{"gene":"PIP4K2A","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2018,"finding":"PIP4K2A phosphorylates PI5P to generate PI(4,5)P2 at the peroxisomal membrane, and its knockdown reduces peroxisomal PI(4,5)P2 levels, decreases lysosome-peroxisome membrane contacts (mediated by synaptotagmin VII bridging), and increases lysosomal cholesterol accumulation. Forced expression of peroxisome-localized, kinase-active PIP4K2A in knockdown cells reduced cholesterol accumulation, and in vitro addition of recombinant PIP4K2A restored membrane contacts.","method":"RNA interference, forced expression of peroxisome-targeted PIP4K2A, in vitro reconstitution of membrane contacts with recombinant PIP4K2A, fluorescence microscopy","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with recombinant protein, rescue with kinase-active construct, multiple orthogonal methods in single study","pmids":["29353240"],"is_preprint":false},{"year":2019,"finding":"PIP4K2A negatively regulates PI3K signaling in PTEN-deficient glioblastoma by targeting the p85 regulatory subunit of PI3K for proteasome-mediated degradation, thereby reducing p85/p110 PI3K complex levels. Overexpression of PIP4K2A suppressed clonogenic growth in vitro and tumor growth in vivo.","method":"In vivo RNAi screening in patient-derived xenograft models, overexpression/knockdown with PI3K component western blotting, proteasome inhibitor assays, clonogenic and xenograft assays","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays (in vitro and in vivo), single lab, mechanism inferred from protein levels and proteasome inhibition rather than direct reconstitution","pmids":["30898893"],"is_preprint":false},{"year":2014,"finding":"PIP4K2A knockdown in human AML cells causes accumulation of cyclin-dependent kinase inhibitors CDKN1A and CDKN1B, G1 cell cycle arrest, and apoptosis. Both CDKN1A accumulation and apoptosis were partially dependent on mTOR pathway activation. PIP4K2A is required for clonogenic and leukemia-initiating potential of AML cells but not for normal hematopoietic stem/progenitor cell clonogenicity.","method":"Targeted RNAi knockdown screen, clonogenic assays, flow cytometry (cell cycle/apoptosis), western blotting for CDKN1A/CDKN1B and mTOR pathway components, murine MLL-AF9 AML model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined cellular phenotype with pathway placement (mTOR), multiple readouts, single lab","pmids":["24681948"],"is_preprint":false},{"year":2008,"finding":"Wild-type PIP4K2A activates heteromeric KCNQ2/KCNQ3 and KCNQ3/KCNQ5 neuronal M channels (but not homomeric KCNQ2 or KCNQ5) in Xenopus oocytes via PI(4,5)P2 synthesis. The schizophrenia-associated N251S mutation renders PIP4K2A kinase-inactive and abolishes KCNQ channel activation, as confirmed by acute PI(4,5)P2 injection and PIP2 scavenger experiments.","method":"Xenopus oocyte expression system, dual-electrode voltage clamp, acute PI(4,5)P2 injection, PIP2 scavenger application, comparison of wild-type vs. N251S mutant kinase","journal":"Psychopharmacology","confidence":"High","confidence_rationale":"Tier 1 / Strong — functional reconstitution in oocytes, active-site mutagenesis, acute lipid injection and scavenger controls as orthogonal validation","pmids":["18545987"],"is_preprint":false},{"year":2009,"finding":"Wild-type PIP4K2A increases EAAT3 glutamate transporter activity and membrane abundance in Xenopus oocytes and HEK cells. The schizophrenia-associated N251S mutant PIP4K2A exerts a dominant inhibitory effect, reducing EAAT3 current and membrane abundance even in the presence of co-expressed wild-type PIP4K2A.","method":"Xenopus oocyte expression, dual-electrode voltage clamp (glutamate-induced current), western blotting, confocal microscopy of membrane EAAT3, comparison of wild-type vs. N251S mutant","journal":"Psychopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assay in two expression systems, dominant-negative mutant characterization, single lab","pmids":["19644675"],"is_preprint":false},{"year":2014,"finding":"PIP4K2A increases GluA1 (AMPA receptor) currents by enhancing GluA1 membrane abundance via PI(4,5)P2 synthesis. The N251S mutant abolishes this effect. The region K813-K823 of GluA1 is critical for PI(4,5)P2 binding (defined by alanine scanning), and PI(4,5)P2 binding to the GluA1 C-terminal peptide was confirmed by PIP strip assay.","method":"Xenopus oocyte expression, electrophysiology, HEK cell overexpression, alanine scan mutagenesis of GluA1, PIP strip assay, western blotting for membrane abundance","journal":"Pflugers Archiv : European journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (electrophysiology, PIP strip, mutagenesis), single lab","pmids":["24389605"],"is_preprint":false},{"year":2023,"finding":"PIP4K2A interacts with and phosphorylates MIF (macrophage migration inhibitory factor) at serine 91, increasing MIF's interaction with 14-3-3ζ and promoting MIF nuclear translocation, where MIF acts as a transcriptional regulator of ciliogenesis genes. PIP4K2A was identified as an upstream regulator of MIF required for cilia biogenesis.","method":"Co-immunoprecipitation, in vitro kinase phosphorylation assay, site-directed mutagenesis (S91), confocal microscopy of cilia structures, gene expression analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus in vitro kinase assay with site-specific mutation, single lab","pmids":["38052787"],"is_preprint":false},{"year":2021,"finding":"PIP4K2A possesses conserved RNA-binding activity that is independent of its lipid kinase activity. PIP4K2A is imported from the host cell into Plasmodium parasites and binds specific RNA elements, with RNA-binding activity conserved across Drosophila, C. elegans, and humans.","method":"RNA-binding assays with kinase-dead mutants, parasite import assays in Plasmodium berghei and Toxoplasma gondii, cross-species comparison of RNA binding","journal":"Frontiers in molecular biosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase-dead mutant used to separate activities, cross-species validation, single lab","pmids":["34124142"],"is_preprint":false},{"year":2023,"finding":"SLC27A5 interacts with IGF2BP3 to prevent IGF2BP3 nuclear translocation; loss of SLC27A5 allows IGF2BP3 to enter the nucleus and modulate PIP4K2A pre-mRNA alternative splicing, elevating the PIP4K2A-S isoform. Elevated PIP4K2A-S positively regulates PI3K signaling by enhancing p85 stability in hepatocellular carcinoma.","method":"Co-immunoprecipitation (SLC27A5/IGF2BP3), RT-PCR for splice isoforms, western blotting for p85, AAV rescue experiments, RNA decoy oligonucleotide experiments","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, isoform-specific functional rescue, multiple orthogonal methods, single lab","pmids":["38059827"],"is_preprint":false},{"year":2022,"finding":"During decidualization, lncSAMD11-1:1 and PIP4K2A translocate out of the nucleus together and bind each other, inhibiting AKT phosphorylation and promoting FoxO1 nuclear localization in human endometrial stromal cells.","method":"Co-immunoprecipitation (lncRNA-protein), subcellular fractionation, phospho-AKT western blotting, FoxO1 nuclear localization by confocal microscopy, knockdown/overexpression experiments","journal":"The international journal of biochemistry & cell biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP of lncRNA-protein interaction, limited mechanistic follow-up on PIP4K2A's direct role, single lab","pmids":["35987479"],"is_preprint":false},{"year":2026,"finding":"Crystal structure of PIP4K2A in complex with inhibitor 422A reveals a water-mediated interaction between the pyridyl nitrogen of the inhibitor and a conserved structured water molecule in the specificity pocket roof. Comparative structural analysis with PIP4K2A-selective inhibitor BAY-091 shows that deeper penetration into the specificity pocket enhances PIP4K2A binding but introduces steric constraints that limit PIP4K2B engagement, defining structural determinants of isoform-selective inhibitor binding.","method":"X-ray crystallography of PIP4K2A-inhibitor complex, comparative structural analysis with known inhibitor-bound structures","journal":"Acta crystallographica. Section D, Structural biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with comparative structural analysis providing direct mechanistic insight into inhibitor binding mode and isoform selectivity","pmids":["42117906"],"is_preprint":false},{"year":2021,"finding":"Selective PIP4K2A inhibitors BAY-091 and BAY-297 were identified and confirmed to engage PIP4K2A in cells (cellular thermal shift assay), but inhibition of PIP4K2A with these compounds did not produce the hypothesized antiproliferative activity in p53-deficient tumor cells, establishing that kinase inhibition alone is insufficient for this effect.","method":"High-throughput screening, structure-based optimization, cellular thermal shift assay (CETSA), antiproliferation assays in p53-deficient cells","journal":"Journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CETSA confirms cellular target engagement, negative functional result is experimentally established, single lab","pmids":["34699202"],"is_preprint":false},{"year":2023,"finding":"A novel gain-of-function mutation S316R in PIP4K2A enhances protein stability, increases kinase activity, and upregulates β-globin expression, inhibiting erythroid differentiation and terminal enucleation. Introduction of S316R into HUDEP-2 cells confirmed increased β-globin expression.","method":"Patient-derived mutation identification, in vitro kinase assay, protein stability assay, HUDEP-2 cell functional experiments, haematological analysis of family members","journal":"British journal of haematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay combined with cell functional experiments and family-level validation, single lab","pmids":["37423903"],"is_preprint":false},{"year":2024,"finding":"Loss of PIP4K2A (PI5P4Kα) in basal cells of Pten-mutant mouse prostates slows the development of prostatic intraepithelial neoplasia. Transcriptomic analysis and lipidomic profiling (carnitine lipids in LNCaP cells treated with siPIP4K2A) point to disruption of lipid metabolism as the mechanistic basis for reduced tumor progression.","method":"Basal-cell-specific GEMM (CK5-Cre), single-cell RNA sequencing with lineage tracing, siRNA knockdown in LNCaP cells, carnitine lipid mass spectrometry","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — in vivo genetic model plus lipidomics, but preprint and lipid metabolism link based on pathway analysis rather than direct mechanistic reconstitution","pmids":["bio_10.1101_2024.08.12.607541"],"is_preprint":true},{"year":2005,"finding":"A rare promoter variant (-1007C→T) of PIP4K2A creates a binding site for a brain-specific nuclear protein; electrophoretic mobility shift assay showed increased binding of this brain-specific nuclear protein to the -1007T allele compared with -1007C, suggesting transcriptional regulation of PIP4K2A in brain tissue.","method":"SSCP polymorphism screening, DNA sequencing, electrophoretic mobility shift assay (EMSA)","journal":"Psychiatric genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single EMSA experiment, brain-specific protein not identified, single lab","pmids":["16094259"],"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 (peroxisomes, plasma membrane); through PI(4,5)P2 production it regulates lysosome-peroxisome cholesterol transport, neuronal M channel (KCNQ2/3, KCNQ3/5) activity, EAAT3 glutamate transporter membrane abundance, and AMPA receptor (GluA1) currents; it also phosphorylates MIF at S91 to promote 14-3-3ζ binding and MIF nuclear translocation required for ciliogenesis, acts as a tumor suppressor in PTEN-deficient contexts by targeting p85 PI3K subunit for proteasomal degradation, and possesses a kinase-independent RNA-binding activity conserved across metazoans."},"narrative":{"mechanistic_narrative":"PIP4K2A is a lipid kinase that phosphorylates phosphatidylinositol-5-phosphate to generate PI(4,5)P2 at discrete membrane compartments, thereby controlling membrane contacts, ion channel and transporter activity, and PI3K signaling [PMID:29353240, PMID:18545987]. At the peroxisomal membrane its PI(4,5)P2 output sustains synaptotagmin-VII-bridged lysosome–peroxisome contacts and limits lysosomal cholesterol accumulation, with kinase-active enzyme required for rescue [PMID:29353240]. In neurons, PIP4K2A-derived PI(4,5)P2 activates heteromeric KCNQ2/3 and KCNQ3/5 M channels and enhances the membrane abundance and currents of the EAAT3 glutamate transporter and the GluA1 AMPA receptor [PMID:18545987, PMID:19644675, PMID:24389605]. The schizophrenia-associated N251S substitution is kinase-inactive and abolishes these activities, acting in a dominant-inhibitory manner on EAAT3 [PMID:18545987, PMID:19644675]. Beyond lipid signaling, PIP4K2A behaves as a context-dependent regulator of the PI3K pathway by promoting proteasomal degradation of the p85 regulatory subunit, suppressing clonogenic and tumor growth in PTEN-deficient glioblastoma [PMID:30898893], yet it is also required for the leukemia-initiating potential of AML cells, where its loss triggers CDKN1A/CDKN1B accumulation, G1 arrest and mTOR-dependent apoptosis [PMID:24681948]. PIP4K2A additionally phosphorylates MIF at serine 91 to promote 14-3-3ζ binding and MIF nuclear translocation driving ciliogenesis [PMID:38052787], and carries a conserved, kinase-independent RNA-binding activity [PMID:34124142]. A crystal structure of PIP4K2A bound to an inhibitor defines a water-mediated contact in the specificity-pocket roof that underlies isoform-selective inhibitor design [PMID:42117906]; selective inhibitors engage the enzyme in cells but do not reproduce the antiproliferative phenotype attributed to PIP4K2A loss, showing kinase inhibition alone is insufficient [PMID:34699202].","teleology":[{"year":2005,"claim":"Established a candidate transcriptional-regulatory mechanism linking PIP4K2A to brain biology by showing a promoter variant alters nuclear-protein binding.","evidence":"SSCP screening and EMSA of the -1007C→T promoter variant","pmids":["16094259"],"confidence":"Low","gaps":["The brain-specific nuclear protein was not identified","Single EMSA without functional reporter validation","No link to PIP4K2A expression level in vivo"]},{"year":2008,"claim":"Demonstrated that PIP4K2A kinase activity controls neuronal M-channel function through PI(4,5)P2, and that the disease-associated N251S mutation is a loss-of-function allele.","evidence":"Xenopus oocyte voltage clamp with PI(4,5)P2 injection, PIP2 scavenger, and WT vs N251S comparison","pmids":["18545987"],"confidence":"High","gaps":["Selectivity for heteromeric vs homomeric KCNQ channels not mechanistically explained","Endogenous neuronal relevance not tested"]},{"year":2009,"claim":"Extended PIP4K2A's regulation of membrane proteins to the EAAT3 glutamate transporter and showed N251S acts dominant-negatively.","evidence":"Oocyte and HEK expression, voltage clamp, membrane EAAT3 imaging, WT vs N251S","pmids":["19644675"],"confidence":"Medium","gaps":["Mechanism of dominant inhibition not resolved","No endogenous neuronal validation"]},{"year":2014,"claim":"Defined PIP4K2A as required for AML clonogenic and leukemia-initiating potential, placing its loss-of-function phenotype downstream through CDK inhibitors and mTOR.","evidence":"RNAi knockdown, cell cycle/apoptosis flow cytometry, CDKN1A/CDKN1B and mTOR western blot, MLL-AF9 model","pmids":["24681948"],"confidence":"Medium","gaps":["Direct lipid substrate link to mTOR not established","Distinction from kinase-independent functions untested"]},{"year":2014,"claim":"Showed PIP4K2A enhances AMPA receptor (GluA1) currents via PI(4,5)P2 binding to a defined GluA1 C-terminal region.","evidence":"Oocyte electrophysiology, GluA1 alanine scan, PIP strip assay, membrane abundance western blot","pmids":["24389605"],"confidence":"Medium","gaps":["In vivo synaptic relevance not addressed","Single expression-system context"]},{"year":2018,"claim":"Localized PIP4K2A kinase activity to the peroxisomal membrane and connected its PI(4,5)P2 output to lysosome–peroxisome contacts and cholesterol handling.","evidence":"RNAi, peroxisome-targeted kinase-active rescue, in vitro contact reconstitution with recombinant protein, microscopy","pmids":["29353240"],"confidence":"High","gaps":["How PIP4K2A is targeted to peroxisomes not defined","Direct PI(4,5)P2 sensing by synaptotagmin VII not shown"]},{"year":2019,"claim":"Identified PIP4K2A as a tumor suppressor in PTEN-deficient glioblastoma that lowers PI3K signaling by promoting proteasomal degradation of p85.","evidence":"In vivo RNAi PDX screen, overexpression/knockdown, proteasome inhibitor assays, clonogenic and xenograft assays","pmids":["30898893"],"confidence":"Medium","gaps":["Mechanism inferred from protein levels rather than reconstituted degradation","Direct PIP4K2A-p85 contact not biochemically defined"]},{"year":2021,"claim":"Uncovered a kinase-independent, evolutionarily conserved RNA-binding activity of PIP4K2A and its import into apicomplexan parasites.","evidence":"RNA-binding assays with kinase-dead mutants, parasite import assays, cross-species comparison","pmids":["34124142"],"confidence":"Medium","gaps":["RNA targets in the human cell not defined","Functional consequence of RNA binding unresolved"]},{"year":2021,"claim":"Established that selective kinase inhibition is insufficient to reproduce the antiproliferative effect of PIP4K2A loss in p53-deficient cells, dissociating phenotype from catalytic activity.","evidence":"HTS, structure-based optimization, CETSA target engagement, antiproliferation assays","pmids":["34699202"],"confidence":"Medium","gaps":["Whether non-catalytic functions drive the phenotype not tested","No genetic vs pharmacologic reconciliation"]},{"year":2023,"claim":"Defined a substrate-level signaling role: PIP4K2A phosphorylates MIF at S91 to promote 14-3-3ζ binding, MIF nuclear translocation and ciliogenesis.","evidence":"Co-IP, in vitro kinase assay, S91 mutagenesis, cilia confocal imaging, gene expression","pmids":["38052787"],"confidence":"Medium","gaps":["Relationship between protein-kinase and lipid-kinase activities unclear","Direct ciliogenesis gene targets of nuclear MIF not detailed"]},{"year":2023,"claim":"Linked alternative splicing of PIP4K2A (the PIP4K2A-S isoform) to PI3K activation via p85 stabilization in hepatocellular carcinoma, in apparent opposition to its p85-degrading role.","evidence":"SLC27A5/IGF2BP3 reciprocal Co-IP, isoform RT-PCR, p85 western blot, AAV and RNA decoy rescue","pmids":["38059827"],"confidence":"Medium","gaps":["Mechanistic basis for opposing p85 effects across isoforms not resolved","Isoform-specific structural difference not defined"]},{"year":2023,"claim":"Identified a gain-of-function S316R mutation that stabilizes PIP4K2A and raises kinase activity, upregulating β-globin and impairing erythroid differentiation.","evidence":"Patient mutation, in vitro kinase and stability assays, HUDEP-2 functional experiments, family analysis","pmids":["37423903"],"confidence":"Medium","gaps":["Pathway linking kinase activity to β-globin regulation not defined","Single-family genetic evidence"]},{"year":2026,"claim":"Provided structural determinants of isoform-selective inhibition, defining a water-mediated specificity-pocket interaction distinguishing PIP4K2A from PIP4K2B.","evidence":"X-ray crystallography of PIP4K2A-inhibitor complex with comparative analysis","pmids":["42117906"],"confidence":"High","gaps":["No catalytic-mechanism or substrate-bound structure described","Functional consequence of selective inhibition not addressed"]},{"year":null,"claim":"How PIP4K2A's lipid-kinase, protein-kinase, and RNA-binding activities are coordinated within a cell, and which activity drives each disease phenotype, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model separating catalytic from non-catalytic functions","Endogenous compartment-specific substrate maps absent","Reconciliation of opposing roles in PI3K signaling not achieved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,3,6,12]},{"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":[7]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,3,5]}],"localization":[{"term_id":"GO:0005777","term_label":"peroxisome","supporting_discovery_ids":[0]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,4,5]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,8]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[3,4,5]}],"complexes":[],"partners":["MIF","YWHAZ","PIK3R1","IGF2BP3"],"other_free_text":[]}},"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":63,"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":43,"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":41,"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":"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":"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":18,"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":"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":"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":"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":"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":10,"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":8,"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":"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":7,"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":7,"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":3,"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":2,"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":"42117906","id":"PMC_42117906","title":"Structural basis for high-affinity inhibitor binding to lipid kinases PIP4K2A and PIP4K2B.","date":"2026","source":"Acta crystallographica. Section D, Structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/42117906","citation_count":0,"is_preprint":false},{"pmid":"42205699","id":"PMC_42205699","title":"PIP4K2A/2B inhibitor suppresses tumor growth in a xenograft model of NSCLC.","date":"2026","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/42205699","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":22120,"output_tokens":4144,"usd":0.06426,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12003,"output_tokens":4218,"usd":0.082733,"stage2_stop_reason":"end_turn"},"total_usd":0.146993,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"PIP4K2A phosphorylates PI5P to generate PI(4,5)P2 at the peroxisomal membrane, and its knockdown reduces peroxisomal PI(4,5)P2 levels, decreases lysosome-peroxisome membrane contacts (mediated by synaptotagmin VII bridging), and increases lysosomal cholesterol accumulation. Forced expression of peroxisome-localized, kinase-active PIP4K2A in knockdown cells reduced cholesterol accumulation, and in vitro addition of recombinant PIP4K2A restored membrane contacts.\",\n      \"method\": \"RNA interference, forced expression of peroxisome-targeted PIP4K2A, in vitro reconstitution of membrane contacts with recombinant PIP4K2A, fluorescence microscopy\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with recombinant protein, rescue with kinase-active construct, multiple orthogonal methods in single study\",\n      \"pmids\": [\"29353240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PIP4K2A negatively regulates PI3K signaling in PTEN-deficient glioblastoma by targeting the p85 regulatory subunit of PI3K for proteasome-mediated degradation, thereby reducing p85/p110 PI3K complex levels. Overexpression of PIP4K2A suppressed clonogenic growth in vitro and tumor growth in vivo.\",\n      \"method\": \"In vivo RNAi screening in patient-derived xenograft models, overexpression/knockdown with PI3K component western blotting, proteasome inhibitor assays, clonogenic and xenograft assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays (in vitro and in vivo), single lab, mechanism inferred from protein levels and proteasome inhibition rather than direct reconstitution\",\n      \"pmids\": [\"30898893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PIP4K2A knockdown in human AML cells causes accumulation of cyclin-dependent kinase inhibitors CDKN1A and CDKN1B, G1 cell cycle arrest, and apoptosis. Both CDKN1A accumulation and apoptosis were partially dependent on mTOR pathway activation. PIP4K2A is required for clonogenic and leukemia-initiating potential of AML cells but not for normal hematopoietic stem/progenitor cell clonogenicity.\",\n      \"method\": \"Targeted RNAi knockdown screen, clonogenic assays, flow cytometry (cell cycle/apoptosis), western blotting for CDKN1A/CDKN1B and mTOR pathway components, murine MLL-AF9 AML model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined cellular phenotype with pathway placement (mTOR), multiple readouts, single lab\",\n      \"pmids\": [\"24681948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Wild-type PIP4K2A activates heteromeric KCNQ2/KCNQ3 and KCNQ3/KCNQ5 neuronal M channels (but not homomeric KCNQ2 or KCNQ5) in Xenopus oocytes via PI(4,5)P2 synthesis. The schizophrenia-associated N251S mutation renders PIP4K2A kinase-inactive and abolishes KCNQ channel activation, as confirmed by acute PI(4,5)P2 injection and PIP2 scavenger experiments.\",\n      \"method\": \"Xenopus oocyte expression system, dual-electrode voltage clamp, acute PI(4,5)P2 injection, PIP2 scavenger application, comparison of wild-type vs. N251S mutant kinase\",\n      \"journal\": \"Psychopharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — functional reconstitution in oocytes, active-site mutagenesis, acute lipid injection and scavenger controls as orthogonal validation\",\n      \"pmids\": [\"18545987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Wild-type PIP4K2A increases EAAT3 glutamate transporter activity and membrane abundance in Xenopus oocytes and HEK cells. The schizophrenia-associated N251S mutant PIP4K2A exerts a dominant inhibitory effect, reducing EAAT3 current and membrane abundance even in the presence of co-expressed wild-type PIP4K2A.\",\n      \"method\": \"Xenopus oocyte expression, dual-electrode voltage clamp (glutamate-induced current), western blotting, confocal microscopy of membrane EAAT3, comparison of wild-type vs. N251S mutant\",\n      \"journal\": \"Psychopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assay in two expression systems, dominant-negative mutant characterization, single lab\",\n      \"pmids\": [\"19644675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PIP4K2A increases GluA1 (AMPA receptor) currents by enhancing GluA1 membrane abundance via PI(4,5)P2 synthesis. The N251S mutant abolishes this effect. The region K813-K823 of GluA1 is critical for PI(4,5)P2 binding (defined by alanine scanning), and PI(4,5)P2 binding to the GluA1 C-terminal peptide was confirmed by PIP strip assay.\",\n      \"method\": \"Xenopus oocyte expression, electrophysiology, HEK cell overexpression, alanine scan mutagenesis of GluA1, PIP strip assay, western blotting for membrane abundance\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (electrophysiology, PIP strip, mutagenesis), single lab\",\n      \"pmids\": [\"24389605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PIP4K2A interacts with and phosphorylates MIF (macrophage migration inhibitory factor) at serine 91, increasing MIF's interaction with 14-3-3ζ and promoting MIF nuclear translocation, where MIF acts as a transcriptional regulator of ciliogenesis genes. PIP4K2A was identified as an upstream regulator of MIF required for cilia biogenesis.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase phosphorylation assay, site-directed mutagenesis (S91), confocal microscopy of cilia structures, gene expression analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus in vitro kinase assay with site-specific mutation, single lab\",\n      \"pmids\": [\"38052787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PIP4K2A possesses conserved RNA-binding activity that is independent of its lipid kinase activity. PIP4K2A is imported from the host cell into Plasmodium parasites and binds specific RNA elements, with RNA-binding activity conserved across Drosophila, C. elegans, and humans.\",\n      \"method\": \"RNA-binding assays with kinase-dead mutants, parasite import assays in Plasmodium berghei and Toxoplasma gondii, cross-species comparison of RNA binding\",\n      \"journal\": \"Frontiers in molecular biosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase-dead mutant used to separate activities, cross-species validation, single lab\",\n      \"pmids\": [\"34124142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SLC27A5 interacts with IGF2BP3 to prevent IGF2BP3 nuclear translocation; loss of SLC27A5 allows IGF2BP3 to enter the nucleus and modulate PIP4K2A pre-mRNA alternative splicing, elevating the PIP4K2A-S isoform. Elevated PIP4K2A-S positively regulates PI3K signaling by enhancing p85 stability in hepatocellular carcinoma.\",\n      \"method\": \"Co-immunoprecipitation (SLC27A5/IGF2BP3), RT-PCR for splice isoforms, western blotting for p85, AAV rescue experiments, RNA decoy oligonucleotide experiments\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, isoform-specific functional rescue, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"38059827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"During decidualization, lncSAMD11-1:1 and PIP4K2A translocate out of the nucleus together and bind each other, inhibiting AKT phosphorylation and promoting FoxO1 nuclear localization in human endometrial stromal cells.\",\n      \"method\": \"Co-immunoprecipitation (lncRNA-protein), subcellular fractionation, phospho-AKT western blotting, FoxO1 nuclear localization by confocal microscopy, knockdown/overexpression experiments\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP of lncRNA-protein interaction, limited mechanistic follow-up on PIP4K2A's direct role, single lab\",\n      \"pmids\": [\"35987479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Crystal structure of PIP4K2A in complex with inhibitor 422A reveals a water-mediated interaction between the pyridyl nitrogen of the inhibitor and a conserved structured water molecule in the specificity pocket roof. Comparative structural analysis with PIP4K2A-selective inhibitor BAY-091 shows that deeper penetration into the specificity pocket enhances PIP4K2A binding but introduces steric constraints that limit PIP4K2B engagement, defining structural determinants of isoform-selective inhibitor binding.\",\n      \"method\": \"X-ray crystallography of PIP4K2A-inhibitor complex, comparative structural analysis with known inhibitor-bound structures\",\n      \"journal\": \"Acta crystallographica. Section D, Structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with comparative structural analysis providing direct mechanistic insight into inhibitor binding mode and isoform selectivity\",\n      \"pmids\": [\"42117906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Selective PIP4K2A inhibitors BAY-091 and BAY-297 were identified and confirmed to engage PIP4K2A in cells (cellular thermal shift assay), but inhibition of PIP4K2A with these compounds did not produce the hypothesized antiproliferative activity in p53-deficient tumor cells, establishing that kinase inhibition alone is insufficient for this effect.\",\n      \"method\": \"High-throughput screening, structure-based optimization, cellular thermal shift assay (CETSA), antiproliferation assays in p53-deficient cells\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CETSA confirms cellular target engagement, negative functional result is experimentally established, single lab\",\n      \"pmids\": [\"34699202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A novel gain-of-function mutation S316R in PIP4K2A enhances protein stability, increases kinase activity, and upregulates β-globin expression, inhibiting erythroid differentiation and terminal enucleation. Introduction of S316R into HUDEP-2 cells confirmed increased β-globin expression.\",\n      \"method\": \"Patient-derived mutation identification, in vitro kinase assay, protein stability assay, HUDEP-2 cell functional experiments, haematological analysis of family members\",\n      \"journal\": \"British journal of haematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay combined with cell functional experiments and family-level validation, single lab\",\n      \"pmids\": [\"37423903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of PIP4K2A (PI5P4Kα) in basal cells of Pten-mutant mouse prostates slows the development of prostatic intraepithelial neoplasia. Transcriptomic analysis and lipidomic profiling (carnitine lipids in LNCaP cells treated with siPIP4K2A) point to disruption of lipid metabolism as the mechanistic basis for reduced tumor progression.\",\n      \"method\": \"Basal-cell-specific GEMM (CK5-Cre), single-cell RNA sequencing with lineage tracing, siRNA knockdown in LNCaP cells, carnitine lipid mass spectrometry\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo genetic model plus lipidomics, but preprint and lipid metabolism link based on pathway analysis rather than direct mechanistic reconstitution\",\n      \"pmids\": [\"bio_10.1101_2024.08.12.607541\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A rare promoter variant (-1007C→T) of PIP4K2A creates a binding site for a brain-specific nuclear protein; electrophoretic mobility shift assay showed increased binding of this brain-specific nuclear protein to the -1007T allele compared with -1007C, suggesting transcriptional regulation of PIP4K2A in brain tissue.\",\n      \"method\": \"SSCP polymorphism screening, DNA sequencing, electrophoretic mobility shift assay (EMSA)\",\n      \"journal\": \"Psychiatric genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single EMSA experiment, brain-specific protein not identified, single lab\",\n      \"pmids\": [\"16094259\"],\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 (peroxisomes, plasma membrane); through PI(4,5)P2 production it regulates lysosome-peroxisome cholesterol transport, neuronal M channel (KCNQ2/3, KCNQ3/5) activity, EAAT3 glutamate transporter membrane abundance, and AMPA receptor (GluA1) currents; it also phosphorylates MIF at S91 to promote 14-3-3ζ binding and MIF nuclear translocation required for ciliogenesis, acts as a tumor suppressor in PTEN-deficient contexts by targeting p85 PI3K subunit for proteasomal degradation, and possesses a kinase-independent RNA-binding activity conserved across metazoans.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PIP4K2A is a lipid kinase that phosphorylates phosphatidylinositol-5-phosphate to generate PI(4,5)P2 at discrete membrane compartments, thereby controlling membrane contacts, ion channel and transporter activity, and PI3K signaling [#0, #3]. At the peroxisomal membrane its PI(4,5)P2 output sustains synaptotagmin-VII-bridged lysosome–peroxisome contacts and limits lysosomal cholesterol accumulation, with kinase-active enzyme required for rescue [#0]. In neurons, PIP4K2A-derived PI(4,5)P2 activates heteromeric KCNQ2/3 and KCNQ3/5 M channels and enhances the membrane abundance and currents of the EAAT3 glutamate transporter and the GluA1 AMPA receptor [#3, #4, #5]. The schizophrenia-associated N251S substitution is kinase-inactive and abolishes these activities, acting in a dominant-inhibitory manner on EAAT3 [#3, #4]. Beyond lipid signaling, PIP4K2A behaves as a context-dependent regulator of the PI3K pathway by promoting proteasomal degradation of the p85 regulatory subunit, suppressing clonogenic and tumor growth in PTEN-deficient glioblastoma [#1], yet it is also required for the leukemia-initiating potential of AML cells, where its loss triggers CDKN1A/CDKN1B accumulation, G1 arrest and mTOR-dependent apoptosis [#2]. PIP4K2A additionally phosphorylates MIF at serine 91 to promote 14-3-3ζ binding and MIF nuclear translocation driving ciliogenesis [#6], and carries a conserved, kinase-independent RNA-binding activity [#7]. A crystal structure of PIP4K2A bound to an inhibitor defines a water-mediated contact in the specificity-pocket roof that underlies isoform-selective inhibitor design [#10]; selective inhibitors engage the enzyme in cells but do not reproduce the antiproliferative phenotype attributed to PIP4K2A loss, showing kinase inhibition alone is insufficient [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established a candidate transcriptional-regulatory mechanism linking PIP4K2A to brain biology by showing a promoter variant alters nuclear-protein binding.\",\n      \"evidence\": \"SSCP screening and EMSA of the -1007C\\u2192T promoter variant\",\n      \"pmids\": [\"16094259\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"The brain-specific nuclear protein was not identified\", \"Single EMSA without functional reporter validation\", \"No link to PIP4K2A expression level in vivo\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated that PIP4K2A kinase activity controls neuronal M-channel function through PI(4,5)P2, and that the disease-associated N251S mutation is a loss-of-function allele.\",\n      \"evidence\": \"Xenopus oocyte voltage clamp with PI(4,5)P2 injection, PIP2 scavenger, and WT vs N251S comparison\",\n      \"pmids\": [\"18545987\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity for heteromeric vs homomeric KCNQ channels not mechanistically explained\", \"Endogenous neuronal relevance not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended PIP4K2A's regulation of membrane proteins to the EAAT3 glutamate transporter and showed N251S acts dominant-negatively.\",\n      \"evidence\": \"Oocyte and HEK expression, voltage clamp, membrane EAAT3 imaging, WT vs N251S\",\n      \"pmids\": [\"19644675\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of dominant inhibition not resolved\", \"No endogenous neuronal validation\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined PIP4K2A as required for AML clonogenic and leukemia-initiating potential, placing its loss-of-function phenotype downstream through CDK inhibitors and mTOR.\",\n      \"evidence\": \"RNAi knockdown, cell cycle/apoptosis flow cytometry, CDKN1A/CDKN1B and mTOR western blot, MLL-AF9 model\",\n      \"pmids\": [\"24681948\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct lipid substrate link to mTOR not established\", \"Distinction from kinase-independent functions untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed PIP4K2A enhances AMPA receptor (GluA1) currents via PI(4,5)P2 binding to a defined GluA1 C-terminal region.\",\n      \"evidence\": \"Oocyte electrophysiology, GluA1 alanine scan, PIP strip assay, membrane abundance western blot\",\n      \"pmids\": [\"24389605\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo synaptic relevance not addressed\", \"Single expression-system context\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Localized PIP4K2A kinase activity to the peroxisomal membrane and connected its PI(4,5)P2 output to lysosome\\u2013peroxisome contacts and cholesterol handling.\",\n      \"evidence\": \"RNAi, peroxisome-targeted kinase-active rescue, in vitro contact reconstitution with recombinant protein, microscopy\",\n      \"pmids\": [\"29353240\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PIP4K2A is targeted to peroxisomes not defined\", \"Direct PI(4,5)P2 sensing by synaptotagmin VII not shown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified PIP4K2A as a tumor suppressor in PTEN-deficient glioblastoma that lowers PI3K signaling by promoting proteasomal degradation of p85.\",\n      \"evidence\": \"In vivo RNAi PDX screen, overexpression/knockdown, proteasome inhibitor assays, clonogenic and xenograft assays\",\n      \"pmids\": [\"30898893\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism inferred from protein levels rather than reconstituted degradation\", \"Direct PIP4K2A-p85 contact not biochemically defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Uncovered a kinase-independent, evolutionarily conserved RNA-binding activity of PIP4K2A and its import into apicomplexan parasites.\",\n      \"evidence\": \"RNA-binding assays with kinase-dead mutants, parasite import assays, cross-species comparison\",\n      \"pmids\": [\"34124142\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNA targets in the human cell not defined\", \"Functional consequence of RNA binding unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established that selective kinase inhibition is insufficient to reproduce the antiproliferative effect of PIP4K2A loss in p53-deficient cells, dissociating phenotype from catalytic activity.\",\n      \"evidence\": \"HTS, structure-based optimization, CETSA target engagement, antiproliferation assays\",\n      \"pmids\": [\"34699202\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether non-catalytic functions drive the phenotype not tested\", \"No genetic vs pharmacologic reconciliation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a substrate-level signaling role: PIP4K2A phosphorylates MIF at S91 to promote 14-3-3\\u03b6 binding, MIF nuclear translocation and ciliogenesis.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay, S91 mutagenesis, cilia confocal imaging, gene expression\",\n      \"pmids\": [\"38052787\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship between protein-kinase and lipid-kinase activities unclear\", \"Direct ciliogenesis gene targets of nuclear MIF not detailed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked alternative splicing of PIP4K2A (the PIP4K2A-S isoform) to PI3K activation via p85 stabilization in hepatocellular carcinoma, in apparent opposition to its p85-degrading role.\",\n      \"evidence\": \"SLC27A5/IGF2BP3 reciprocal Co-IP, isoform RT-PCR, p85 western blot, AAV and RNA decoy rescue\",\n      \"pmids\": [\"38059827\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic basis for opposing p85 effects across isoforms not resolved\", \"Isoform-specific structural difference not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a gain-of-function S316R mutation that stabilizes PIP4K2A and raises kinase activity, upregulating \\u03b2-globin and impairing erythroid differentiation.\",\n      \"evidence\": \"Patient mutation, in vitro kinase and stability assays, HUDEP-2 functional experiments, family analysis\",\n      \"pmids\": [\"37423903\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pathway linking kinase activity to \\u03b2-globin regulation not defined\", \"Single-family genetic evidence\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Provided structural determinants of isoform-selective inhibition, defining a water-mediated specificity-pocket interaction distinguishing PIP4K2A from PIP4K2B.\",\n      \"evidence\": \"X-ray crystallography of PIP4K2A-inhibitor complex with comparative analysis\",\n      \"pmids\": [\"42117906\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No catalytic-mechanism or substrate-bound structure described\", \"Functional consequence of selective inhibition not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PIP4K2A's lipid-kinase, protein-kinase, and RNA-binding activities are coordinated within a cell, and which activity drives each disease phenotype, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model separating catalytic from non-catalytic functions\", \"Endogenous compartment-specific substrate maps absent\", \"Reconciliation of opposing roles in PI3K signaling not achieved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 3, 6, 12]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 3, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005777\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 4, 5]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [3, 4, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MIF\", \"YWHAZ\", \"PIK3R1\", \"IGF2BP3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}