-associated structures including membrane ruffles via its CaaX motif, and induces dendritic morphology in fibroblasts; the CaaX motif is required for morphological alteration but not membrane localization per se. Transfection of COS-7 cells with enzymatic activity assay; morphological analysis of transfected fibroblasts; CaaX deletion/point mutants Biochemical and biophysical research communications Medium 10405344
2012 INPP5E is targeted to the primary cilium through a C-terminal motif and PDE6D-dependent mechanisms. ARL13B (but not ARL2 or ARL3) facilitates ciliary targeting of INPP5E. ARL13B missense mutations causing Joubert syndrome disrupt the ARL13B-INPP5E interaction. INPP5E also interacts with CEP164. ARL13B, INPP5E, PDE6D, and CEP164 form a distinct functional network. Protein-protein interaction studies (Co-IP/pulldown); genetic analysis of ARL13B JBTS mutations; ciliary targeting assays with deletion/mutant constructs Proceedings of the National Academy of Sciences of the United States of America High 23150559
2014 PDE6D acts as a prenyl-binding carrier for farnesylated INPP5E and is required for INPP5E ciliary targeting. Mutant PDE6D shows reduced binding to INPP5E, causing INPP5E to fail to localize to primary cilia. GTP-bound ARL3 acts as a cargo-release factor for PDE6D-bound INPP5E. Proteomic identification of PDE6D-INPP5E interaction; biochemical binding assays with mutant PDE6D; patient fibroblast immunofluorescence; zebrafish knockdown rescue experiments Human mutation High 24166846
2014 INPP5E interacts with AURKA (Aurora kinase A). AURKA phosphorylates INPP5E and increases its 5-phosphatase activity. This increased phosphatase activity in turn promotes transcriptional downregulation of AURKA partly through an AKT-dependent mechanism, establishing a feedback loop that maintains primary cilia stability. Co-immunoprecipitation; in vitro kinase assay; phosphatase activity assay; AKT pathway analysis; cilia stability readout Journal of cell science Medium 25395580
2016 INPP5E's phosphoinositide substrates PI(4,5)P2 and PI(3,4,5)P3 accumulate at the transition zone in Hedgehog-stimulated Inpp5e-null cells, associated with reduced TZ scaffolding proteins and reduced Smoothened at cilia. Expression of wild-type but not catalytically dead INPP5E restores TZ molecular organization and Smoothened accumulation, identifying INPP5E as a convergence point between Hedgehog and phosphoinositide signaling at the cilia transition zone. Inpp5e knockout mouse genetics; phosphoinositide immunofluorescence at transition zone; Smoothened M2 (constitutively active) genetic rescue; catalytic-dead INPP5E rescue experiment The Journal of cell biology High 27998989
2016 PIPKIγ and INPP5E counteract each other at the centrosome/basal body to regulate TTBK2 recruitment and thereby CP110 removal and axoneme elongation during ciliogenesis initiation. INPP5E produces PtdIns(4)P at the centrosome in non-ciliated cells; PtdIns(4)P binds TTBK2 and CEP164, impairing the TTBK2-CEP164 interaction and inhibiting TTBK2 recruitment. Phosphoinositide binding assays; co-immunoprecipitation; centrosome localization studies; ciliogenesis initiation assay; overexpression/knockdown in cell lines Nature communications Medium 26916822
2016 INPP5E is required for autophagosome-lysosome fusion in neuronal cells. A fraction of INPP5E localizes to lysosomes; both lysosomal localization and enzymatic activity are necessary. INPP5E decreases lysosomal PI(3,5)P2 levels, counteracting cortactin-mediated actin filament stabilization on lysosomes that is needed for fusion. Patient-derived INPP5E mutations cause defects in autophagy. INPP5E knockdown in neuronal cells; autophagy flux assays; lysosomal fractionation/immunofluorescence localization; PI(3,5)P2 measurement; actin filament analysis; cortactin assays; patient mutation functional testing The EMBO journal High 27340123
2016 ARL13B regulates IFT-A-mediated retrograde protein trafficking within cilia, and this function requires its interaction with INPP5E. ARL13B-knockout cells show aberrant localization of INPP5E and accumulation of IFT-A and IFT-B at ciliary tips; GPR161 cannot exit cilia in response to Smoothened agonist. Rescue with wild-type ARL13B but not INPP5E-binding-defective ARL13B mutant restored retrograde transport. Visible immunoprecipitation assay; ARL13B knockout cells; IFT complex localization by immunofluorescence; GPR161 exit assay with Smoothened agonist; rescue with ARL13B mutants Journal of cell science High 27927754
2016 PDE6δ-mediated sorting of INPP5E exclusively into cilia depends on high-affinity binding to PDE6δ and selective release by the ciliary ARL3 (not by non-ciliary ARL2). Structures of PDE6δ/cargo complexes reveal that sorting signal depends on residues at -1 and -3 positions relative to the farnesylated cysteine. A structure-guided low-affinity INPP5E mutant loses exclusive ciliary localization. Crystal structures of PDE6δ/cargo complexes; affinity measurements; structure-guided mutagenesis; ARL2/ARL3 release assays; ciliary localization assay Nature communications High 27063844
2016 Inpp5e enzymatic activity at the apical membrane directs apical docking of basal bodies in renal epithelia. Knockdown or knockout of inpp5e in zebrafish leads to defects in cell polarity, cortical F-actin organization, and apical segregation of PtdIns(4,5)P2 and PtdIns(3,4,5)P3. PI3K inhibition rescued cellular, phenotypic and renal functional defects. Ezrin overexpression also rescued inpp5e morphants, placing INPP5E upstream of PtdIns(3,4,5)P3-Ezrin-F-actin-basal body apical recruitment. Zebrafish inpp5e knockdown/knockout; PI3K inhibitor rescue; ezrin overexpression rescue; F-actin and phosphoinositide immunofluorescence; basal body localization assay Journal of the American Society of Nephrology Medium 27401686
2015 MKS1 functions at the transition zone to regulate ciliary INPP5E levels through an ARL13B-dependent mechanism; fibroblasts from MKS1-related Joubert syndrome patients show decreased ciliary ARL13B and INPP5E, indicating that MKS1 → ARL13B → INPP5E represents a pathway controlling ciliary INPP5E content. Immunofluorescence of ARL13B and INPP5E in patient fibroblasts; 3D spheroid rescue assay with MKS1 mutant alleles Journal of medical genetics Medium 26490104
2011 Pharbin (INPP5E) negatively regulates IGF-1/PI3K/Akt signaling; ectopic expression suppresses IGF-1-induced Akt phosphorylation and downstream p70 S6K and 4E-BP1 phosphorylation, while pharbin silencing increases Akt phosphorylation, without affecting p42/44 MAP kinase. Ectopic expression and siRNA knockdown in cell lines; immunoblot for Akt, S6K, 4E-BP1, and MAPK phosphorylation after IGF-1 stimulation Journal of biochemistry Medium 21436142
2014 Inpp5e interacts functionally with Rab20 on phagosomes; Inpp5e deficiency in macrophages decreases phagosomal Rab20 and Rab5 association, reduces PtdIns3P accumulation on phagosomes, and accelerates phagosome acidification. Constitutively active Rab5b rescues PtdIns3P accumulation; overexpression of Rab20 increases phagosomal PtdIns3P and delays its elimination. shRNA-mediated Inpp5e knockdown in RAW264.7 macrophages; phagosomal fractionation; PtdIns3P and PtdIns(3,4,5)P3 measurements; Rab5 and Rab20 localization; constitutively active Rab5b rescue; phagocytosis and acidification assays The Biochemical journal Medium 25269936
2016 INPP5E promotes Sonic Hedgehog signaling in SHH medulloblastoma by negatively regulating a cilia-compartmentalized PI3K/AKT/GSK3β signaling axis that maintains cilia. Inpp5e deletion increases cilia-localized PtdIns(3,4,5)P3, pAKT, and pGSK3β and promotes cilia loss on tumor cells. PI3K inhibition or wild-type (not catalytically inactive) INPP5E rescued cilia loss. Conditional deletion in murine SHH medulloblastoma model; phosphoinositide immunofluorescence at cilia; PI3K inhibitor rescue; catalytic-dead mutant rescue; pAKT/pGSK3β localization assay Oncogene Medium 28650469
2016 Inpp5e conditional inactivation in mouse kidney epithelium causes severe PKD associated with hyperactivation of PI3K/Akt and downstream mTORC1 signaling. Treatment with an mTORC1 inhibitor improved kidney morphology and function without affecting cilia number or length, identifying INPP5E as an essential inhibitor of the PI3K/Akt/mTORC1 axis in renal epithelial cells. Conditional kidney-specific Inpp5e knockout mouse; mTORC1 inhibitor treatment; kidney morphology and function assays; PI3K/Akt/mTORC1 signaling immunoblots; cilia number/length measurement Human molecular genetics High 27056978
2018 INPP5E ciliary entry requires PDE6δ and the dynein transport system for sorting and entry, while inner-ciliary movement is regulated solely by the IFT system independent of PDE6δ and farnesylation. ARL3 moves into and within cilia by diffusion independently of IFT. A farnesylation-defective INPP5E CaaX mutant loses exclusive ciliary localization and accumulates at centrioles, suggesting an affinity-trap mechanism for ciliary entry overcome by PDE6δ interaction. Live cell fluorescence microscopy; FRAP analysis; pharmacological inhibition of dynein and IFT; PDE6δ-deficient and farnesylation-mutant constructs; centriole accumulation assay Biological chemistry Medium 29140789
2016 RPGR interacts with PDE6δ (via its C-terminus) and with INPP5E (via its N-terminus). INPP5E ciliary trafficking depends on the ciliary localization of RPGR, and PDE6δ binding is critical for RPGR's own ciliary localization, establishing a PDE6δ-RPGR-INPP5E ciliary trafficking cascade. Proteomic analysis and Co-IP/pulldown; domain mapping of RPGR-PDE6δ and RPGR-INPP5E interactions; ciliary localization assays Human molecular genetics Medium 28172980
2018 TULP3 is required for ciliary localization of the membrane-associated proteins ARL13B and INPP5E; TULP3-KO cells fail to localize these proteins to cilia, and this defect is rescued by wild-type TULP3 but not by a TULP3 mutant unable to bind IFT-A, demonstrating that TULP3 targets INPP5E to cilia via IFT-A interaction. TULP3 knockout RPE1 cells; immunofluorescence for ARL13B and INPP5E ciliary localization; rescue with wild-type and IFT-A-binding-deficient TULP3 mutants Biochemical and biophysical research communications Medium 30583862
2020 Inpp5e plays a positive and negative role in Shh signaling in the neural tube; Inpp5e function largely depends on the presence of cilia and on Smoothened, the obligate transducer of Shh signaling. Genetically restoring Gli3 repressor rescues the decreased indirect neurogenesis in Inpp5e mutants, placing Inpp5e upstream of Gli3 repressor in the Shh pathway. Inpp5e forward genetic mutant mouse (rdg allele); neural tube patterning analysis; epistasis with Gli3 genetic rescue; Smoothened dependence test Development (Cambridge, England) Medium 31964774
2020 Loss of Inpp5e in mouse olfactory sensory neurons causes redistribution of PI(4,5)P2 from its normal proximal segment restriction to the entire ciliary length, with reduction of PI(3,4)P2 and elevation of PI(3,4,5)P3 in the dendritic knob. This altered phosphoinositide distribution impairs odor adaptation and recovery kinetics. Adenoviral Inpp5e gene replacement restores ciliary PI(4,5)P2 localization and odor response kinetics. Conditional Inpp5e knockout in olfactory sensory neurons; phosphoinositide immunofluorescence; electrophysiology (odor-evoked response); Ca2+ imaging; adenoviral rescue Journal of cell science High 33771931
2017 INPP5E is required for genomic stability through regulation of mitosis; INPP5E silencing or knockout impairs the spindle assembly checkpoint, centrosome and spindle function, and chromosomal integrity. INPP5E expression peaks at mitotic entry; it localizes to centrosomes, chromosomes, and kinetochores in early mitosis and shuttles to the midzone spindle at mitotic exit. INPP5E siRNA knockdown and genetic KO in human and murine cells; spindle assembly checkpoint assay; centrosome/spindle imaging; chromosome integrity assay; cell cycle expression profiling; immunofluorescence localization throughout mitosis Molecular and cellular biology Medium 28031327
2021 Retina-specific deletion of Inpp5e prevents photoreceptor axoneme formation and disc morphogenesis. Loss of INPP5E causes accumulation of IFT-A and IFT-B particles at the distal ends of connecting cilia, suggesting disrupted intraflagellar transport, and prevents assembly of axonemal and disc components despite delivery of outer segment proteins via the secretory pathway. Retina-specific Inpp5e conditional KO mouse (Six3Cre); electron microscopy of outer segment ultrastructure; IFT particle localization by immunofluorescence; outer segment protein localization The Journal of biological chemistry High 33711342
2021 ATG16L1 interacts with INPP5E and perturbation of the ATG16L1/IFT20 complex alters INPP5E trafficking to the primary cilium. ATG16L1-deficient cells show aberrant ciliary structures accumulating PI(4,5)P2 while PI4P (product of INPP5E) is absent from cilia. Co-immunoprecipitation; ATG16L1-deficient cell immunofluorescence; phosphoinositide localization assay; stable RPE1 cell lines with fluorescent phosphoinositide probes Cell reports Medium 33910006
2022 INPP5E ciliary targeting requires its folded catalytic domain and four conserved ciliary localization signals (CLS1-4): LLxPIR motif (CLS1), W383 (CLS2), FDRxLYL motif (CLS3), and CaaX box (CLS4). CLS4 recruits PDE6D, RPGR, and ARL13B; CLS2-CLS3 regulate association with TULP3, ARL13B, and CEP164; CLS1 and CLS4 cooperate in ATG16L1 binding. Some Joubert syndrome mutations disrupt INPP5E ciliary targeting. Mutagenesis of ciliary localization signals; interaction assays with PDE6D, RPGR, ARL13B, TULP3, CEP164, ATG16L1; ciliary targeting assay; patient mutation analysis eLife High 36063381
2019 INPP5E contributes to antiviral innate immunity by altering virus attachment. Viral infection induces expression of an INPP5E mRNA variant lacking repressive upstream ORFs in its 5' leader, leading to enhanced translational efficiency of INPP5E. Translatomic analysis of infected cancer cells; identification of alternative 5' leader INPP5E mRNA variant; uORF analysis; virus attachment assay with INPP5E manipulation Cell reports Medium 31851930
2022 Deletion of ARL16 in mouse embryonic fibroblasts causes loss of INPP5E and IFT140 from cilia, with both proteins accumulating at the Golgi, indicating ARL16 regulates a specific Golgi-to-cilia trafficking pathway for INPP5E and IFT140. ARL16 knockout MEFs; immunofluorescence for ciliary and Golgi INPP5E/IFT140 localization; comparison with other IFT proteins Molecular biology of the cell Medium 35196065
2023 INPP5E is enriched at the immune synapse in Jurkat T-cells during TCR engagement and forms a complex with CD3ζ, ZAP-70, and Lck. INPP5E silencing impairs polarized CD3ζ distribution at the immune synapse, correlates with failure of PI(4,5)P2 clearance at the synapse center, decreases phosphorylation of CD3ζ and ZAP-70, and attenuates IL-2 secretion. Immunofluorescence of immune synapse; Co-immunoprecipitation (INPP5E complex with CD3ζ/ZAP-70/Lck); INPP5E siRNA knockdown; PI(4,5)P2 imaging; phospho-CD3ζ/ZAP-70 immunoblot; IL-2 ELISA Communications biology Medium 37670137
2024 INPP5E regulates PI(4,5)P2 and PI4P distribution on cilia in RPE1 cells; KO of INPP5E causes PI(4,5)P2 to redistribute along the ciliary membrane and PI4P to disappear from cilia, demonstrating INPP5E is the enzyme responsible for maintaining the PI4P-enriched, PI(4,5)P2-excluded composition of the ciliary membrane. CRISPR/Cas9 INPP5E KO RPE1 cells; stable cell lines expressing fluorescent PI4P and PI(4,5)P2 biosensors; immunofluorescence quantification Journal of clinical laboratory analysis Medium 38514901
2025 INPP5E plays a crucial role in maintaining photoreceptor outer segment morphology and the normal process of outer segment renewal (disc morphogenesis). Loss of Inpp5e causes outer segment shortening, reduction in newly forming discs, Golgi structural abnormalities, mislocalized rhodopsin, extracellular vesicle accumulation, and disruption of the actin network at disc morphogenesis sites. Conditional and inducible Inpp5e knockout mice (deletion during and after outer segment formation); electron microscopy; immunofluorescence for rhodopsin and actin; Golgi morphology analysis Journal of cell science High 39871753
2026 ICMT (isoprenylcysteine carboxyl methyltransferase) methylates the CAAX protein INPP5E as an ICMT-dependent substrate; ICMT inhibition reduces INPP5E methylation, displaces INPP5E from membranes, and increases PI(4,5)P2. Forced INPP5E membrane targeting partially rescues growth defects caused by ICMT inhibition in BRAFV600E-mutant melanoma cells. Genetic and pharmacologic ICMT inhibition; INPP5E methylation assay; membrane fractionation; PI(4,5)P2 measurement; forced membrane targeting rescue experiment; proliferation/invasion assays Proceedings of the National Academy of Sciences of the United States of America Medium 42127111
2025 Loss of INPP5E in human iPSC-derived retinal organoids leads to altered localization of ARL13B and Rhodopsin in mature photoreceptors and elongated outer segment membranes in both cone and rod photoreceptors, indicating a role in outer segment membrane biogenesis in human photoreceptors. CRISPR/Cas9 INPP5E knockout iPSCs; retinal organoid differentiation; proteomic and immunofluorescence analysis of photoreceptor structure and protein localization bioRxivpreprint Low
2020 In Inpp5e mutant mice, loss of Inpp5e leads to reduced Gli3 repressor levels coinciding with ciliary structural changes, and genetically restoring Gli3 repressor rescues decreased indirect neurogenesis, placing Inpp5e function upstream of Gli3 repressor production in cortical development. Inpp5e mutant mouse genetics; cortical neuron subtype analysis; Gli3 genetic rescue; ciliary structure analysis eLife Medium 32840212

Source papers

Stage 0 corpus · 56 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies. Nature genetics 342 19668216
2009 INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human and mouse. Nature genetics 295 19668215
2012 ARL13B, PDE6D, and CEP164 form a functional network for INPP5E ciliary targeting. Proceedings of the National Academy of Sciences of the United States of America 199 23150559
2014 A homozygous PDE6D mutation in Joubert syndrome impairs targeting of farnesylated INPP5E protein to the primary cilium. Human mutation 110 24166846
2016 Autophagosome-lysosome fusion in neurons requires INPP5E, a protein associated with Joubert syndrome. The EMBO journal 104 27340123
2016 INPP5E regulates phosphoinositide-dependent cilia transition zone function. The Journal of cell biology 95 27998989
2016 Regulation of ciliary retrograde protein trafficking by the Joubert syndrome proteins ARL13B and INPP5E. Journal of cell science 81 27927754
2016 Phosphatidylinositol phosphate kinase PIPKIγ and phosphatase INPP5E coordinate initiation of ciliogenesis. Nature communications 73 26916822
2014 INPP5E interacts with AURKA, linking phosphoinositide signaling to primary cilium stability. Journal of cell science 71 25395580
2016 PDE6δ-mediated sorting of INPP5E into the cilium is determined by cargo-carrier affinity. Nature communications 70 27063844
2013 Phenotypic spectrum and prevalence of INPP5E mutations in Joubert syndrome and related disorders. European journal of human genetics : EJHG 57 23386033
2018 TULP3 is required for localization of membrane-associated proteins ARL13B and INPP5E to primary cilia. Biochemical and biophysical research communications 51 30583862
2016 Inpp5e suppresses polycystic kidney disease via inhibition of PI3K/Akt-dependent mTORC1 signaling. Human molecular genetics 46 27056978
2015 MKS1 regulates ciliary INPP5E levels in Joubert syndrome. Journal of medical genetics 42 26490104
2015 Role of reverse phenotyping in interpretation of next generation sequencing data and a review of INPP5E related disorders. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society 42 26748598
2016 The Joubert Syndrome Protein Inpp5e Controls Ciliogenesis by Regulating Phosphoinositides at the Apical Membrane. Journal of the American Society of Nephrology : JASN 41 27401686
2017 A compartmentalized phosphoinositide signaling axis at cilia is regulated by INPP5E to maintain cilia and promote Sonic Hedgehog medulloblastoma. Oncogene 40 28650469
2016 Prenylated retinal ciliopathy protein RPGR interacts with PDE6δ and regulates ciliary localization of Joubert syndrome-associated protein INPP5E. Human molecular genetics 37 28172980
2012 Evidence of a role of inositol polyphosphate 5-phosphatase INPP5E in cilia formation in zebrafish. Vision research 35 23022135
1999 Pharbin, a novel inositol polyphosphate 5-phosphatase, induces dendritic appearances in fibroblasts. Biochemical and biophysical research communications 35 10405344
2021 Deletion of the phosphatase INPP5E in the murine retina impairs photoreceptor axoneme formation and prevents disc morphogenesis. The Journal of biological chemistry 25 33711342
2022 Multiple ciliary localization signals control INPP5E ciliary targeting. eLife 23 36063381
2021 The autophagy protein ATG16L1 cooperates with IFT20 and INPP5E to regulate the turnover of phosphoinositides at the primary cilium. Cell reports 23 33910006
2020 The ciliary phosphatidylinositol phosphatase Inpp5e plays positive and negative regulatory roles in Shh signaling. Development (Cambridge, England) 21 31964774
2018 Mechanism and dynamics of INPP5E transport into and inside the ciliary compartment. Biological chemistry 21 29140789
2017 Defective ciliogenesis in INPP5E-related Joubert syndrome. American journal of medical genetics. Part A 21 29052317
2016 Regulation of lysosomal phosphoinositide balance by INPP5E is essential for autophagosome-lysosome fusion. Autophagy 21 27715391
2021 Broadening INPP5E phenotypic spectrum: detection of rare variants in syndromic and non-syndromic IRD. NPJ genomic medicine 20 34188062
2020 A transient role of the ciliary gene Inpp5e in controlling direct versus indirect neurogenesis in cortical development. eLife 19 32840212
2021 INPP5E controls ciliary localization of phospholipids and the odor response in olfactory sensory neurons. Journal of cell science 18 33771931
2020 Defective INPP5E distribution in NPHP1-related Senior-Loken syndrome. Molecular genetics & genomic medicine 17 33306870
2014 Inpp5e increases the Rab5 association and phosphatidylinositol 3-phosphate accumulation at the phagosome through an interaction with Rab20. The Biochemical journal 17 25269936
2019 Induction of an Alternative mRNA 5' Leader Enhances Translation of the Ciliopathy Gene Inpp5e and Resistance to Oncolytic Virus Infection. Cell reports 16 31851930
2017 Upregulation of miR‑598 promotes cell proliferation and cell cycle progression in human colorectal carcinoma by suppressing INPP5E expression. Molecular medicine reports 16 29257251
2021 The Major Ciliary Isoforms of RPGR Build Different Interaction Complexes with INPP5E and RPGRIP1L. International journal of molecular sciences 15 33808286
2022 The ciliary gene INPP5E confers dorsal telencephalic identity to human cortical organoids by negatively regulating Sonic hedgehog signaling. Cell reports 14 35584663
2022 Phylogenetic profiling and cellular analyses of ARL16 reveal roles in traffic of IFT140 and INPP5E. Molecular biology of the cell 13 35196065
2011 Regulation of IGF-1/PI3K/Akt signalling by the phosphoinositide phosphatase pharbin. Journal of biochemistry 12 21436142
2022 TMEM67 is required for the gating function of the transition zone that controls entry of membrane-associated proteins ARL13B and INPP5E into primary cilia. Biochemical and biophysical research communications 11 36334440
2019 BBS5 and INPP5E mutations associated with ciliopathy disorders in families from Pakistan. Annals of human genetics 11 31173343
2022 INPP5E and Coordination of Signaling Networks in Cilia. Frontiers in molecular biosciences 10 35463949
2017 INPP5E Preserves Genomic Stability through Regulation of Mitosis. Molecular and cellular biology 9 28031327
2021 Novel Insights Into Monogenic Obesity Syndrome Due to INPP5E Gene Variant: A Case Report of a Female Patient. Frontiers in endocrinology 8 34211432
2021 Down-Regulation of Inpp5e Associated With Abnormal Ciliogenesis During Embryonic Neurodevelopment Under Inositol Deficiency. Frontiers in neurology 7 34093381
2018 A splice site variant in INPP5E causes diffuse cystic renal dysplasia and hepatic fibrosis in dogs. PloS one 7 30235266
2023 INPP5E regulates CD3ζ enrichment at the immune synapse by phosphoinositide distribution control. Communications biology 6 37670137
2017 A Homozygous Missense Variant in INPP5E Associated with Joubert Syndrome and Related Disorders. Molecular syndromology 6 29230161
2025 Inpp5e is crucial for photoreceptor outer segment maintenance. Journal of cell science 4 39871753
2024 Inpp5e Regulated the Cilium-Related Genes Contributing to the Neural Tube Defects Under 5-Fluorouracil Exposure. Molecular neurobiology 4 38285286
2025 Regulation of INPP5E in Ciliogenesis, Development, and Disease. International journal of biological sciences 3 39781470
2024 Utilization of automated cilia analysis to characterize novel INPP5E variants in patients with non-syndromic retinitis pigmentosa. European journal of human genetics : EJHG 3 38806661
2025 Longitudinal Multimodal Assessment of Structure and Function in INPP5E-Related Retinopathy. Genes 1 41465079
2024 INPP5E Regulates the Distribution of Phospholipids on Cilia in RPE1 Cells. Journal of clinical laboratory analysis 1 38514901
2026 The EH Binding protein EHBP1 operates in a ciliary functional module affected by INPP5E dysfunction. Journal of cell science 0 41805112
2026 ICMT supports BRAFV600E-driven tumor growth by membrane targeting of the CAAX protein INPP5E. Proceedings of the National Academy of Sciences of the United States of America 0 42127111
2024 Inpp5e Is Critical for Photoreceptor Outer Segment Maintenance. bioRxiv : the preprint server for biology 0 39253441

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