{"gene":"PIP5K1C","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2007,"finding":"A homozygous D253N missense mutation in PIP5K1C abrogates the kinase activity of PIP5Kγ, preventing phosphorylation of PI(4)P to generate PI(4,5)P2, and causes lethal congenital contractural syndrome type 3 (LCCS3) in humans.","method":"Positional cloning, sequencing, and functional kinase activity assay of mutant protein","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct kinase activity assay demonstrating loss of function, single lab but with both genetic mapping and biochemical validation","pmids":["17701898"],"is_preprint":false},{"year":2018,"finding":"The disease-causing D253N mutation in PIP5Kγ severely disorders the glycine-rich loop of the ATP-binding site and destabilizes key electrostatic interactions around ATP, impairing effective ATP binding without altering the overall catalytic site architecture or Km toward ATP, establishing the mechanism by which this mutation abolishes kinase activity.","method":"X-ray crystallography of zebrafish ortholog mutant, molecular dynamics simulation, kinase activity assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure combined with MD simulation and in vitro kinase assay, single lab with multiple orthogonal methods","pmids":["29959184"],"is_preprint":false},{"year":2009,"finding":"PIP5K1C (PIP5K-γ) is required for the attachment phase of FcγR-mediated phagocytosis; PIP5K-γ knockout macrophages show hyperpolymerized actin, defective IgG-opsonized particle attachment, reduced Rac1 and elevated RhoA activation, and exogenous PIP2 rescues these defects. PIP5K-γ is transiently activated by Syk (spleen tyrosine kinase)-mediated phosphorylation during phagocytosis.","method":"Knockout mouse-derived macrophages, RNAi, exogenous PIP2 rescue, pharmacological RhoA/Rac1 manipulation, kinase activity assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO combined with RNAi, rescue experiment, and pathway epistasis in a peer-reviewed study","pmids":["19153220"],"is_preprint":false},{"year":2010,"finding":"PIP5K1C deficiency impairs neutrophil adhesion and recruitment by failing to activate RhoA GTPase and integrins in response to chemoattractants. The PIP5K1C-90 isoform is polarized to uropods via intracellular vesicle transport in an integrin-dependent, chemoattractant-independent manner, providing a directional cue for RhoA activation and enabling leading-edge formation for transendothelial migration.","method":"PIP5K1C knockout mice, in vivo neutrophil recruitment assay, live imaging of vesicle transport, RhoA/Rac1 activation assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO with in vivo phenotype, live imaging, and GTPase activation assays, single lab with multiple orthogonal methods","pmids":["20850356"],"is_preprint":false},{"year":2010,"finding":"SIRT1 physically binds PIP5K1C and deacetylates two specific lysine residues (K265/K268), thereby enhancing PIP5K1C kinase activity and promoting PI(4,5)P2 production and TSH exocytosis in pituitary thyrotropes.","method":"LC/MS-based interactomics, Co-immunoprecipitation, in vitro deacetylation assay, PIP5K1C knockdown, SIRT1 knockout mice","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — MS-identified interaction confirmed by Co-IP, enzymatic activity assay showing deacetylation enhances kinase activity, validated in KO mice","pmids":["20668706"],"is_preprint":false},{"year":2011,"finding":"EZH2 binds the PIP5K1C promoter to suppress its transcription in proliferating mesenchymal stem cells; upon neuronal differentiation induction, EZH2 decreases, derepressing PIP5K1C expression, which raises PI(4,5)P2 levels and intracellular Ca2+ release via IP3, driving neuronal differentiation.","method":"Chromatin immunoprecipitation (ChIP) of EZH2 at PIP5K1C promoter, EZH2 and PIP5K1C knockdown, PI(4,5)P2 and Ca2+ measurement, in vitro and in vivo differentiation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming direct promoter binding, siRNA knockdown with PI(4,5)P2 and Ca2+ readouts, single lab","pmids":["21216957"],"is_preprint":false},{"year":2014,"finding":"PIP5K1C is the dominant PIP5K isoform in dorsal root ganglion (DRG) neurons and generates at least half of all PI(4,5)P2 there. Pip5k1c haploinsufficiency reduces PI(4,5)P2 levels, attenuates pronociceptive receptor signaling and TRPV1 sensitization, and decreases thermal and mechanical hypersensitivity in chronic pain mouse models.","method":"Pip5k1c heterozygous knockout mice, PI(4,5)P2 quantification in DRG, TRPV1 sensitization assays, behavioral pain models, small-molecule inhibitor (UNC3230) validation","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic haploinsufficiency plus pharmacological inhibition with multiple functional readouts including lipid quantification and behavioral models","pmids":["24853942"],"is_preprint":false},{"year":2017,"finding":"Conditional deletion of PIP5K1C in sensory neurons (DRG-selective) accelerates recovery from thermal hypersensitivity and mechanical allodynia following hindpaw inflammation, but does not affect acute thermosensation or mechanosensation, indicating PIP5K1C regulates nociceptive sensitization beyond DRG in additional CNS regions.","method":"Tamoxifen-inducible Cre-mediated conditional knockout (Brn3a-Cre-ERT2 and Advillin-Cre-ERT2) with behavioral pain testing","journal":"Molecular pain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent inducible Cre lines with behavioral phenotyping, single lab","pmids":["29020859"],"is_preprint":false},{"year":2018,"finding":"PKD1 (protein kinase D1) phosphorylates PIP5K1C at serine residue 448 (S448); this phosphorylation regulates focal adhesion dynamics and cell attachment through site-specific PI(4,5)P2 formation, and is downregulated in invasive ductal breast carcinoma alongside reduced PKD1 expression.","method":"Immunohistochemistry with phospho-specific antibody (pS448), comparison of normal vs. carcinoma tissues, PKD1 kinase link established from prior literature cited in paper","journal":"Oncotarget","confidence":"Low","confidence_rationale":"Tier 3 / Weak — phospho-specific IHC in tissue sections; kinase-substrate relationship with PKD1 cited from prior work, not directly demonstrated in this paper","pmids":["30555634"],"is_preprint":false},{"year":2022,"finding":"Arf6 recruits PIP5K1C to late vesicles near the plasma membrane, where PIP5K1C rapidly converts PI(4)P to PI(4,5)P2, driving exocyst complex recruitment and membrane tethering. Each exocyst subcomplex independently binds PI(4,5)P2, which is minimally sufficient for membrane tethering.","method":"Reconstitution of functional octameric human exocyst in vitro, liposome-based tethering assay, epithelial cell biology experiments with Arf6 and PIP5K1C manipulation","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of exocyst tethering combined with cell biology experiments, multiple orthogonal methods in a single rigorous study","pmids":["35609603"],"is_preprint":false},{"year":2022,"finding":"Loss of Pip5k1c in mesenchymal stem cells impairs cytoplasmic Ca2+ influx and inactivates Ca2+/calmodulin-dependent protein kinase (CaMK), which reduces Runx2 stability and suppresses osteoblast differentiation while promoting adipogenesis. Pip5k1c loss also reduces RANKL (but not OPG) expression in osteoblasts, impairing osteoclast formation support.","method":"Prx1-Cre conditional knockout mice, bone histomorphometry, micro-CT, Ca2+ flux assays, western blotting for CaMK and Runx2, in vitro differentiation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with multiple downstream mechanistic readouts (Ca2+ flux, CaMK activity, Runx2 levels), single lab","pmids":["35090892"],"is_preprint":false},{"year":2023,"finding":"PIP5K1C deficiency in PIKFYVE-dependent cancer cells defines their sensitivity to PIKFYVE inhibition; overexpression of PIP5K1C in sensitive cells confers resistance to the PIKFYVE inhibitor WX8, establishing PIP5K1C and PIKFYVE as operating in parallel pathways for PI(4,5)P2 synthesis required for lysosome homeostasis and autophagy.","method":"PIP5K1C knockdown/overexpression in cancer cell lines, PIKFYVE inhibitor treatment, phosphoinositide mass spectrometry, lysosome function and autophagy assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic rescue and loss-of-function with lipid mass spectrometry and functional pathway readouts, single lab","pmids":["36803256"],"is_preprint":false},{"year":2023,"finding":"PIP5K1C (PIP5Kγ90 isoform) forms a functional complex with Merlin and LATS1 at the PI(4,5)P2-rich plasma membrane, activating the Hippo pathway by phosphorylating and inhibiting YAP. This requires PIP5K1C catalytic activity. PIP5Kγ90 also interacts with Hsc70, which contributes to Hippo pathway activation. Knockdown or inhibition (UNC3230) of PIP5K1C enhances YAP-dependent colony formation.","method":"Co-immunoprecipitation, kinase-dead mutant analysis, ectopic expression of splice variants, YAP phosphorylation assays, colony formation assays with UNC3230 inhibitor","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — reciprocal Co-IP, kinase-dead mutant, and pharmacological inhibition with functional readouts, single lab","pmids":["37834234"],"is_preprint":false},{"year":2023,"finding":"Loss of Pip5k1c in chondrocytes dramatically downregulates focal adhesion proteins (activated integrin β1, talin, vinculin), impairing chondrocyte adhesion and spreading on ECM, and promotes extracellular matrix degradation, chondrocyte hypertrophy, and apoptosis in aged mice, leading to spontaneous osteoarthritis-like lesions.","method":"Inducible chondrocyte-specific conditional knockout (aggrecan-Cre), histology, immunofluorescence, western blotting for FA proteins, cell adhesion assays","journal":"Aging and disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with multiple molecular readouts including FA protein quantification and functional adhesion assays, single lab","pmids":["37008048"],"is_preprint":false},{"year":2024,"finding":"PIP5K1C inhibition prevents ACE2-mediated endocytosis of SARS-CoV-2, identifying PIP5K1C-dependent PI(4,5)P2 synthesis as required for viral endosomal entry.","method":"Dual inhibitor UNI418 treatment of cells, SARS-CoV-2 entry assays, endocytosis assays","journal":"Experimental & molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological inhibition with dual-specificity compound (PIP5K1C and PIKfyve), single lab, cannot fully attribute effect to PIP5K1C alone","pmids":["39085352"],"is_preprint":false},{"year":2025,"finding":"Inhibition of PIP5K1C can restore ciliogenesis in TBC1D19-null cells that have abrogated ciliary localization of INPP5E, suggesting PIP5K1C activity opposes INPP5E-dependent phosphoinositide homeostasis required for cilium assembly and maintenance.","method":"PIP5K1C inhibition in TBC1D19 knockout cells with ciliogenesis readout","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single pharmacological inhibition experiment in a preprint, PIP5K1C is a secondary finding in a study focused on TBC1D19/TPGC","pmids":[],"is_preprint":true}],"current_model":"PIP5K1C (PIP5Kγ) is a PI(4)P 5-kinase that phosphorylates PI(4)P to generate PI(4,5)P2 at the plasma membrane; its catalytic activity is enhanced by SIRT1-mediated deacetylation at K265/K268 and regulated by PKD1-mediated phosphorylation at S448, and PIP5K1C functions in multiple processes including Arf6-dependent exocyst-mediated vesicle tethering, FcγR-mediated phagocytosis (acting upstream of RhoA/Rac1 balance), integrin-dependent neutrophil polarization via uropod-localized PIP5K1C-90, nociceptive sensitization in DRG neurons via TRPV1 and pronociceptive receptor signaling, Hippo-YAP pathway activation through a Merlin-LATS1 complex at the plasma membrane, and calcium/CaMK/Runx2-dependent osteoblast differentiation."},"narrative":{"mechanistic_narrative":"PIP5K1C (PIP5Kγ) is a phosphatidylinositol-4-phosphate 5-kinase that phosphorylates PI(4)P to generate PI(4,5)P2 at the plasma membrane and on membrane vesicles, supplying a localized lipid signal that governs cytoskeletal dynamics, vesicle tethering, membrane receptor signaling, and cell-fate decisions [PMID:17701898, PMID:35609603]. Its catalytic activity is enhanced by SIRT1-mediated deacetylation of K265/K268 [PMID:20668706] and modulated by phosphorylation; Syk transiently activates it during phagocytosis [PMID:19153220]. By controlling PI(4,5)P2 pools, PIP5K1C acts upstream of RhoA/Rac1 balance to drive Fcγ-receptor–mediated phagocytosis and integrin/RhoA-dependent neutrophil polarization, with the PIP5K1C-90 isoform delivered to uropods to provide a directional cue [PMID:19153220, PMID:20850356]. At late vesicles, Arf6 recruits PIP5K1C to produce PI(4,5)P2 that drives exocyst complex recruitment and membrane tethering [PMID:35609603]. PIP5K1C-derived PI(4,5)P2 also couples to IP3/Ca2+ signaling that drives neuronal and CaMK/Runx2-dependent osteoblast differentiation [PMID:21216957, PMID:35090892], supports focal-adhesion–dependent adhesion of chondrocytes [PMID:37008048], sensitizes nociceptive DRG neurons through TRPV1 and pronociceptive receptor signaling [PMID:24853942], and, via a Merlin–LATS1 complex, activates the Hippo pathway to inhibit YAP [PMID:37834234]. A homozygous kinase-dead D253N mutation causes lethal congenital contractural syndrome type 3 (LCCS3) in humans by disordering the ATP-binding glycine-rich loop [PMID:17701898, PMID:29959184].","teleology":[{"year":2007,"claim":"Established PIP5K1C as a disease gene by showing that loss of its PI(4)P 5-kinase activity causes a human Mendelian syndrome, directly linking PI(4,5)P2 production to a developmental phenotype.","evidence":"Positional cloning and kinase activity assay of the D253N mutant protein causing LCCS3","pmids":["17701898"],"confidence":"High","gaps":["Did not define the structural basis of activity loss","Did not identify the affected downstream developmental pathway"]},{"year":2009,"claim":"Defined PIP5K1C as a regulator of the actin cytoskeleton during Fcγ-receptor phagocytosis, placing it upstream of the RhoA/Rac1 balance and downstream of Syk activation.","evidence":"Knockout macrophages, RNAi, exogenous PIP2 rescue, and RhoA/Rac1 epistasis","pmids":["19153220"],"confidence":"High","gaps":["Mechanism by which Syk phosphorylation activates the kinase not resolved at the residue level","Spatial control of PI(4,5)P2 during particle attachment not defined"]},{"year":2010,"claim":"Showed PIP5K1C governs leukocyte motility through integrin-dependent uropod targeting of the PIP5K1C-90 isoform and chemoattractant-induced RhoA activation, and identified SIRT1 deacetylation of K265/K268 as a direct activity-enhancing modification linked to regulated exocytosis.","evidence":"PIP5K1C knockout mice with in vivo recruitment and live vesicle imaging; LC/MS interactomics, Co-IP, in vitro deacetylation assay, and SIRT1 knockout mice","pmids":["20850356","20668706"],"confidence":"High","gaps":["How acetylation status is dynamically set in vivo not established","Vesicle-transport machinery delivering the -90 isoform to uropods not defined"]},{"year":2011,"claim":"Connected PIP5K1C expression to a cell-fate switch, showing EZH2-mediated transcriptional repression must be relieved to raise PI(4,5)P2 and IP3/Ca2+ for neuronal differentiation.","evidence":"ChIP of EZH2 at the PIP5K1C promoter with knockdown and PI(4,5)P2/Ca2+ readouts in mesenchymal stem cells","pmids":["21216957"],"confidence":"Medium","gaps":["Signal triggering EZH2 loss at the promoter not identified","Direct chain from PI(4,5)P2 to IP3 receptor activation in this context not fully reconstituted"]},{"year":2014,"claim":"Identified PIP5K1C as the dominant PI(4,5)P2 source in DRG neurons and a driver of nociceptive sensitization, validating it as a pharmacological pain target.","evidence":"Pip5k1c haploinsufficient mice with DRG lipid quantification, TRPV1 sensitization, behavioral pain models, and the UNC3230 inhibitor","pmids":["24853942"],"confidence":"High","gaps":["Which pronociceptive receptors converge on PIP5K1C not fully enumerated","Contribution of CNS sites versus DRG not separated"]},{"year":2017,"claim":"Refined the site of nociceptive action by showing DRG-selective deletion accelerates recovery from inflammatory hypersensitivity without affecting acute sensation, implying additional CNS contributions.","evidence":"Two inducible Cre lines with behavioral pain testing","pmids":["29020859"],"confidence":"Medium","gaps":["CNS regions mediating residual sensitization not identified","Molecular target downstream of PI(4,5)P2 in sensitization recovery unresolved"]},{"year":2018,"claim":"Resolved the structural basis of the LCCS3 mutation, showing D253N disorders the glycine-rich loop and ATP electrostatics to abolish catalysis without altering active-site architecture.","evidence":"X-ray crystallography of the zebrafish ortholog mutant, MD simulation, and kinase assay","pmids":["29959184"],"confidence":"High","gaps":["Structure of the human protein-substrate complex not solved","How loss of activity produces the contractural developmental phenotype not mechanistically traced"]},{"year":2018,"claim":"Proposed PKD1 phosphorylation of S448 as a regulatory input controlling focal adhesion dynamics, with downregulation in breast carcinoma.","evidence":"Phospho-specific IHC in normal versus carcinoma tissue; PKD1-substrate relationship cited from prior work","pmids":["30555634"],"confidence":"Low","gaps":["Direct PKD1-mediated phosphorylation of S448 not demonstrated in this study","Functional consequence of S448 phosphorylation on kinase activity not measured"]},{"year":2022,"claim":"Demonstrated a vesicle-tethering function in which Arf6-recruited PIP5K1C generates PI(4,5)P2 that is minimally sufficient to recruit the exocyst, mechanistically linking lipid synthesis to membrane fusion-site assembly.","evidence":"In vitro reconstitution of octameric exocyst, liposome tethering assays, and Arf6/PIP5K1C manipulation in epithelial cells","pmids":["35609603"],"confidence":"High","gaps":["How Arf6 spatially restricts recruitment in vivo not detailed","Coordination with cargo selection not addressed"]},{"year":2022,"claim":"Showed PIP5K1C controls a mesenchymal lineage decision via Ca2+/CaMK signaling that stabilizes Runx2 to favor osteoblast over adipocyte fate and supports osteoclastogenesis through RANKL.","evidence":"Prx1-Cre conditional knockout mice with histomorphometry, micro-CT, Ca2+ flux, and CaMK/Runx2 western blots","pmids":["35090892"],"confidence":"Medium","gaps":["Link from PI(4,5)P2 to the Ca2+ influx channel not defined","Direct effect on RANKL transcription not mechanistically traced"]},{"year":2023,"claim":"Placed PIP5K1C as a parallel PI(4,5)P2 source to PIKFYVE that sets cancer-cell sensitivity to PIKFYVE inhibition in lysosome/autophagy homeostasis.","evidence":"Knockdown/overexpression rescue with PIKFYVE inhibitor WX8, phosphoinositide mass spectrometry, and lysosome/autophagy assays","pmids":["36803256"],"confidence":"Medium","gaps":["Subcellular site of the relevant PI(4,5)P2 pool not defined","Whether the two enzymes act on shared or distinct substrate pools unresolved"]},{"year":2023,"claim":"Identified a Hippo-regulatory role in which the PIP5Kγ90 isoform forms a Merlin-LATS1 complex requiring catalytic activity to phosphorylate and inhibit YAP, restraining YAP-driven colony formation.","evidence":"Reciprocal Co-IP, kinase-dead mutant analysis, splice-variant expression, YAP phosphorylation, and UNC3230 colony assays","pmids":["37834234"],"confidence":"Medium","gaps":["How PI(4,5)P2 production mechanistically activates LATS1 not resolved","Role of the Hsc70 interaction not fully defined"]},{"year":2023,"claim":"Demonstrated PIP5K1C maintains chondrocyte adhesion via focal adhesion proteins, with loss promoting matrix degradation and spontaneous osteoarthritis-like lesions in aged mice.","evidence":"Inducible chondrocyte-specific knockout with histology, FA-protein western blots, and adhesion assays","pmids":["37008048"],"confidence":"Medium","gaps":["Mechanism linking PI(4,5)P2 to integrin β1 activation in chondrocytes not detailed","Whether the adhesion defect is cell-autonomous in driving OA not established"]},{"year":2024,"claim":"Implicated PIP5K1C-dependent PI(4,5)P2 in ACE2-mediated SARS-CoV-2 endosomal entry.","evidence":"Dual inhibitor UNI418 treatment with viral entry and endocytosis assays","pmids":["39085352"],"confidence":"Low","gaps":["Dual-specificity inhibitor cannot isolate PIP5K1C from PIKfyve","No genetic loss-of-function validation"]},{"year":2025,"claim":"Indicated PIP5K1C activity opposes INPP5E-dependent phosphoinositide homeostasis required for ciliogenesis.","evidence":"PIP5K1C inhibition restoring ciliogenesis in TBC1D19-null cells (preprint)","pmids":[],"confidence":"Low","gaps":["Single pharmacological experiment in a preprint, not independently confirmed","PIP5K1C is a secondary finding in a TBC1D19-focused study","No direct measurement of ciliary phosphoinositide changes attributable to PIP5K1C"]},{"year":null,"claim":"How PIP5K1C activity, isoform choice, and subcellular targeting are integrated to generate distinct PI(4,5)P2 pools for each downstream process remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model of how post-translational modifications and recruitment factors select among phagocytic, migratory, exocytic, Hippo, and differentiation outputs","Endogenous regulation of S448 phosphorylation and acetylation in tissue contexts undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,9]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,9,12]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3,9]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[9,4]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[12,6]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,10]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[11]}],"complexes":["Merlin-LATS1 complex"],"partners":["SIRT1","SYK","ARF6","PKD1","MERLIN (NF2)","LATS1","HSC70"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60331","full_name":"Phosphatidylinositol 4-phosphate 5-kinase type-1 gamma","aliases":["Type I phosphatidylinositol 4-phosphate 5-kinase gamma"],"length_aa":668,"mass_kda":73.3,"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:12422219, PubMed:22942276). 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) (Probable). PIP5K1A-mediated phosphorylation of PtdIns(4)P is the predominant pathway for PtdIns(4,5)P2 synthesis (By similarity). Together with PIP5K1A, is required for phagocytosis, both enzymes regulating different types of actin remodeling at sequential steps (By similarity). Promotes particle attachment by generating the pool of PtdIns(4,5)P2 that induces controlled actin depolymerization to facilitate Fc-gamma-R clustering. Mediates RAC1-dependent reorganization of actin filaments. Required for synaptic vesicle transport (By similarity). Controls the plasma membrane pool of PtdIns(4,5)P2 implicated in synaptic vesicle endocytosis and exocytosis (PubMed:12847086). Plays a role in endocytosis mediated by clathrin and AP-2 (adaptor protein complex 2) (PubMed:12847086). Required for clathrin-coated pits assembly at the synapse (PubMed:17261850). Participates in cell junction assembly (PubMed:17261850). Modulates adherens junctions formation by facilitating CDH1/cadherin trafficking (PubMed:17261850). Required for focal adhesion dynamics. Modulates the targeting of talins (TLN1 and TLN2) to the plasma membrane and their efficient assembly into focal adhesions (PubMed:12422219). Regulates the interaction between talins (TLN1 and TLN2) and beta-integrins (PubMed:12422219). Required for uropodium formation and retraction of the cell rear during directed migration (By similarity). Has a role in growth factor-stimulated directional cell migration and adhesion (By similarity). Required for talin assembly into nascent adhesions forming at the leading edge toward the direction of the growth factor (PubMed:17635937). Negative regulator of T-cell activation and adhesion (By similarity). Negatively regulates integrin alpha-L/beta-2 (LFA-1) polarization and adhesion induced by T-cell receptor (By similarity). Together with PIP5K1A has a role during embryogenesis and together with PIP5K1B may have a role immediately after birth (By similarity)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/O60331/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PIP5K1C","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000186111","cell_line_id":"CID000167","localizations":[{"compartment":"membrane","grade":3},{"compartment":"cytoplasmic","grade":2},{"compartment":"vesicles","grade":1}],"interactors":[{"gene":"PGBD5","stoichiometry":0.2},{"gene":"SNX4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000167","total_profiled":1310},"omim":[{"mim_id":"614915","title":"LETHAL CONGENITAL CONTRACTURE SYNDROME 4; LCCS4","url":"https://www.omim.org/entry/614915"},{"mim_id":"612971","title":"PDZ DOMAIN-CONTAINING 7; PDZD7","url":"https://www.omim.org/entry/612971"},{"mim_id":"611369","title":"LETHAL CONGENITAL CONTRACTURE SYNDROME 3; LCCS3","url":"https://www.omim.org/entry/611369"},{"mim_id":"607598","title":"LETHAL CONGENITAL CONTRACTURE SYNDROME 2; LCCS2","url":"https://www.omim.org/entry/607598"},{"mim_id":"607349","title":"TALIN 2; TLN2","url":"https://www.omim.org/entry/607349"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":116.0}],"url":"https://www.proteinatlas.org/search/PIP5K1C"},"hgnc":{"alias_symbol":["PIP5Kgamma","KIAA0589","LCCS3"],"prev_symbol":[]},"alphafold":{"accession":"O60331","domains":[{"cath_id":"3.30.800.10","chopping":"58-241","consensus_level":"medium","plddt":90.758,"start":58,"end":241},{"cath_id":"3.30.810.10","chopping":"242-334_353-364_376-449","consensus_level":"medium","plddt":83.4335,"start":242,"end":449}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60331","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60331-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60331-F1-predicted_aligned_error_v6.png","plddt_mean":63.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PIP5K1C","jax_strain_url":"https://www.jax.org/strain/search?query=PIP5K1C"},"sequence":{"accession":"O60331","fasta_url":"https://rest.uniprot.org/uniprotkb/O60331.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60331/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60331"}},"corpus_meta":[{"pmid":"17701898","id":"PMC_17701898","title":"Lethal contractural syndrome type 3 (LCCS3) is caused by a mutation in PIP5K1C, which encodes PIPKI gamma of the phophatidylinsitol pathway.","date":"2007","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17701898","citation_count":88,"is_preprint":false},{"pmid":"19153220","id":"PMC_19153220","title":"Essential and unique roles of PIP5K-gamma and -alpha in Fcgamma receptor-mediated phagocytosis.","date":"2009","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19153220","citation_count":82,"is_preprint":false},{"pmid":"24853942","id":"PMC_24853942","title":"The lipid kinase PIP5K1C regulates pain signaling and sensitization.","date":"2014","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/24853942","citation_count":71,"is_preprint":false},{"pmid":"20850356","id":"PMC_20850356","title":"Integrin-induced PIP5K1C kinase polarization regulates neutrophil polarization, directionality, and in vivo 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disease","url":"https://pubmed.ncbi.nlm.nih.gov/37008048","citation_count":13,"is_preprint":false},{"pmid":"37803350","id":"PMC_37803350","title":"MiR-4649-5p acts as a tumor-suppressive microRNA in triple negative breast cancer by direct interaction with PIP5K1C, thereby potentiating growth-inhibitory effects of the AKT inhibitor capivasertib.","date":"2023","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/37803350","citation_count":11,"is_preprint":false},{"pmid":"39085352","id":"PMC_39085352","title":"A dual inhibitor of PIP5K1C and PIKfyve prevents SARS-CoV-2 entry into cells.","date":"2024","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39085352","citation_count":9,"is_preprint":false},{"pmid":"34996482","id":"PMC_34996482","title":"Adipocyte-specific deletion of PIP5K1c reduces diet-induced obesity and insulin resistance by increasing energy expenditure.","date":"2022","source":"Lipids in health and 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maintenance","date":"2025-03-04","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.03.641315","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17280,"output_tokens":4261,"usd":0.057877,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12140,"output_tokens":4934,"usd":0.092025,"stage2_stop_reason":"end_turn"},"total_usd":0.149902,"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\": 2007,\n      \"finding\": \"A homozygous D253N missense mutation in PIP5K1C abrogates the kinase activity of PIP5Kγ, preventing phosphorylation of PI(4)P to generate PI(4,5)P2, and causes lethal congenital contractural syndrome type 3 (LCCS3) in humans.\",\n      \"method\": \"Positional cloning, sequencing, and functional kinase activity assay of mutant protein\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct kinase activity assay demonstrating loss of function, single lab but with both genetic mapping and biochemical validation\",\n      \"pmids\": [\"17701898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The disease-causing D253N mutation in PIP5Kγ severely disorders the glycine-rich loop of the ATP-binding site and destabilizes key electrostatic interactions around ATP, impairing effective ATP binding without altering the overall catalytic site architecture or Km toward ATP, establishing the mechanism by which this mutation abolishes kinase activity.\",\n      \"method\": \"X-ray crystallography of zebrafish ortholog mutant, molecular dynamics simulation, kinase activity assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure combined with MD simulation and in vitro kinase assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29959184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PIP5K1C (PIP5K-γ) is required for the attachment phase of FcγR-mediated phagocytosis; PIP5K-γ knockout macrophages show hyperpolymerized actin, defective IgG-opsonized particle attachment, reduced Rac1 and elevated RhoA activation, and exogenous PIP2 rescues these defects. PIP5K-γ is transiently activated by Syk (spleen tyrosine kinase)-mediated phosphorylation during phagocytosis.\",\n      \"method\": \"Knockout mouse-derived macrophages, RNAi, exogenous PIP2 rescue, pharmacological RhoA/Rac1 manipulation, kinase activity assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO combined with RNAi, rescue experiment, and pathway epistasis in a peer-reviewed study\",\n      \"pmids\": [\"19153220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PIP5K1C deficiency impairs neutrophil adhesion and recruitment by failing to activate RhoA GTPase and integrins in response to chemoattractants. The PIP5K1C-90 isoform is polarized to uropods via intracellular vesicle transport in an integrin-dependent, chemoattractant-independent manner, providing a directional cue for RhoA activation and enabling leading-edge formation for transendothelial migration.\",\n      \"method\": \"PIP5K1C knockout mice, in vivo neutrophil recruitment assay, live imaging of vesicle transport, RhoA/Rac1 activation assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with in vivo phenotype, live imaging, and GTPase activation assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"20850356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SIRT1 physically binds PIP5K1C and deacetylates two specific lysine residues (K265/K268), thereby enhancing PIP5K1C kinase activity and promoting PI(4,5)P2 production and TSH exocytosis in pituitary thyrotropes.\",\n      \"method\": \"LC/MS-based interactomics, Co-immunoprecipitation, in vitro deacetylation assay, PIP5K1C knockdown, SIRT1 knockout mice\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — MS-identified interaction confirmed by Co-IP, enzymatic activity assay showing deacetylation enhances kinase activity, validated in KO mice\",\n      \"pmids\": [\"20668706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"EZH2 binds the PIP5K1C promoter to suppress its transcription in proliferating mesenchymal stem cells; upon neuronal differentiation induction, EZH2 decreases, derepressing PIP5K1C expression, which raises PI(4,5)P2 levels and intracellular Ca2+ release via IP3, driving neuronal differentiation.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) of EZH2 at PIP5K1C promoter, EZH2 and PIP5K1C knockdown, PI(4,5)P2 and Ca2+ measurement, in vitro and in vivo differentiation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming direct promoter binding, siRNA knockdown with PI(4,5)P2 and Ca2+ readouts, single lab\",\n      \"pmids\": [\"21216957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PIP5K1C is the dominant PIP5K isoform in dorsal root ganglion (DRG) neurons and generates at least half of all PI(4,5)P2 there. Pip5k1c haploinsufficiency reduces PI(4,5)P2 levels, attenuates pronociceptive receptor signaling and TRPV1 sensitization, and decreases thermal and mechanical hypersensitivity in chronic pain mouse models.\",\n      \"method\": \"Pip5k1c heterozygous knockout mice, PI(4,5)P2 quantification in DRG, TRPV1 sensitization assays, behavioral pain models, small-molecule inhibitor (UNC3230) validation\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic haploinsufficiency plus pharmacological inhibition with multiple functional readouts including lipid quantification and behavioral models\",\n      \"pmids\": [\"24853942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Conditional deletion of PIP5K1C in sensory neurons (DRG-selective) accelerates recovery from thermal hypersensitivity and mechanical allodynia following hindpaw inflammation, but does not affect acute thermosensation or mechanosensation, indicating PIP5K1C regulates nociceptive sensitization beyond DRG in additional CNS regions.\",\n      \"method\": \"Tamoxifen-inducible Cre-mediated conditional knockout (Brn3a-Cre-ERT2 and Advillin-Cre-ERT2) with behavioral pain testing\",\n      \"journal\": \"Molecular pain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent inducible Cre lines with behavioral phenotyping, single lab\",\n      \"pmids\": [\"29020859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PKD1 (protein kinase D1) phosphorylates PIP5K1C at serine residue 448 (S448); this phosphorylation regulates focal adhesion dynamics and cell attachment through site-specific PI(4,5)P2 formation, and is downregulated in invasive ductal breast carcinoma alongside reduced PKD1 expression.\",\n      \"method\": \"Immunohistochemistry with phospho-specific antibody (pS448), comparison of normal vs. carcinoma tissues, PKD1 kinase link established from prior literature cited in paper\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — phospho-specific IHC in tissue sections; kinase-substrate relationship with PKD1 cited from prior work, not directly demonstrated in this paper\",\n      \"pmids\": [\"30555634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Arf6 recruits PIP5K1C to late vesicles near the plasma membrane, where PIP5K1C rapidly converts PI(4)P to PI(4,5)P2, driving exocyst complex recruitment and membrane tethering. Each exocyst subcomplex independently binds PI(4,5)P2, which is minimally sufficient for membrane tethering.\",\n      \"method\": \"Reconstitution of functional octameric human exocyst in vitro, liposome-based tethering assay, epithelial cell biology experiments with Arf6 and PIP5K1C manipulation\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of exocyst tethering combined with cell biology experiments, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"35609603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Loss of Pip5k1c in mesenchymal stem cells impairs cytoplasmic Ca2+ influx and inactivates Ca2+/calmodulin-dependent protein kinase (CaMK), which reduces Runx2 stability and suppresses osteoblast differentiation while promoting adipogenesis. Pip5k1c loss also reduces RANKL (but not OPG) expression in osteoblasts, impairing osteoclast formation support.\",\n      \"method\": \"Prx1-Cre conditional knockout mice, bone histomorphometry, micro-CT, Ca2+ flux assays, western blotting for CaMK and Runx2, in vitro differentiation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with multiple downstream mechanistic readouts (Ca2+ flux, CaMK activity, Runx2 levels), single lab\",\n      \"pmids\": [\"35090892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PIP5K1C deficiency in PIKFYVE-dependent cancer cells defines their sensitivity to PIKFYVE inhibition; overexpression of PIP5K1C in sensitive cells confers resistance to the PIKFYVE inhibitor WX8, establishing PIP5K1C and PIKFYVE as operating in parallel pathways for PI(4,5)P2 synthesis required for lysosome homeostasis and autophagy.\",\n      \"method\": \"PIP5K1C knockdown/overexpression in cancer cell lines, PIKFYVE inhibitor treatment, phosphoinositide mass spectrometry, lysosome function and autophagy assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue and loss-of-function with lipid mass spectrometry and functional pathway readouts, single lab\",\n      \"pmids\": [\"36803256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PIP5K1C (PIP5Kγ90 isoform) forms a functional complex with Merlin and LATS1 at the PI(4,5)P2-rich plasma membrane, activating the Hippo pathway by phosphorylating and inhibiting YAP. This requires PIP5K1C catalytic activity. PIP5Kγ90 also interacts with Hsc70, which contributes to Hippo pathway activation. Knockdown or inhibition (UNC3230) of PIP5K1C enhances YAP-dependent colony formation.\",\n      \"method\": \"Co-immunoprecipitation, kinase-dead mutant analysis, ectopic expression of splice variants, YAP phosphorylation assays, colony formation assays with UNC3230 inhibitor\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — reciprocal Co-IP, kinase-dead mutant, and pharmacological inhibition with functional readouts, single lab\",\n      \"pmids\": [\"37834234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Loss of Pip5k1c in chondrocytes dramatically downregulates focal adhesion proteins (activated integrin β1, talin, vinculin), impairing chondrocyte adhesion and spreading on ECM, and promotes extracellular matrix degradation, chondrocyte hypertrophy, and apoptosis in aged mice, leading to spontaneous osteoarthritis-like lesions.\",\n      \"method\": \"Inducible chondrocyte-specific conditional knockout (aggrecan-Cre), histology, immunofluorescence, western blotting for FA proteins, cell adhesion assays\",\n      \"journal\": \"Aging and disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with multiple molecular readouts including FA protein quantification and functional adhesion assays, single lab\",\n      \"pmids\": [\"37008048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PIP5K1C inhibition prevents ACE2-mediated endocytosis of SARS-CoV-2, identifying PIP5K1C-dependent PI(4,5)P2 synthesis as required for viral endosomal entry.\",\n      \"method\": \"Dual inhibitor UNI418 treatment of cells, SARS-CoV-2 entry assays, endocytosis assays\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological inhibition with dual-specificity compound (PIP5K1C and PIKfyve), single lab, cannot fully attribute effect to PIP5K1C alone\",\n      \"pmids\": [\"39085352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Inhibition of PIP5K1C can restore ciliogenesis in TBC1D19-null cells that have abrogated ciliary localization of INPP5E, suggesting PIP5K1C activity opposes INPP5E-dependent phosphoinositide homeostasis required for cilium assembly and maintenance.\",\n      \"method\": \"PIP5K1C inhibition in TBC1D19 knockout cells with ciliogenesis readout\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single pharmacological inhibition experiment in a preprint, PIP5K1C is a secondary finding in a study focused on TBC1D19/TPGC\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PIP5K1C (PIP5Kγ) is a PI(4)P 5-kinase that phosphorylates PI(4)P to generate PI(4,5)P2 at the plasma membrane; its catalytic activity is enhanced by SIRT1-mediated deacetylation at K265/K268 and regulated by PKD1-mediated phosphorylation at S448, and PIP5K1C functions in multiple processes including Arf6-dependent exocyst-mediated vesicle tethering, FcγR-mediated phagocytosis (acting upstream of RhoA/Rac1 balance), integrin-dependent neutrophil polarization via uropod-localized PIP5K1C-90, nociceptive sensitization in DRG neurons via TRPV1 and pronociceptive receptor signaling, Hippo-YAP pathway activation through a Merlin-LATS1 complex at the plasma membrane, and calcium/CaMK/Runx2-dependent osteoblast differentiation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PIP5K1C (PIP5Kγ) is a phosphatidylinositol-4-phosphate 5-kinase that phosphorylates PI(4)P to generate PI(4,5)P2 at the plasma membrane and on membrane vesicles, supplying a localized lipid signal that governs cytoskeletal dynamics, vesicle tethering, membrane receptor signaling, and cell-fate decisions [#0, #9]. Its catalytic activity is enhanced by SIRT1-mediated deacetylation of K265/K268 [#4] and modulated by phosphorylation; Syk transiently activates it during phagocytosis [#2]. By controlling PI(4,5)P2 pools, PIP5K1C acts upstream of RhoA/Rac1 balance to drive Fcγ-receptor–mediated phagocytosis and integrin/RhoA-dependent neutrophil polarization, with the PIP5K1C-90 isoform delivered to uropods to provide a directional cue [#2, #3]. At late vesicles, Arf6 recruits PIP5K1C to produce PI(4,5)P2 that drives exocyst complex recruitment and membrane tethering [#9]. PIP5K1C-derived PI(4,5)P2 also couples to IP3/Ca2+ signaling that drives neuronal and CaMK/Runx2-dependent osteoblast differentiation [#5, #10], supports focal-adhesion–dependent adhesion of chondrocytes [#13], sensitizes nociceptive DRG neurons through TRPV1 and pronociceptive receptor signaling [#6], and, via a Merlin–LATS1 complex, activates the Hippo pathway to inhibit YAP [#12]. A homozygous kinase-dead D253N mutation causes lethal congenital contractural syndrome type 3 (LCCS3) in humans by disordering the ATP-binding glycine-rich loop [#0, #1].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established PIP5K1C as a disease gene by showing that loss of its PI(4)P 5-kinase activity causes a human Mendelian syndrome, directly linking PI(4,5)P2 production to a developmental phenotype.\",\n      \"evidence\": \"Positional cloning and kinase activity assay of the D253N mutant protein causing LCCS3\",\n      \"pmids\": [\"17701898\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the structural basis of activity loss\", \"Did not identify the affected downstream developmental pathway\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined PIP5K1C as a regulator of the actin cytoskeleton during Fcγ-receptor phagocytosis, placing it upstream of the RhoA/Rac1 balance and downstream of Syk activation.\",\n      \"evidence\": \"Knockout macrophages, RNAi, exogenous PIP2 rescue, and RhoA/Rac1 epistasis\",\n      \"pmids\": [\"19153220\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Syk phosphorylation activates the kinase not resolved at the residue level\", \"Spatial control of PI(4,5)P2 during particle attachment not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed PIP5K1C governs leukocyte motility through integrin-dependent uropod targeting of the PIP5K1C-90 isoform and chemoattractant-induced RhoA activation, and identified SIRT1 deacetylation of K265/K268 as a direct activity-enhancing modification linked to regulated exocytosis.\",\n      \"evidence\": \"PIP5K1C knockout mice with in vivo recruitment and live vesicle imaging; LC/MS interactomics, Co-IP, in vitro deacetylation assay, and SIRT1 knockout mice\",\n      \"pmids\": [\"20850356\", \"20668706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How acetylation status is dynamically set in vivo not established\", \"Vesicle-transport machinery delivering the -90 isoform to uropods not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected PIP5K1C expression to a cell-fate switch, showing EZH2-mediated transcriptional repression must be relieved to raise PI(4,5)P2 and IP3/Ca2+ for neuronal differentiation.\",\n      \"evidence\": \"ChIP of EZH2 at the PIP5K1C promoter with knockdown and PI(4,5)P2/Ca2+ readouts in mesenchymal stem cells\",\n      \"pmids\": [\"21216957\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signal triggering EZH2 loss at the promoter not identified\", \"Direct chain from PI(4,5)P2 to IP3 receptor activation in this context not fully reconstituted\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified PIP5K1C as the dominant PI(4,5)P2 source in DRG neurons and a driver of nociceptive sensitization, validating it as a pharmacological pain target.\",\n      \"evidence\": \"Pip5k1c haploinsufficient mice with DRG lipid quantification, TRPV1 sensitization, behavioral pain models, and the UNC3230 inhibitor\",\n      \"pmids\": [\"24853942\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which pronociceptive receptors converge on PIP5K1C not fully enumerated\", \"Contribution of CNS sites versus DRG not separated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Refined the site of nociceptive action by showing DRG-selective deletion accelerates recovery from inflammatory hypersensitivity without affecting acute sensation, implying additional CNS contributions.\",\n      \"evidence\": \"Two inducible Cre lines with behavioral pain testing\",\n      \"pmids\": [\"29020859\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CNS regions mediating residual sensitization not identified\", \"Molecular target downstream of PI(4,5)P2 in sensitization recovery unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved the structural basis of the LCCS3 mutation, showing D253N disorders the glycine-rich loop and ATP electrostatics to abolish catalysis without altering active-site architecture.\",\n      \"evidence\": \"X-ray crystallography of the zebrafish ortholog mutant, MD simulation, and kinase assay\",\n      \"pmids\": [\"29959184\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the human protein-substrate complex not solved\", \"How loss of activity produces the contractural developmental phenotype not mechanistically traced\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Proposed PKD1 phosphorylation of S448 as a regulatory input controlling focal adhesion dynamics, with downregulation in breast carcinoma.\",\n      \"evidence\": \"Phospho-specific IHC in normal versus carcinoma tissue; PKD1-substrate relationship cited from prior work\",\n      \"pmids\": [\"30555634\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Direct PKD1-mediated phosphorylation of S448 not demonstrated in this study\", \"Functional consequence of S448 phosphorylation on kinase activity not measured\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated a vesicle-tethering function in which Arf6-recruited PIP5K1C generates PI(4,5)P2 that is minimally sufficient to recruit the exocyst, mechanistically linking lipid synthesis to membrane fusion-site assembly.\",\n      \"evidence\": \"In vitro reconstitution of octameric exocyst, liposome tethering assays, and Arf6/PIP5K1C manipulation in epithelial cells\",\n      \"pmids\": [\"35609603\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Arf6 spatially restricts recruitment in vivo not detailed\", \"Coordination with cargo selection not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed PIP5K1C controls a mesenchymal lineage decision via Ca2+/CaMK signaling that stabilizes Runx2 to favor osteoblast over adipocyte fate and supports osteoclastogenesis through RANKL.\",\n      \"evidence\": \"Prx1-Cre conditional knockout mice with histomorphometry, micro-CT, Ca2+ flux, and CaMK/Runx2 western blots\",\n      \"pmids\": [\"35090892\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link from PI(4,5)P2 to the Ca2+ influx channel not defined\", \"Direct effect on RANKL transcription not mechanistically traced\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed PIP5K1C as a parallel PI(4,5)P2 source to PIKFYVE that sets cancer-cell sensitivity to PIKFYVE inhibition in lysosome/autophagy homeostasis.\",\n      \"evidence\": \"Knockdown/overexpression rescue with PIKFYVE inhibitor WX8, phosphoinositide mass spectrometry, and lysosome/autophagy assays\",\n      \"pmids\": [\"36803256\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Subcellular site of the relevant PI(4,5)P2 pool not defined\", \"Whether the two enzymes act on shared or distinct substrate pools unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a Hippo-regulatory role in which the PIP5Kγ90 isoform forms a Merlin-LATS1 complex requiring catalytic activity to phosphorylate and inhibit YAP, restraining YAP-driven colony formation.\",\n      \"evidence\": \"Reciprocal Co-IP, kinase-dead mutant analysis, splice-variant expression, YAP phosphorylation, and UNC3230 colony assays\",\n      \"pmids\": [\"37834234\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How PI(4,5)P2 production mechanistically activates LATS1 not resolved\", \"Role of the Hsc70 interaction not fully defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated PIP5K1C maintains chondrocyte adhesion via focal adhesion proteins, with loss promoting matrix degradation and spontaneous osteoarthritis-like lesions in aged mice.\",\n      \"evidence\": \"Inducible chondrocyte-specific knockout with histology, FA-protein western blots, and adhesion assays\",\n      \"pmids\": [\"37008048\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking PI(4,5)P2 to integrin β1 activation in chondrocytes not detailed\", \"Whether the adhesion defect is cell-autonomous in driving OA not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated PIP5K1C-dependent PI(4,5)P2 in ACE2-mediated SARS-CoV-2 endosomal entry.\",\n      \"evidence\": \"Dual inhibitor UNI418 treatment with viral entry and endocytosis assays\",\n      \"pmids\": [\"39085352\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Dual-specificity inhibitor cannot isolate PIP5K1C from PIKfyve\", \"No genetic loss-of-function validation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Indicated PIP5K1C activity opposes INPP5E-dependent phosphoinositide homeostasis required for ciliogenesis.\",\n      \"evidence\": \"PIP5K1C inhibition restoring ciliogenesis in TBC1D19-null cells (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single pharmacological experiment in a preprint, not independently confirmed\", \"PIP5K1C is a secondary finding in a TBC1D19-focused study\", \"No direct measurement of ciliary phosphoinositide changes attributable to PIP5K1C\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PIP5K1C activity, isoform choice, and subcellular targeting are integrated to generate distinct PI(4,5)P2 pools for each downstream process remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model of how post-translational modifications and recruitment factors select among phagocytic, migratory, exocytic, Hippo, and differentiation outputs\", \"Endogenous regulation of S448 phosphorylation and acetylation in tissue contexts undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 9]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 9, 12]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [9, 4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12, 6]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 10]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"complexes\": [\"Merlin-LATS1 complex\"],\n    \"partners\": [\"SIRT1\", \"Syk\", \"Arf6\", \"PKD1\", \"Merlin (NF2)\", \"LATS1\", \"Hsc70\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}