Affinage

INPP4B

Inositol polyphosphate 4-phosphatase type II · UniProt O15327

Length
924 aa
Mass
104.7 kDa
Annotated
2026-06-10
77 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

INPP4B is a dual-specificity phosphoinositide phosphatase whose principal biochemical activity is hydrolysis of PI(3,4)P2 to PI(3)P, with additional direct PtdIns(3,4,5)P3 3-phosphatase activity and an intrinsic protein tyrosine phosphatase activity—the lipid and protein phosphatase functions being separable through distinct catalytic-site residues (K846 for lipid, D847 for protein activity) (PMID:24070612, PMID:25883023). Through these activities it negatively regulates PI3K/AKT signaling, and combined loss of Inpp4b and Pten synergistically elevates PtdIns(3,4,5)P3 and AKT activation to drive metastatic thyroid cancer, establishing INPP4B as a tumor suppressor that acts non-epistatically with PTEN (PMID:25883022, PMID:25883023). Its functional output is governed by subcellular localization: at late endosomes, Rab7-dependent INPP4B converts PI(3,4)P2 to PI(3)P to drive lysosomal GSK3β degradation and Wnt/β-catenin signaling, and the same PI(3,4)P2-to-PI(3)P conversion activates SGK3 (downstream of PIK3CA) to promote proliferation, invasion, and tumorigenesis in a manner independent of AKT (PMID:25458846, PMID:34035258, PMID:29343273). INPP4B controls endosomal phosphoinositide pools that regulate receptor trafficking—restraining EGFR/MET recycling and signaling duration and enabling TGFβ receptor endocytosis and Smad2/3 activation—and maintains lysosomal homeostasis and autophagy by limiting VPS34-driven lysosomal PtdIns(3)P (PMID:32513774, PMID:31913757, PMID:35760104). Beyond cancer cell signaling, INPP4B suppresses hepatic AKT/PKC signaling and SREBP1 cleavage to maintain insulin sensitivity and restrain lipogenesis, and supports AKT-dependent survival of tissue-resident ILC1s and B-1 cells (PMID:33772116, PMID:38197946, PMID:37389566). Its expression is transcriptionally controlled in a context-specific manner by androgen receptor/NCoR, ERβ1, Ets-1, and IRF2 (PMID:21224358, PMID:26411369, PMID:28579269, PMID:33020300).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 2006 Medium

    Established INPP4B's domain architecture and isoform-specific localization, framing it as a lipid-interacting phosphatase with potentially distinct cytosolic versus Golgi functions.

    Evidence cDNA isolation, C2-domain lipid-binding assays, and subcellular fractionation/imaging of two isoforms

    PMID:16631325

    Open questions at the time
    • Catalytic substrate not directly demonstrated in this study
    • Functional consequence of isoform localization untested
  2. 2011 Medium

    Demonstrated that INPP4B dephosphorylates PI(3,4)P2 to suppress AKT and proliferation, and that androgen receptor/NCoR drives its expression, positioning it as a PI3K/AKT tumor suppressor.

    Evidence siRNA knockdown with p-Akt Western blot and AR/NCoR transcriptional induction assays in prostate cancer cells

    PMID:21224358

    Open questions at the time
    • Did not address direct PIP3 hydrolysis
    • In vivo tumor suppression not tested here
  3. 2013 High

    Resolved that INPP4B carries separable lipid and protein tyrosine phosphatase activities through distinct active-site residues, expanding its enzymatic repertoire beyond a single lipid substrate.

    Evidence In vitro pNPP/DiFMUP assays with systematic CX5R-motif mutagenesis and Akt1 tyrosine-phosphorylation readout

    PMID:24070612

    Open questions at the time
    • Physiological protein substrates of the PTP activity not identified
    • Relative cellular contribution of each activity unquantified
  4. 2013 Medium

    Linked INPP4B to metabolic reprogramming, showing it can promote aerobic glycolysis and radioresistance via Akt-mTOR-driven HK2, an early sign of context-dependent oncogenic output.

    Evidence Overexpression/knockdown, glycolysis and HK2 measurement, pathway inhibitor and co-depletion experiments in laryngeal cancer cells

    PMID:24051093

    Open questions at the time
    • Mechanism reconciling AKT suppression vs Akt-mTOR-HK2 activation unclear
    • Single cancer context
  5. 2014 High

    Identified SGK3 as an AKT-independent effector of INPP4B, explaining how INPP4B can promote proliferation, invasion, and tumorigenesis while suppressing AKT.

    Evidence Reciprocal gain/loss-of-function, 3D proliferation/invasion assays, in vivo tumorigenesis, and p-SGK3/NDRG1 readouts

    PMID:25458846

    Open questions at the time
    • Lipid product (PI(3)P) driving SGK3 not directly measured here
    • Subcellular site of SGK3 activation not defined
  6. 2014 Medium

    Showed INPP4B can suppress invasion through PKC rather than PI3K/Akt, broadening its effector landscape beyond phosphoinositide-AKT signaling.

    Evidence De novo expression in PC-3 cells, invasion assays, gene expression profiling, and PKC vs PI3K/Akt inhibitor comparisons

    PMID:25248616

    Open questions at the time
    • Direct biochemical link between INPP4B and PKC not established
    • Whether effect depends on lipid or protein phosphatase activity untested
  7. 2015 High

    Established INPP4B as a bona fide tumor suppressor with direct PIP3 3-phosphatase activity that acts non-epistatically with PTEN in vivo.

    Evidence Two concurrent studies: direct in vitro PIP3 dephosphorylation, endosomal localization, isoform-specific AKT2 inhibition, and Pten+/-×Inpp4b-/- mouse thyroid cancer models

    PMID:25883022 PMID:25883023

    Open questions at the time
    • Relative in vivo contribution of PI(3,4)P2 vs PIP3 hydrolysis unresolved
    • Why AKT2 but not AKT1 is targeted mechanistically unclear
  8. 2015 Medium

    Implicated INPP4B in DNA repair by showing it stabilizes a BRCA1/ATM/ATR complex and confers PARP-inhibitor sensitivity when lost.

    Evidence GST pulldown and 293T co-overexpression, comet/γH2AX/RAD51/53BP1 foci, and PARP inhibitor sensitivity in xenografts

    PMID:25868852

    Open questions at the time
    • Interaction shown by overexpression Co-IP without reciprocal endogenous validation
    • Mechanism by which a phosphatase stabilizes repair proteins unknown
  9. 2015 Medium

    Revealed an oncogenic, phosphatase-dependent but Akt-independent role for INPP4B in conferring AML chemoresistance, formalizing its context-dependent duality.

    Evidence Wild-type vs phosphatase-dead C842A overexpression in drug resistance assays in vitro and in xenografts

    PMID:25736313

    Open questions at the time
    • Downstream effector of the Akt-independent resistance not defined here
    • Relevant phosphoinositide product not measured
  10. 2015 Medium

    Showed Ets-1-driven INPP4B promotes Akt and SGK3 activation in colon cancer, reinforcing transcriptional control and the SGK3 oncogenic axis.

    Evidence Ets-1 promoter assays, knockdown/overexpression, p-Akt/p-SGK3 Westerns, and xenograft growth

    PMID:26411369

    Open questions at the time
    • Claimed PTEN inactivation via protein phosphatase activity not biochemically demonstrated
    • Direct substrate undefined
  11. 2016 Medium

    Connected INPP4B chemoresistance in AML to ATM-dependent DNA repair via an NF-κB(p65)-to-ATM relay, linking the resistance and DNA-repair phenotypes.

    Evidence Knockdown with DNA-repair marker Westerns, p65 nuclear localization, and p65 rescue experiments

    PMID:27342972

    Open questions at the time
    • How INPP4B phosphatase activity regulates p65 not established
    • Single lab, correlative pathway placement
  12. 2017 Medium

    Uncovered a PI(3,4)P2 negative-feedback mechanism whereby accumulated PI(3,4)P2 inhibits PI3K and modulates PI3K-inhibitor sensitivity in PTEN-null TNBC.

    Evidence Knockdown/overexpression in PTEN-null TNBC lines with p-Akt Westerns and isoform-selective PI3K inhibitor assays

    PMID:28196852

    Open questions at the time
    • Molecular target of the inhibitory PI(3,4)P2 signal not identified
    • Generalizability beyond PTEN-null context untested
  13. 2017 Medium

    Added IRF2 as an upstream transcriptional activator of INPP4B governing AML growth and apoptosis.

    Evidence IRF2 promoter binding, INPP4B rescue after IRF2 knockdown, colony formation and apoptosis assays

    PMID:28579269

    Open questions at the time
    • Direct promoter occupancy via rigorous ChIP not detailed
    • Downstream INPP4B effector in this axis unspecified
  14. 2018 Medium

    Confirmed that endosomal PI(3,4)P2-to-PI(3)P conversion by INPP4B drives SGK3-dependent survival in NPM1-mutant AML independent of Akt.

    Evidence Overexpression/knockdown, SGK3 knockdown rescue, PI(3,4)P2/PI(3)P ELISA, and ERK/Ets-1 analysis

    PMID:29343273

    Open questions at the time
    • Subcellular site of lipid conversion not imaged
    • How SGK3 promotes survival downstream not detailed
  15. 2019 Medium

    Demonstrated that Inpp4b loss cooperates with SV40 T-Large to promote transformation via elevated p-Akt, but is insufficient alone, defining it as a context-dependent suppressor.

    Evidence MEF transformation assays with Inpp4b knockout/overexpression across oncogene combinations and p-Akt Westerns

    PMID:31695845

    Open questions at the time
    • Mechanism of cooperativity with T-Large not dissected
    • Specific lipid substrate change not measured
  16. 2020 High

    Defined the late-endosomal, Rab7-anchored pool of INPP4B that produces PI(3)P to drive lysosomal GSK3β degradation and oncogenic Wnt/β-catenin signaling in PIK3CA-mutant breast cancer.

    Evidence Integrated proteomics/imaging, Rab7 interaction, phosphoinositide measurement, GSK3β degradation, Wnt reporters, Hrs-depletion rescue, and in vivo growth

    PMID:34035258

    Open questions at the time
    • Determinants of late- vs early-endosomal targeting incompletely defined
    • Generalizability beyond PIK3CA-mutant ER+ breast cancer untested
  17. 2020 High

    Showed INPP4B restrains endocytic PI(3,4)P2 to limit EGFR/MET recycling and signaling duration, with its loss amplifying both AKT and MEK/ERK in TNBC.

    Evidence INPP4B-knockout TNBC mouse model, phosphoinositide localization, RTK pulse-chase trafficking, and PI3K/MEK inhibitor sensitivity in vivo

    PMID:32513774

    Open questions at the time
    • Direct adaptor linking INPP4B to specific RTK endosomes not identified
    • Whether protein phosphatase activity contributes unaddressed
  18. 2020 Medium

    Established that INPP4B is required for TGFβ receptor endocytosis and Smad2/3 activation through sequential phosphoinositide conversion with synaptojanin1 and PI3K-C2α.

    Evidence siRNA knockdown of pathway components, live-cell phosphoinositide imaging, receptor endocytosis and Smad phosphorylation assays

    PMID:31913757

    Open questions at the time
    • Direct enzymatic ordering at the membrane inferred, not reconstituted
    • Single-lab knockdown evidence
  19. 2020 Medium

    Identified ERβ1 as an androgen-independent transcriptional inducer of INPP4B that suppresses Akt and migration in prostate cancer.

    Evidence ERβ1 engineering and ligand treatment in PC3 cells with INPP4B/p-Akt Westerns and migration assays

    PMID:33020300

    Open questions at the time
    • Direct ERβ1 promoter binding not shown
    • In vivo relevance untested
  20. 2021 High

    Extended INPP4B function to whole-body metabolism, showing it suppresses hepatic AKT/PKC and SREBP1 cleavage to maintain insulin sensitivity and restrain lipogenesis.

    Evidence Inpp4b knockout mice on high-fat diet with SREBP1 cleavage analysis, AKT/PKC Westerns, metabolic phenotyping, and histology

    PMID:33772116

    Open questions at the time
    • Mechanistic link between INPP4B and SREBP1 protease not defined
    • Tissue-specific contributions not separated
  21. 2022 High

    Revealed INPP4B's requirement for lysosomal homeostasis and autophagy by limiting VPS34-driven lysosomal PtdIns(3)P.

    Evidence Inpp4b-deficient MEFs with PIKfyve inhibition, lysosome imaging, HPLC PtdIns quantification, and VPS34 activity assays

    PMID:35760104

    Open questions at the time
    • How INPP4B suppresses VPS34 activity mechanistically unclear
    • Relationship to its own PI(3)P-generating activity not reconciled
  22. 2023 Medium

    Showed INPP4B, distinct from PTEN, supports EZH2 expression and H3 methylation and engages a unique set of downstream effectors in prostate cells.

    Evidence Knockdown in prostate cancer lines and Inpp4b knockout mouse prostate analysis with EZH2/H3-methylation Westerns and scRNA-seq

    PMID:38001678

    Open questions at the time
    • Mechanism connecting INPP4B to EZH2 unknown
    • Correlative human data
  23. 2023 Medium

    Defined a cell-intrinsic requirement for Inpp4b in B-1 cell maintenance and antibody responses, broadening its role in immune cell homeostasis.

    Evidence Conventional Inpp4b knockout mice, adoptive transfer, flow cytometry, and CD40-mediated B cell proliferation assays

    PMID:37389566

    Open questions at the time
    • Signaling pathway underlying B-1 defect not defined
    • Whether phosphatase activity is required untested
  24. 2024 High

    Established INPP4B as a hallmark of tissue-resident ILC1s and intratumoral NK cells, required for their AKT-dependent survival and antitumor immunity.

    Evidence scRNA-seq, conditional Inpp4b knockout, apoptosis and AKT-phosphorylation assays, and intratumoral immune-cell and tumor-growth quantification

    PMID:38197946

    Open questions at the time
    • How a PI3K/AKT-suppressing phosphatase promotes AKT-dependent survival mechanistically unresolved
    • Lipid substrate in this cell type not measured
  25. 2025 Medium

    Connected INPP4B to lysosomal exocytosis, showing it drives TRPML1-dependent FN1 secretion to promote PDAC migration and invasion.

    Evidence Overexpression/knockdown in PDAC cells, FN1 secretion assays, TRPML1 inhibition/knockdown, F-actin/FAK readouts, and invasion assays

    PMID:40962057

    Open questions at the time
    • Phosphoinositide intermediate linking INPP4B to TRPML1 not identified
    • Single-lab study

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how a single phosphatase produces opposing tumor-suppressive (AKT-suppressing) and oncogenic (SGK3/Wnt-activating) outputs, and what molecular determinants direct its localization and substrate choice across cell types.
  • No unifying model linking localization to substrate selection
  • Physiological protein phosphatase substrates unidentified
  • Mechanism reconciling AKT suppression with AKT-dependent immune-cell survival unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 5 GO:0008289 lipid binding 1 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005764 lysosome 3 GO:0005768 endosome 3 GO:0005794 Golgi apparatus 1 GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-1430728 Metabolism 2 R-HSA-168256 Immune System 2 R-HSA-9612973 Autophagy 1
Partners
ATRBRCA1PIK3C2ARAB7SYNJ1
Complex memberships
BRCA1/ATM/ATR complex

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 INPP4B protein contains a consensus phosphatase catalytic site and a C2 domain; the C2 domain interacts preferentially with phosphatidic acid and PI(3,4,5)P3 lipids. Two isoforms exist: Inpp4bα is mainly cytosolic, while Inpp4bβ localizes to the Golgi apparatus, suggesting distinct cellular functions for each isoform. cDNA isolation, domain characterization, lipid-binding assay (C2 domain binding to lipid panels), subcellular localization by fractionation/imaging Gene Medium 16631325
2011 INPP4B dephosphorylates phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2), leading to reduced Akt phosphorylation and activity. In prostate cancer cells, androgen receptor (AR) induces INPP4B expression (but not PTEN), and this induction requires the transcriptional coactivator NCoR. INPP4B depletion activated Akt and increased cellular proliferation. siRNA knockdown, Western blot for p-Akt, reporter/expression assays for AR-mediated induction, NCoR co-activator studies Cancer research Medium 21224358
2013 INPP4B has protein tyrosine phosphatase (PTP) activity in addition to lipid phosphatase activity, demonstrated by dephosphorylation of synthetic phosphotyrosine analogs (pNPP and DiFMUP). Mutagenesis of the catalytic site (CX5R motif, C842KSAKDR): K843M increased pNPP hydrolysis; K846M abolished lipid phosphatase activity without affecting PTP activity; D847E ablated PTP activity and significantly reduced lipid phosphatase activity. INPP4B, but not PTEN, reduced tyrosine phosphorylation of Akt1, with both lipid and protein phosphatase activities contributing. In vitro phosphatase assays (pNPP, DiFMUP), site-directed mutagenesis of catalytic residues, Western blot for Akt1 tyrosine phosphorylation Biochemical and biophysical research communications High 24070612
2014 SGK3 is activated downstream of PIK3CA in a manner dependent on INPP4B. INPP4B expression enhances SGK3 activation while suppressing Akt phosphorylation. SGK3 activation downstream of PIK3CA/INPP4B is required for 3D proliferation, invasive migration, and tumorigenesis in vivo. SGK3 targets the metastasis suppressor NDRG1 for degradation by Fbw7. Overexpression and knockdown studies, in vitro 3D proliferation and invasion assays, in vivo tumorigenesis, Western blot for p-SGK3 and p-Akt Molecular cell High 25458846
2015 INPP4B is enriched at early endosomes in thyroid cancer cells, where it selectively inhibits AKT2 (but not AKT1) activation, suppressing tumor proliferation and anchorage-independent growth. INPP4B and PTEN do not act epistatically in thyroid oncogenesis; combined heterozygous Pten loss and Inpp4b deletion in mice produces lethal metastatic follicular thyroid cancer, while single knockouts do not. Subcellular fractionation/immunofluorescence (endosome localization), genetic mouse models (Pten+/- × Inpp4b-/-), isoform-specific Akt activation assays, 3D growth assays Cancer discovery High 25883022
2015 INPP4B directly dephosphorylates PtdIns(3,4,5)P3 (PIP3) in vitro, acting as a PIP3 3-phosphatase. In vivo, combined Inpp4b deletion and Pten heterozygosity synergistically increases PtdIns(3,4,5)P3 levels and activates downstream AKT signaling in thyroid cells, inducing malignant thyroid cancer with lung metastases. In vitro phosphatase assay (direct PIP3 dephosphorylation), mouse genetic models (Inpp4bΔ/Δ and Pten+/-), phosphoinositide mass measurement Cancer discovery High 25883023
2015 Loss of INPP4B causes a DNA repair defect associated with reduced BRCA1, ATM, and ATR protein stability. INPP4B forms a protein complex with ATR and BRCA1 (demonstrated by GST pulldown and 293T overexpression assays). INPP4B-deficient cells show increased sensitivity to PARP inhibitors comparable to BRCA1 loss, both in vitro and in vivo xenograft models. GST pulldown, co-overexpression assays in 293T cells, comet assay, γH2AX/RAD51/53BP1 foci quantification, PARP inhibitor sensitivity assays in 2D/3D culture and xenografts Oncotarget Medium 25868852
2015 In AML, INPP4B overexpression confers leukemic resistance to chemotherapy (cytosine arabinoside, daunorubicin, etoposide) through a phosphatase-dependent but Akt-independent mechanism; expression of the phosphatase-dead INPP4B C842A variant failed to confer resistance in vitro or in vivo. Ectopic overexpression of wild-type vs. phosphatase-dead (C842A) INPP4B, in vitro drug resistance assays, in vivo xenograft chemotherapy resistance, siRNA knockdown Blood Medium 25736313
2015 In colon cancer cells, INPP4B upregulation is driven by Ets-1-mediated transcriptional activation. INPP4B promotes Akt and SGK3 activation in colon cancer and this is associated with inactivation of PTEN through its protein phosphatase activity. INPP4B silencing blocks Akt and SGK3 activation and inhibits colon cancer cell proliferation and xenograft growth. Ets-1 promoter activity assays, siRNA knockdown, overexpression studies, Western blot for p-Akt/p-SGK3, xenograft growth assays Oncogene Medium 26411369
2013 INPP4B-mediated resistance to irradiation in laryngeal cancer cells is associated with increased aerobic glycolysis. INPP4B overexpression enhances aerobic glycolysis through upregulation of hexokinase 2 (HK2), mediated via the Akt-mTOR pathway. Co-depletion of INPP4B and HK2 sensitizes radioresistant cells to irradiation and anticancer drugs. INPP4B overexpression/knockdown, glycolysis measurement, HK2 expression analysis, Akt-mTOR pathway inhibitor experiments, co-depletion assays Biochemical and biophysical research communications Medium 24051093
2014 INPP4B suppresses prostate cancer cell invasion in vitro and in vivo. Mechanistically, INPP4B suppresses oncogenic PKC signaling independently of the PI3K/Akt pathway, as PI3K/Akt inhibition did not reproduce INPP4B-mediated suppression of IL-8 but PKC inhibition did. INPP4B reduces phosphorylation of PKC, expression of BIRC5, and downstream target COX-2. De novo INPP4B expression in invasive PC-3 cells, in vitro invasion assays, in vivo invasion assay, global gene expression analysis, PI3K/Akt and PKC pathway inhibitor comparisons Cell communication and signaling Medium 25248616
2020 INPP4B localizes to late endosomes via interaction with Rab7 in PIK3CA-mutant ER+ breast cancer cells. This endosomal localization drives PI3Kα-dependent conversion of PI(3,4)P2 to PI(3)P on late endosomes, increasing late endosome/lysosome number and cargo trafficking, resulting in GSK3β lysosomal degradation and activation of Wnt/β-catenin signaling. INPP4B-mediated proliferation requires the PI(3)P-effector Hrs, and Wnt inhibition blocks INPP4B-driven tumor growth. Integrated proteomics/transcriptomics/imaging, Rab7 interaction assay, phosphoinositide measurement, lysosome number quantification, GSK3β degradation assay, Wnt pathway reporter assays, Hrs depletion rescue experiments, in vivo tumor growth Nature communications High 34035258
2020 INPP4B deficiency increases PI(3,4)P2 levels specifically in endocytic vesicles (not at the plasma membrane), delays EGFR and MET lysosomal degradation while promoting their recycling, thus enhancing RTK signaling duration and amplitude upon growth factor stimulation. Loss of INPP4B in TNBC increases both AKT and MEK/ERK pathway activation. INPP4B knockout mouse model (genetically engineered TNBC), phosphoinositide localization assays, EGFR/MET trafficking assays (pulse-chase, receptor recycling/degradation), PI3K and MEK inhibitor sensitivity in vivo Cancer discovery High 32513774
2020 INPP4B is required for TGFβ receptor endocytosis. Specifically, INPP4B (the 4'-phosphatase), together with synaptojanin1 and PI3K-C2α, mediates sequential phosphoinositide conversions essential for TGFβ-induced endocytosis of TGFβ receptor, Smad2 and Smad3 activation. INPP4B knockdown abolished these signaling events. siRNA-mediated knockdown of INPP4B and pathway components, live-cell phosphoinositide imaging at the plasma membrane, TGFβ receptor endocytosis assays, Smad2/3 phosphorylation assays Molecular biology of the cell Medium 31913757
2017 In PTEN-null TNBC cells, INPP4B loss decreases basal p-Akt and proliferation. Accumulated PI(3,4)P2 (when both PTEN and INPP4B are lost) acts as an inhibitory second messenger toward PI3K, revealing a negative feedback mechanism. INPP4B overexpression desensitizes cells to PI3K inhibitors in a phosphatase activity-dependent manner. siRNA knockdown and overexpression of INPP4B in PTEN-null TNBC lines, phospho-Akt Western blot, PI3K isoform-selective inhibitor sensitivity assays Molecular cancer research Medium 28196852
2018 In NPM1-mutated AML cells, INPP4B promotes cell survival through SGK3 activation without affecting Akt. INPP4B overexpression increases PI(3,4)P2 to PI(3)P conversion (measured by ELISA), and SGK3 knockdown abrogates INPP4B-induced proliferation. High INPP4B levels in NPM1-mutated AML are caused at least partly by the NPM1 mutant acting through ERK/Ets-1 signaling. INPP4B overexpression/knockdown, SGK3 knockdown rescue assay, PI(3,4)P2 and PI(3)P ELISA, ERK/Ets-1 pathway analysis, colony formation and proliferation assays Journal of experimental & clinical cancer research Medium 29343273
2016 In AML, INPP4B-mediated chemoresistance involves enhanced ATM-dependent DNA repair. INPP4B knockdown reduces ATM expression and downstream p-ATM, p-BRCA1, p-ATR, and p-RAD51 activation, as well as nuclear p65 localization. Re-activation of p65 rescues ATM pathway activity after INPP4B knockdown, placing NF-κB (p65) between INPP4B and ATM in the DNA repair pathway. INPP4B knockdown, γH2AX assay, Western blot for ATM/p-ATM/p-BRCA1/p-ATR/p-RAD51, NF-κB p65 nuclear localization assay, p65 rescue experiments, cytarabine sensitivity assays Tumour biology Medium 27342972
2017 IRF2 binds the INPP4B promoter and transcriptionally activates INPP4B expression in AML cells, placing IRF2 upstream of INPP4B in a signaling axis regulating AML cell growth and apoptosis. Restoration of INPP4B expression rescues the effects of IRF2 knockdown on apoptosis and colony formation. IRF2 promoter binding (ChIP-like assay implied), INPP4B rescue after IRF2 knockdown, colony formation and apoptosis assays in AML cell lines Gene Medium 28579269
2021 INPP4B suppresses AKT and PKC signaling in the liver to improve insulin sensitivity. Loss of INPP4B leads to proteolytic cleavage and activation of SREBP1, a key regulator of de novo lipogenesis, driving upregulation of PPARG and lipogenic pathways. Inpp4b-/- mice on a high fat diet develop obesity, NAFLD, type II diabetes, and prostatic intraepithelial neoplasia driven by inflammation. Inpp4b knockout mice, high fat diet model, AKT/PKC phosphorylation assays, SREBP1 cleavage analysis by Western blot, metabolic phenotyping (energy expenditure, respiratory exchange ratio), histology Communications biology High 33772116
2022 INPP4B (Inpp4b) is required for normal lysosomal homeostasis and dynamics. In Inpp4b-deficient mouse embryonic fibroblasts, inhibition of PIKfyve causes massively enlarged lysosomes, disrupted lysosome fusion-fission dynamics, and impaired autophagy. Mechanistically, Inpp4b deficiency causes hyperactivation of VPS34 (PI3K class III), elevating lysosomal PtdIns(3)P levels, which is exacerbated when PIKfyve is inhibited. Inpp4b-deficient MEFs, PIKfyve inhibitor treatment, confocal fluorescence imaging of lysosomes, HPLC scintillation quantification of 3H-myo-inositol labeled PtdIns, PtdIns immunofluorescence, VPS34 activity assays The Journal of biological chemistry High 35760104
2024 INPP4B is a hallmark feature of tissue-resident ILC1s and intratumoral NK cells. Conditional deletion of Inpp4b in ILC1s and NK cells reduces tissue-resident ILC1 homeostasis (but not circulating NK cells) at steady state through increased apoptosis and reduced AKT activation. INPP4B expression is necessary for ILC1/NK cell presence in the intratumoral environment and for antitumor immunity. scRNA-seq atlas, conditional Inpp4b knockout mice, flow cytometry (apoptosis, cell numbers), AKT phosphorylation assays, intratumoral NK/ILC1 quantification, tumor growth assays The Journal of experimental medicine High 38197946
2023 Loss of INPP4B (but not PTEN) in prostate cells decreases EZH2 expression and reduces H3 methylation levels. INPP4B and EZH2 are positively correlated in normal prostate and early-stage tumors (unlike PTEN, which is inversely correlated with EZH2). INPP4B loss elevates p53 protein expression and Akt phosphorylation in murine prostates, but unlike PTEN loss does not affect SMAD4 protein or Pml mRNA. INPP4B knockdown in human prostate cancer cell lines, Inpp4b knockout mouse prostate analysis, Western blot for EZH2 and H3 methylation, single-cell transcriptomic analysis Cancers Medium 38001678
2020 Estrogen receptor β1 (ERβ1) induces INPP4B expression in prostate cancer cells in response to ERβ ligands, leading to inhibition of Akt activity and reduction in cell migration, providing a mechanism for androgen-independent regulation of INPP4B. ERβ1 expression engineering in PC3 cells, ERβ ligand treatment, Western blot for INPP4B and p-Akt, cell migration assay Proceedings of the National Academy of Sciences of the United States of America Medium 33020300
2025 INPP4B promotes fibronectin 1 (FN1) secretion via TRPML1 (transient receptor potential cation channel mucolipin subfamily member 1)-dependent lysosomal exocytosis in pancreatic ductal adenocarcinoma. INPP4B-mediated regulation of F-actin formation, focal adhesion kinase activation, and increased cell migration and invasion depend on FN1 exocytosis. INPP4B overexpression/knockdown in PDAC cells, FN1 secretion assay, TRPML1 inhibitor/knockdown, F-actin staining, FAK phosphorylation Western blot, migration and invasion assays The Journal of biological chemistry Medium 40962057
2023 Inpp4b is required for normal B-1 cell numbers and B cell-mediated antibody production. Inpp4b deficiency intrinsically reduces peritoneal B-1 cells (but not B-2 cells) and impairs thymus-independent and thymus-dependent antigen-induced antibody production. CD40-mediated B cell proliferation is impaired upon Inpp4b ablation. Inpp4b conventional knockout mice, adoptive transfer studies, flow cytometry phenotyping, in vitro B cell activation and proliferation assays (CD40-mediated) Scandinavian journal of immunology Medium 37389566
2019 Inpp4b deficiency cooperates with SV40 T-Large antigen to promote cellular transformation in mouse embryonic fibroblasts, associated with increased phosphorylated-Akt levels. INPP4B overexpression in SV40 T-Large MEFs dampens transformation and reduces p-Akt. Inpp4b deficiency or overexpression was insufficient to induce transformation alone or in combination with H-Ras or E1A. MEF transformation assay with Inpp4b knockout and overexpression, SV40 T-Large/H-Ras/E1A co-expression, p-Akt Western blot Oncotarget Medium 31695845

Source papers

Stage 0 corpus · 77 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 SGK3 mediates INPP4B-dependent PI3K signaling in breast cancer. Molecular cell 128 25458846
2011 Decreased expression and androgen regulation of the tumor suppressor gene INPP4B in prostate cancer. Cancer research 121 21224358
2011 INPP4B: the new kid on the PI3K block. Oncotarget 95 21487159
2015 In Vivo Role of INPP4B in Tumor and Metastasis Suppression through Regulation of PI3K-AKT Signaling at Endosomes. Cancer discovery 85 25883022
2015 INPP4B Is a PtdIns(3,4,5)P3 Phosphatase That Can Act as a Tumor Suppressor. Cancer discovery 67 25883023
2014 Estrogen receptor alpha prevents bladder cancer via INPP4B inhibited akt pathway in vitro and in vivo. Oncotarget 66 25277204
2020 Exosomes derived from human bone marrow mesenchymal stem cells transfer miR-222-3p to suppress acute myeloid leukemia cell proliferation by targeting IRF2/INPP4B. Molecular and cellular probes 64 31968218
2015 INPP4B is an oncogenic regulator in human colon cancer. Oncogene 57 26411369
2016 Mir-765 promotes cell proliferation by downregulating INPP4B expression in human hepatocellular carcinoma. Cancer biomarkers : section A of Disease markers 55 27062697
2021 INPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer. Nature communications 53 34035258
2017 miR-181 elevates Akt signaling by co-targeting PHLPP2 and INPP4B phosphatases in luminal breast cancer. International journal of cancer 50 28224609
2015 Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML. Blood 48 25736313
2015 INPP4B overexpression is associated with poor clinical outcome and therapy resistance in acute myeloid leukemia. Leukemia 47 25736236
2013 INPP4B-mediated tumor resistance is associated with modulation of glucose metabolism via hexokinase 2 regulation in laryngeal cancer cells. Biochemical and biophysical research communications 47 24051093
2020 The INPP4B Tumor Suppressor Modulates EGFR Trafficking and Promotes Triple-Negative Breast Cancer. Cancer discovery 45 32513774
2006 Characterization of the murine Inpp4b gene and identification of a novel isoform. Gene 42 16631325
2018 INPP4B restrains cell proliferation and metastasis via regulation of the PI3K/AKT/SGK pathway. Journal of cellular and molecular medicine 41 29516642
2015 INPP4B is upregulated and functions as an oncogenic driver through SGK3 in a subset of melanomas. Oncotarget 41 26573229
2013 A tumor suppressor function for the lipid phosphatase INPP4B in melanocytic neoplasms. The Journal of investigative dermatology 40 24288008
2013 Phosphoinositide 3-kinase and INPP4B in human breast cancer. Annals of the New York Academy of Sciences 39 23551093
2014 INPP4B suppresses prostate cancer cell invasion. Cell communication and signaling : CCS 37 25248616
2017 miR-1290 Contributes to Colorectal Cancer Cell Proliferation by Targeting INPP4B. Oncology research 34 28915933
2014 Alterations of INPP4B, PIK3CA and pAkt of the PI3K pathway are associated with squamous cell carcinoma of the lung. Cancer medicine 31 24500884
2014 Epigenetic inactivation of inositol polyphosphate 4-phosphatase B (INPP4B), a regulator of PI3K/AKT signaling pathway in EBV-associated nasopharyngeal carcinoma. PloS one 29 25126743
2016 miR-937 contributes to the lung cancer cell proliferation by targeting INPP4B. Life sciences 28 27179609
2017 INPP4B and PTEN Loss Leads to PI-3,4-P2 Accumulation and Inhibition of PI3K in TNBC. Molecular cancer research : MCR 27 28196852
2017 MicroRNA-605 functions as a tumor suppressor by targeting INPP4B in melanoma. Oncology reports 27 28656250
2015 Loss of INPP4B causes a DNA repair defect through loss of BRCA1, ATM and ATR and can be targeted with PARP inhibitor treatment. Oncotarget 25 25868852
2014 An integrative analysis of PIK3CA mutation, PTEN, and INPP4B expression in terms of trastuzumab efficacy in HER2-positive breast cancer. PloS one 25 25542038
2020 TGFβ receptor endocytosis and Smad signaling require synaptojanin1, PI3K-C2α-, and INPP4B-mediated phosphoinositide conversions. Molecular biology of the cell 24 31913757
2019 IRF2-INPP4B-mediated autophagy suppresses apoptosis in acute myeloid leukemia cells. Biological research 24 30876449
2014 INPP4B is highly expressed in prostate intermediate cells and its loss of expression in prostate carcinoma predicts for recurrence and poor long term survival. The Prostate 24 25284366
2016 INPP4B reverses docetaxel resistance and epithelial-to-mesenchymal transition via the PI3K/Akt signaling pathway in prostate cancer. Biochemical and biophysical research communications 22 27318090
2012 Role of the inositol polyphosphate-4-phosphatase type II Inpp4b in the generation of ovarian teratomas. Developmental biology 21 23078915
2018 INPP4B promotes cell survival via SGK3 activation in NPM1-mutated leukemia. Journal of experimental & clinical cancer research : CR 20 29343273
2021 INPP4B protects from metabolic syndrome and associated disorders. Communications biology 19 33772116
2017 INPP4B overexpression suppresses migration, invasion and angiogenesis of human prostate cancer cells. Clinical and experimental pharmacology & physiology 18 28261855
2013 Determinants of the tumor suppressor INPP4B protein and lipid phosphatase activities. Biochemical and biophysical research communications 18 24070612
2022 INPP4B inhibits glioma cell proliferation and immune escape via inhibition of the PI3K/AKT signaling pathway. Frontiers in oncology 17 36147923
2020 INPP4B exerts a dual function in the stemness of colorectal cancer stem-like cells through regulating Sox2 and Nanog expression. Carcinogenesis 16 31179504
2019 INPP4B inhibits cell proliferation, invasion and chemoresistance in human hepatocellular carcinoma. OncoTargets and therapy 16 31123408
2021 The INPP4B paradox: Like PTEN, but different. Advances in biological regulation 15 34216856
2017 IRF2-INPP4B axis participates in the development of acute myeloid leukemia by regulating cell growth and survival. Gene 15 28579269
2016 Basal biomarkers nestin and INPP4b identify intrinsic subtypes accurately in breast cancers that are weakly positive for oestrogen receptor. Histopathology 14 27402148
2020 Estrogen receptor β regulates AKT activity through up-regulation of INPP4B and inhibits migration of prostate cancer cell line PC-3. Proceedings of the National Academy of Sciences of the United States of America 13 33020300
2014 INPP4B overexpression enhances the antitumor efficacy of PARP inhibitor AG014699 in MDA-MB-231 triple-negative breast cancer cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 13 24420152
2022 ELOVL2 restrains cell proliferation, migration, and invasion of prostate cancer via regulation of the tumor suppressor INPP4B. Cellular signalling 12 35640821
2016 INPP4B-mediated DNA repair pathway confers resistance to chemotherapy in acute myeloid leukemia. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 12 27342972
2018 SubID, a non-median dichotomization tool for heterogeneous populations, reveals the pan-cancer significance of INPP4B and its regulation by EVI1 in AML. PloS one 11 29415082
2022 Inhibition of lipid kinase PIKfyve reveals a role for phosphatase Inpp4b in the regulation of PI(3)P-mediated lysosome dynamics through VPS34 activity. The Journal of biological chemistry 10 35760104
2014 INPP4B and RAD50 have an interactive effect on survival after breast cancer. Breast cancer research and treatment 10 25528023
2020 IRF2-INPP4B axis inhibits apoptosis of acute myeloid leukaemia cells via regulating T helper 1/2 cell differentiation. Cell biochemistry and function 9 32115737
2019 INPP4B promotes colorectal cancer cell proliferation by activating mTORC1 signaling and cap-dependent translation. OncoTargets and therapy 9 31114251
2018 INPP4B overexpression and c-KIT downregulation in human achalasia. Neurogastroenterology and motility 8 29644781
2018 Basal biomarkers nestin and INPP4B predict gemcitabine benefit in metastatic breast cancer: Samples from the phase III SBG0102 clinical trial. International journal of cancer 8 30411790
2014 Effects of INPP4B gene transfection combined with PARP inhibitor on castration therapy-resistant prostate cancer cell line, PC3. Urologic oncology 8 24837011
2024 Inositol phosphatase INPP4B sustains ILC1s and intratumoral NK cells through an AKT-driven pathway. The Journal of experimental medicine 7 38197946
2022 The FDA-Approved Drug Pyrvinium Selectively Targets ER+ Breast Cancer Cells with High INPP4B Expression. Cancers 7 36612130
2021 Ese-3 contributes to colon cancer progression by downregulating EHD2 and transactivating INPP4B. American journal of cancer research 7 33520362
2021 Expression and functional characterization of INPP4B in gallbladder cancer patients and gallbladder cancer cells. BMC cancer 7 33879096
2021 lncRNA RAET1K Promotes the Progression of Acute Myeloid Leukemia by Targeting miR-503-5p/INPP4B Axis. OncoTargets and therapy 6 33500628
2015 Biological and clinical significance of loss of heterozygosity at the INPP4B gene locus in Japanese breast cancer. Breast (Edinburgh, Scotland) 6 26577950
2017 Functional identification of a novel transcript variant of INPP4B in human colon and breast cancer cells. Biochemical and biophysical research communications 5 28189677
2025 The IRF2-INPP4B Pathway Aggravates Acute Myeloid Leukemia. Turkish journal of haematology : official journal of Turkish Society of Haematology 4 39960210
2024 INPP4B ensures that ILC1s and NK cells set up a productive home office. The Journal of experimental medicine 4 38329467
2019 Retracted Article: LncRNA ZEB2-AS1 regulates the drug resistance of acute myeloid leukemia via the miR-142-3p/INPP4B axis. RSC advances 4 35540690
2025 Multi-omics integration analysis identifies INPP4B as a T-cell-specific activation suppressor. Clinical and translational medicine 3 40754682
2024 Role of INPP4B in the proliferation, migration, invasion, and survival of human endometrial cancer cells. Histology and histopathology 3 38318760
2024 INPP4B suppresses HER2-induced mesenchymal transition in HER2+ breast cancer and enhances sensitivity to Lapatinib. Biochemical pharmacology 2 38852646
2023 Tumor Suppressor Role of INPP4B in Chemoresistant Retinoblastoma. Journal of oncology 2 36993823
2023 Regulation of B-1 cell numbers and B cell-mediated antibody production by Inpp4b. Scandinavian journal of immunology 2 37389566
2023 Regulation of EZH2 Expression by INPP4B in Normal Prostate and Primary Prostate Cancer. Cancers 2 38001678
2023 Investigating the multifaceted cooperation of autophagy, PI3K/AKT signaling pathways, and INPP4B gene in de novo acute myeloid leukemia patients. Current research in translational medicine 2 38246071
2019 Investigating the duality of Inpp4b function in the cellular transformation of mouse fibroblasts. Oncotarget 2 31695845
2025 Upregulation of miR-151a-5p in high DFI sperm induces DNA damage and mitochondrial dysfunction by targeting INPP4B and VAMP1. Reproductive biology and endocrinology : RB&E 1 41219999
2025 The lipid phosphatase INPP4B controls pancreatic cancer cell migration and invasion by regulating fibronectin exocytosis. The Journal of biological chemistry 0 40962057
2024 [Preliminary Study of the Role of INPP4B in Promoting Colorectal Cancer Metastasis and the Mechanisms Involved]. Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition 0 39507966

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