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INPP5B

Type II inositol 1,4,5-trisphosphate 5-phosphatase · UniProt P32019

Length
993 aa
Mass
112.9 kDa
Annotated
2026-06-10
18 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

INPP5B is an inositol polyphosphate 5-phosphatase that hydrolyzes PI(4,5)P2 (and the soluble substrate IP3 to IP2) to drive membrane remodeling and receptor signaling across multiple cellular contexts (PMID:8125013, PMID:35878408). It is recruited as a Rab5 effector through the adaptor APPL1 to nascent phagosomes and to circular membrane ruffles, where PI(4,5)P2 hydrolysis terminates actin assembly and enables phagosome and macropinosome sealing/scission; loss of the phosphatase or APPL1 prolongs PI(4,5)P2 and actin retention and accentuates Akt activation (PMID:22072788, PMID:33722976). At the B cell plasma membrane, antigen-triggered PI(4,5)P2 dephosphorylation by INPP5B promotes cofilin-mediated actin severing and reduces ezrin-dependent actin–membrane linkage, mobilizing BCR clustering and cell spreading (PMID:35878408). INPP5B also localizes to the early secretory pathway (Golgi/ERGIC) via RAB-protein binding and functions in retrograde ERGIC-to-ER transport, and to primary cilia where it is required for ciliogenesis (PMID:17956944, PMID:23805271). It functionally overlaps with the paralog OCRL: combined loss is embryonic lethal, and tubule-specific inactivation on an Ocrl-null background impairs proximal tubule endocytosis and phenocopies Dent disease, yet INPP5B cannot substitute for OCRL1 in clathrin/AP2-dependent ruffle-mediated remodeling because it lacks clathrin/AP2 binding (PMID:9593760, PMID:27895154, PMID:19700499). In reproductive somatic tissues, INPP5B activity in Sertoli and epididymal cells is required for sperm maturation, motility, and sperm–egg fusion, with effects on ADAM protease processing (PMID:11784089, PMID:20403911). Stability of INPP5B is controlled by NIK, which recruits it into the APPL1 complex to limit ubiquitin-dependent degradation (PMID:41391683).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1994 Medium

    Establishing the molecular identity and catalytic activity of INPP5B answered what the gene encodes — a 5-phosphatase acting on inositol phosphates.

    Evidence Chromosomal mapping by somatic cell hybrids/FISH plus enzymatic substrate characterization (IP3 to IP2)

    PMID:8125013

    Open questions at the time
    • Does not address membrane phosphoinositide substrates
    • No cellular localization or pathway context
  2. 1998 High

    Genetic knockouts answered whether INPP5B has an essential in vivo role and how it relates to its paralog, revealing redundancy with Ocrl1 and a non-redundant requirement in testis.

    Evidence Single and double Inpp5b/Ocrl1 knockout mice with epistasis analysis

    PMID:9593760

    Open questions at the time
    • Molecular basis of compensation not defined
    • Cell-type origin of testicular defect unresolved
  3. 2001 High

    Conditional knockouts answered where in the reproductive system INPP5B acts, localizing the requirement to somatic Sertoli/epididymal cells rather than germ cells and linking it to ADAM2 processing.

    Evidence Conditional and germline knockout mice, IVF assays, ADAM2 immunoblotting, motility analysis

    PMID:11784089

    Open questions at the time
    • Direct phosphoinositide substrate in epididymis not measured
    • Mechanism connecting lipid phosphatase to protease processing unclear
  4. 2007 Medium

    Localization and RAB-binding analysis answered where INPP5B operates in the secretory system and how it differs from OCRL1, placing it at the Golgi/ERGIC in retrograde transport.

    Evidence Fractionation, immunofluorescence, RAB co-IP, BFA and low-temperature transport assays, mutational analysis

    PMID:17956944

    Open questions at the time
    • Which RAB(s) mediate targeting not fully resolved
    • Single-lab observation
  5. 2009 Medium

    Rescue experiments answered why INPP5B cannot replace OCRL1 in Lowe syndrome cells, tracing functional non-equivalence to the absence of AP2/clathrin binding.

    Evidence Rescue in patient fibroblasts with WT/mutant constructs, migration/spreading assays, phosphatase-dead controls

    PMID:19700499

    Open questions at the time
    • Structural basis of differential adaptor binding not defined
    • Single lab
  6. 2011 High

    Phagosome studies answered how INPP5B is targeted to dynamic membranes, identifying APPL1-mediated recruitment as a Rab5 effector that controls PI(4,5)P2 and actin clearance.

    Evidence siRNA knockdown, live imaging of phosphoinositide dynamics, co-IP, dominant-negative Rab5, phagocytosis assays

    PMID:22072788

    Open questions at the time
    • Relative contributions of OCRL vs INPP5B not separated
    • Direct phosphatase–APPL1 contact not mapped
  7. 2013 Medium

    Ciliogenesis assays answered whether INPP5B has a role beyond endosomal trafficking, establishing a requirement in primary cilium formation across cells and zebrafish.

    Evidence siRNA knockdown, zebrafish morpholino, cilia formation and melanosome transport assays

    PMID:23805271

    Open questions at the time
    • Phosphoinositide substrate at cilium not defined
    • Morpholino-based zebrafish data
  8. 2016 High

    Tubule-specific double knockouts answered the physiological consequence of OCRL/INPP5B redundancy in kidney, showing combined loss impairs proximal tubule endocytosis and phenocopies Dent disease.

    Evidence Kidney tubule-specific Inpp5b KO on Ocrl-null background, urine biochemistry, EM, endocytosis assays

    PMID:27895154

    Open questions at the time
    • INPP5B-specific contribution distinct from OCRL not isolated
    • Endocytic substrate selectivity not mapped
  9. 2021 High

    Macropinocytosis imaging answered the precise step at which the phosphatases act, placing PI(4,5)P2 hydrolysis downstream of ruffle formation at the sealing/scission step.

    Evidence siRNA of OCRL/Inpp5b and APPL1, live PI(4,5)P2 imaging, dominant-negative Rab5, SNARE inhibition, PIP5K overexpression

    PMID:33722976

    Open questions at the time
    • INPP5B vs OCRL functional division not resolved
    • Scission machinery linkage not detailed
  10. 2022 High

    B cell studies answered how INPP5B couples PI(4,5)P2 turnover to receptor signaling, linking dephosphorylation to cofilin/ezrin-dependent actin remodeling and BCR clustering.

    Evidence Knockdown/knockout in B cells, BCR clustering and spreading assays, PI(4,5)P2 imaging, cofilin/ezrin functional assays

    PMID:35878408

    Open questions at the time
    • Recruitment mechanism to BCR sites not defined
    • In vivo immune consequence not tested
  11. 2025 Medium

    Stability studies answered how INPP5B protein levels are controlled, identifying NIK-driven recruitment into APPL1 as a mechanism limiting ubiquitin-dependent degradation with downstream effects on AKT/lipogenesis.

    Evidence Co-IP, ubiquitination immunoblotting, NIK hepatocyte-specific KO mice, omics, in vivo and in vitro loss-of-function

    PMID:41391683

    Open questions at the time
    • E3 ligase targeting INPP5B not identified
    • Single lab
  12. 2026 Low

    PCIF1 manipulation studies raised the possibility that INPP5B influences PI(3,4)P2 levels and AKT-dependent invasion in glioblastoma.

    Evidence PCIF1 knockdown/overexpression, PI(3,4)P2 measurement, AKT immunoblotting, migration/invasion assays

    PMID:42145053

    Open questions at the time
    • INPP5B-specific mechanism inferred indirectly from PCIF1 context
    • Direct PI(3,4)P2 phosphatase activity of INPP5B not demonstrated here
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the division of labor between INPP5B and OCRL is established at distinct membranes, and what determines INPP5B substrate selectivity in vivo, remains unresolved.
  • No structural model of INPP5B substrate/adaptor selectivity
  • Tissue-specific substrate preference (PI(4,5)P2 vs PI(3,4)P2 vs IP3) not systematically mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 4 GO:0140098 catalytic activity, acting on RNA 1
Localization
GO:0005783 endoplasmic reticulum 1 GO:0005794 Golgi apparatus 1 GO:0005886 plasma membrane 1 GO:0005929 cilium 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 2
Partners
APPL1NIKOCRLRAB5
Complex memberships
APPL1 complex

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 Inpp5b encodes a phosphatidylinositol bisphosphate 5-phosphatase that has functionally overlapping activity with Ocrl1 in vivo; double knockout of both Ocrl1 and Inpp5b causes early embryonic lethality in mice, whereas single Inpp5b knockout mice are viable but show testicular degeneration in males, demonstrating that Inpp5b provides compensatory PI(4,5)P2 5-phosphatase activity in the absence of Ocrl1. Targeted gene disruption in mice (single and double knockout), genetic epistasis The Journal of clinical investigation High 9593760
2007 INPP5B localizes to the early secretory pathway (Golgi apparatus and ERGIC) via binding to specific RAB proteins; mutational analysis showed RAB binding is required for efficient Golgi targeting. Unlike OCRL1, INPP5B does not interact with clathrin or alpha-adaptin. Expression of INPP5B (but not OCRL1) causes accumulation of ERGIC53 in the ERGIC under conditions that block retrograde transport, indicating a role for INPP5B in retrograde ERGIC-to-ER transport. Subcellular fractionation, immunofluorescence localization, mutational analysis, co-immunoprecipitation with RAB proteins, brefeldin A and low-temperature transport assays Journal of cell science Medium 17956944
2009 INPP5B cannot rescue OCRL1-dependent cell migration and spreading defects in Lowe syndrome patient fibroblasts, in contrast to wild-type OCRL1; this functional non-equivalence is linked to the absence of AP2/clathrin binding by INPP5B, as OCRL1 variants lacking AP2/clathrin binding are similarly unable to rescue. INPP5B therefore lacks the ruffle-mediated membrane remodeling function of OCRL1. Rescue experiments in patient-derived fibroblasts with wild-type and mutant constructs, cell migration and spreading assays, phosphatase-dead mutant controls Human molecular genetics Medium 19700499
2011 OCRL and Inpp5B are recruited to nascent phagosomes as Rab5 effectors via the adaptor protein APPL1, where they hydrolyze PtdIns(4,5)P2; knockdown of APPL1 or inhibition of Rab5 impairs phagosomal recruitment of both phosphatases, prolongs PtdIns(4,5)P2 and actin presence on phagosomal membranes, and accentuates Akt activation. Knockdown (siRNA), live-cell imaging of phosphoinositide dynamics, co-immunoprecipitation, dominant-negative Rab5, phagocytosis assays Molecular biology of the cell High 22072788
2001 Inpp5b is expressed in Sertoli cells and epididymal epithelial cells; its deficiency in these somatic cells (not in spermatids themselves, as shown by conditional knockout) causes reduced sperm motility, impaired sperm-egg membrane fusion, and defective proteolytic processing of fertilin beta (ADAM2) during epididymal sperm maturation, revealing a role for phosphoinositides in sperm maturation. Conditional and germline knockout mice, in vitro fertilization assays, immunoblotting for ADAM2 processing, sperm motility analysis Developmental biology High 11784089
2010 In Inpp5b-null sperm, ADAM2 and ADAM3 proteolytic cleavage are only modestly and variably impaired between individual males; reduced fertilization correlates with impaired sperm binding to and fusion with the egg plasma membrane; IZUMO1 localization appears normal in Inpp5b-null sperm, indicating the fusion defect is not due to mislocalization of this fusogen. In vitro fertilization assays, mating trials, immunofluorescence for IZUMO1, immunoblotting for ADAM2/ADAM3, multivariate correlation analysis Molecular human reproduction Medium 20403911
2013 INPP5B localizes to primary cilia in human retinal pigmented epithelial cells; silencing INPP5B causes defects in cilia formation in cultured cells and in zebrafish Kupffer's vesicles (inpp5b morphants), and impairs cilia-dependent melanosome transport, demonstrating a functional role for INPP5B in primary ciliogenesis. siRNA knockdown with immunofluorescence, morpholino knockdown in zebrafish, cilia formation assay, melanosome transport assay PloS one Medium 23805271
2016 Kidney tubule-specific inactivation of Inpp5b on a global Ocrl-knockout background causes low molecular weight proteinuria, phosphaturia, and acidemia, with striking impairment of both clathrin-dependent and clathrin-independent endocytosis in proximal tubules, phenocopying Dent disease. This establishes that OCRL and INPP5B have redundant functions in maintaining proximal tubule endocytic function. Conditional double knockout mice (kidney tubule-specific Inpp5b KO on Ocrl-null background), urine biochemistry, electron microscopy, endocytosis assays in proximal tubule cells Journal of the American Society of Nephrology High 27895154
2021 Rab5 recruits OCRL and Inpp5b to circular membrane ruffles via APPL1, where the phosphatases hydrolyze PtdIns(4,5)P2 to promote macropinosome sealing and scission; knockdown of both phosphatases or APPL1 prevents macropinosome closure without affecting ruffle formation, indicating the phosphatases act downstream of ruffling specifically at the sealing step. siRNA knockdown of OCRL/Inpp5b and APPL1, live-cell imaging of PtdIns(4,5)P2 dynamics, dominant-negative Rab5, SNARE inhibition, phosphatidylinositol-4-phosphate 5-kinase overexpression Journal of cell science High 33722976
2022 INPP5B regulates B cell receptor (BCR) clustering and downstream signaling by dephosphorylating PI(4,5)P2 at the plasma membrane upon antigen stimulation; PI(4,5)P2 hydrolysis by INPP5B promotes actin disassembly via cofilin severing and reduces actin-plasma membrane linkage via ezrin, enabling BCR mobilization and cell spreading. INPP5B knockdown and knockout in B cells, BCR clustering assays, PI(4,5)P2 imaging, actin dynamics measurements, cofilin and ezrin functional assays, antigen-coated surface spreading assay The Journal of cell biology High 35878408
2025 NIK (NF-κB-inducing kinase) stabilizes INPP5B by recruiting it into the APPL1 adaptor complex, thereby reducing INPP5B ubiquitination and proteasomal degradation; stabilized INPP5B suppresses AKT signaling to reduce ACLY-mediated lipogenesis in liver during chronic ethanol exposure. Co-immunoprecipitation, immunoblotting for ubiquitination, NIK hepatocyte-specific knockout mice, transcriptomics and proteomics, loss-of-function in vivo and in vitro Life sciences Medium 41391683
2026 PCIF1 knockdown upregulates INPP5B, causing accumulation of PI(3,4)P2 and enhanced AKT activation in glioblastoma cells; this indicates that INPP5B, as a lipid 5-phosphatase, influences PI(3,4)P2 levels and thereby modulates AKT-dependent cell migration and invasion. PCIF1 knockdown/overexpression, PI(3,4)P2 measurement, immunoblotting for AKT activation, cell migration and invasion assays Acta biochimica et biophysica Sinica Low 42145053
1994 The INPP5B gene (encoding the 75-kDa type II inositol polyphosphate-5-phosphatase originally described in platelets) was mapped to human chromosome band 1p34 using somatic cell hybrids and fluorescence in situ hybridization; the enzyme dephosphorylates inositol-1,4,5-trisphosphate (IP3) to inositol-1,4-bisphosphate (IP2). Somatic cell hybrid panel, fluorescence in situ hybridization, enzymatic characterization Cytogenetics and cell genetics Medium 8125013

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Functional overlap between murine Inpp5b and Ocrl1 may explain why deficiency of the murine ortholog for OCRL1 does not cause Lowe syndrome in mice. The Journal of clinical investigation 137 9593760
2011 Recruitment of OCRL and Inpp5B to phagosomes by Rab5 and APPL1 depletes phosphoinositides and attenuates Akt signaling. Molecular biology of the cell 115 22072788
2009 Lowe syndrome patient fibroblasts display Ocrl1-specific cell migration defects that cannot be rescued by the homologous Inpp5b phosphatase. Human molecular genetics 47 19700499
2007 Targeting of the type II inositol polyphosphate 5-phosphatase INPP5B to the early secretory pathway. Journal of cell science 43 17956944
2013 Compensatory Role of Inositol 5-Phosphatase INPP5B to OCRL in Primary Cilia Formation in Oculocerebrorenal Syndrome of Lowe. PloS one 41 23805271
2001 Disrupted sperm function and fertilin beta processing in mice deficient in the inositol polyphosphate 5-phosphatase Inpp5b. Developmental biology 36 11784089
2010 Species-specific difference in expression and splice-site choice in Inpp5b, an inositol polyphosphate 5-phosphatase paralogous to the enzyme deficient in Lowe Syndrome. Mammalian genome : official journal of the International Mammalian Genome Society 33 20872266
2014 OCRL-mutated fibroblasts from patients with Dent-2 disease exhibit INPP5B-independent phenotypic variability relatively to Lowe syndrome cells. Human molecular genetics 31 25305077
2021 Rab5 regulates macropinocytosis by recruiting the inositol 5-phosphatases OCRL and Inpp5b that hydrolyse PtdIns(4,5)P2. Journal of cell science 30 33722976
2016 Kidney Tubular Ablation of Ocrl/Inpp5b Phenocopies Lowe Syndrome Tubulopathy. Journal of the American Society of Nephrology : JASN 24 27895154
2010 Multivariate analysis of male reproductive function in Inpp5b-/- mice reveals heterogeneity in defects in fertility, sperm-egg membrane interaction and proteolytic cleavage of sperm ADAMs. Molecular human reproduction 19 20403911
2022 The inositol 5-phosphatase INPP5B regulates B cell receptor clustering and signaling. The Journal of cell biology 11 35878408
2010 X-inactivation analysis of embryonic lethality in Ocrl wt/-; Inpp5b-/- mice. Mammalian genome : official journal of the International Mammalian Genome Society 11 20195868
1994 Localization of the 75-kDa inositol polyphosphate-5-phosphatase (INPP5B) to human chromosome band 1p34. Cytogenetics and cell genetics 7 8125013
1995 Mapping of the 75-kDa inositol polyphosphate-5-phosphatase (Inpp5b) to distal mouse chromosome 4 and its exclusion as a candidate gene for dysgenetic lens. Genomics 6 8530037
2025 The inositol 5-phosphatases OCRL and INPP5B: Cellular functions and roles in disease. Biochimica et biophysica acta. Molecular and cell biology of lipids 3 40618840
2025 NIK suppresses AKT/ACLY pathway-mediated lipogenesis in liver by stabilizing INPP5B during chronic ethanol exposure. Life sciences 1 41391683
2026 PCIF1 modulates glioblastoma cell migration and invasion by altering PI(3,4)P2 levels through the PI5-phosphatase INPP5B. Acta biochimica et biophysica Sinica 0 42145053

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