{"gene":"PIP5K1A","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2015,"finding":"Crystal structure of the catalytic domain of zebrafish PIP5K1A resolved at 3.3 Å reveals a side-to-side dimer. Mutagenesis identified two adjacent interfaces for dimerization and interaction with the DIX domain of Dishevelled. Binding at these interfaces (either through dimerization or DIX interaction) stimulates PIP5K1A catalytic activity; DIX binding additionally enhances substrate binding.","method":"X-ray crystallography, site-directed mutagenesis, in vitro kinase activity assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus in vitro catalytic assays in a single rigorous study","pmids":["26365782"],"is_preprint":false},{"year":2018,"finding":"PIP5K1A is a KRAS-specific interactor (not shared with NRAS or HRAS), binding to a unique region in KRAS. PIP5K1A depletion specifically reduces oncogenic KRAS signaling and proliferation, and sensitizes pancreatic cancer cell lines to MAPK inhibitors.","method":"BirA proximity-dependent biotin identification (BioID) interactome, CRISPR-Cas9 loss-of-function screen, co-immunoprecipitation mapping of binding region, cell proliferation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — BioID interactome combined with CRISPR functional screen and biochemical binding mapping in one study","pmids":["30194290"],"is_preprint":false},{"year":2017,"finding":"Upon HGF stimulation, PIP5K1A is recruited to c-Met in an Arf6 activity-dependent manner, where it generates PIP2 and subsequently PIP3 to activate Akt and drive hepatocyte proliferation. In vivo, Pip5k1a knockout mice show suppressed hepatocyte proliferation and liver regeneration after partial hepatectomy.","method":"siRNA knockdown in HepG2 cells, co-immunoprecipitation/recruitment assay to c-Met, PI3P/PIP2/PIP3 measurement, Pip5k1a knockout mouse hepatectomy model","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal biochemical recruitment assay, KO mouse model, and multiple orthogonal readouts (lipid measurement, Akt activation, proliferation)","pmids":["28842595"],"is_preprint":false},{"year":2021,"finding":"CLIC1 recruits PIP5K1A and PIP5K1C from the cytoplasm to the leading edge of the plasma membrane in response to migration stimuli, where PIP5K1A generates a PIP2-rich microdomain that induces integrin-mediated cell-matrix adhesion formation and cytoskeletal extension signaling.","method":"Comparative proteomics, co-immunoprecipitation, subcellular fractionation/live imaging of protein recruitment, siRNA knockdown with adhesion and metastasis readouts, mouse lung metastasis model","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct protein recruitment demonstrated biochemically and by imaging, combined with in vivo metastasis model and functional adhesion assays","pmids":["33079727"],"is_preprint":false},{"year":2019,"finding":"Multiscale molecular dynamics simulations show that monomeric PIP5K1A binds specifically to PI4P-containing membranes (not zwitterionic or anionic membranes lacking PIPs), with initial encounter followed by reorientation to a productive binding pose; dimeric PIP5K1A cannot bind via both active sites simultaneously, suggesting conformational change or bilayer distortion is needed.","method":"Coarse-grained and atomistic molecular dynamics simulations","journal":"Structure","confidence":"Low","confidence_rationale":"Tier 4 / Moderate — computational simulation only, no experimental validation of predicted binding mode","pmids":["31204251"],"is_preprint":false},{"year":2023,"finding":"PIP5K1A interacts with nuclear export protein XPO5 in the nucleus to regulate mature let-7 miRNA levels by blocking XPO5 binding to pre-let-7, thereby reducing nuclear export of pre-miRNA; this role is kinase-independent. The ortholog PPK-1 in C. elegans functions in the lin-28/let-7 heterochronic pathway.","method":"Co-immunoprecipitation (PIP5K1A–XPO5 interaction), kinase-dead mutant analysis, C. elegans genetic pathway analysis, quantitative miRNA level measurement in human cells","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus kinase-dead mutant plus C. elegans epistasis, single lab","pmids":["37655623"],"is_preprint":false},{"year":2025,"finding":"PIP5K1A competitively binds the Kelch domain of KEAP1 in a kinase-independent manner, preventing NRF2 ubiquitination and degradation, thereby promoting NRF2-dependent transcription and suppressing ferroptosis in hepatocellular carcinoma cells.","method":"Co-immunoprecipitation (PIP5K1A–KEAP1 interaction), ubiquitination assays, kinase-dead mutant analysis, siRNA knockdown with lipid peroxidation and ferroptosis readouts, pharmacological inhibition (ISA-2011B)","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus kinase-dead mutant plus functional assays, single lab","pmids":["40405713"],"is_preprint":false},{"year":2024,"finding":"PIP5K1A functions upstream of the Akt/GSK-3β pathway to regulate CDK2 and cyclin D1 expression and cell cycle progression in colorectal cancer; rupatadine inhibits PIP5K1A kinase activity (confirmed by kinase activity assay and bio-layer interferometry) and suppresses CRC proliferation in vitro and in vivo.","method":"Kinase activity assay, bio-layer interferometry, western blot, cell proliferation assays, in vivo xenograft","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct kinase activity measurement and binding assay combined with cellular pathway analysis, single lab","pmids":["38838507"],"is_preprint":false},{"year":2026,"finding":"DCLK1 interacts with PIP5K1A and inhibits its threonine phosphorylation, thereby facilitating PIP5K1A membrane localization and downstream PI3K-AKT signaling activation in pancreatic cancer under high matrix stiffness conditions.","method":"Co-immunoprecipitation, phosphorylation analysis, subcellular fractionation of PIP5K1A localization, in vitro and in vivo tumor models with DCLK1 knockdown/overexpression","journal":"Experimental hematology & oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus phosphorylation analysis plus localization assay, single lab","pmids":["41692802"],"is_preprint":false},{"year":2026,"finding":"In porcine embryos, PIP5K1A residue Q169 mediates interaction with RhoA; the PIPB motif anchors PIP5K1A to the plasma membrane; the activation loop drives catalytic activity and is required for proper RhoA membrane localization. PIP5K1A-enriched membrane clusters serve as hubs for RhoA recruitment during cytokinesis. PIP5K1A also sustains PLC-IP3-Ca2+ signaling for vesicle fusion and cytoskeletal remodeling.","method":"Structure-function mutagenesis (Q169, PIPB motif, activation loop), live imaging of membrane localization, maternal depletion and overexpression in porcine embryos, co-localization with RhoA","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with functional readouts in intact embryos plus co-localization, single lab","pmids":["42212321"],"is_preprint":false},{"year":2025,"finding":"PIP5K1A (referred to as PIP5KA in the paper) produces a dedicated PI(4,5)P2 pool at the plasma membrane in collaboration with the scaffolding protein EFR3A, which is required for sorting AT1R angiotensin II receptors into an AP2-positive compartment for rapid GPCR re-sensitization without receptor internalization.","method":"Genetic perturbation of PIP5K1A and EFR3A, PI(4,5)P2 reporter assays, GPCR re-sensitization assays, AP2 co-localization imaging","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (lipid reporter, genetic KO, co-localization), single lab, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.03.28.645988"],"is_preprint":true}],"current_model":"PIP5K1A is a type I phosphatidylinositol 4-phosphate 5-kinase that phosphorylates PI4P to generate PI(4,5)P2 at the plasma membrane, where it is regulated by dimerization and by binding partners (including Dishevelled-DIX, KRAS, Arf6/c-Met, CLIC1, and DCLK1) that stimulate its catalytic activity or control its membrane recruitment; it also performs kinase-independent functions including competitive binding to KEAP1 to stabilize NRF2 and interaction with nuclear XPO5 to restrict pre-let-7 miRNA export, placing PIP5K1A at a signaling nexus controlling PI3K-AKT activation, actin/cytoskeletal dynamics, GPCR re-sensitization, RhoA membrane recruitment, and gene expression."},"narrative":{"mechanistic_narrative":"PIP5K1A is a type I phosphatidylinositol 4-phosphate 5-kinase that generates plasma-membrane PI(4,5)P2 pools to coordinate growth-factor signaling, cytoskeletal dynamics, and receptor trafficking [PMID:28842595, PMID:33079727]. Its catalytic domain forms a side-to-side dimer, and binding at adjacent dimerization/partner interfaces—including the DIX domain of Dishevelled—stimulates catalytic activity, with DIX engagement additionally enhancing substrate binding [PMID:26365782]. Membrane recruitment and activation are controlled by multiple partners: PIP5K1A is recruited to c-Met in an Arf6-dependent manner upon HGF stimulation to drive PIP2/PIP3 production, Akt activation, and hepatocyte proliferation [PMID:28842595]; CLIC1 relocates it to the leading edge to build PIP2-rich microdomains supporting integrin-mediated adhesion and migration [PMID:33079727]; and DCLK1 suppresses its inhibitory threonine phosphorylation to promote membrane localization and PI3K-AKT activation under high matrix stiffness [PMID:41692802]. These functions place PIP5K1A within KRAS-driven oncogenic signaling, where it is a KRAS-specific interactor whose depletion reduces oncogenic KRAS signaling and proliferation [PMID:30194290], and upstream of an Akt/GSK-3β–CDK2/cyclin D1 axis controlling cell-cycle progression [PMID:38838507]. The kinase also produces dedicated PI(4,5)P2 with the scaffold EFR3A to enable AP2-dependent GPCR re-sensitization [PMID:bio_10.1101_2025.03.28.645988] and organizes membrane clusters that recruit RhoA during cytokinesis [PMID:42212321]. Independent of its catalytic activity, PIP5K1A performs scaffolding roles: it competitively binds the KEAP1 Kelch domain to stabilize NRF2 and suppress ferroptosis [PMID:40405713], and binds nuclear XPO5 to restrict pre-let-7 miRNA export [PMID:37655623].","teleology":[{"year":2015,"claim":"Established the structural basis for how PIP5K1A catalytic activity is switched on, showing dimerization and partner binding at defined interfaces stimulate the kinase.","evidence":"X-ray crystallography of zebrafish catalytic domain with site-directed mutagenesis and in vitro kinase assays","pmids":["26365782"],"confidence":"High","gaps":["Structure is of the isolated catalytic domain, not the full-length human enzyme on a membrane","How DIX binding mechanistically enhances substrate binding is not resolved at atomic detail"]},{"year":2017,"claim":"Defined a receptor-coupled activation route, showing Arf6-dependent recruitment to c-Met links PIP5K1A lipid production to Akt activation and proliferation in vivo.","evidence":"siRNA knockdown in HepG2, recruitment co-IP, lipid measurement, and Pip5k1a knockout mouse hepatectomy model","pmids":["28842595"],"confidence":"High","gaps":["Direct binding interface between PIP5K1A and c-Met/Arf6 not mapped","Whether PIP3 is produced directly or via downstream PI3K is not fully delineated"]},{"year":2018,"claim":"Identified PIP5K1A as a selective effector of oncogenic KRAS, establishing it as a vulnerability in KRAS-driven cancers.","evidence":"BioID interactome, CRISPR loss-of-function screen, co-IP binding mapping, proliferation assays in pancreatic cancer lines","pmids":["30194290"],"confidence":"High","gaps":["Structural basis of KRAS-specific (vs NRAS/HRAS) binding not resolved","Whether the effect requires PIP5K1A catalytic activity not directly tested"]},{"year":2019,"claim":"Probed the membrane-engagement mechanism, predicting monomeric PIP5K1A binds PI4P membranes via a reorientation step while dimers cannot engage both active sites simultaneously.","evidence":"Coarse-grained and atomistic molecular dynamics simulations","pmids":["31204251"],"confidence":"Low","gaps":["Computational only — predicted binding modes lack experimental validation","Proposed conformational change or bilayer distortion for dimer binding untested","No link to in-cell membrane behavior"]},{"year":2021,"claim":"Showed how PIP5K1A is spatially targeted during migration, with CLIC1 delivering it to the leading edge to build adhesion-promoting PIP2 microdomains.","evidence":"Comparative proteomics, co-IP, fractionation/live imaging, siRNA with adhesion and mouse lung metastasis readouts","pmids":["33079727"],"confidence":"High","gaps":["Mechanism by which CLIC1 selects PIP5K1A/PIP5K1C is not detailed","How PIP2 microdomains organize integrin clustering at molecular level unresolved"]},{"year":2023,"claim":"Revealed a kinase-independent nuclear function, showing PIP5K1A blocks XPO5–pre-let-7 binding to restrict miRNA export.","evidence":"Co-IP, kinase-dead mutant analysis, C. elegans lin-28/let-7 epistasis, quantitative miRNA measurement","pmids":["37655623"],"confidence":"Medium","gaps":["Single lab; nuclear localization mechanism of PIP5K1A not established","Whether interaction with XPO5 is direct vs complex-mediated unconfirmed","Generality across miRNAs beyond let-7 untested"]},{"year":2024,"claim":"Placed PIP5K1A upstream of an Akt/GSK-3β–CDK2/cyclin D1 cell-cycle axis and identified rupatadine as a kinase inhibitor.","evidence":"Kinase activity assay, bio-layer interferometry, western blot, proliferation assays, xenograft","pmids":["38838507"],"confidence":"Medium","gaps":["Single lab; direct kinase substrates linking to GSK-3β not defined","Specificity of rupatadine for PIP5K1A vs other PIP kinases not fully characterized"]},{"year":2025,"claim":"Demonstrated a second kinase-independent scaffolding role, with PIP5K1A competing for the KEAP1 Kelch domain to stabilize NRF2 and suppress ferroptosis.","evidence":"Co-IP, ubiquitination assays, kinase-dead mutant, siRNA with lipid peroxidation readouts, ISA-2011B inhibition","pmids":["40405713"],"confidence":"Medium","gaps":["Single lab; binding stoichiometry/affinity with KEAP1 not quantified","Whether this competes with endogenous KEAP1 substrates beyond NRF2 unknown"]},{"year":2025,"claim":"Linked a dedicated PIP5K1A PI(4,5)P2 pool to GPCR re-sensitization, acting with EFR3A to sort AT1R into an AP2 compartment.","evidence":"Genetic perturbation of PIP5K1A/EFR3A, PI(4,5)P2 reporters, re-sensitization assays, AP2 co-localization imaging (preprint)","pmids":["bio_10.1101_2025.03.28.645988"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Direct PIP5K1A–EFR3A interaction interface not mapped","Generality across other GPCRs untested"]},{"year":2026,"claim":"Dissected structural determinants linking PIP5K1A membrane anchoring to RhoA recruitment and cytokinesis.","evidence":"Structure-function mutagenesis (Q169, PIPB motif, activation loop), live imaging, maternal depletion/overexpression in porcine embryos, RhoA co-localization","pmids":["42212321"],"confidence":"Medium","gaps":["Single lab in porcine embryo system; human relevance not directly shown","Mechanism by which PIP2 clusters recruit RhoA not fully resolved"]},{"year":2026,"claim":"Identified a phosphoregulatory partner, showing DCLK1 inhibits PIP5K1A threonine phosphorylation to promote its membrane localization and PI3K-AKT signaling under stiff matrix.","evidence":"Co-IP, phosphorylation analysis, subcellular fractionation, in vitro/in vivo pancreatic tumor models with DCLK1 perturbation","pmids":["41692802"],"confidence":"Medium","gaps":["Single lab; the kinase/phosphatase acting on the threonine site not identified","Whether DCLK1 acts directly or recruits a phosphatase unclear"]},{"year":null,"claim":"How the catalytic and scaffolding (KEAP1-, XPO5-binding) activities of PIP5K1A are partitioned across subcellular compartments and integrated with its many activating partners remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model for how partner choice (DIX, KRAS, Arf6, CLIC1, DCLK1) dictates output","Full-length human enzyme structure on membrane lacking","Mechanism of nuclear targeting for kinase-independent roles unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2,7]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[4,10]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,3,9,10]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,1,8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,6,7]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[10]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[5]}],"complexes":[],"partners":["KRAS","MET","ARF6","CLIC1","XPO5","KEAP1","DCLK1","RHOA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99755","full_name":"Phosphatidylinositol 4-phosphate 5-kinase type-1 alpha","aliases":["68 kDa type I phosphatidylinositol 4-phosphate 5-kinase alpha","Phosphatidylinositol 4-phosphate 5-kinase type I alpha","PIP5KIalpha"],"length_aa":562,"mass_kda":62.6,"function":"Catalyzes the phosphorylation of phosphatidylinositol 4-phosphate (PtdIns(4)P/PI4P) to form phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2/PIP2), a lipid second messenger that regulates several cellular processes such as signal transduction, vesicle trafficking, actin cytoskeleton dynamics, cell adhesion, and cell motility (PubMed:21477596, PubMed:22942276, PubMed:8955136). PtdIns(4,5)P2 can directly act as a second messenger or can be utilized as a precursor to generate other second messengers: inositol 1,4,5-trisphosphate (IP3), diacylglycerol (DAG) or phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3/PIP3) (PubMed:19158393, PubMed:20660631). PIP5K1A-mediated phosphorylation of PtdIns(4)P is the predominant pathway for PtdIns(4,5)P2 synthesis (By similarity). Can also use phosphatidylinositol (PtdIns) as substrate in vitro (PubMed:22942276). Together with PIP5K1C, is required for phagocytosis, both enzymes regulating different types of actin remodeling at sequential steps (By similarity). Promotes particle ingestion by activating the WAS GTPase-binding protein that induces Arp2/3 dependent actin polymerization at the nascent phagocytic cup (By similarity). Together with PIP5K1B, is required, after stimulation by G-protein coupled receptors, for the synthesis of IP3 that will induce stable platelet adhesion (By similarity). Recruited to the plasma membrane by the E-cadherin/beta-catenin complex where it provides the substrate PtdIns(4,5)P2 for the production of PtdIns(3,4,5)P3, IP3 and DAG, that will mobilize internal calcium and drive keratinocyte differentiation (PubMed:19158393). Positively regulates insulin-induced translocation of SLC2A4 to the cell membrane in adipocytes (By similarity). Together with PIP5K1C has a role during embryogenesis (By similarity). Independently of its catalytic activity, is required for membrane ruffling formation, actin organization and focal adhesion formation during directional cell migration by controlling integrin-induced translocation of the small GTPase RAC1 to the plasma membrane (PubMed:20660631). Also functions in the nucleus where it acts as an activator of TUT1 adenylyltransferase activity in nuclear speckles, thereby regulating mRNA polyadenylation of a select set of mRNAs (PubMed:18288197)","subcellular_location":"Cell membrane; Cytoplasm; Nucleus; Nucleus speckle; Cell projection, ruffle; Cell projection, lamellipodium","url":"https://www.uniprot.org/uniprotkb/Q99755/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PIP5K1A","classification":"Common Essential","n_dependent_lines":624,"n_total_lines":1208,"dependency_fraction":0.5165562913907285},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000143398","cell_line_id":"CID000141","localizations":[{"compartment":"membrane","grade":3},{"compartment":"cytoplasmic","grade":1},{"compartment":"vesicles","grade":1}],"interactors":[{"gene":"PARP1","stoichiometry":0.2},{"gene":"ALDH1A1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000141","total_profiled":1310},"omim":[{"mim_id":"614442","title":"PLECKSTRIN AND SEC7 DOMAINS-CONTAINING PROTEIN 4; PSD4","url":"https://www.omim.org/entry/614442"},{"mim_id":"614439","title":"ADP-RIBOSYLATION FACTOR-LIKE GTPase 14; ARL14","url":"https://www.omim.org/entry/614439"},{"mim_id":"612865","title":"PHOSPHATIDYLINOSITOL 4-PHOSPHATE-5-KINASE-LIKE 1; PIP5KL1","url":"https://www.omim.org/entry/612865"},{"mim_id":"606102","title":"PHOSPHATIDYLINOSITOL 4-PHOSPHATE 5-KINASE, TYPE I, GAMMA; PIP5K1C","url":"https://www.omim.org/entry/606102"},{"mim_id":"603275","title":"PHOSPHATIDYLINOSITOL 4-PHOSPHATE 5-KINASE, TYPE I, ALPHA; PIP5K1A","url":"https://www.omim.org/entry/603275"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PIP5K1A"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q99755","domains":[{"cath_id":"3.30.800.10","chopping":"60-247","consensus_level":"medium","plddt":89.591,"start":60,"end":247},{"cath_id":"3.30.810.10","chopping":"249-338_357-371_383-456","consensus_level":"medium","plddt":83.5198,"start":249,"end":456}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99755","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99755-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99755-F1-predicted_aligned_error_v6.png","plddt_mean":69.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PIP5K1A","jax_strain_url":"https://www.jax.org/strain/search?query=PIP5K1A"},"sequence":{"accession":"Q99755","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99755.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99755/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99755"}},"corpus_meta":[{"pmid":"30194290","id":"PMC_30194290","title":"Interrogating the protein interactomes of RAS isoforms identifies PIP5K1A as a KRAS-specific vulnerability.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30194290","citation_count":73,"is_preprint":false},{"pmid":"31558874","id":"PMC_31558874","title":"Circular RNA PIP5K1A promotes colon cancer development through inhibiting miR-1273a.","date":"2019","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/31558874","citation_count":71,"is_preprint":false},{"pmid":"33079727","id":"PMC_33079727","title":"CLIC1 recruits PIP5K1A/C to induce cell-matrix adhesions for tumor metastasis.","date":"2021","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/33079727","citation_count":59,"is_preprint":false},{"pmid":"33413401","id":"PMC_33413401","title":"CircRNA PIP5K1A promotes the progression of glioma through upregulation of the TCF12/PI3K/AKT pathway by sponging miR-515-5p.","date":"2021","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/33413401","citation_count":48,"is_preprint":false},{"pmid":"33570734","id":"PMC_33570734","title":"Exosomal circ_PIP5K1A regulates the progression of non-small cell lung cancer and cisplatin sensitivity by miR-101/ABCC1 axis.","date":"2021","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33570734","citation_count":47,"is_preprint":false},{"pmid":"26365782","id":"PMC_26365782","title":"Resolution of structure of PIP5K1A reveals molecular mechanism for its regulation by dimerization and dishevelled.","date":"2015","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/26365782","citation_count":46,"is_preprint":false},{"pmid":"25368680","id":"PMC_25368680","title":"Amplification of Chromosome 1q Genes Encoding the Phosphoinositide Signalling Enzymes PI4KB, AKT3, PIP5K1A and PI3KC2B in Breast Cancer.","date":"2014","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/25368680","citation_count":32,"is_preprint":false},{"pmid":"34537072","id":"PMC_34537072","title":"Circ_PIP5K1A regulates cisplatin resistance and malignant progression in non-small cell lung cancer cells and xenograft murine model via depending on miR-493-5p/ROCK1 axis.","date":"2021","source":"Respiratory research","url":"https://pubmed.ncbi.nlm.nih.gov/34537072","citation_count":27,"is_preprint":false},{"pmid":"31204251","id":"PMC_31204251","title":"Membrane Recognition and Binding by the Phosphatidylinositol Phosphate Kinase PIP5K1A: A Multiscale Simulation Study.","date":"2019","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/31204251","citation_count":18,"is_preprint":false},{"pmid":"28842595","id":"PMC_28842595","title":"Regulation of HGF-induced hepatocyte proliferation by the small GTPase Arf6 through the PIP2-producing enzyme PIP5K1A.","date":"2017","source":"Scientific 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England)","url":"https://pubmed.ncbi.nlm.nih.gov/35852640","citation_count":13,"is_preprint":false},{"pmid":"37966664","id":"PMC_37966664","title":"Circular RNA PIP5K1A Promotes Glucose and Lipid Metabolism Disorders and Inflammation in Type 2 Diabetes Mellitus.","date":"2023","source":"Molecular biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/37966664","citation_count":11,"is_preprint":false},{"pmid":"34546850","id":"PMC_34546850","title":"Circular RNA PIP5K1A (circPIP5K1A) accelerates endometriosis progression by regulating the miR-153-3p/Thymosin Beta-4 X-Linked (TMSB4X) pathway.","date":"2021","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/34546850","citation_count":9,"is_preprint":false},{"pmid":"40405713","id":"PMC_40405713","title":"PIP5K1A Suppresses Ferroptosis and Induces Sorafenib Resistance by Stabilizing NRF2 in Hepatocellular Carcinoma.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40405713","citation_count":8,"is_preprint":false},{"pmid":"38838507","id":"PMC_38838507","title":"Rupatadine inhibits colorectal cancer cell proliferation through the PIP5K1A/Akt/CDK2 pathway.","date":"2024","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/38838507","citation_count":5,"is_preprint":false},{"pmid":"40865673","id":"PMC_40865673","title":"Extrachromosomal DNA (ecDNA) drives hepatocellular carcinoma malignancy through high-copy amplification of chromosome 1q21-derived PIP5K1A oncogene.","date":"2025","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/40865673","citation_count":3,"is_preprint":false},{"pmid":"37655623","id":"PMC_37655623","title":"Lipid kinase PIP5K1A regulates let-7 microRNA biogenesis through interacting with nuclear export protein XPO5.","date":"2023","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/37655623","citation_count":3,"is_preprint":false},{"pmid":"39799498","id":"PMC_39799498","title":"Functional analysis of the PIP5K1A gene in Liaoning Cashmere goats: an investigation based on bioinformatics, tissue localization, and biological functions.","date":"2025","source":"Cellular and molecular biology (Noisy-le-Grand, France)","url":"https://pubmed.ncbi.nlm.nih.gov/39799498","citation_count":0,"is_preprint":false},{"pmid":"42212321","id":"PMC_42212321","title":"PIP5K1A-PIP2-RhoA Signaling Orchestrates Membrane Remodeling during Early Porcine Embryo Development.","date":"2026","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/42212321","citation_count":0,"is_preprint":false},{"pmid":"41692802","id":"PMC_41692802","title":"Matrix stiffness induces Ca2+-DCLK1-PIP5K1A mechanotransduction as a context-specific amplifier in pancreatic cancer progression and chemotherapy resistance.","date":"2026","source":"Experimental hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41692802","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.28.645988","title":"FAST RESENSITIZATION OF G PROTEIN-COUPLED RECEPTORS REQUIRES THEIR PI(4,5)P  <sub>2</sub>  -DEPENDENT SORTING INTO AN AP2 POSITIVE COMPARTMENT","date":"2025-04-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.28.645988","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14724,"output_tokens":2864,"usd":0.043566,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10252,"output_tokens":4141,"usd":0.077393,"stage2_stop_reason":"end_turn"},"total_usd":0.120959,"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\": 2015,\n      \"finding\": \"Crystal structure of the catalytic domain of zebrafish PIP5K1A resolved at 3.3 Å reveals a side-to-side dimer. Mutagenesis identified two adjacent interfaces for dimerization and interaction with the DIX domain of Dishevelled. Binding at these interfaces (either through dimerization or DIX interaction) stimulates PIP5K1A catalytic activity; DIX binding additionally enhances substrate binding.\",\n      \"method\": \"X-ray crystallography, site-directed mutagenesis, in vitro kinase activity assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus in vitro catalytic assays in a single rigorous study\",\n      \"pmids\": [\"26365782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PIP5K1A is a KRAS-specific interactor (not shared with NRAS or HRAS), binding to a unique region in KRAS. PIP5K1A depletion specifically reduces oncogenic KRAS signaling and proliferation, and sensitizes pancreatic cancer cell lines to MAPK inhibitors.\",\n      \"method\": \"BirA proximity-dependent biotin identification (BioID) interactome, CRISPR-Cas9 loss-of-function screen, co-immunoprecipitation mapping of binding region, cell proliferation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — BioID interactome combined with CRISPR functional screen and biochemical binding mapping in one study\",\n      \"pmids\": [\"30194290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Upon HGF stimulation, PIP5K1A is recruited to c-Met in an Arf6 activity-dependent manner, where it generates PIP2 and subsequently PIP3 to activate Akt and drive hepatocyte proliferation. In vivo, Pip5k1a knockout mice show suppressed hepatocyte proliferation and liver regeneration after partial hepatectomy.\",\n      \"method\": \"siRNA knockdown in HepG2 cells, co-immunoprecipitation/recruitment assay to c-Met, PI3P/PIP2/PIP3 measurement, Pip5k1a knockout mouse hepatectomy model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal biochemical recruitment assay, KO mouse model, and multiple orthogonal readouts (lipid measurement, Akt activation, proliferation)\",\n      \"pmids\": [\"28842595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CLIC1 recruits PIP5K1A and PIP5K1C from the cytoplasm to the leading edge of the plasma membrane in response to migration stimuli, where PIP5K1A generates a PIP2-rich microdomain that induces integrin-mediated cell-matrix adhesion formation and cytoskeletal extension signaling.\",\n      \"method\": \"Comparative proteomics, co-immunoprecipitation, subcellular fractionation/live imaging of protein recruitment, siRNA knockdown with adhesion and metastasis readouts, mouse lung metastasis model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct protein recruitment demonstrated biochemically and by imaging, combined with in vivo metastasis model and functional adhesion assays\",\n      \"pmids\": [\"33079727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Multiscale molecular dynamics simulations show that monomeric PIP5K1A binds specifically to PI4P-containing membranes (not zwitterionic or anionic membranes lacking PIPs), with initial encounter followed by reorientation to a productive binding pose; dimeric PIP5K1A cannot bind via both active sites simultaneously, suggesting conformational change or bilayer distortion is needed.\",\n      \"method\": \"Coarse-grained and atomistic molecular dynamics simulations\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Moderate — computational simulation only, no experimental validation of predicted binding mode\",\n      \"pmids\": [\"31204251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PIP5K1A interacts with nuclear export protein XPO5 in the nucleus to regulate mature let-7 miRNA levels by blocking XPO5 binding to pre-let-7, thereby reducing nuclear export of pre-miRNA; this role is kinase-independent. The ortholog PPK-1 in C. elegans functions in the lin-28/let-7 heterochronic pathway.\",\n      \"method\": \"Co-immunoprecipitation (PIP5K1A–XPO5 interaction), kinase-dead mutant analysis, C. elegans genetic pathway analysis, quantitative miRNA level measurement in human cells\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus kinase-dead mutant plus C. elegans epistasis, single lab\",\n      \"pmids\": [\"37655623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PIP5K1A competitively binds the Kelch domain of KEAP1 in a kinase-independent manner, preventing NRF2 ubiquitination and degradation, thereby promoting NRF2-dependent transcription and suppressing ferroptosis in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation (PIP5K1A–KEAP1 interaction), ubiquitination assays, kinase-dead mutant analysis, siRNA knockdown with lipid peroxidation and ferroptosis readouts, pharmacological inhibition (ISA-2011B)\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus kinase-dead mutant plus functional assays, single lab\",\n      \"pmids\": [\"40405713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PIP5K1A functions upstream of the Akt/GSK-3β pathway to regulate CDK2 and cyclin D1 expression and cell cycle progression in colorectal cancer; rupatadine inhibits PIP5K1A kinase activity (confirmed by kinase activity assay and bio-layer interferometry) and suppresses CRC proliferation in vitro and in vivo.\",\n      \"method\": \"Kinase activity assay, bio-layer interferometry, western blot, cell proliferation assays, in vivo xenograft\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct kinase activity measurement and binding assay combined with cellular pathway analysis, single lab\",\n      \"pmids\": [\"38838507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DCLK1 interacts with PIP5K1A and inhibits its threonine phosphorylation, thereby facilitating PIP5K1A membrane localization and downstream PI3K-AKT signaling activation in pancreatic cancer under high matrix stiffness conditions.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation analysis, subcellular fractionation of PIP5K1A localization, in vitro and in vivo tumor models with DCLK1 knockdown/overexpression\",\n      \"journal\": \"Experimental hematology & oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus phosphorylation analysis plus localization assay, single lab\",\n      \"pmids\": [\"41692802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In porcine embryos, PIP5K1A residue Q169 mediates interaction with RhoA; the PIPB motif anchors PIP5K1A to the plasma membrane; the activation loop drives catalytic activity and is required for proper RhoA membrane localization. PIP5K1A-enriched membrane clusters serve as hubs for RhoA recruitment during cytokinesis. PIP5K1A also sustains PLC-IP3-Ca2+ signaling for vesicle fusion and cytoskeletal remodeling.\",\n      \"method\": \"Structure-function mutagenesis (Q169, PIPB motif, activation loop), live imaging of membrane localization, maternal depletion and overexpression in porcine embryos, co-localization with RhoA\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with functional readouts in intact embryos plus co-localization, single lab\",\n      \"pmids\": [\"42212321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PIP5K1A (referred to as PIP5KA in the paper) produces a dedicated PI(4,5)P2 pool at the plasma membrane in collaboration with the scaffolding protein EFR3A, which is required for sorting AT1R angiotensin II receptors into an AP2-positive compartment for rapid GPCR re-sensitization without receptor internalization.\",\n      \"method\": \"Genetic perturbation of PIP5K1A and EFR3A, PI(4,5)P2 reporter assays, GPCR re-sensitization assays, AP2 co-localization imaging\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (lipid reporter, genetic KO, co-localization), single lab, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.03.28.645988\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PIP5K1A is a type I phosphatidylinositol 4-phosphate 5-kinase that phosphorylates PI4P to generate PI(4,5)P2 at the plasma membrane, where it is regulated by dimerization and by binding partners (including Dishevelled-DIX, KRAS, Arf6/c-Met, CLIC1, and DCLK1) that stimulate its catalytic activity or control its membrane recruitment; it also performs kinase-independent functions including competitive binding to KEAP1 to stabilize NRF2 and interaction with nuclear XPO5 to restrict pre-let-7 miRNA export, placing PIP5K1A at a signaling nexus controlling PI3K-AKT activation, actin/cytoskeletal dynamics, GPCR re-sensitization, RhoA membrane recruitment, and gene expression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PIP5K1A is a type I phosphatidylinositol 4-phosphate 5-kinase that generates plasma-membrane PI(4,5)P2 pools to coordinate growth-factor signaling, cytoskeletal dynamics, and receptor trafficking [#2, #3]. Its catalytic domain forms a side-to-side dimer, and binding at adjacent dimerization/partner interfaces—including the DIX domain of Dishevelled—stimulates catalytic activity, with DIX engagement additionally enhancing substrate binding [#0]. Membrane recruitment and activation are controlled by multiple partners: PIP5K1A is recruited to c-Met in an Arf6-dependent manner upon HGF stimulation to drive PIP2/PIP3 production, Akt activation, and hepatocyte proliferation [#2]; CLIC1 relocates it to the leading edge to build PIP2-rich microdomains supporting integrin-mediated adhesion and migration [#3]; and DCLK1 suppresses its inhibitory threonine phosphorylation to promote membrane localization and PI3K-AKT activation under high matrix stiffness [#8]. These functions place PIP5K1A within KRAS-driven oncogenic signaling, where it is a KRAS-specific interactor whose depletion reduces oncogenic KRAS signaling and proliferation [#1], and upstream of an Akt/GSK-3β–CDK2/cyclin D1 axis controlling cell-cycle progression [#7]. The kinase also produces dedicated PI(4,5)P2 with the scaffold EFR3A to enable AP2-dependent GPCR re-sensitization [#10] and organizes membrane clusters that recruit RhoA during cytokinesis [#9]. Independent of its catalytic activity, PIP5K1A performs scaffolding roles: it competitively binds the KEAP1 Kelch domain to stabilize NRF2 and suppress ferroptosis [#6], and binds nuclear XPO5 to restrict pre-let-7 miRNA export [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established the structural basis for how PIP5K1A catalytic activity is switched on, showing dimerization and partner binding at defined interfaces stimulate the kinase.\",\n      \"evidence\": \"X-ray crystallography of zebrafish catalytic domain with site-directed mutagenesis and in vitro kinase assays\",\n      \"pmids\": [\"26365782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structure is of the isolated catalytic domain, not the full-length human enzyme on a membrane\",\n        \"How DIX binding mechanistically enhances substrate binding is not resolved at atomic detail\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined a receptor-coupled activation route, showing Arf6-dependent recruitment to c-Met links PIP5K1A lipid production to Akt activation and proliferation in vivo.\",\n      \"evidence\": \"siRNA knockdown in HepG2, recruitment co-IP, lipid measurement, and Pip5k1a knockout mouse hepatectomy model\",\n      \"pmids\": [\"28842595\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct binding interface between PIP5K1A and c-Met/Arf6 not mapped\",\n        \"Whether PIP3 is produced directly or via downstream PI3K is not fully delineated\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified PIP5K1A as a selective effector of oncogenic KRAS, establishing it as a vulnerability in KRAS-driven cancers.\",\n      \"evidence\": \"BioID interactome, CRISPR loss-of-function screen, co-IP binding mapping, proliferation assays in pancreatic cancer lines\",\n      \"pmids\": [\"30194290\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of KRAS-specific (vs NRAS/HRAS) binding not resolved\",\n        \"Whether the effect requires PIP5K1A catalytic activity not directly tested\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Probed the membrane-engagement mechanism, predicting monomeric PIP5K1A binds PI4P membranes via a reorientation step while dimers cannot engage both active sites simultaneously.\",\n      \"evidence\": \"Coarse-grained and atomistic molecular dynamics simulations\",\n      \"pmids\": [\"31204251\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Computational only — predicted binding modes lack experimental validation\",\n        \"Proposed conformational change or bilayer distortion for dimer binding untested\",\n        \"No link to in-cell membrane behavior\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed how PIP5K1A is spatially targeted during migration, with CLIC1 delivering it to the leading edge to build adhesion-promoting PIP2 microdomains.\",\n      \"evidence\": \"Comparative proteomics, co-IP, fractionation/live imaging, siRNA with adhesion and mouse lung metastasis readouts\",\n      \"pmids\": [\"33079727\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which CLIC1 selects PIP5K1A/PIP5K1C is not detailed\",\n        \"How PIP2 microdomains organize integrin clustering at molecular level unresolved\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a kinase-independent nuclear function, showing PIP5K1A blocks XPO5–pre-let-7 binding to restrict miRNA export.\",\n      \"evidence\": \"Co-IP, kinase-dead mutant analysis, C. elegans lin-28/let-7 epistasis, quantitative miRNA measurement\",\n      \"pmids\": [\"37655623\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab; nuclear localization mechanism of PIP5K1A not established\",\n        \"Whether interaction with XPO5 is direct vs complex-mediated unconfirmed\",\n        \"Generality across miRNAs beyond let-7 untested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed PIP5K1A upstream of an Akt/GSK-3β–CDK2/cyclin D1 cell-cycle axis and identified rupatadine as a kinase inhibitor.\",\n      \"evidence\": \"Kinase activity assay, bio-layer interferometry, western blot, proliferation assays, xenograft\",\n      \"pmids\": [\"38838507\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab; direct kinase substrates linking to GSK-3β not defined\",\n        \"Specificity of rupatadine for PIP5K1A vs other PIP kinases not fully characterized\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated a second kinase-independent scaffolding role, with PIP5K1A competing for the KEAP1 Kelch domain to stabilize NRF2 and suppress ferroptosis.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, kinase-dead mutant, siRNA with lipid peroxidation readouts, ISA-2011B inhibition\",\n      \"pmids\": [\"40405713\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab; binding stoichiometry/affinity with KEAP1 not quantified\",\n        \"Whether this competes with endogenous KEAP1 substrates beyond NRF2 unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked a dedicated PIP5K1A PI(4,5)P2 pool to GPCR re-sensitization, acting with EFR3A to sort AT1R into an AP2 compartment.\",\n      \"evidence\": \"Genetic perturbation of PIP5K1A/EFR3A, PI(4,5)P2 reporters, re-sensitization assays, AP2 co-localization imaging (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.03.28.645988\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint, not yet peer-reviewed\",\n        \"Direct PIP5K1A–EFR3A interaction interface not mapped\",\n        \"Generality across other GPCRs untested\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Dissected structural determinants linking PIP5K1A membrane anchoring to RhoA recruitment and cytokinesis.\",\n      \"evidence\": \"Structure-function mutagenesis (Q169, PIPB motif, activation loop), live imaging, maternal depletion/overexpression in porcine embryos, RhoA co-localization\",\n      \"pmids\": [\"42212321\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab in porcine embryo system; human relevance not directly shown\",\n        \"Mechanism by which PIP2 clusters recruit RhoA not fully resolved\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified a phosphoregulatory partner, showing DCLK1 inhibits PIP5K1A threonine phosphorylation to promote its membrane localization and PI3K-AKT signaling under stiff matrix.\",\n      \"evidence\": \"Co-IP, phosphorylation analysis, subcellular fractionation, in vitro/in vivo pancreatic tumor models with DCLK1 perturbation\",\n      \"pmids\": [\"41692802\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab; the kinase/phosphatase acting on the threonine site not identified\",\n        \"Whether DCLK1 acts directly or recruits a phosphatase unclear\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the catalytic and scaffolding (KEAP1-, XPO5-binding) activities of PIP5K1A are partitioned across subcellular compartments and integrated with its many activating partners remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No unifying model for how partner choice (DIX, KRAS, Arf6, CLIC1, DCLK1) dictates output\",\n        \"Full-length human enzyme structure on membrane lacking\",\n        \"Mechanism of nuclear targeting for kinase-independent roles unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2, 7]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [4, 10]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 3, 9, 10]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 1, 8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 6, 7]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"KRAS\", \"MET\", \"ARF6\", \"CLIC1\", \"XPO5\", \"KEAP1\", \"DCLK1\", \"RHOA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}