{"gene":"PIP4K2A","run_date":"2026-04-28T19:45:44","timeline":{"discoveries":[{"year":2014,"finding":"PIP4K2A kinase activity is required for AML cell proliferation and survival; its knockdown results in accumulation of CDKN1A and CDKN1B, G1 cell cycle arrest, and apoptosis, with both CDKN1A accumulation and apoptosis partially dependent on mTOR pathway activation.","method":"Targeted RNAi knockdown screen in human AML cells and murine MLL-AF9 AML cells, clonogenic assays, cell cycle analysis, Western blotting for downstream effectors","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — clean KD with defined cellular phenotype and pathway placement (mTOR), replicated in multiple cell systems including primary human AML cells","pmids":["24681948"],"is_preprint":false},{"year":2018,"finding":"PIP4K2A localizes to peroxisomal membranes where it generates PI(4,5)P2, which is required for lysosome-peroxisome membrane contact formation that facilitates LDL-derived cholesterol transport from lysosomes to peroxisomes; kinase-active but not kinase-dead peroxisome-targeted PIP4K2A rescues the cholesterol transport defect caused by PIP4K2A knockdown.","method":"RNAi knockdown, forced expression of peroxisome-targeted kinase-active/inactive PIP4K2A, in vitro membrane contact reconstitution with recombinant PIP4K2A, fluorescence microscopy of lysosome-peroxisome contacts, cholesterol accumulation assays","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of membrane contacts with recombinant protein, coupled with rescue experiments using kinase-active vs. inactive constructs","pmids":["29353240"],"is_preprint":false},{"year":2008,"finding":"Wild-type PIP4K2A activates heteromeric KCNQ2/KCNQ3 and KCNQ3/KCNQ5 neuronal M channels via PI(4,5)P2 synthesis; the schizophrenia-associated N251S mutation renders PIP4K2A catalytically inactive and fails to activate these channels. KCNQ3 in the channel complex is required for the kinase-mediated effect.","method":"Xenopus oocyte expression system with electrophysiology (voltage clamp), acute PI(4,5)P2 injection, PIP2 scavenger experiments, comparison of WT vs. N251S mutant","journal":"Psychopharmacology","confidence":"High","confidence_rationale":"Tier 1 — in vitro functional assay with mutagenesis, acute lipid injection controls, and mechanistic dissection of subunit requirements","pmids":["18545987"],"is_preprint":false},{"year":2009,"finding":"PIP4K2A enhances excitatory amino acid transporter EAAT3 activity and membrane abundance; wild-type PIP4K2A increases EAAT3 glutamate-induced current and membrane protein levels, while the N251S dominant-negative mutant decreases both. The effect on EAAT3 membrane abundance was confirmed in HEK293 cells.","method":"Xenopus oocyte expression with dual electrode voltage clamp, Western blotting of membrane fractions, confocal microscopy in HEK293 cells","journal":"Psychopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — functional assay in two cell systems with WT vs. mutant comparison, but single lab","pmids":["19644675"],"is_preprint":false},{"year":2014,"finding":"PIP4K2A increases GluA1 (AMPA receptor) membrane abundance and glutamate-induced currents via PI(4,5)P2 production; the N251S mutation ablates this effect. The region K813-K823 of GluA1 was identified as critical for PI(4,5)P2 interaction by alanine scanning, and direct PI(4,5)P2 binding to the GluA1 C-terminal peptide was demonstrated by PIP strip assay.","method":"Xenopus oocyte expression with electrophysiology, alanine scanning mutagenesis of GluA1, PIP strip lipid-binding assay, Western blotting of membrane fractions in HEK293 cells","journal":"Pflugers Archiv : European journal of physiology","confidence":"Medium","confidence_rationale":"Tier 1-2 — mutagenesis combined with direct lipid-binding assay; single lab","pmids":["24389605"],"is_preprint":false},{"year":2019,"finding":"PIP4K2A acts as a negative regulator of PI3K signaling in PTEN-deficient GBM by targeting the p85 regulatory subunit of PI3K for proteasome-mediated degradation, thereby reducing p85/p110 PI3K complex levels; PIP4K2A overexpression suppressed clonogenic growth in vitro and tumor growth in vivo.","method":"In vivo RNAi screen in patient-derived xenograft GBM models, overexpression studies, proteasome inhibitor experiments, in vitro and in vivo tumor growth assays","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo RNAi screen validated by overexpression with mechanistic follow-up on proteasome pathway; single lab","pmids":["30898893"],"is_preprint":false},{"year":2023,"finding":"PIP4K2A phosphorylates MIF (macrophage migration inhibitory factor) at serine 91, which increases MIF interaction with 14-3-3ζ and promotes MIF nuclear translocation; nuclear MIF then functions as a transcriptional regulator of ciliogenesis genes and regulates TTBK2 recruitment to the basal body, CP110 removal, CEP290 accumulation at centriolar satellites, and IFT protein trafficking, establishing PIP4K2A as an upstream regulator of cilia biogenesis.","method":"Co-immunoprecipitation, phosphorylation assays, site-directed mutagenesis (S91 of MIF), confocal microscopy, cilia formation assays, gene expression analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 1-2 — kinase-substrate relationship defined with mutagenesis and functional cilia phenotype; single lab","pmids":["38052787"],"is_preprint":false},{"year":2023,"finding":"SLC27A5 interacts with IGF2BP3 to prevent its nuclear translocation, thereby inhibiting IGF2BP3 binding to PIP4K2A pre-mRNA and preventing alternative splicing that produces the short PIP4K2A-S isoform. Loss of SLC27A5 increases PIP4K2A-S levels, which stabilizes p85 and enhances PI3K signaling to promote HCC metastasis.","method":"Co-immunoprecipitation of SLC27A5 with IGF2BP3, RNA immunoprecipitation for mRNA binding, alternative splicing analysis, p85 stability assays, in vivo AAV rescue experiments","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP and RNA-IP with functional pathway validation; single lab","pmids":["38059827"],"is_preprint":false},{"year":2022,"finding":"During decidualization, PIP4K2A translocates from the nucleus to the cytoplasm and binds lncSAMD11-1:1; this interaction inhibits AKT phosphorylation and promotes FoxO1 nuclear localization, thereby supporting endometrial stromal cell decidualization.","method":"Knockdown and overexpression of lncSAMD11-1:1 in human endometrial stromal cells, co-immunoprecipitation of lncRNA with PIP4K2A, AKT phosphorylation assays, FoxO1 localization by confocal microscopy, in vitro decidualization assays","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP of lncRNA-protein interaction with functional decidualization phenotype; single lab","pmids":["35987479"],"is_preprint":false},{"year":2021,"finding":"PIP4K2A exhibits RNA-binding activity that is independent of its lipid kinase activity; this RNA-binding capacity is conserved from Drosophila and C. elegans to humans.","method":"RNA binding assays with kinase-dead PIP4K2A mutants, cross-species functional comparison, RNA immunoprecipitation","journal":"Frontiers in molecular biosciences","confidence":"Low","confidence_rationale":"Tier 3 — single lab, limited mechanistic follow-up on the human protein specifically","pmids":["34124142"],"is_preprint":false},{"year":2021,"finding":"PIP4K2A is identified as an off-target of the PLK1 inhibitor volasertib (but not of onvansertib), as demonstrated by thermal proteome profiling showing stabilization of PIP4K2A by volasertib.","method":"Thermal proteome profiling (TPP), mass spectrometry, comparison between two PLK1 inhibitors","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — unbiased proteome-wide TPP with inhibitor selectivity comparison","pmids":["34143546"],"is_preprint":false},{"year":2021,"finding":"Novel selective PIP4K2A inhibitors BAY-091 and BAY-297 were identified; cellular target engagement was confirmed by cellular thermal shift assay. However, pharmacological PIP4K2A inhibition did not induce antiproliferative activity in p53-deficient tumor cells, dissociating kinase inhibition from the proposed tumor-suppressive mechanism.","method":"High-throughput screening, structure-based optimization, crystal structure-guided design, cellular thermal shift assay (CETSA), antiproliferative assays in p53-deficient cell lines","journal":"Journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 — structure-based inhibitor development with CETSA target engagement validation and negative functional result","pmids":["34699202"],"is_preprint":false},{"year":2023,"finding":"A gain-of-function PIP4K2A mutation (S316R) exhibits enhanced protein stability, increased kinase activity, and upregulates β-globin expression, leading to a more imbalanced β/α-globin ratio and increased Hb H inclusion bodies; introduction of S316R into HUDEP-2 cells confirmed increased β-globin expression and inhibited erythroid differentiation and terminal enucleation.","method":"Family haematological analysis, kinase activity assays, protein stability assays, lentiviral introduction of S316R into HUDEP-2 erythroid cells, erythroid differentiation assays","journal":"British journal of haematology","confidence":"Medium","confidence_rationale":"Tier 1-2 — kinase activity measured in vitro, functional validation in human erythroid cell model; single lab","pmids":["37423903"],"is_preprint":false},{"year":2024,"finding":"Loss of PIP4K2A (PI5P4Kα) in basal prostate epithelial cells slows the progression of Pten mutant mouse prostatic intraepithelial neoplasia; PIP4K2A is enriched in basal cells and its loss disrupts lipid metabolism (particularly carnitine lipids), pointing to lipid metabolic disruption as a mechanism for reduced tumor progression.","method":"Basal cell-specific GEMM with CK5-Cre, combined Pip4k2a/Pten knockout, lineage tracing with single-cell RNA sequencing, siPIP4K2A in LNCaP cells with lipidomic analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo GEMM with scRNA-seq and lipidomics functional support; preprint, single lab","pmids":["bio_10.1101_2024.08.12.607541"],"is_preprint":true},{"year":2015,"finding":"PIP4K2A is localized to both the cytoplasm and nucleus in leukocytes and leukemia cells, as determined by subcellular fractionation; its expression is reduced in leukemia cell lines compared to normal leukocytes.","method":"Subcellular fractionation, Western blotting, immunofluorescence","journal":"Blood cells, molecules & diseases","confidence":"Low","confidence_rationale":"Tier 3 — localization determined by fractionation but without defined functional consequence of nuclear vs. cytoplasmic distribution","pmids":["26227852"],"is_preprint":false}],"current_model":"PIP4K2A is a lipid kinase that phosphorylates phosphatidylinositol-5-phosphate (PI5P) to generate PI(4,5)P2 at multiple subcellular compartments including peroxisomal membranes (enabling lysosome-peroxisome cholesterol transport via synaptotagmin VII contacts), the plasma membrane (activating KCNQ neuronal M channels and regulating EAAT3 and GluA1 membrane abundance), and nuclear/cytoplasmic compartments (where, in complex with lncSAMD11-1:1, it inhibits AKT to promote FoxO1 nuclear retention during decidualization); it also acts as a direct kinase for MIF at S91 to drive cilia biogenesis, negatively regulates PI3K signaling in PTEN-deficient GBM via p85 proteasomal degradation, and is required for AML cell survival through modulation of CDKN1A/CDKN1B and mTOR signaling, while the schizophrenia-associated N251S mutation abolishes kinase activity and disrupts all PI(4,5)P2-dependent downstream functions."},"narrative":{"teleology":[{"year":2008,"claim":"Establishing that PIP4K2A lipid kinase activity directly controls neuronal ion channel function resolved how PI(4,5)P2 synthesis couples to electrical excitability, and the schizophrenia-associated N251S mutation provided a loss-of-function tool linking kinase activity to channel activation.","evidence":"Xenopus oocyte electrophysiology with WT vs. N251S PIP4K2A, acute PI(4,5)P2 injection controls, and subunit requirement analysis for KCNQ2/3 and KCNQ3/5 channels","pmids":["18545987"],"confidence":"High","gaps":["Whether PIP4K2A-dependent KCNQ activation occurs at endogenous expression levels in mammalian neurons","Structural basis for how N251S abolishes kinase activity","Whether other PIP4K family members compensate in vivo"]},{"year":2009,"claim":"Demonstrating that PIP4K2A promotes EAAT3 membrane abundance and glutamate transport extended PI(4,5)P2-dependent membrane trafficking beyond ion channels to neurotransmitter transporters.","evidence":"Xenopus oocyte dual electrode voltage clamp and HEK293 membrane fractionation comparing WT and N251S PIP4K2A effects on EAAT3","pmids":["19644675"],"confidence":"Medium","gaps":["Whether PI(4,5)P2 directly binds EAAT3 or acts through an intermediary","In vivo relevance in neuronal glutamate homeostasis","Single lab observation"]},{"year":2014,"claim":"Identification of PIP4K2A as essential for AML cell proliferation, with its loss causing CDKN1A/CDKN1B accumulation and mTOR-dependent apoptosis, established the kinase as a cancer dependency factor and linked its activity to cell cycle control.","evidence":"RNAi knockdown screen in human and murine MLL-AF9 AML cells, clonogenic assays, and Western blotting for downstream mTOR and CDK inhibitor effectors","pmids":["24681948"],"confidence":"High","gaps":["Whether the requirement is for lipid kinase activity specifically versus a scaffolding function","The direct mechanistic link between PI(4,5)P2 pools and CDKN1A/CDKN1B stabilization","Whether selective PIP4K2A inhibitors phenocopy knockdown in AML"]},{"year":2014,"claim":"Mapping the PI(4,5)P2-binding site on GluA1 (K813–K823) and showing PIP4K2A-dependent membrane insertion of AMPA receptors broadened the kinase's role to excitatory synaptic receptor trafficking.","evidence":"Alanine scanning mutagenesis of GluA1 C-terminus, PIP strip lipid-binding assay, Xenopus oocyte electrophysiology, and HEK293 membrane fractionation","pmids":["24389605"],"confidence":"Medium","gaps":["Endogenous validation in hippocampal or cortical neurons","Whether the effect involves direct PI(4,5)P2–GluA1 interaction in a bilayer context","Single lab"]},{"year":2018,"claim":"Reconstitution of PIP4K2A-generated PI(4,5)P2 at peroxisomal membranes as the trigger for lysosome–peroxisome contact formation and cholesterol transport revealed a new organelle contact site regulated by this kinase.","evidence":"In vitro membrane contact reconstitution with recombinant PIP4K2A, rescue with peroxisome-targeted kinase-active vs. kinase-dead constructs, and cholesterol accumulation assays","pmids":["29353240"],"confidence":"High","gaps":["Identity of the PI(4,5)P2 effector tethering the two organelle membranes beyond synaptotagmin VII","Physiological consequences in tissues with high cholesterol flux","Whether PIP4K2B or PIP4K2C contribute at peroxisomes"]},{"year":2019,"claim":"Showing that PIP4K2A promotes proteasomal degradation of p85 to restrain PI3K signaling in PTEN-deficient GBM uncovered a tumor-suppressive mechanism operating through PI3K complex destabilization rather than through PI(4,5)P2 itself.","evidence":"In vivo RNAi screen in patient-derived xenograft GBM models, PIP4K2A overexpression with proteasome inhibitor experiments, and tumor growth assays","pmids":["30898893"],"confidence":"Medium","gaps":["Whether PIP4K2A directly ubiquitinates or recruits an E3 ligase for p85","Whether this mechanism operates outside of PTEN-null contexts","Single lab"]},{"year":2021,"claim":"Discovery of conserved RNA-binding activity independent of kinase function suggested PIP4K2A has a moonlighting role beyond lipid phosphorylation, though the functional significance remains undefined.","evidence":"RNA binding assays with kinase-dead mutants, cross-species comparison in Drosophila, C. elegans, and human cells","pmids":["34124142"],"confidence":"Low","gaps":["Limited mechanistic follow-up on human PIP4K2A RNA targets","No defined biological function for the RNA-binding activity","Single lab with no independent replication"]},{"year":2021,"claim":"Selective chemical inhibitors (BAY-091 and BAY-297) confirmed cellular target engagement but failed to reproduce the antiproliferative phenotype predicted from genetic loss in p53-deficient cells, dissociating kinase activity from at least some proposed tumor-suppressive functions.","evidence":"High-throughput screening, crystal structure-guided design, CETSA target engagement, and antiproliferative assays in p53-deficient cell lines","pmids":["34699202"],"confidence":"Medium","gaps":["Whether kinase-independent scaffolding functions explain the discrepancy between genetic and pharmacological perturbation","Whether longer treatment durations or specific cancer genotypes would reveal sensitivity","Impact of inhibitors on PI5P pools not assessed"]},{"year":2022,"claim":"Identification of lncSAMD11-1:1 as a PIP4K2A-binding partner that redirects the kinase to the cytoplasm to inhibit AKT and promote FoxO1 nuclear retention during decidualization revealed a physiological context where non-catalytic protein–RNA interactions control kinase signaling output.","evidence":"Co-immunoprecipitation of lncRNA with PIP4K2A, AKT phosphorylation assays, FoxO1 localization by confocal microscopy in primary human endometrial stromal cells","pmids":["35987479"],"confidence":"Medium","gaps":["Whether the PIP4K2A–lncRNA interaction requires the RNA-binding activity described separately","Mechanism by which PIP4K2A binding to lncSAMD11-1:1 inhibits AKT","Single lab, no reciprocal validation of lncRNA specificity"]},{"year":2023,"claim":"Discovery that PIP4K2A directly phosphorylates the non-lipid substrate MIF at Ser91 to promote its nuclear import and transcriptional activation of ciliogenesis genes fundamentally expanded the kinase's substrate repertoire from lipids to proteins.","evidence":"Co-immunoprecipitation, in vitro phosphorylation assays, S91A mutagenesis, confocal microscopy of cilia formation, and gene expression analysis","pmids":["38052787"],"confidence":"Medium","gaps":["Whether PIP4K2A phosphorylates other protein substrates","In vivo validation of cilia defects upon PIP4K2A loss","Single lab, not independently replicated"]},{"year":2023,"claim":"Identification of the gain-of-function S316R mutation causing enhanced kinase activity, upregulated β-globin expression, and impaired erythroid differentiation linked PIP4K2A to hemoglobin gene regulation and erythropoiesis.","evidence":"Family hematological analysis, kinase activity and protein stability assays, lentiviral S316R expression in HUDEP-2 erythroid cells","pmids":["37423903"],"confidence":"Medium","gaps":["Mechanism connecting PI(4,5)P2 levels to β-globin transcriptional regulation","Whether loss-of-function PIP4K2A mutations produce reciprocal erythroid phenotypes","Single lab, single family"]},{"year":null,"claim":"The relative contributions of lipid kinase activity, protein kinase activity, RNA binding, and scaffolding functions to PIP4K2A's diverse cellular roles remain unresolved, as does the question of which functions are pharmacologically targetable.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model integrating lipid kinase, protein kinase, and RNA-binding functions","Discrepancy between genetic and pharmacological perturbation in cancer models is unexplained","Structural basis for protein substrate recognition (e.g., MIF Ser91) is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,2,4,6,12]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1,2]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[6]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[9]}],"localization":[{"term_id":"GO:0005777","term_label":"peroxisome","supporting_discovery_ids":[1]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,3,4]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,14]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8,14]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5,8]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1,6]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[1]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[2,3,4]}],"complexes":[],"partners":["MIF","KCNQ3","EAAT3","GRIA1","PIK3R1"],"other_free_text":[]},"mechanistic_narrative":"PIP4K2A is a phosphatidylinositol-5-phosphate 4-kinase that generates PI(4,5)P2 at multiple subcellular compartments, thereby regulating diverse membrane-associated and signaling processes including ion channel activation, receptor trafficking, organelle contact site formation, and PI3K pathway modulation. At peroxisomal membranes, PIP4K2A-generated PI(4,5)P2 is required for lysosome–peroxisome membrane contacts that mediate LDL-derived cholesterol transport [PMID:29353240], while at the plasma membrane its lipid kinase activity activates KCNQ2/3 and KCNQ3/5 neuronal M channels [PMID:18545987] and increases surface abundance of EAAT3 and GluA1 [PMID:19644675, PMID:24389605]. Beyond canonical lipid kinase functions, PIP4K2A directly phosphorylates MIF at Ser91 to drive cilia biogenesis through MIF nuclear translocation and transcriptional regulation of ciliogenesis genes [PMID:38052787], negatively regulates PI3K signaling in PTEN-deficient glioblastoma by promoting proteasomal degradation of the p85 regulatory subunit [PMID:30898893], and is essential for AML cell survival through control of CDKN1A/CDKN1B levels and mTOR signaling [PMID:24681948]."},"prefetch_data":{"uniprot":{"accession":"P48426","full_name":"Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha","aliases":["1-phosphatidylinositol 5-phosphate 4-kinase 2-alpha","Diphosphoinositide kinase 2-alpha","PIP5KIII","Phosphatidylinositol 5-Phosphate 4-Kinase","PI5P4Kalpha","Phosphatidylinositol 5-phosphate 4-kinase type II alpha","PI(5)P 4-kinase type II alpha","PIP4KII-alpha","PtdIns(4)P-5-kinase B isoform","PtdIns(4)P-5-kinase C isoform","PtdIns(5)P-4-kinase isoform 2-alpha"],"length_aa":406,"mass_kda":46.2,"function":"Catalyzes the phosphorylation of phosphatidylinositol 5-phosphate (PtdIns5P) on the fourth hydroxyl of the myo-inositol ring, to form phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) (PubMed:23326584, PubMed:9367159). Has both ATP- and GTP-dependent kinase activities (PubMed:26774281). May exert its function by regulating the levels of PtdIns5P, which functions in the cytosol by increasing AKT activity and in the nucleus signals through ING2 (PubMed:18364242). May regulate the pool of cytosolic PtdIns5P in response to the activation of tyrosine phosphorylation (By similarity). Required for lysosome-peroxisome membrane contacts and intracellular cholesterol transport through modulating peroxisomal PtdIns(4,5)P2 level (PubMed:29353240). In collaboration with PIP4K2B, has a role in mediating autophagy in times of nutrient stress (By similarity). Required for autophagosome-lysosome fusion and the regulation of cellular lipid metabolism (PubMed:31091439). May be involved in thrombopoiesis, and the terminal maturation of megakaryocytes and regulation of their size (By similarity). Negatively regulates insulin signaling through a catalytic-independent mechanism (PubMed:31091439). PIP4Ks interact with PIP5Ks and suppress PIP5K-mediated PtdIns(4,5)P2 synthesis and insulin-dependent conversion to PtdIns(3,4,5)P3 (PubMed:31091439)","subcellular_location":"Cell membrane; Nucleus; Lysosome; Cytoplasm; Photoreceptor inner segment; Cell projection, cilium, photoreceptor outer segment","url":"https://www.uniprot.org/uniprotkb/P48426/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PIP4K2A","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000150867","cell_line_id":"CID000154","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"membrane","grade":2},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"PIP4K2C","stoichiometry":10.0},{"gene":"AHCYL1","stoichiometry":10.0},{"gene":"RPS23","stoichiometry":4.0},{"gene":"PIP5K2B","stoichiometry":4.0},{"gene":"RPL30","stoichiometry":0.2},{"gene":"RPS14","stoichiometry":0.2},{"gene":"PIP4K2B","stoichiometry":0.2},{"gene":"UBE2O","stoichiometry":0.2},{"gene":"EIF3K","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000154","total_profiled":1310},"omim":[{"mim_id":"620604","title":"PROSTAGLANDIN REDUCTASE 3; PTGR3","url":"https://www.omim.org/entry/620604"},{"mim_id":"617104","title":"PHOSPHATIDYLINOSITOL 5-PHOSPHATE 4-KINASE, TYPE II, GAMMA; PIP4K2C","url":"https://www.omim.org/entry/617104"},{"mim_id":"603140","title":"PHOSPHATIDYLINOSITOL 5-PHOSPHATE 4-KINASE, TYPE II, ALPHA; PIP4K2A","url":"https://www.omim.org/entry/603140"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":238.6}],"url":"https://www.proteinatlas.org/search/PIP4K2A"},"hgnc":{"alias_symbol":["PIP5KIIA","PIP5KIIalpha"],"prev_symbol":["PIP5K2A"]},"alphafold":{"accession":"P48426","domains":[{"cath_id":"3.30.800.10","chopping":"31-198","consensus_level":"medium","plddt":93.9103,"start":31,"end":198},{"cath_id":"3.30.810.10","chopping":"203-286_330-406","consensus_level":"medium","plddt":92.2552,"start":203,"end":406}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P48426","model_url":"https://alphafold.ebi.ac.uk/files/AF-P48426-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P48426-F1-predicted_aligned_error_v6.png","plddt_mean":85.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PIP4K2A","jax_strain_url":"https://www.jax.org/strain/search?query=PIP4K2A"},"sequence":{"accession":"P48426","fasta_url":"https://rest.uniprot.org/uniprotkb/P48426.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P48426/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P48426"}},"corpus_meta":[{"pmid":"24681948","id":"PMC_24681948","title":"A targeted knockdown screen of genes coding for phosphoinositide modulators identifies PIP4K2A as required for acute myeloid leukemia cell proliferation and survival.","date":"2014","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/24681948","citation_count":74,"is_preprint":false},{"pmid":"29353240","id":"PMC_29353240","title":"PIP4K2A regulates intracellular cholesterol transport through modulating PI(4,5)P2 homeostasis.","date":"2018","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/29353240","citation_count":61,"is_preprint":false},{"pmid":"17410640","id":"PMC_17410640","title":"The PIP5K2A and RGS4 genes are differentially associated with deficit and non-deficit schizophrenia.","date":"2007","source":"Genes, brain, and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/17410640","citation_count":55,"is_preprint":false},{"pmid":"16801950","id":"PMC_16801950","title":"Evidence for association of DNA sequence variants in the phosphatidylinositol-4-phosphate 5-kinase IIalpha gene (PIP5K2A) with schizophrenia.","date":"2006","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/16801950","citation_count":42,"is_preprint":false},{"pmid":"14582145","id":"PMC_14582145","title":"Polymorphism screening of PIP5K2A: a candidate gene for chromosome 10p-linked psychiatric disorders.","date":"2003","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14582145","citation_count":39,"is_preprint":false},{"pmid":"30898893","id":"PMC_30898893","title":"PIP4K2A as a negative regulator of PI3K in PTEN-deficient glioblastoma.","date":"2019","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30898893","citation_count":39,"is_preprint":false},{"pmid":"18545987","id":"PMC_18545987","title":"A schizophrenia-linked mutation in PIP5K2A fails to activate neuronal M channels.","date":"2008","source":"Psychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/18545987","citation_count":33,"is_preprint":false},{"pmid":"19644675","id":"PMC_19644675","title":"PIP5K2A-dependent regulation of excitatory amino acid transporter EAAT3.","date":"2009","source":"Psychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/19644675","citation_count":28,"is_preprint":false},{"pmid":"31109595","id":"PMC_31109595","title":"PIP4K2A and PIP4K2C transcript levels are associated with cytogenetic risk and survival outcomes in acute myeloid leukemia.","date":"2019","source":"Cancer genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31109595","citation_count":24,"is_preprint":false},{"pmid":"27149463","id":"PMC_27149463","title":"Association Between PIP4K2A Polymorphisms and Acute Lymphoblastic Leukemia Susceptibility.","date":"2016","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27149463","citation_count":21,"is_preprint":false},{"pmid":"17555944","id":"PMC_17555944","title":"The PIP5K2A gene and schizophrenia in the Chinese population--a case-control study.","date":"2007","source":"Schizophrenia research","url":"https://pubmed.ncbi.nlm.nih.gov/17555944","citation_count":17,"is_preprint":false},{"pmid":"34699202","id":"PMC_34699202","title":"Discovery and Characterization of the Potent and Highly Selective 1,7-Naphthyridine-Based Inhibitors BAY-091 and BAY-297 of the Kinase PIP4K2A.","date":"2021","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34699202","citation_count":16,"is_preprint":false},{"pmid":"38059827","id":"PMC_38059827","title":"Metabolic Enzyme SLC27A5 Regulates PIP4K2A pre-mRNA Splicing as a Noncanonical Mechanism to Suppress Hepatocellular Carcinoma Metastasis.","date":"2023","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/38059827","citation_count":15,"is_preprint":false},{"pmid":"16094259","id":"PMC_16094259","title":"Screening of PIP5K2A promoter region for mutations in bipolar disorder and schizophrenia.","date":"2005","source":"Psychiatric genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16094259","citation_count":15,"is_preprint":false},{"pmid":"24389605","id":"PMC_24389605","title":"Structural basis of PI(4,5)P2-dependent regulation of GluA1 by phosphatidylinositol-5-phosphate 4-kinase, type II, alpha (PIP5K2A).","date":"2014","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/24389605","citation_count":14,"is_preprint":false},{"pmid":"33193575","id":"PMC_33193575","title":"NRG1, PIP4K2A, and HTR2C as Potential Candidate Biomarker Genes for Several Clinical Subphenotypes of Depression and Bipolar Disorder.","date":"2020","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33193575","citation_count":13,"is_preprint":false},{"pmid":"25025909","id":"PMC_25025909","title":"Genetic variations of PIP4K2A confer vulnerability to poor antipsychotic response in severely ill schizophrenia patients.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25025909","citation_count":12,"is_preprint":false},{"pmid":"19475563","id":"PMC_19475563","title":"Association analysis of the PIP4K2A gene on chromosome 10p12 and schizophrenia in the Irish study of high density schizophrenia families (ISHDSF) and the Irish case-control study of schizophrenia (ICCSS).","date":"2010","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19475563","citation_count":12,"is_preprint":false},{"pmid":"23739505","id":"PMC_23739505","title":"[Association of (N251S)-PIP5K2A with schizophrenic disorders: a study of the Russian population of Siberia].","date":"2013","source":"Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova","url":"https://pubmed.ncbi.nlm.nih.gov/23739505","citation_count":11,"is_preprint":false},{"pmid":"34143546","id":"PMC_34143546","title":"Thermal proteome profiling identifies PIP4K2A and ZADH2 as off-targets of Polo-like kinase 1 inhibitor volasertib.","date":"2021","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/34143546","citation_count":9,"is_preprint":false},{"pmid":"32218783","id":"PMC_32218783","title":"Discovery and Differential Processing of HLA Class II-Restricted Minor Histocompatibility Antigen LB-PIP4K2A-1S and Its Allelic Variant by Asparagine Endopeptidase.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32218783","citation_count":8,"is_preprint":false},{"pmid":"35987479","id":"PMC_35987479","title":"A novel lncRNA lncSAMD11-1: 1 interacts with PIP4K2A to promote endometrial decidualization by stabilizing FoxO1 nuclear localization.","date":"2022","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/35987479","citation_count":8,"is_preprint":false},{"pmid":"16823801","id":"PMC_16823801","title":"Association study between genetic variants at the PIP5K2A gene locus and schizophrenia and bipolar affective disorder.","date":"2006","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16823801","citation_count":8,"is_preprint":false},{"pmid":"26227852","id":"PMC_26227852","title":"Differential profile of PIP4K2A expression in hematological malignancies.","date":"2015","source":"Blood cells, molecules & diseases","url":"https://pubmed.ncbi.nlm.nih.gov/26227852","citation_count":7,"is_preprint":false},{"pmid":"34124142","id":"PMC_34124142","title":"Conserved RNA Binding Activity of Phosphatidyl Inositol 5-Phosphate 4-Kinase (PIP4K2A).","date":"2021","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/34124142","citation_count":6,"is_preprint":false},{"pmid":"38052787","id":"PMC_38052787","title":"Phosphorylation of MIF by PIP4K2a is necessary for cilia biogenesis.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/38052787","citation_count":6,"is_preprint":false},{"pmid":"18314871","id":"PMC_18314871","title":"Association of PIP5K2A with schizophrenia: a study in an indonesian family sample.","date":"2008","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18314871","citation_count":6,"is_preprint":false},{"pmid":"33092542","id":"PMC_33092542","title":"Genetic polymorphisms of PIP5K2A and course of schizophrenia.","date":"2020","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33092542","citation_count":5,"is_preprint":false},{"pmid":"34681036","id":"PMC_34681036","title":"Association of PIP4K2A Polymorphisms with Alcohol Use Disorder.","date":"2021","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/34681036","citation_count":5,"is_preprint":false},{"pmid":"36756602","id":"PMC_36756602","title":"Modelling PIP4K2A inhibitory activity of 1,7-naphthyridine analogues using machine learning and molecular docking studies.","date":"2023","source":"RSC advances","url":"https://pubmed.ncbi.nlm.nih.gov/36756602","citation_count":5,"is_preprint":false},{"pmid":"28638032","id":"PMC_28638032","title":"[Association of polymorphic variants of PIP5K2A and HTR2C genes with response to antidepressant therapy of patients with a current depressive episode].","date":"2017","source":"Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova","url":"https://pubmed.ncbi.nlm.nih.gov/28638032","citation_count":5,"is_preprint":false},{"pmid":"38928345","id":"PMC_38928345","title":"Exploring the Potential Role of Oligodendrocyte-Associated PIP4K2A in Alzheimer's Disease Complicated with Type 2 Diabetes Mellitus via Multi-Omic Analysis.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38928345","citation_count":4,"is_preprint":false},{"pmid":"36952466","id":"PMC_36952466","title":"Contributions of ARID5B, IKZF1, PIP4K2A, and GATA3 Gene Polymorphisms to Childhood Acute Lymphoblastic Leukemia in a Chinese Population.","date":"2023","source":"Journal of pediatric hematology/oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36952466","citation_count":2,"is_preprint":false},{"pmid":"37423903","id":"PMC_37423903","title":"A novel gain-of-function PIP4K2A mutation elevates the expression of β-globin and aggravates the severity of α-thalassemia.","date":"2023","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/37423903","citation_count":1,"is_preprint":false},{"pmid":"40505929","id":"PMC_40505929","title":"Non-canonical functions of PIP4K2A and its role in cancer biology: A review.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/40505929","citation_count":0,"is_preprint":false},{"pmid":"41217726","id":"PMC_41217726","title":"PIP4K2A: A Novel CD8+ T Cell-Related Biomarker Associated with Lung Function Decline in COPD.","date":"2025","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41217726","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.08.12.607541","title":"Loss of PI5P4Kα slows the progression of a<i>Pten</i>mutant basal cell model of prostate cancer","date":"2024-08-12","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.12.607541","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20432,"output_tokens":3937,"usd":0.060175},"stage2":{"model":"claude-opus-4-6","input_tokens":7358,"output_tokens":3483,"usd":0.185798},"total_usd":0.245973,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"PIP4K2A kinase activity is required for AML cell proliferation and survival; its knockdown results in accumulation of CDKN1A and CDKN1B, G1 cell cycle arrest, and apoptosis, with both CDKN1A accumulation and apoptosis partially dependent on mTOR pathway activation.\",\n      \"method\": \"Targeted RNAi knockdown screen in human AML cells and murine MLL-AF9 AML cells, clonogenic assays, cell cycle analysis, Western blotting for downstream effectors\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cellular phenotype and pathway placement (mTOR), replicated in multiple cell systems including primary human AML cells\",\n      \"pmids\": [\"24681948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PIP4K2A localizes to peroxisomal membranes where it generates PI(4,5)P2, which is required for lysosome-peroxisome membrane contact formation that facilitates LDL-derived cholesterol transport from lysosomes to peroxisomes; kinase-active but not kinase-dead peroxisome-targeted PIP4K2A rescues the cholesterol transport defect caused by PIP4K2A knockdown.\",\n      \"method\": \"RNAi knockdown, forced expression of peroxisome-targeted kinase-active/inactive PIP4K2A, in vitro membrane contact reconstitution with recombinant PIP4K2A, fluorescence microscopy of lysosome-peroxisome contacts, cholesterol accumulation assays\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of membrane contacts with recombinant protein, coupled with rescue experiments using kinase-active vs. inactive constructs\",\n      \"pmids\": [\"29353240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Wild-type PIP4K2A activates heteromeric KCNQ2/KCNQ3 and KCNQ3/KCNQ5 neuronal M channels via PI(4,5)P2 synthesis; the schizophrenia-associated N251S mutation renders PIP4K2A catalytically inactive and fails to activate these channels. KCNQ3 in the channel complex is required for the kinase-mediated effect.\",\n      \"method\": \"Xenopus oocyte expression system with electrophysiology (voltage clamp), acute PI(4,5)P2 injection, PIP2 scavenger experiments, comparison of WT vs. N251S mutant\",\n      \"journal\": \"Psychopharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro functional assay with mutagenesis, acute lipid injection controls, and mechanistic dissection of subunit requirements\",\n      \"pmids\": [\"18545987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PIP4K2A enhances excitatory amino acid transporter EAAT3 activity and membrane abundance; wild-type PIP4K2A increases EAAT3 glutamate-induced current and membrane protein levels, while the N251S dominant-negative mutant decreases both. The effect on EAAT3 membrane abundance was confirmed in HEK293 cells.\",\n      \"method\": \"Xenopus oocyte expression with dual electrode voltage clamp, Western blotting of membrane fractions, confocal microscopy in HEK293 cells\",\n      \"journal\": \"Psychopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional assay in two cell systems with WT vs. mutant comparison, but single lab\",\n      \"pmids\": [\"19644675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PIP4K2A increases GluA1 (AMPA receptor) membrane abundance and glutamate-induced currents via PI(4,5)P2 production; the N251S mutation ablates this effect. The region K813-K823 of GluA1 was identified as critical for PI(4,5)P2 interaction by alanine scanning, and direct PI(4,5)P2 binding to the GluA1 C-terminal peptide was demonstrated by PIP strip assay.\",\n      \"method\": \"Xenopus oocyte expression with electrophysiology, alanine scanning mutagenesis of GluA1, PIP strip lipid-binding assay, Western blotting of membrane fractions in HEK293 cells\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis combined with direct lipid-binding assay; single lab\",\n      \"pmids\": [\"24389605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PIP4K2A acts as a negative regulator of PI3K signaling in PTEN-deficient GBM by targeting the p85 regulatory subunit of PI3K for proteasome-mediated degradation, thereby reducing p85/p110 PI3K complex levels; PIP4K2A overexpression suppressed clonogenic growth in vitro and tumor growth in vivo.\",\n      \"method\": \"In vivo RNAi screen in patient-derived xenograft GBM models, overexpression studies, proteasome inhibitor experiments, in vitro and in vivo tumor growth assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo RNAi screen validated by overexpression with mechanistic follow-up on proteasome pathway; single lab\",\n      \"pmids\": [\"30898893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PIP4K2A phosphorylates MIF (macrophage migration inhibitory factor) at serine 91, which increases MIF interaction with 14-3-3ζ and promotes MIF nuclear translocation; nuclear MIF then functions as a transcriptional regulator of ciliogenesis genes and regulates TTBK2 recruitment to the basal body, CP110 removal, CEP290 accumulation at centriolar satellites, and IFT protein trafficking, establishing PIP4K2A as an upstream regulator of cilia biogenesis.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays, site-directed mutagenesis (S91 of MIF), confocal microscopy, cilia formation assays, gene expression analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — kinase-substrate relationship defined with mutagenesis and functional cilia phenotype; single lab\",\n      \"pmids\": [\"38052787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SLC27A5 interacts with IGF2BP3 to prevent its nuclear translocation, thereby inhibiting IGF2BP3 binding to PIP4K2A pre-mRNA and preventing alternative splicing that produces the short PIP4K2A-S isoform. Loss of SLC27A5 increases PIP4K2A-S levels, which stabilizes p85 and enhances PI3K signaling to promote HCC metastasis.\",\n      \"method\": \"Co-immunoprecipitation of SLC27A5 with IGF2BP3, RNA immunoprecipitation for mRNA binding, alternative splicing analysis, p85 stability assays, in vivo AAV rescue experiments\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and RNA-IP with functional pathway validation; single lab\",\n      \"pmids\": [\"38059827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"During decidualization, PIP4K2A translocates from the nucleus to the cytoplasm and binds lncSAMD11-1:1; this interaction inhibits AKT phosphorylation and promotes FoxO1 nuclear localization, thereby supporting endometrial stromal cell decidualization.\",\n      \"method\": \"Knockdown and overexpression of lncSAMD11-1:1 in human endometrial stromal cells, co-immunoprecipitation of lncRNA with PIP4K2A, AKT phosphorylation assays, FoxO1 localization by confocal microscopy, in vitro decidualization assays\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP of lncRNA-protein interaction with functional decidualization phenotype; single lab\",\n      \"pmids\": [\"35987479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PIP4K2A exhibits RNA-binding activity that is independent of its lipid kinase activity; this RNA-binding capacity is conserved from Drosophila and C. elegans to humans.\",\n      \"method\": \"RNA binding assays with kinase-dead PIP4K2A mutants, cross-species functional comparison, RNA immunoprecipitation\",\n      \"journal\": \"Frontiers in molecular biosciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, limited mechanistic follow-up on the human protein specifically\",\n      \"pmids\": [\"34124142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PIP4K2A is identified as an off-target of the PLK1 inhibitor volasertib (but not of onvansertib), as demonstrated by thermal proteome profiling showing stabilization of PIP4K2A by volasertib.\",\n      \"method\": \"Thermal proteome profiling (TPP), mass spectrometry, comparison between two PLK1 inhibitors\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — unbiased proteome-wide TPP with inhibitor selectivity comparison\",\n      \"pmids\": [\"34143546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Novel selective PIP4K2A inhibitors BAY-091 and BAY-297 were identified; cellular target engagement was confirmed by cellular thermal shift assay. However, pharmacological PIP4K2A inhibition did not induce antiproliferative activity in p53-deficient tumor cells, dissociating kinase inhibition from the proposed tumor-suppressive mechanism.\",\n      \"method\": \"High-throughput screening, structure-based optimization, crystal structure-guided design, cellular thermal shift assay (CETSA), antiproliferative assays in p53-deficient cell lines\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — structure-based inhibitor development with CETSA target engagement validation and negative functional result\",\n      \"pmids\": [\"34699202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A gain-of-function PIP4K2A mutation (S316R) exhibits enhanced protein stability, increased kinase activity, and upregulates β-globin expression, leading to a more imbalanced β/α-globin ratio and increased Hb H inclusion bodies; introduction of S316R into HUDEP-2 cells confirmed increased β-globin expression and inhibited erythroid differentiation and terminal enucleation.\",\n      \"method\": \"Family haematological analysis, kinase activity assays, protein stability assays, lentiviral introduction of S316R into HUDEP-2 erythroid cells, erythroid differentiation assays\",\n      \"journal\": \"British journal of haematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — kinase activity measured in vitro, functional validation in human erythroid cell model; single lab\",\n      \"pmids\": [\"37423903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of PIP4K2A (PI5P4Kα) in basal prostate epithelial cells slows the progression of Pten mutant mouse prostatic intraepithelial neoplasia; PIP4K2A is enriched in basal cells and its loss disrupts lipid metabolism (particularly carnitine lipids), pointing to lipid metabolic disruption as a mechanism for reduced tumor progression.\",\n      \"method\": \"Basal cell-specific GEMM with CK5-Cre, combined Pip4k2a/Pten knockout, lineage tracing with single-cell RNA sequencing, siPIP4K2A in LNCaP cells with lipidomic analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo GEMM with scRNA-seq and lipidomics functional support; preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2024.08.12.607541\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PIP4K2A is localized to both the cytoplasm and nucleus in leukocytes and leukemia cells, as determined by subcellular fractionation; its expression is reduced in leukemia cell lines compared to normal leukocytes.\",\n      \"method\": \"Subcellular fractionation, Western blotting, immunofluorescence\",\n      \"journal\": \"Blood cells, molecules & diseases\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — localization determined by fractionation but without defined functional consequence of nuclear vs. cytoplasmic distribution\",\n      \"pmids\": [\"26227852\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PIP4K2A is a lipid kinase that phosphorylates phosphatidylinositol-5-phosphate (PI5P) to generate PI(4,5)P2 at multiple subcellular compartments including peroxisomal membranes (enabling lysosome-peroxisome cholesterol transport via synaptotagmin VII contacts), the plasma membrane (activating KCNQ neuronal M channels and regulating EAAT3 and GluA1 membrane abundance), and nuclear/cytoplasmic compartments (where, in complex with lncSAMD11-1:1, it inhibits AKT to promote FoxO1 nuclear retention during decidualization); it also acts as a direct kinase for MIF at S91 to drive cilia biogenesis, negatively regulates PI3K signaling in PTEN-deficient GBM via p85 proteasomal degradation, and is required for AML cell survival through modulation of CDKN1A/CDKN1B and mTOR signaling, while the schizophrenia-associated N251S mutation abolishes kinase activity and disrupts all PI(4,5)P2-dependent downstream functions.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PIP4K2A is a phosphatidylinositol-5-phosphate 4-kinase that generates PI(4,5)P2 at multiple subcellular compartments, thereby regulating diverse membrane-associated and signaling processes including ion channel activation, receptor trafficking, organelle contact site formation, and PI3K pathway modulation. At peroxisomal membranes, PIP4K2A-generated PI(4,5)P2 is required for lysosome–peroxisome membrane contacts that mediate LDL-derived cholesterol transport [PMID:29353240], while at the plasma membrane its lipid kinase activity activates KCNQ2/3 and KCNQ3/5 neuronal M channels [PMID:18545987] and increases surface abundance of EAAT3 and GluA1 [PMID:19644675, PMID:24389605]. Beyond canonical lipid kinase functions, PIP4K2A directly phosphorylates MIF at Ser91 to drive cilia biogenesis through MIF nuclear translocation and transcriptional regulation of ciliogenesis genes [PMID:38052787], negatively regulates PI3K signaling in PTEN-deficient glioblastoma by promoting proteasomal degradation of the p85 regulatory subunit [PMID:30898893], and is essential for AML cell survival through control of CDKN1A/CDKN1B levels and mTOR signaling [PMID:24681948].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Establishing that PIP4K2A lipid kinase activity directly controls neuronal ion channel function resolved how PI(4,5)P2 synthesis couples to electrical excitability, and the schizophrenia-associated N251S mutation provided a loss-of-function tool linking kinase activity to channel activation.\",\n      \"evidence\": \"Xenopus oocyte electrophysiology with WT vs. N251S PIP4K2A, acute PI(4,5)P2 injection controls, and subunit requirement analysis for KCNQ2/3 and KCNQ3/5 channels\",\n      \"pmids\": [\"18545987\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether PIP4K2A-dependent KCNQ activation occurs at endogenous expression levels in mammalian neurons\",\n        \"Structural basis for how N251S abolishes kinase activity\",\n        \"Whether other PIP4K family members compensate in vivo\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrating that PIP4K2A promotes EAAT3 membrane abundance and glutamate transport extended PI(4,5)P2-dependent membrane trafficking beyond ion channels to neurotransmitter transporters.\",\n      \"evidence\": \"Xenopus oocyte dual electrode voltage clamp and HEK293 membrane fractionation comparing WT and N251S PIP4K2A effects on EAAT3\",\n      \"pmids\": [\"19644675\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether PI(4,5)P2 directly binds EAAT3 or acts through an intermediary\",\n        \"In vivo relevance in neuronal glutamate homeostasis\",\n        \"Single lab observation\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identification of PIP4K2A as essential for AML cell proliferation, with its loss causing CDKN1A/CDKN1B accumulation and mTOR-dependent apoptosis, established the kinase as a cancer dependency factor and linked its activity to cell cycle control.\",\n      \"evidence\": \"RNAi knockdown screen in human and murine MLL-AF9 AML cells, clonogenic assays, and Western blotting for downstream mTOR and CDK inhibitor effectors\",\n      \"pmids\": [\"24681948\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the requirement is for lipid kinase activity specifically versus a scaffolding function\",\n        \"The direct mechanistic link between PI(4,5)P2 pools and CDKN1A/CDKN1B stabilization\",\n        \"Whether selective PIP4K2A inhibitors phenocopy knockdown in AML\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapping the PI(4,5)P2-binding site on GluA1 (K813–K823) and showing PIP4K2A-dependent membrane insertion of AMPA receptors broadened the kinase's role to excitatory synaptic receptor trafficking.\",\n      \"evidence\": \"Alanine scanning mutagenesis of GluA1 C-terminus, PIP strip lipid-binding assay, Xenopus oocyte electrophysiology, and HEK293 membrane fractionation\",\n      \"pmids\": [\"24389605\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Endogenous validation in hippocampal or cortical neurons\",\n        \"Whether the effect involves direct PI(4,5)P2–GluA1 interaction in a bilayer context\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Reconstitution of PIP4K2A-generated PI(4,5)P2 at peroxisomal membranes as the trigger for lysosome–peroxisome contact formation and cholesterol transport revealed a new organelle contact site regulated by this kinase.\",\n      \"evidence\": \"In vitro membrane contact reconstitution with recombinant PIP4K2A, rescue with peroxisome-targeted kinase-active vs. kinase-dead constructs, and cholesterol accumulation assays\",\n      \"pmids\": [\"29353240\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of the PI(4,5)P2 effector tethering the two organelle membranes beyond synaptotagmin VII\",\n        \"Physiological consequences in tissues with high cholesterol flux\",\n        \"Whether PIP4K2B or PIP4K2C contribute at peroxisomes\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showing that PIP4K2A promotes proteasomal degradation of p85 to restrain PI3K signaling in PTEN-deficient GBM uncovered a tumor-suppressive mechanism operating through PI3K complex destabilization rather than through PI(4,5)P2 itself.\",\n      \"evidence\": \"In vivo RNAi screen in patient-derived xenograft GBM models, PIP4K2A overexpression with proteasome inhibitor experiments, and tumor growth assays\",\n      \"pmids\": [\"30898893\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether PIP4K2A directly ubiquitinates or recruits an E3 ligase for p85\",\n        \"Whether this mechanism operates outside of PTEN-null contexts\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery of conserved RNA-binding activity independent of kinase function suggested PIP4K2A has a moonlighting role beyond lipid phosphorylation, though the functional significance remains undefined.\",\n      \"evidence\": \"RNA binding assays with kinase-dead mutants, cross-species comparison in Drosophila, C. elegans, and human cells\",\n      \"pmids\": [\"34124142\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Limited mechanistic follow-up on human PIP4K2A RNA targets\",\n        \"No defined biological function for the RNA-binding activity\",\n        \"Single lab with no independent replication\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Selective chemical inhibitors (BAY-091 and BAY-297) confirmed cellular target engagement but failed to reproduce the antiproliferative phenotype predicted from genetic loss in p53-deficient cells, dissociating kinase activity from at least some proposed tumor-suppressive functions.\",\n      \"evidence\": \"High-throughput screening, crystal structure-guided design, CETSA target engagement, and antiproliferative assays in p53-deficient cell lines\",\n      \"pmids\": [\"34699202\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether kinase-independent scaffolding functions explain the discrepancy between genetic and pharmacological perturbation\",\n        \"Whether longer treatment durations or specific cancer genotypes would reveal sensitivity\",\n        \"Impact of inhibitors on PI5P pools not assessed\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of lncSAMD11-1:1 as a PIP4K2A-binding partner that redirects the kinase to the cytoplasm to inhibit AKT and promote FoxO1 nuclear retention during decidualization revealed a physiological context where non-catalytic protein–RNA interactions control kinase signaling output.\",\n      \"evidence\": \"Co-immunoprecipitation of lncRNA with PIP4K2A, AKT phosphorylation assays, FoxO1 localization by confocal microscopy in primary human endometrial stromal cells\",\n      \"pmids\": [\"35987479\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether the PIP4K2A–lncRNA interaction requires the RNA-binding activity described separately\",\n        \"Mechanism by which PIP4K2A binding to lncSAMD11-1:1 inhibits AKT\",\n        \"Single lab, no reciprocal validation of lncRNA specificity\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery that PIP4K2A directly phosphorylates the non-lipid substrate MIF at Ser91 to promote its nuclear import and transcriptional activation of ciliogenesis genes fundamentally expanded the kinase's substrate repertoire from lipids to proteins.\",\n      \"evidence\": \"Co-immunoprecipitation, in vitro phosphorylation assays, S91A mutagenesis, confocal microscopy of cilia formation, and gene expression analysis\",\n      \"pmids\": [\"38052787\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether PIP4K2A phosphorylates other protein substrates\",\n        \"In vivo validation of cilia defects upon PIP4K2A loss\",\n        \"Single lab, not independently replicated\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of the gain-of-function S316R mutation causing enhanced kinase activity, upregulated β-globin expression, and impaired erythroid differentiation linked PIP4K2A to hemoglobin gene regulation and erythropoiesis.\",\n      \"evidence\": \"Family hematological analysis, kinase activity and protein stability assays, lentiviral S316R expression in HUDEP-2 erythroid cells\",\n      \"pmids\": [\"37423903\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism connecting PI(4,5)P2 levels to β-globin transcriptional regulation\",\n        \"Whether loss-of-function PIP4K2A mutations produce reciprocal erythroid phenotypes\",\n        \"Single lab, single family\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The relative contributions of lipid kinase activity, protein kinase activity, RNA binding, and scaffolding functions to PIP4K2A's diverse cellular roles remain unresolved, as does the question of which functions are pharmacologically targetable.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No unified model integrating lipid kinase, protein kinase, and RNA-binding functions\",\n        \"Discrepancy between genetic and pharmacological perturbation in cancer models is unexplained\",\n        \"Structural basis for protein substrate recognition (e.g., MIF Ser91) is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 2, 4, 6, 12]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005777\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 3, 4]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 14]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5, 8]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [2, 3, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"MIF\",\n      \"KCNQ3\",\n      \"EAAT3\",\n      \"GRIA1\",\n      \"PIK3R1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}