| 2007 |
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. |
Itpkb knockout mice, BCR stimulation assays, exogenous Ins(1,3,4,5)P4 rescue experiments, immunological phenotyping |
Nature immunology |
High |
17417640
|
| 2004 |
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. |
Confocal microscopy of EGFP-fusion fragments, in vitro F-actin co-sedimentation with bacterially expressed GST-fusion protein, site-directed mutagenesis |
The Biochemical journal |
High |
15130091
|
| 2010 |
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. |
Mutagenesis of NES/NLS sequences, exportin-1 inhibition (leptomycin B), confocal live-cell imaging, subcellular fractionation |
The Journal of biological chemistry |
High |
21148483
|
| 2016 |
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. |
Itpkb knockout mice, genetic epistasis with Akt/mTOR/glucose metabolism inhibitors, pre-TCR stimulation assays, metabolic activation readouts |
eLife |
High |
26880557
|
| 2015 |
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. |
Conditional Itpkb knockout mice, small-molecule Itpkb inhibitors, intracellular Ca2+ measurements, apoptosis assays (FasL/Bim induction), in vivo arthritis model |
PloS one |
High |
26121493
|
| 2016 |
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. |
miR-132 knockout AD mouse model, ITPKB overexpression/knockdown, ERK1/2 and BACE1 activity assays, TAU phosphorylation measurements, validation in human AD patient cohorts |
EMBO molecular medicine |
Medium |
27485122
|
| 2021 |
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. |
ITPKB knockdown/overexpression in primary neurons, pharmacological ITPKB inhibition, α-synuclein preformed fibril (PFF) treatment, mitochondrial calcium measurements, MCU complex inhibitors, autophagy assays |
Proceedings of the National Academy of Sciences of the United States of America |
High |
33443159
|
| 2022 |
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. |
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 |
Oncogene |
High |
35039634
|
| 2024 |
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. |
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) |
Signal transduction and targeted therapy |
Medium |
38438346
|
| 2015 |
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. |
PC12 cell overexpression, GFP-tagged wild-type and kinase-dead Itpkb mutants, NGF-induced neurite outgrowth assays, quantitative neurite length measurements |
The FEBS journal |
Medium |
25892505
|
| 2018 |
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). |
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 |
The Biochemical journal |
Medium |
29871874
|
| 2019 |
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. |
miR-711 overexpression in BV2 microglia, EV isolation and injection in rmTBI mice, Tau phosphorylation assays, microglia phenotype analysis, neurological/cognitive function tests |
Frontiers in cell and developmental biology |
Medium |
33240878
|
| 2019 |
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. |
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 |
International journal of biological macromolecules |
Medium |
41611162
|