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Showing PIP4K2B — PIP5K2B is a alias.

PIP4K2B

Phosphatidylinositol 5-phosphate 4-kinase type-2 beta · UniProt P78356

Length
416 aa
Mass
47.4 kDa
Annotated
2026-06-10
34 papers in source corpus 13 papers cited in narrative 13 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

PIP4K2B is a predominantly nuclear phosphatidylinositol-5-phosphate 4-kinase that converts PI5P to PI(4,5)P2 and couples phosphoinositide metabolism to stress responses, gene transcription, autophagy, and mechanosensing (PMID:25728392, PMID:31091439, PMID:24845568). It regulates nuclear PI5P pools that are read out by the PHD finger of the transcription factor TAF3, whose PI-modulated association with H3K4me3-marked chromatin transduces PIP4K2B activity into changes in myogenic gene expression (PMID:25866244). Beyond its catalytic role, PIP4K2B exerts a non-catalytic function: it directly binds and suppresses PIP5K, thereby restraining PI(4,5)P2 and insulin-stimulated PI(3,4,5)P3 synthesis, an activity preserved by kinase-dead enzyme and mapped to its N-terminal VMLΦPDD motif (PMID:31091439). Together with PIP4K2A, it is required for autophagosome clearance and lipid homeostasis during nutrient deprivation across mouse and C. elegans models (PMID:29727621). PIP4K2B acts as a mechanoresponsive node whose protein levels fall on soft substrates, lowering the epigenetic regulator UHRF1, remodeling chromatin and nuclear mechanics, and driving YAP cytoplasmic retention (PMID:36918565); its transcription is positively controlled by NSD1 through an H3K36me2-dependent mechanism in head and neck cancer (PMID:38539515). PIP4K2B sustains E-cadherin expression and suppresses TGF-β-induced EMT (PMID:24127122), and is synthetically lethal with TP53 loss, rendering it essential for the growth of p53-null tumors (PMID:24209622).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1997 Medium

    Established the first protein partner and an upstream signaling input for PIP4K2B by linking it to inflammatory receptor signaling, answering how PI turnover might be triggered at the membrane.

    Evidence Yeast two-hybrid screen and in vitro pulldown with recombinant fusion proteins, plus cellular PIP5K activity assay after TNF-alpha in HeLa cells

    PMID:9038203

    Open questions at the time
    • Reciprocal validation in cells and the structural basis of the TNFR1 juxtamembrane interaction not resolved
    • Whether the measured PIP5K activity increase reflects PIP4K2B catalysis directly is not distinguished
    • Downstream consequences of TNFR1-PIP4K2B coupling not defined
  2. 2013 High

    Defined a therapeutically actionable genetic dependency by showing PIP4K2B is synthetically lethal with TP53 loss and required for p53-null tumor growth.

    Evidence shRNA knockdown in breast cancer lines, xenografts, germline mouse knockouts, and ROS measurement

    PMID:24209622

    Open questions at the time
    • Molecular mechanism connecting PIP4K2B loss to ROS elevation and senescence not fully resolved
    • Relative contributions of catalytic versus non-catalytic functions to the dependency unclear
  3. 2013 Medium

    Connected PIP4K2B to epithelial identity by showing it maintains E-cadherin transcription and suppresses EMT, framing a tumor-suppressive role distinct from its growth dependency.

    Evidence shRNA knockdown in MCF10A and MCF7 cells, qRT-PCR/western for CDH1, TGF-β-induced EMT assay

    PMID:24127122

    Open questions at the time
    • Mechanism linking PIP4K2B to CDH1 transcription not defined
    • Whether the effect is catalytic or signaling-dependent untested
  4. 2014 Medium

    Validated PIP4K2B kinase activity as a druggable and physiologically relevant target through a selective inhibitor with metabolic effects in vivo.

    Evidence High-throughput enzymatic screen, in vitro kinase and cellular assays, and dosing in Zucker diabetic fatty rats

    PMID:24845568

    Open questions at the time
    • In vivo glucose-lowering not mechanistically tied to a specific PIP4K2B substrate pool
    • Off-target and isoform selectivity in vivo not fully resolved
  5. 2015 High

    Identified the nuclear effector mechanism by which PIP4K2B-controlled PI5P is read into transcription, via TAF3 PHD-finger PI binding and chromatin association.

    Evidence shRNA knockdown, lipid-binding screen, TAF3 PHD mutagenesis, ChIP, and in vitro PI-binding assays during myoblast differentiation

    PMID:25728392 PMID:25866244

    Open questions at the time
    • How PIP4K2B activity quantitatively sets nuclear PI5P at specific loci not mapped
    • Generality of the TAF3 readout beyond myogenic genes unknown
  6. 2017 Medium

    Placed PIP4K2B downstream of MANF in hypothalamic insulin signaling, linking its ER localization and activity to feeding behavior and insulin resistance.

    Evidence In vivo hypothalamic MANF overexpression and knockdown with measurement of PIP4K2B ER localization/activity and feeding phenotypes

    PMID:28924165

    Open questions at the time
    • Direct biochemical link between MANF and PIP4K2B not established
    • ER versus nuclear pool contributions to the phenotype not separated
  7. 2018 High

    Demonstrated a conserved metabolic function in autophagy, showing the PI5P→PI(4,5)P2 pathway is required for autophagosome clearance and lipid homeostasis during nutrient stress.

    Evidence Liver-specific and MEF double Pip4k2a/2b knockouts, electron microscopy, lipid droplet staining, autophagy flux assays, and a C. elegans ortholog model

    PMID:29727621

    Open questions at the time
    • Isoform-specific contribution of PIP4K2B versus PIP4K2A not separated
    • Step in autophagosome maturation/clearance controlled by the lipid product not pinpointed
  8. 2019 High

    Resolved a paradoxical regulatory role by showing PIP4K2B suppresses PI(4,5)P2 and PI3K signaling non-catalytically through direct binding to PIP5K via its N-terminal VMLΦPDD motif.

    Evidence CRISPR triple knockout, phosphoinositide mass spectrometry, wild-type versus kinase-dead rescue, direct binding assay, and N-terminal motif mutagenesis

    PMID:31091439

    Open questions at the time
    • Structural basis of the PIP4K-PIP5K binding interaction not solved
    • Balance between catalytic and non-catalytic outputs in different cell contexts unclear
  9. 2020 Medium

    Mapped PIP4K2B expression to developing neurons and synaptic compartments, suggesting a neuronal role not yet functionally tested.

    Evidence KO-validated immunofluorescence, dual-label imaging, and immuno-EM in mouse and primate/human brain

    PMID:32449185

    Open questions at the time
    • No demonstrated functional consequence of synaptic PIP4K2B localization
    • Substrate and signaling role at axon terminals/dendritic spines undefined
  10. 2023 High

    Identified PIP4K2B as a mechanoresponsive regulator linking substrate stiffness to chromatin state and YAP activity through a PIP4K2B→UHRF1→chromatin→YAP axis.

    Evidence Soft/stiff substrate culture, knockdown and pharmacological inhibition, nuclear mechanics measurements, UHRF1 quantification, YAP imaging, and migration assays

    PMID:36918565

    Open questions at the time
    • Mechanism by which substrate softness lowers PIP4K2B protein not defined
    • Whether catalytic activity or scaffolding drives UHRF1 reduction unresolved
  11. 2024 Medium

    Established upstream transcriptional control of PIP4K2B by NSD1 via H3K36me2 and tied PIP4K2B to mTOR signaling and growth in head and neck cancer.

    Evidence RPPA, NSD1 knockdown, H3K36me2 chromatin studies, PIP4K2B shRNA, mTOR western blot, and rescue overexpression

    PMID:38539515

    Open questions at the time
    • Direct NSD1 occupancy at the PIP4K2B locus not fully characterized
    • Basis of context-dependent rescue between tumor subsites unexplained
  12. 2026 Medium

    Provided a structural rationale for isoform-selective inhibition, explaining why most inhibitors are less potent against PIP4K2B than PIP4K2A.

    Evidence X-ray crystallography of a PIP4K2A-inhibitor complex with comparative structural analysis of PIP4K2B

    PMID:42117906

    Open questions at the time
    • No PIP4K2B crystal structure with inhibitor; isoform inference is comparative/modeled
    • Specificity-pocket conclusions not experimentally validated for PIP4K2B

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PIP4K2B's catalytic (PI5P→PI(4,5)P2) and non-catalytic (PIP5K suppression) activities are partitioned across nuclear, ER, autophagic, and synaptic compartments to produce distinct physiological outputs remains unresolved.
  • No unified model assigning each phenotype to a specific lipid pool or compartment
  • Structure of full-length PIP4K2B and its PIP5K complex not solved
  • Regulation of PIP4K2B protein stability by mechanical and metabolic cues mechanistically undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 2 GO:0008289 lipid binding 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005634 nucleus 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1430728 Metabolism 2 R-HSA-162582 Signal Transduction 2 R-HSA-1643685 Disease 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-9612973 Autophagy 1
Partners
MANFNSD1PIP5KTAF3TNFRSF1AUHRF1

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 PIP4K2B (PIP5KIIbeta) directly binds the juxtamembrane region of the p55 TNF receptor (TNFR1) but not the p75 TNF receptor, Fas antigen, or p75 neurotrophin receptor. In vitro experiments with recombinant fusion proteins confirmed the specific interaction. TNF-alpha treatment of HeLa cells resulted in increased PIP5K activity, linking p55 TNFR signaling to phosphatidylinositol turnover via PIP4K2B. Yeast two-hybrid screen, in vitro pulldown with recombinant fusion proteins, cellular PIP5K activity assay after TNF-alpha treatment The Journal of biological chemistry Medium 9038203
2013 PIP4K2B is synthetically lethal with TP53 loss in vivo: mice homozygous for deletion of both TP53 and PIP4K2B were not viable. Knockdown of PI5P4Kα and β in p53-deficient breast cancer cells impaired growth and elevated reactive oxygen species leading to senescence. PIP4K2A−/−, PIP4K2B+/−, TP53−/− mice showed dramatically reduced tumor formation compared to TP53−/− littermates, establishing PIP4K2B as essential for growth of p53-null tumors. shRNA knockdown in breast cancer cell lines, xenograft assays, genetic mouse models (germline knockout), ROS measurement Cell High 24209622
2015 PIP4K2B localizes predominantly to the nucleus and regulates nuclear PI5P levels and expression of myogenic genes during myoblast differentiation. A targeted screen identified the PHD finger of TAF3 (a TATA box binding protein-associated factor) as a nuclear PI interactor, and PI binding by TAF3 modulates its association with H3K4me3 in vitro and with chromatin in vivo. TAF3 mutant analysis demonstrated that TAF3 transduces PIP4K2B-mediated alterations in PI into changes in specific gene transcription. shRNA knockdown of PIP4K2B, lipid-binding screen, chromatin immunoprecipitation, TAF3 PHD finger mutagenesis, in vitro PI-binding assays Molecular cell High 25866244
2015 PIP4K2B isoform localizes predominantly to the nucleus among the three PIP4K isoforms, consistent with its role in regulating nuclear phosphoinositide levels. Subcellular fractionation and localization studies (reviewed/summarized in the context of PIP4K isoform biology) Biochimica et biophysica acta Medium 25728392
2017 MANF triggers hypothalamic insulin resistance by enhancing the ER localization and activity of PIP4K2B. Increased hypothalamic MANF protein levels caused hyperphagia and enhanced PIP4K2B ER activity, while decreased MANF caused hypophagia, placing PIP4K2B downstream of MANF in hypothalamic insulin signaling. In vivo manipulation of hypothalamic MANF levels (overexpression and knockdown), measurement of PIP4K2B ER localization and activity, food intake and body weight phenotyping Nature communications Medium 28924165
2018 Deletion of both Pip4k2a and Pip4k2b in mouse liver causes accumulation of lipid droplets and autophagic vesicles during fasting due to a defect in autophagosome clearance (impaired autophagic flux). Similar defects occur in nutrient-starved Pip4k2a−/−Pip4k2b−/− MEFs and in C. elegans lacking the PI5P4K ortholog, establishing that this PI5P→PI(4,5)P2 synthesis pathway is required for autophagy-mediated nutrient recycling. Liver-specific and MEF double knockout mouse models, electron microscopy of autophagic vesicles, lipid droplet staining, autophagy flux assays, C. elegans genetic model Molecular cell High 29727621
2019 PIP4K2B (together with PIP4K2A and PIP4K2C) suppresses PI(4,5)P2 synthesis and insulin-dependent PI3K signaling through a catalytic-independent mechanism. Loss of all three PIP4Ks paradoxically increased PI(4,5)P2 and insulin-stimulated PI(3,4,5)P3. Reintroduction of either wild-type or kinase-dead PIP4K mutants restored PI(4,5)P2 levels, indicating the mechanism is non-catalytic. PIP4Ks suppress PIP5K activity through a direct binding interaction mediated by the N-terminal VMLΦPDD motif of PIP4K. CRISPR/Cas9 triple knockout of PIP4K2A/2B/2C, phosphoinositide mass spectrometry, reintroduction of wild-type vs. kinase-dead mutants, direct PIP4K–PIP5K binding assay, N-terminal motif mutagenesis Cell reports High 31091439
2013 Knockdown of PIP4K2B in normal (MCF10A) and tumor (MCF7) breast epithelial cells decreased transcription and expression of E-cadherin (CDH1) and enhanced TGF-β-induced epithelial-to-mesenchymal transition (EMT), linking PIP4K2B activity to E-cadherin regulation and EMT suppression. shRNA-mediated knockdown of PIP4K2B in breast epithelial cell lines, qRT-PCR and western blot for CDH1, TGF-β-induced EMT assay Cancer research Medium 24127122
2014 PIP4K2B has enzymatic activity that can be pharmacologically inhibited: a small-molecule inhibitor (SAR088) identified by high-throughput screening showed potency and selectivity against PIP4K2B in enzymatic and cellular assays, and lowered blood glucose in obese hyperglycemic rats in vivo, validating PIP4K2B kinase activity as relevant to insulin/glucose regulation. High-throughput enzymatic screening, in vitro kinase assay, cellular assay, in vivo dosing in Zucker diabetic fatty rats Biochemical and biophysical research communications Medium 24845568
2020 In mouse brain, PI5P4Kβ (encoded by PIP4K2B) is expressed early in development and localizes to neuronal populations, especially hippocampus and cortex, co-localizing with the neuronal marker NeuN. Ultrastructural analysis showed PI5P4Kβ is present in axon terminals and dendritic spines adjacent to the synaptic membrane. Immunofluorescence with antibodies validated by genetic deletion of pip4k2b, dual-label immunofluorescence, electron microscopy/immunoperoxidase in mouse and primate/human brain The Journal of comparative neurology Medium 32449185
2023 PIP4K2B is mechanoresponsive: its protein level decreases in cells growing on soft substrates. Direct silencing or pharmacological inhibition of PIP4K2B reduces the epigenetic regulator UHRF1, alters nuclear polarity, nuclear envelope tension, and chromatin compaction, causes YAP cytoplasmic retention and impaired transcriptional activity, and leads to defects in cell spreading and motility. Soft vs. stiff substrate cell culture, siRNA/shRNA knockdown, pharmacological inhibition, nuclear mechanics measurements, UHRF1 protein quantification, YAP localization imaging, migration/spreading assays Nature communications High 36918565
2024 PIP4K2B is a downstream target of the histone methyltransferase NSD1 in HNSCC. NSD1 positively regulates PIP4K2B gene transcription through an H3K36me2-dependent mechanism. PIP4K2B depletion in HNSCC downregulates the mTOR pathway and reduces cell growth in vitro, with context-dependent effects (rescuable by PIP4K2B overexpression in laryngeal but not tongue/hypopharynx cells). RPPA analysis, NSD1 knockdown with PIP4K2B measurement, chromatin studies for H3K36me2, PIP4K2B shRNA knockdown, mTOR pathway western blot, rescue overexpression experiment Cancers Medium 38539515
2026 Crystal structure of PIP4K2A in complex with a dual α/β inhibitor (422A) reveals a water-mediated interaction in the specificity pocket. Comparative structural analysis with PIP4K2B indicates that deeper penetration into the specificity pocket enhances PIP4K2A binding but is less well tolerated in PIP4K2B due to local steric constraints, explaining why most inhibitors have lower potency toward PIP4K2B. X-ray crystallography of PIP4K2A–inhibitor complex, comparative structural analysis with PIP4K2B Acta crystallographica. Section D, Structural biology Medium 42117906

Source papers

Stage 0 corpus · 34 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Targets of gene amplification and overexpression at 17q in gastric cancer. Cancer research 165 11980659
2013 Depletion of a putatively druggable class of phosphatidylinositol kinases inhibits growth of p53-null tumors. Cell 162 24209622
1997 A novel interaction between the juxtamembrane region of the p55 tumor necrosis factor receptor and phosphatidylinositol-4-phosphate 5-kinase. The Journal of biological chemistry 91 9038203
2018 Phosphatidylinositol-5-Phosphate 4-Kinases Regulate Cellular Lipid Metabolism By Facilitating Autophagy. Molecular cell 88 29727621
2015 The basal transcription complex component TAF3 transduces changes in nuclear phosphoinositides into transcriptional output. Molecular cell 59 25866244
2008 High-throughput screening of mouse knockout lines identifies true lean and obese phenotypes. Obesity (Silver Spring, Md.) 54 18719666
2019 PIP4Ks Suppress Insulin Signaling through a Catalytic-Independent Mechanism. Cell reports 52 31091439
2019 Long non-coding RNA PXN-AS1 suppresses pancreatic cancer progression by acting as a competing endogenous RNA of miR-3064 to upregulate PIP4K2B expression. Journal of experimental & clinical cancer research : CR 51 31488171
2017 MANF regulates hypothalamic control of food intake and body weight. Nature communications 51 28924165
2015 PIP4K and the role of nuclear phosphoinositides in tumour suppression. Biochimica et biophysica acta 50 25728392
2013 Low PIP4K2B expression in human breast tumors correlates with reduced patient survival: A role for PIP4K2B in the regulation of E-cadherin expression. Cancer research 41 24127122
2018 The response to neoadjuvant chemoradiotherapy with 5-fluorouracil in locally advanced rectal cancer patients: a predictive proteomic signature. Clinical proteomics 33 29681787
2021 High-throughput proteomics of breast cancer interstitial fluid: identification of tumor subtype-specific serologically relevant biomarkers. Molecular oncology 32 33176066
2014 Discovery and pharmacological characterization of a novel small molecule inhibitor of phosphatidylinositol-5-phosphate 4-kinase, type II, beta. Biochemical and biophysical research communications 30 24845568
2018 Genetical genomics of growth in a chicken model. BMC genomics 27 29361907
2019 PIP4K2A and PIP4K2C transcript levels are associated with cytogenetic risk and survival outcomes in acute myeloid leukemia. Cancer genetics 24 31109595
2005 Stepwise occurrence of a complex unbalanced translocation in neuroblastoma leading to insertion of a telomere sequence and late chromosome 17q gain. Oncogene 24 15735707
2023 PIP4K2B is mechanoresponsive and controls heterochromatin-driven nuclear softening through UHRF1. Nature communications 21 36918565
2018 The correlation analysis of miRNAs and target genes in metastasis of cervical squamous cell carcinoma. Epigenomics 19 29343084
2021 Identification of Metabolic-Associated Genes for the Prediction of Colon and Rectal Adenocarcinoma. OncoTargets and therapy 16 33833525
2004 Identification and characterization of human ARHGAP23 gene in silico. International journal of oncology 15 15254754
2020 Distribution and localization of phosphatidylinositol 5-phosphate, 4-kinase alpha and beta in the brain. The Journal of comparative neurology 9 32449185
2023 PIP5K1C phosphoinositide kinase deficiency distinguishes PIKFYVE-dependent cancer cells from non-malignant cells. Autophagy 8 36803256
2023 Autoantibodies against PIP4K2B and AKT3 Are Associated with Skin and Lung Fibrosis in Patients with Systemic Sclerosis. International journal of molecular sciences 7 36982700
2023 Pharmacological Inhibition of PIP4K2 Potentiates Venetoclax-Induced Apoptosis in Acute Myeloid Leukemia. International journal of molecular sciences 6 38069220
2024 PIP4K2B Protein Regulation by NSD1 in HPV-Negative Head and Neck Squamous Cell Carcinoma. Cancers 5 38539515
2002 Mutagenic transgene insertion into a region of high gene density and multiple linkage disruptions on mouse chromosome 11. Cytogenetic and genome research 5 12438746
2016 PIP4K2B: Coupling GTP Sensing to PtdIns5P Levels to Regulate Tumorigenesis. Trends in biochemical sciences 4 27132569
2024 Potency and efficacy of pharmacological PIP4K2 inhibitors in acute lymphoblastic leukemia. European journal of pharmacology 3 38851560
2025 Differential expression of lncRNAs and mRNAs in bone marrow-derived mesenchymal stem cells under continuous and intermittent teriparatide treatment. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2 40609214
2020 Correction to: Long non-coding RNA PXN-AS1 suppresses pancreatic cancer progression by acting as a competing endogenous RNA of miR-3064 to upregulate PIP4K2B expression. Journal of experimental & clinical cancer research : CR 1 32381033
2026 Oat grass improves meat tenderness and flavor, reduces fat deposition in small-tailed Han sheep. Food chemistry. Molecular sciences 0 41695382
2026 Structural basis for high-affinity inhibitor binding to lipid kinases PIP4K2A and PIP4K2B. Acta crystallographica. Section D, Structural biology 0 42117906
2025 Correction: Topchu et al. PIP4K2B Protein Regulation by NSD1 in HPV-Negative Head and Neck Squamous Cell Carcinoma. Cancers 2024, 16, 1180. Cancers 0 41301084

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