{"gene":"ITPKB","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2007,"finding":"Itpkb converts Ins(1,4,5)P3 to Ins(1,3,4,5)P4, and this product inhibits store-operated Ca2+ channels (SOCs) in B lymphocytes. Itpkb-deficient B cells showed enhanced SOC activity after BCR stimulation, which was reversed by exogenous Ins(1,3,4,5)P4, establishing ITPKB's enzymatic product as a direct inhibitor of SOC-mediated calcium entry and a regulator of B cell selection and activation.","method":"Itpkb knockout mice, BCR stimulation assays, exogenous Ins(1,3,4,5)P4 rescue experiments, immunological phenotyping","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic and pharmacological rescue in vivo and in vitro, multiple orthogonal methods, replicated across B cell developmental and functional assays","pmids":["17417640"],"is_preprint":false},{"year":2004,"finding":"The N-terminal non-catalytic domain of IP3K-B (amino acids 108–170) is a discrete actin-binding domain that binds specifically to F-actin but not G-actin. Helix-breaking mutations within this segment abolished F-actin binding both in vitro and in cells, demonstrating that intact secondary structure is required for actin targeting.","method":"Confocal microscopy of EGFP-fusion fragments, in vitro F-actin co-sedimentation with bacterially expressed GST-fusion protein, site-directed mutagenesis","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified protein, mutagenesis validation both in vitro and in cells, single lab but multiple orthogonal methods","pmids":["15130091"],"is_preprint":false},{"year":2010,"finding":"Human IP3KB shuttles between nucleus and cytoplasm via an exportin-1 (CRM1)-dependent nuclear export signal (NES: residues 134–143, LQRELQNVQV) and a nuclear localization signal (residues 129–132, RKLR). These two signals, together with the F-actin binding activity, reside within a single multitargeting domain (MTD, aa 104–165). IP3KB is also specifically enriched at nuclear envelope invaginations in rapidly growing cells, suggesting a role in nuclear Ca2+ signaling.","method":"Mutagenesis of NES/NLS sequences, exportin-1 inhibition (leptomycin B), confocal live-cell imaging, subcellular fractionation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus pharmacological inhibition plus direct imaging, single lab but multiple orthogonal methods","pmids":["21148483"],"is_preprint":false},{"year":2016,"finding":"Itpkb produces IP4, a soluble antagonist of the PI3K lipid product PIP3, thereby dampening pre-TCR-induced PI3K/Akt/mTOR signaling during β-selection. Itpkb-deficient thymocytes hyperactivate Akt and downstream mTOR and metabolism, enabling Notch-independent T cell development; this phenotype was reversed by pharmacological inhibition of Akt, mTOR, or glucose metabolism, establishing epistatic placement of Itpkb upstream of PI3K/Akt in thymocyte β-selection.","method":"Itpkb knockout mice, genetic epistasis with Akt/mTOR/glucose metabolism inhibitors, pre-TCR stimulation assays, metabolic activation readouts","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with pharmacological rescue across multiple downstream targets, multiple orthogonal readouts, mechanistically rigorous","pmids":["26880557"],"is_preprint":false},{"year":2015,"finding":"ITPKB, through its product IP4, inhibits the Orai1/Stim1 calcium channel in mature T lymphocytes. Conditional knockout or pharmacological inhibition of Itpkb in T cells elevates intracellular Ca2+, induces FasL and Bim expression, and causes T cell apoptosis. Itpkb deletion or inhibitors blocked T cell-dependent antibody responses and prevented T cell-driven arthritis in rats.","method":"Conditional Itpkb knockout mice, small-molecule Itpkb inhibitors, intracellular Ca2+ measurements, apoptosis assays (FasL/Bim induction), in vivo arthritis model","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional genetic deletion combined with pharmacological inhibition, in vitro and in vivo validation, multiple mechanistic readouts","pmids":["26121493"],"is_preprint":false},{"year":2016,"finding":"miR-132 directly represses ITPKB; loss of miR-132 leads to ITPKB upregulation, which in turn increases ERK1/2 and BACE1 activity and elevated TAU phosphorylation, exacerbating amyloid and TAU pathology in an AD mouse model.","method":"miR-132 knockout AD mouse model, ITPKB overexpression/knockdown, ERK1/2 and BACE1 activity assays, TAU phosphorylation measurements, validation in human AD patient cohorts","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in vivo with defined molecular pathway readouts, single lab, confirmed in human cohorts but mechanistic link is correlative at the ERK/BACE1 step","pmids":["27485122"],"is_preprint":false},{"year":2021,"finding":"ITPKB inhibits ER-to-mitochondria calcium transfer by inactivating IP3. Knockdown or pharmacological inhibition of ITPKB in neurons increases intracellular Ca2+, causes mitochondrial calcium accumulation, increases mitochondrial respiration, and inhibits autophagy initiation, leading to increased phosphorylated insoluble α-synuclein pathology. Conversely, ITPKB overexpression reduced α-synuclein aggregation. Pretreatment with mitochondrial calcium uniporter (MCU) complex inhibitors prevented the mitochondrial calcium and respiration effects and reduced α-synuclein pathology.","method":"ITPKB knockdown/overexpression in primary neurons, pharmacological ITPKB inhibition, α-synuclein preformed fibril (PFF) treatment, mitochondrial calcium measurements, MCU complex inhibitors, autophagy assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal genetic and pharmacological interventions with rescue experiments, defined mechanistic pathway from ITPKB to IP3/Ca2+/mitochondria/autophagy/α-synuclein","pmids":["33443159"],"is_preprint":false},{"year":2022,"finding":"CAMK2G directly phosphorylates ITPKB at serine 174 in response to ROS (both basal and cisplatin-induced), and this phosphorylation directly regulates ITPKB enzymatic activity to modulate ROS homeostasis and drive cisplatin resistance in ovarian cancer cells.","method":"Kinase inhibitor screen, pharmacological CAMK2G inhibition, in vitro kinase assay, phospho-specific antibody for ITPKB pS174, cisplatin sensitivity assays in vitro and in vivo xenograft models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct kinase-substrate relationship established with in vitro kinase assay and phospho-site specific antibody, validated in vivo, single lab but multiple orthogonal methods","pmids":["35039634"],"is_preprint":false},{"year":2024,"finding":"The E3 ubiquitin ligase Trim25 ubiquitinates ITPKB to promote its degradation; decreased phosphorylation of Trim25 at S100 in recurrent GBM reduces ITPKB ubiquitination, elevating ITPKB protein stability. Elevated ITPKB impairs NOX-dependent ROS production, conferring TMZ resistance.","method":"Mass spectrometry proteomics, glioma tissue arrays, Trim25 phosphorylation analysis, ubiquitination assays, ITPKB depletion in TMZ-resistant cells, ROS/NOX activity assays, xenograft mouse model with GNF362 (ITPKB inhibitor)","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay and in vivo xenograft validation, single lab, mechanism partially established through pharmacological and genetic approaches","pmids":["38438346"],"is_preprint":false},{"year":2015,"finding":"Overexpression of Itpkb inhibits NGF-induced neurite outgrowth in PC12 cells through two mechanisms: F-actin binding (N-terminal domain) and localized Ins(1,4,5)P3 3-kinase catalytic activity. Kinase-dead Itpkb mutants reduced neurite length less than wild-type, confirming a contribution of catalytic activity in addition to actin binding.","method":"PC12 cell overexpression, GFP-tagged wild-type and kinase-dead Itpkb mutants, NGF-induced neurite outgrowth assays, quantitative neurite length measurements","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — overexpression and kinase-dead mutagenesis in a cell model, single lab, two orthogonal mechanistic contributions identified","pmids":["25892505"],"is_preprint":false},{"year":2018,"finding":"ITPKB bundles F-actin in cell-free systems; however, stable expression of ITPKB in H1299 lung cancer cells did not significantly affect actin structure. ITPKB negatively controls transmigration of H1299 cells in vitro by blocking Ins(1,4,5)P3-mediated calcium release. Colony formation was stimulated by ITPKB independent of Ins(1,4,5)P3-mediated calcium signals. ITPKB expression did not suppress dissemination of H1299 cells in NOD scid gamma mice (negative result for tumor suppressor activity in vivo).","method":"Cell-free F-actin bundling assay, stable ITPKB expression in H1299 cells, transmigration assays, colony formation assays, intracellular calcium measurements, in vivo mouse dissemination model","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vitro and in vivo assays in single lab; includes both positive (Ca2+-dependent transmigration control) and negative (no actin structure effect, no in vivo suppression) findings","pmids":["29871874"],"is_preprint":false},{"year":2019,"finding":"miR-711 targets and inhibits Itpkb; Itpkb inhibition represses Tau phosphorylation and increases the M2/M1 microglia ratio. Microglia-derived extracellular vesicles carrying miR-711 delivered this suppression of Itpkb to reduce neurodegeneration in an AD mouse model.","method":"miR-711 overexpression in BV2 microglia, EV isolation and injection in rmTBI mice, Tau phosphorylation assays, microglia phenotype analysis, neurological/cognitive function tests","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional miRNA-target validation and downstream pathway readout in vivo, single lab, mechanism of Itpkb to Tau phosphorylation inferred through overexpression/knockdown","pmids":["33240878"],"is_preprint":false},{"year":2019,"finding":"Loss of ITPKB prevents ubiquitination-mediated degradation of PARP1, leading to PARP1 stabilization. Stabilized PARP1 acts as a transcriptional co-activator for NF-κB, triggering IL-8 secretion, which recruits neutrophils and induces neutrophil extracellular trap (NET) formation, facilitating tumor cell migration and therapy resistance in ccRCC.","method":"Dual-luciferase reporter assay (miR-301b-3p targeting ITPKB), ITPKB loss-of-function, PARP1 ubiquitination assays, NF-κB transcription assays, IL-8 ELISA, in vivo NET disruption with DNase1","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mechanistic assays in single lab with in vivo validation; ITPKB-PARP1 ubiquitination link is novel and supported by multiple methods","pmids":["41611162"],"is_preprint":false}],"current_model":"ITPKB is an inositol 1,4,5-trisphosphate (IP3) 3-kinase that phosphorylates IP3 to produce IP4, thereby reducing IP3 availability for ER calcium release and directly inhibiting store-operated calcium channels (Orai1/Stim1); IP4 also acts as a soluble antagonist of PI3K-generated PIP3 to dampen Akt/mTOR signaling in lymphocytes; the protein localizes to F-actin via an N-terminal actin-binding domain (aa 108–170) and shuttles between nucleus and cytoplasm through an exportin-1-dependent NES and NLS within a single multitargeting domain; ITPKB is phosphorylated and activated by CAMK2G at S174 in response to ROS, and is ubiquitinated by Trim25 for proteasomal degradation; by controlling ER-to-mitochondria calcium flux, ITPKB suppresses mitochondrial calcium overload and preserves autophagy to limit α-synuclein aggregation in neurons; loss of ITPKB also stabilizes PARP1, activating NF-κB/IL-8 signaling and promoting neutrophil extracellular trap formation."},"narrative":{"mechanistic_narrative":"ITPKB is an inositol 1,4,5-trisphosphate (IP3) 3-kinase that converts IP3 to IP4, positioning it as a central regulator of cellular calcium signaling and downstream lipid-signaling pathways [PMID:17417640]. By depleting IP3, ITPKB limits ER calcium release, and its product IP4 directly inhibits store-operated calcium entry through the Orai1/Stim1 channel in lymphocytes [PMID:17417640, PMID:26121493]; IP4 also acts as a soluble antagonist of the PI3K product PIP3, restraining Akt/mTOR signaling and metabolic activation during thymocyte development [PMID:26880557]. Through this calcium-restraining activity ITPKB regulates immune cell selection, activation, and survival, with its loss elevating intracellular calcium to drive FasL/Bim-dependent T cell apoptosis [PMID:26121493]. Beyond catalysis, ITPKB carries an N-terminal F-actin-binding domain (aa 108–170) that binds F-actin but not G-actin and requires intact secondary structure [PMID:15130091], and this domain coincides with a single multitargeting region (aa 104–165) housing an exportin-1-dependent NES and an NLS that mediate nucleocytoplasmic shuttling and nuclear envelope enrichment [PMID:21148483]. In neurons, ITPKB inactivates IP3 to suppress ER-to-mitochondria calcium transfer, preventing mitochondrial calcium overload and preserving autophagy initiation to limit α-synuclein aggregation [PMID:33443159]. ITPKB activity and abundance are themselves regulated: CAMK2G directly phosphorylates ITPKB at Ser174 in response to ROS to modulate its enzymatic activity and ROS homeostasis [PMID:35039634], and the E3 ligase Trim25 ubiquitinates ITPKB to drive its proteasomal degradation [PMID:38438346].","teleology":[{"year":2004,"claim":"Established that ITPKB is not solely a soluble enzyme but is targeted to the cytoskeleton, defining a discrete N-terminal F-actin-binding module distinct from its catalytic domain.","evidence":"Confocal imaging of EGFP fragments, in vitro F-actin co-sedimentation with GST fusions, and helix-breaking mutagenesis","pmids":["15130091"],"confidence":"High","gaps":["Functional consequence of actin binding for IP3 phosphorylation not resolved","No structure of the actin-bound complex"]},{"year":2007,"claim":"Answered how ITPKB controls calcium entry by showing its enzymatic product IP4 directly inhibits store-operated calcium channels, linking ITPKB to B cell selection and activation.","evidence":"Itpkb knockout mice with BCR stimulation and exogenous IP4 rescue","pmids":["17417640"],"confidence":"High","gaps":["Direct molecular target of IP4 on the SOC complex not identified at this stage","Channel subunit interaction not structurally defined"]},{"year":2010,"claim":"Showed ITPKB shuttles between nucleus and cytoplasm via an exportin-1-dependent NES and an adjacent NLS that overlap the actin-binding domain, defining a single multitargeting domain and implicating nuclear calcium signaling.","evidence":"NES/NLS mutagenesis, leptomycin B inhibition, live-cell imaging, and subcellular fractionation","pmids":["21148483"],"confidence":"High","gaps":["Functional role of nuclear envelope enrichment not established","Signals governing shuttling dynamics unknown"]},{"year":2015,"claim":"Extended ITPKB's calcium-channel control to mature T cells and demonstrated that its loss triggers calcium-driven apoptosis, validating ITPKB as an immunomodulatory drug target.","evidence":"Conditional Itpkb knockout, small-molecule inhibitors, calcium and apoptosis assays, in vivo arthritis model","pmids":["26121493"],"confidence":"High","gaps":["Cell-type specificity of the apoptotic threshold not delineated"]},{"year":2015,"claim":"Dissected the dual mechanism by which ITPKB restrains neurite outgrowth, separating contributions of F-actin binding from catalytic activity.","evidence":"PC12 overexpression of wild-type versus kinase-dead Itpkb with neurite length quantification","pmids":["25892505"],"confidence":"Medium","gaps":["Overexpression model may not reflect endogenous stoichiometry","Relative weighting of the two mechanisms in vivo unclear"]},{"year":2016,"claim":"Placed ITPKB epistatically upstream of PI3K/Akt by showing IP4 antagonizes PIP3 to dampen Akt/mTOR signaling during β-selection, connecting calcium-pathway enzymology to lymphocyte metabolism.","evidence":"Itpkb knockout thymocytes with genetic epistasis against Akt/mTOR/glucose-metabolism inhibitors","pmids":["26880557"],"confidence":"High","gaps":["Direct biophysical IP4–PIP3 competition at effectors not measured here"]},{"year":2016,"claim":"Identified ITPKB as a target of miR-132 whose derepression drives ERK1/2, BACE1, and TAU phosphorylation, linking ITPKB dosage to Alzheimer-type pathology.","evidence":"miR-132 knockout AD mouse model, ITPKB perturbation, ERK/BACE1 activity and TAU readouts, human cohort validation","pmids":["27485122"],"confidence":"Medium","gaps":["Link from ITPKB to ERK/BACE1 is correlative","Mechanism connecting IP4 to BACE1 activity undefined"]},{"year":2019,"claim":"Showed microglial miR-711 suppression of Itpkb reduces Tau phosphorylation and shifts microglia toward an M2 phenotype, demonstrating an extracellular-vesicle-deliverable route to modulate ITPKB in neurodegeneration.","evidence":"miR-711 overexpression in BV2 microglia, EV injection in rmTBI mice, Tau and microglial phenotype readouts","pmids":["33240878"],"confidence":"Medium","gaps":["Direct mechanism from Itpkb to Tau phosphorylation inferred from knockdown","Microglia-to-neuron signaling step not fully resolved"]},{"year":2019,"claim":"Uncovered a non-canonical role in which ITPKB loss stabilizes PARP1 to co-activate NF-κB, driving IL-8 secretion and neutrophil extracellular trap formation in renal cancer.","evidence":"Luciferase reporters, PARP1 ubiquitination assays, NF-κB and IL-8 readouts, in vivo NET disruption with DNase1","pmids":["41611162"],"confidence":"Medium","gaps":["Mechanism by which ITPKB promotes PARP1 ubiquitination not defined","Whether this is catalytic-activity dependent unknown"]},{"year":2018,"claim":"Tested ITPKB's tumor-relevant functions, confirming Ca2+-dependent control of transmigration while showing actin bundling does not alter cellular actin structure and ITPKB does not suppress dissemination in vivo.","evidence":"Cell-free actin bundling, stable ITPKB expression in H1299 cells, transmigration/colony assays, in vivo dissemination model","pmids":["29871874"],"confidence":"Medium","gaps":["Discrepancy between in vitro actin bundling and lack of cellular actin effect unexplained","Negative in vivo result limits tumor-suppressor interpretation"]},{"year":2021,"claim":"Established ITPKB as a guardian against mitochondrial calcium overload, showing it inactivates IP3 to limit ER-to-mitochondria calcium transfer, preserve autophagy, and suppress α-synuclein aggregation.","evidence":"ITPKB knockdown/overexpression in primary neurons, PFF treatment, mitochondrial calcium and autophagy assays, MCU inhibitor rescue","pmids":["33443159"],"confidence":"High","gaps":["Spatial coupling of ITPKB to ER-mitochondria contact sites not defined","Step linking autophagy block to α-synuclein accumulation incompletely mapped"]},{"year":2022,"claim":"Identified the first direct upstream regulator of ITPKB activity, showing CAMK2G phosphorylates ITPKB at Ser174 in response to ROS to modulate ROS homeostasis and cisplatin resistance.","evidence":"Kinase inhibitor screen, in vitro kinase assay, phospho-S174-specific antibody, cisplatin sensitivity in vitro and in xenografts","pmids":["35039634"],"confidence":"High","gaps":["Structural basis of how S174 phosphorylation alters catalysis unknown","Whether other kinases target this site not addressed"]},{"year":2024,"claim":"Defined how ITPKB protein levels are controlled, showing Trim25-mediated ubiquitination drives ITPKB degradation and that reduced Trim25 activity stabilizes ITPKB to impair NOX-dependent ROS and confer temozolomide resistance.","evidence":"Mass spectrometry, ubiquitination assays, Trim25 phosphorylation analysis, ITPKB depletion, ROS/NOX assays, xenografts with ITPKB inhibitor","pmids":["38438346"],"confidence":"Medium","gaps":["Ubiquitination site on ITPKB not mapped","Direct vs indirect Trim25–ITPKB interaction not fully validated"]},{"year":null,"claim":"How ITPKB integrates its catalytic, actin-binding, and nucleocytoplasmic-shuttling activities into a single spatially regulated calcium-control function across immune, neuronal, and cancer contexts remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure linking the multitargeting domain to catalytic regulation","Unclear whether disease phenotypes depend on catalysis, actin binding, or both","Spatial determinants of IP4 antagonism of PIP3 versus SOC inhibition not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,3,6,9]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[7]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,4]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,3,4]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6]}],"complexes":[],"partners":["CAMK2G","TRIM25","F-ACTIN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P27987","full_name":"Inositol-trisphosphate 3-kinase B","aliases":["Inositol 1,4,5-trisphosphate 3-kinase B","IP3 3-kinase B","IP3K B","InsP 3-kinase B"],"length_aa":946,"mass_kda":102.4,"function":"Catalyzes the phosphorylation of 1D-myo-inositol 1,4,5-trisphosphate (InsP3) into 1D-myo-inositol 1,3,4,5-tetrakisphosphate and participates to the regulation of calcium homeostasis","subcellular_location":"Cytoplasm, cytoskeleton; Cytoplasm; Endoplasmic reticulum","url":"https://www.uniprot.org/uniprotkb/P27987/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ITPKB","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ITPKB","total_profiled":1310},"omim":[{"mim_id":"606992","title":"INOSITOL HEXAPHOSPHATE KINASE 2; IP6K2","url":"https://www.omim.org/entry/606992"},{"mim_id":"606476","title":"INOSITOL 1,4,5-TRISPHOSPHATE 3-KINASE C; ITPKC","url":"https://www.omim.org/entry/606476"},{"mim_id":"147522","title":"INOSITOL 1,4,5-TRISPHOSPHATE 3-KINASE B; ITPKB","url":"https://www.omim.org/entry/147522"},{"mim_id":"147521","title":"INOSITOL 1,4,5-TRISPHOSPHATE 3-KINASE A; ITPKA","url":"https://www.omim.org/entry/147521"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":98.8},{"tissue":"choroid plexus","ntpm":90.2}],"url":"https://www.proteinatlas.org/search/ITPKB"},"hgnc":{"alias_symbol":["IP3KB","IP3-3KB"],"prev_symbol":[]},"alphafold":{"accession":"P27987","domains":[{"cath_id":"3.30.470.160","chopping":"673-749_811-942","consensus_level":"medium","plddt":94.0829,"start":673,"end":942},{"cath_id":"-","chopping":"755-809","consensus_level":"medium","plddt":90.5891,"start":755,"end":809}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P27987","model_url":"https://alphafold.ebi.ac.uk/files/AF-P27987-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P27987-F1-predicted_aligned_error_v6.png","plddt_mean":55.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ITPKB","jax_strain_url":"https://www.jax.org/strain/search?query=ITPKB"},"sequence":{"accession":"P27987","fasta_url":"https://rest.uniprot.org/uniprotkb/P27987.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P27987/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P27987"}},"corpus_meta":[{"pmid":"27485122","id":"PMC_27485122","title":"miR-132 loss de-represses ITPKB and aggravates amyloid and TAU pathology in Alzheimer's brain.","date":"2016","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27485122","citation_count":138,"is_preprint":false},{"pmid":"17417640","id":"PMC_17417640","title":"Production of Ins(1,3,4,5)P4 mediated by the kinase Itpkb inhibits store-operated calcium channels and regulates B cell selection and activation.","date":"2007","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17417640","citation_count":71,"is_preprint":false},{"pmid":"33443159","id":"PMC_33443159","title":"The Parkinson's disease-associated gene ITPKB protects against α-synuclein aggregation by regulating ER-to-mitochondria calcium release.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/33443159","citation_count":52,"is_preprint":false},{"pmid":"38438346","id":"PMC_38438346","title":"Suppression of ITPKB degradation by Trim25 confers TMZ resistance in glioblastoma through ROS homeostasis.","date":"2024","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/38438346","citation_count":39,"is_preprint":false},{"pmid":"33240878","id":"PMC_33240878","title":"Microglia-Derived Extracellular Vesicles Carrying miR-711 Alleviate Neurodegeneration in a Murine Alzheimer's Disease Model by Binding to Itpkb.","date":"2020","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/33240878","citation_count":33,"is_preprint":false},{"pmid":"21148483","id":"PMC_21148483","title":"Human inositol 1,4,5-trisphosphate 3-kinase isoform B (IP3KB) is a nucleocytoplasmic shuttling protein specifically enriched at cortical actin filaments and at invaginations of the nuclear envelope.","date":"2010","source":"The Journal of biological 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Itpkb-deficient B cells showed enhanced SOC activity after BCR stimulation, which was reversed by exogenous Ins(1,3,4,5)P4, establishing ITPKB's enzymatic product as a direct inhibitor of SOC-mediated calcium entry and a regulator of B cell selection and activation.\",\n      \"method\": \"Itpkb knockout mice, BCR stimulation assays, exogenous Ins(1,3,4,5)P4 rescue experiments, immunological phenotyping\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic and pharmacological rescue in vivo and in vitro, multiple orthogonal methods, replicated across B cell developmental and functional assays\",\n      \"pmids\": [\"17417640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The N-terminal non-catalytic domain of IP3K-B (amino acids 108–170) is a discrete actin-binding domain that binds specifically to F-actin but not G-actin. Helix-breaking mutations within this segment abolished F-actin binding both in vitro and in cells, demonstrating that intact secondary structure is required for actin targeting.\",\n      \"method\": \"Confocal microscopy of EGFP-fusion fragments, in vitro F-actin co-sedimentation with bacterially expressed GST-fusion protein, site-directed mutagenesis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified protein, mutagenesis validation both in vitro and in cells, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"15130091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Human IP3KB shuttles between nucleus and cytoplasm via an exportin-1 (CRM1)-dependent nuclear export signal (NES: residues 134–143, LQRELQNVQV) and a nuclear localization signal (residues 129–132, RKLR). These two signals, together with the F-actin binding activity, reside within a single multitargeting domain (MTD, aa 104–165). IP3KB is also specifically enriched at nuclear envelope invaginations in rapidly growing cells, suggesting a role in nuclear Ca2+ signaling.\",\n      \"method\": \"Mutagenesis of NES/NLS sequences, exportin-1 inhibition (leptomycin B), confocal live-cell imaging, subcellular fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus pharmacological inhibition plus direct imaging, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"21148483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Itpkb produces IP4, a soluble antagonist of the PI3K lipid product PIP3, thereby dampening pre-TCR-induced PI3K/Akt/mTOR signaling during β-selection. Itpkb-deficient thymocytes hyperactivate Akt and downstream mTOR and metabolism, enabling Notch-independent T cell development; this phenotype was reversed by pharmacological inhibition of Akt, mTOR, or glucose metabolism, establishing epistatic placement of Itpkb upstream of PI3K/Akt in thymocyte β-selection.\",\n      \"method\": \"Itpkb knockout mice, genetic epistasis with Akt/mTOR/glucose metabolism inhibitors, pre-TCR stimulation assays, metabolic activation readouts\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with pharmacological rescue across multiple downstream targets, multiple orthogonal readouts, mechanistically rigorous\",\n      \"pmids\": [\"26880557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ITPKB, through its product IP4, inhibits the Orai1/Stim1 calcium channel in mature T lymphocytes. Conditional knockout or pharmacological inhibition of Itpkb in T cells elevates intracellular Ca2+, induces FasL and Bim expression, and causes T cell apoptosis. Itpkb deletion or inhibitors blocked T cell-dependent antibody responses and prevented T cell-driven arthritis in rats.\",\n      \"method\": \"Conditional Itpkb knockout mice, small-molecule Itpkb inhibitors, intracellular Ca2+ measurements, apoptosis assays (FasL/Bim induction), in vivo arthritis model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional genetic deletion combined with pharmacological inhibition, in vitro and in vivo validation, multiple mechanistic readouts\",\n      \"pmids\": [\"26121493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-132 directly represses ITPKB; loss of miR-132 leads to ITPKB upregulation, which in turn increases ERK1/2 and BACE1 activity and elevated TAU phosphorylation, exacerbating amyloid and TAU pathology in an AD mouse model.\",\n      \"method\": \"miR-132 knockout AD mouse model, ITPKB overexpression/knockdown, ERK1/2 and BACE1 activity assays, TAU phosphorylation measurements, validation in human AD patient cohorts\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in vivo with defined molecular pathway readouts, single lab, confirmed in human cohorts but mechanistic link is correlative at the ERK/BACE1 step\",\n      \"pmids\": [\"27485122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ITPKB inhibits ER-to-mitochondria calcium transfer by inactivating IP3. Knockdown or pharmacological inhibition of ITPKB in neurons increases intracellular Ca2+, causes mitochondrial calcium accumulation, increases mitochondrial respiration, and inhibits autophagy initiation, leading to increased phosphorylated insoluble α-synuclein pathology. Conversely, ITPKB overexpression reduced α-synuclein aggregation. Pretreatment with mitochondrial calcium uniporter (MCU) complex inhibitors prevented the mitochondrial calcium and respiration effects and reduced α-synuclein pathology.\",\n      \"method\": \"ITPKB knockdown/overexpression in primary neurons, pharmacological ITPKB inhibition, α-synuclein preformed fibril (PFF) treatment, mitochondrial calcium measurements, MCU complex inhibitors, autophagy assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal genetic and pharmacological interventions with rescue experiments, defined mechanistic pathway from ITPKB to IP3/Ca2+/mitochondria/autophagy/α-synuclein\",\n      \"pmids\": [\"33443159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CAMK2G directly phosphorylates ITPKB at serine 174 in response to ROS (both basal and cisplatin-induced), and this phosphorylation directly regulates ITPKB enzymatic activity to modulate ROS homeostasis and drive cisplatin resistance in ovarian cancer cells.\",\n      \"method\": \"Kinase inhibitor screen, pharmacological CAMK2G inhibition, in vitro kinase assay, phospho-specific antibody for ITPKB pS174, cisplatin sensitivity assays in vitro and in vivo xenograft models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct kinase-substrate relationship established with in vitro kinase assay and phospho-site specific antibody, validated in vivo, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"35039634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The E3 ubiquitin ligase Trim25 ubiquitinates ITPKB to promote its degradation; decreased phosphorylation of Trim25 at S100 in recurrent GBM reduces ITPKB ubiquitination, elevating ITPKB protein stability. Elevated ITPKB impairs NOX-dependent ROS production, conferring TMZ resistance.\",\n      \"method\": \"Mass spectrometry proteomics, glioma tissue arrays, Trim25 phosphorylation analysis, ubiquitination assays, ITPKB depletion in TMZ-resistant cells, ROS/NOX activity assays, xenograft mouse model with GNF362 (ITPKB inhibitor)\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay and in vivo xenograft validation, single lab, mechanism partially established through pharmacological and genetic approaches\",\n      \"pmids\": [\"38438346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Overexpression of Itpkb inhibits NGF-induced neurite outgrowth in PC12 cells through two mechanisms: F-actin binding (N-terminal domain) and localized Ins(1,4,5)P3 3-kinase catalytic activity. Kinase-dead Itpkb mutants reduced neurite length less than wild-type, confirming a contribution of catalytic activity in addition to actin binding.\",\n      \"method\": \"PC12 cell overexpression, GFP-tagged wild-type and kinase-dead Itpkb mutants, NGF-induced neurite outgrowth assays, quantitative neurite length measurements\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — overexpression and kinase-dead mutagenesis in a cell model, single lab, two orthogonal mechanistic contributions identified\",\n      \"pmids\": [\"25892505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ITPKB bundles F-actin in cell-free systems; however, stable expression of ITPKB in H1299 lung cancer cells did not significantly affect actin structure. ITPKB negatively controls transmigration of H1299 cells in vitro by blocking Ins(1,4,5)P3-mediated calcium release. Colony formation was stimulated by ITPKB independent of Ins(1,4,5)P3-mediated calcium signals. ITPKB expression did not suppress dissemination of H1299 cells in NOD scid gamma mice (negative result for tumor suppressor activity in vivo).\",\n      \"method\": \"Cell-free F-actin bundling assay, stable ITPKB expression in H1299 cells, transmigration assays, colony formation assays, intracellular calcium measurements, in vivo mouse dissemination model\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vitro and in vivo assays in single lab; includes both positive (Ca2+-dependent transmigration control) and negative (no actin structure effect, no in vivo suppression) findings\",\n      \"pmids\": [\"29871874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-711 targets and inhibits Itpkb; Itpkb inhibition represses Tau phosphorylation and increases the M2/M1 microglia ratio. Microglia-derived extracellular vesicles carrying miR-711 delivered this suppression of Itpkb to reduce neurodegeneration in an AD mouse model.\",\n      \"method\": \"miR-711 overexpression in BV2 microglia, EV isolation and injection in rmTBI mice, Tau phosphorylation assays, microglia phenotype analysis, neurological/cognitive function tests\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional miRNA-target validation and downstream pathway readout in vivo, single lab, mechanism of Itpkb to Tau phosphorylation inferred through overexpression/knockdown\",\n      \"pmids\": [\"33240878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Loss of ITPKB prevents ubiquitination-mediated degradation of PARP1, leading to PARP1 stabilization. Stabilized PARP1 acts as a transcriptional co-activator for NF-κB, triggering IL-8 secretion, which recruits neutrophils and induces neutrophil extracellular trap (NET) formation, facilitating tumor cell migration and therapy resistance in ccRCC.\",\n      \"method\": \"Dual-luciferase reporter assay (miR-301b-3p targeting ITPKB), ITPKB loss-of-function, PARP1 ubiquitination assays, NF-κB transcription assays, IL-8 ELISA, in vivo NET disruption with DNase1\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mechanistic assays in single lab with in vivo validation; ITPKB-PARP1 ubiquitination link is novel and supported by multiple methods\",\n      \"pmids\": [\"41611162\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ITPKB is an inositol 1,4,5-trisphosphate (IP3) 3-kinase that phosphorylates IP3 to produce IP4, thereby reducing IP3 availability for ER calcium release and directly inhibiting store-operated calcium channels (Orai1/Stim1); IP4 also acts as a soluble antagonist of PI3K-generated PIP3 to dampen Akt/mTOR signaling in lymphocytes; the protein localizes to F-actin via an N-terminal actin-binding domain (aa 108–170) and shuttles between nucleus and cytoplasm through an exportin-1-dependent NES and NLS within a single multitargeting domain; ITPKB is phosphorylated and activated by CAMK2G at S174 in response to ROS, and is ubiquitinated by Trim25 for proteasomal degradation; by controlling ER-to-mitochondria calcium flux, ITPKB suppresses mitochondrial calcium overload and preserves autophagy to limit α-synuclein aggregation in neurons; loss of ITPKB also stabilizes PARP1, activating NF-κB/IL-8 signaling and promoting neutrophil extracellular trap formation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ITPKB is an inositol 1,4,5-trisphosphate (IP3) 3-kinase that converts IP3 to IP4, positioning it as a central regulator of cellular calcium signaling and downstream lipid-signaling pathways [#0]. By depleting IP3, ITPKB limits ER calcium release, and its product IP4 directly inhibits store-operated calcium entry through the Orai1/Stim1 channel in lymphocytes [#0, #4]; IP4 also acts as a soluble antagonist of the PI3K product PIP3, restraining Akt/mTOR signaling and metabolic activation during thymocyte development [#3]. Through this calcium-restraining activity ITPKB regulates immune cell selection, activation, and survival, with its loss elevating intracellular calcium to drive FasL/Bim-dependent T cell apoptosis [#4]. Beyond catalysis, ITPKB carries an N-terminal F-actin-binding domain (aa 108–170) that binds F-actin but not G-actin and requires intact secondary structure [#1], and this domain coincides with a single multitargeting region (aa 104–165) housing an exportin-1-dependent NES and an NLS that mediate nucleocytoplasmic shuttling and nuclear envelope enrichment [#2]. In neurons, ITPKB inactivates IP3 to suppress ER-to-mitochondria calcium transfer, preventing mitochondrial calcium overload and preserving autophagy initiation to limit α-synuclein aggregation [#6]. ITPKB activity and abundance are themselves regulated: CAMK2G directly phosphorylates ITPKB at Ser174 in response to ROS to modulate its enzymatic activity and ROS homeostasis [#7], and the E3 ligase Trim25 ubiquitinates ITPKB to drive its proteasomal degradation [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that ITPKB is not solely a soluble enzyme but is targeted to the cytoskeleton, defining a discrete N-terminal F-actin-binding module distinct from its catalytic domain.\",\n      \"evidence\": \"Confocal imaging of EGFP fragments, in vitro F-actin co-sedimentation with GST fusions, and helix-breaking mutagenesis\",\n      \"pmids\": [\"15130091\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of actin binding for IP3 phosphorylation not resolved\", \"No structure of the actin-bound complex\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Answered how ITPKB controls calcium entry by showing its enzymatic product IP4 directly inhibits store-operated calcium channels, linking ITPKB to B cell selection and activation.\",\n      \"evidence\": \"Itpkb knockout mice with BCR stimulation and exogenous IP4 rescue\",\n      \"pmids\": [\"17417640\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular target of IP4 on the SOC complex not identified at this stage\", \"Channel subunit interaction not structurally defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed ITPKB shuttles between nucleus and cytoplasm via an exportin-1-dependent NES and an adjacent NLS that overlap the actin-binding domain, defining a single multitargeting domain and implicating nuclear calcium signaling.\",\n      \"evidence\": \"NES/NLS mutagenesis, leptomycin B inhibition, live-cell imaging, and subcellular fractionation\",\n      \"pmids\": [\"21148483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of nuclear envelope enrichment not established\", \"Signals governing shuttling dynamics unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended ITPKB's calcium-channel control to mature T cells and demonstrated that its loss triggers calcium-driven apoptosis, validating ITPKB as an immunomodulatory drug target.\",\n      \"evidence\": \"Conditional Itpkb knockout, small-molecule inhibitors, calcium and apoptosis assays, in vivo arthritis model\",\n      \"pmids\": [\"26121493\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type specificity of the apoptotic threshold not delineated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Dissected the dual mechanism by which ITPKB restrains neurite outgrowth, separating contributions of F-actin binding from catalytic activity.\",\n      \"evidence\": \"PC12 overexpression of wild-type versus kinase-dead Itpkb with neurite length quantification\",\n      \"pmids\": [\"25892505\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression model may not reflect endogenous stoichiometry\", \"Relative weighting of the two mechanisms in vivo unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed ITPKB epistatically upstream of PI3K/Akt by showing IP4 antagonizes PIP3 to dampen Akt/mTOR signaling during β-selection, connecting calcium-pathway enzymology to lymphocyte metabolism.\",\n      \"evidence\": \"Itpkb knockout thymocytes with genetic epistasis against Akt/mTOR/glucose-metabolism inhibitors\",\n      \"pmids\": [\"26880557\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biophysical IP4–PIP3 competition at effectors not measured here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified ITPKB as a target of miR-132 whose derepression drives ERK1/2, BACE1, and TAU phosphorylation, linking ITPKB dosage to Alzheimer-type pathology.\",\n      \"evidence\": \"miR-132 knockout AD mouse model, ITPKB perturbation, ERK/BACE1 activity and TAU readouts, human cohort validation\",\n      \"pmids\": [\"27485122\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link from ITPKB to ERK/BACE1 is correlative\", \"Mechanism connecting IP4 to BACE1 activity undefined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed microglial miR-711 suppression of Itpkb reduces Tau phosphorylation and shifts microglia toward an M2 phenotype, demonstrating an extracellular-vesicle-deliverable route to modulate ITPKB in neurodegeneration.\",\n      \"evidence\": \"miR-711 overexpression in BV2 microglia, EV injection in rmTBI mice, Tau and microglial phenotype readouts\",\n      \"pmids\": [\"33240878\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism from Itpkb to Tau phosphorylation inferred from knockdown\", \"Microglia-to-neuron signaling step not fully resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Uncovered a non-canonical role in which ITPKB loss stabilizes PARP1 to co-activate NF-κB, driving IL-8 secretion and neutrophil extracellular trap formation in renal cancer.\",\n      \"evidence\": \"Luciferase reporters, PARP1 ubiquitination assays, NF-κB and IL-8 readouts, in vivo NET disruption with DNase1\",\n      \"pmids\": [\"41611162\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ITPKB promotes PARP1 ubiquitination not defined\", \"Whether this is catalytic-activity dependent unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Tested ITPKB's tumor-relevant functions, confirming Ca2+-dependent control of transmigration while showing actin bundling does not alter cellular actin structure and ITPKB does not suppress dissemination in vivo.\",\n      \"evidence\": \"Cell-free actin bundling, stable ITPKB expression in H1299 cells, transmigration/colony assays, in vivo dissemination model\",\n      \"pmids\": [\"29871874\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Discrepancy between in vitro actin bundling and lack of cellular actin effect unexplained\", \"Negative in vivo result limits tumor-suppressor interpretation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established ITPKB as a guardian against mitochondrial calcium overload, showing it inactivates IP3 to limit ER-to-mitochondria calcium transfer, preserve autophagy, and suppress α-synuclein aggregation.\",\n      \"evidence\": \"ITPKB knockdown/overexpression in primary neurons, PFF treatment, mitochondrial calcium and autophagy assays, MCU inhibitor rescue\",\n      \"pmids\": [\"33443159\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spatial coupling of ITPKB to ER-mitochondria contact sites not defined\", \"Step linking autophagy block to α-synuclein accumulation incompletely mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified the first direct upstream regulator of ITPKB activity, showing CAMK2G phosphorylates ITPKB at Ser174 in response to ROS to modulate ROS homeostasis and cisplatin resistance.\",\n      \"evidence\": \"Kinase inhibitor screen, in vitro kinase assay, phospho-S174-specific antibody, cisplatin sensitivity in vitro and in xenografts\",\n      \"pmids\": [\"35039634\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of how S174 phosphorylation alters catalysis unknown\", \"Whether other kinases target this site not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined how ITPKB protein levels are controlled, showing Trim25-mediated ubiquitination drives ITPKB degradation and that reduced Trim25 activity stabilizes ITPKB to impair NOX-dependent ROS and confer temozolomide resistance.\",\n      \"evidence\": \"Mass spectrometry, ubiquitination assays, Trim25 phosphorylation analysis, ITPKB depletion, ROS/NOX assays, xenografts with ITPKB inhibitor\",\n      \"pmids\": [\"38438346\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination site on ITPKB not mapped\", \"Direct vs indirect Trim25–ITPKB interaction not fully validated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ITPKB integrates its catalytic, actin-binding, and nucleocytoplasmic-shuttling activities into a single spatially regulated calcium-control function across immune, neuronal, and cancer contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure linking the multitargeting domain to catalytic regulation\", \"Unclear whether disease phenotypes depend on catalysis, actin binding, or both\", \"Spatial determinants of IP4 antagonism of PIP3 versus SOC inhibition not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 3, 6, 9]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CAMK2G\", \"Trim25\", \"F-actin\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}