{"gene":"IP6K2","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2001,"finding":"IP6K2 (RID-2) is post-transcriptionally induced by IFN-beta in ovarian carcinoma cells and mediates IFN-beta-induced apoptosis; a mutant IP6K2 with substitutions in the putative inositol phosphate binding domain abrogates IFN-beta-induced apoptosis, demonstrating the kinase activity is required.","method":"Antisense technical knockout, mutant overexpression, apoptosis assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and dominant-negative mutant with defined apoptotic phenotype, single lab, multiple methods","pmids":["11337497"],"is_preprint":false},{"year":2002,"finding":"IP6K2 overexpression enhances radiosensitivity and IFN-beta-induced apoptosis in ovarian carcinoma cells, associated with increased caspase-8 mRNA induction, and both IFN-beta and gamma-irradiation induce apoptosis through the extrinsic receptor-mediated pathway (TRAIL/DR4/caspase-8), positively regulated by IP6K2.","method":"Overexpression, colony forming assay, caspase-8 and TRAIL mRNA analysis, dominant negative DR5 mutant","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in single lab, defined pathway placement via dominant-negative and RNA analyses","pmids":["11896621"],"is_preprint":false},{"year":2005,"finding":"IP6K2 (IHPK2) translocates from the cytoplasm/perinuclear region to the nucleus upon IFN-beta treatment, and nuclear localization is required for IFN-beta-induced apoptosis; point mutations in the NLS trap IP6K2 in the cytoplasm and confer resistance to IFN-beta.","method":"IHPK2-eGFP live imaging, NLS point mutant overexpression, IC50 apoptosis assays","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with NLS mutant functionally linked to apoptosis resistance, single lab","pmids":["15634191"],"is_preprint":false},{"year":2007,"finding":"IP6K2 binds directly to TRAF2 via residues Ser-347 and Ser-359, and this interaction interferes with TAK1 phosphorylation, thereby inhibiting NF-kappaB signaling downstream of TNF-alpha; mutations at S347A/S359A abolish TRAF2 binding and increase NF-kappaB activity 6-10-fold.","method":"Co-immunoprecipitation, site-directed mutagenesis, TAK1 phosphorylation assay, NF-kappaB DNA binding assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding and mutagenesis with defined downstream signaling readout, single lab","pmids":["17379600"],"is_preprint":false},{"year":2008,"finding":"HSP90 physically binds IP6K2 and inhibits its catalytic (IP7-synthesizing) activity; disruption of HSP90-IP6K2 binding (by drugs or selective mutations) activates IP6K2 and leads to cell death, establishing HSP90's pro-survival function as inhibition of IP6K2.","method":"Co-immunoprecipitation, catalytic activity assay, mutagenesis, pharmacological HSP90 inhibitors","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding demonstrated, enzymatic activity measured, both pharmacological and genetic disruption tested in single rigorous study","pmids":["18195352"],"is_preprint":false},{"year":2009,"finding":"IP6K2 knockout mice develop normally but show 4-fold increased incidence of invasive squamous cell carcinoma upon carcinogen exposure; direct microinjection of 5-PP-Ins(1,2,3,4,6)P5 (the IP6K2 product) induces cell death in squamous carcinoma cells, whereas IP6 (the substrate) does not, establishing the enzymatic product as the death-inducing agent.","method":"IP6K2 knockout mice, 4-NQO carcinogen treatment, direct microinjection of IP7 vs IP6, comet assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO model replicated multiple phenotypes plus direct product microinjection distinguishing substrate from product","pmids":["19430495"],"is_preprint":false},{"year":2010,"finding":"IP6K2 is required for p53-mediated apoptosis: gene disruption of IP6K2 in colorectal cancer cells selectively impairs p53-mediated apoptosis (shifting response toward cell-cycle arrest), and IP6K2 acts by binding directly to p53 and decreasing expression of pro-arrest targets such as p21.","method":"IP6K2 gene disruption (HCT116), apoptosis vs. cell cycle arrest assays, co-immunoprecipitation, p21/p53 target gene expression","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined apoptotic vs. arrest phenotype plus direct IP6K2-p53 binding by Co-IP, single lab but multiple orthogonal methods","pmids":["21078964"],"is_preprint":false},{"year":2010,"finding":"IP6K2 acts as an effector of the vertebrate Hedgehog (Hh) signaling pathway: IP6K2 depletion in zebrafish inhibited Hh target gene expression and caused craniofacial/somite defects; IP6K2 overexpression enhanced Hh pathway response in mammalian cells; IP6K2 acts at the level of or downstream of Smoothened but upstream of Gli1.","method":"Zebrafish morpholino knockdown, mammalian cell Hh reporter assays, mRNA rescue, epistasis with smoM2/gli1 overexpression","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in two model systems, rescue experiments, single lab","pmids":["20980661"],"is_preprint":false},{"year":2011,"finding":"CK2 (casein kinase-2) phosphorylates IP6K2 at residues S347 and S356 within a PEST sequence, triggering its ubiquitination and proteasomal degradation; IP6K2 mutants at these sites are resistant to CK2-mediated phosphorylation and are metabolically stable; HCT116 cells depleted of IP6K2 are resistant to cell death elicited by CK2 inhibitors.","method":"In vitro kinase assay, site-directed mutagenesis, ubiquitination assay, protein stability analysis, CK2 inhibitor treatment","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro phosphorylation, mutagenesis defining specific residues, ubiquitination assay, and functional KD rescue all in one study","pmids":["21262846"],"is_preprint":false},{"year":2014,"finding":"IP7 generated by IP6K2 binds CK2 to enhance CK2 phosphorylation of the TTT cochaperone complex (Tti1/Tel2), thereby stabilizing DNA-PKcs and ATM; this leads to p53 phosphorylation at serine 15 and activation of the apoptotic program in human cancer cells and murine B cells.","method":"In vitro binding assay (IP7-CK2), CK2 kinase assay, TTT complex phosphorylation assay, p53-S15 phosphorylation, IP6K2 depletion/overexpression in cell lines and mouse B cells","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct IP7-CK2 binding, in vitro kinase assay, genetic depletion in two cell contexts with defined molecular cascade","pmids":["24657168"],"is_preprint":false},{"year":2014,"finding":"Crystal structure of an Entamoeba histolytica hybrid IP6K/IP3K was determined; molecular modelling and mutagenesis extrapolated to human IP6K2 revealed two structural elements (an alpha-helical pair and a two-turn 310 helix) forming a substrate-binding pocket with open clamshell geometry; InsP6 contacts both elements while InsP3 rotates 55° relative to InsP6, closer to the alpha-helices. Human IP6K2 retains vestigial IP3K activity.","method":"X-ray crystallography, molecular modelling, mutagenesis, kinase activity assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mutagenesis and enzymatic validation; direct structural determination of catalytic mechanism","pmids":["24956979"],"is_preprint":false},{"year":2015,"finding":"IP6K2, via IP7 synthesis, promotes cancer cell migration and tumor metastasis by enhancing cell-matrix adhesion and decreasing cell-cell adhesion; this is mediated by IP7-elicited nuclear sequestration and inactivation of the tumor suppressor LKB1.","method":"IP6K2 overexpression/knockdown, cell migration/invasion assays, tumor metastasis in mice, LKB1 localization by fractionation and imaging, IP6K2 inhibitor","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo migration/metastasis with proposed LKB1 mechanism, single lab","pmids":["25617365"],"is_preprint":false},{"year":2017,"finding":"IP6K2 RNAi and pan-IP6K inhibitor (TNP) restore 5-IP7 levels in PPIP5K-knockout cells to wild-type without rescuing 1,5-IP8; this attenuation of IP6K reverses p53 upregulation, demonstrating that 5-IP7 (produced by IP6K2 among others) regulates p53 expression.","method":"CRISPR knockout, RNAi, IP6K inhibitor, inositol phosphate profiling, p53/p21 western blot","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological depletion of IP6K2 with specific molecular readout; single lab but multiple perturbation approaches","pmids":["29078269"],"is_preprint":false},{"year":2018,"finding":"IP6K2 binds protein 4.1N with high affinity and specificity; nuclear translocation of 4.1N is dependent on IP6K2; both proteins are highly expressed in cerebellar granule cells where their interaction regulates Purkinje cell morphology, cerebellar synapses, and locomotor function; disruption of IP6K2-4.1N interactions impairs cell viability.","method":"Co-immunoprecipitation, IP6K2 KO mice, immunofluorescence/localization, synaptic morphology analysis, motor behavior assays","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding by Co-IP, KO mice with defined phenotype, localization experiments functionally linked, single lab","pmids":["30006360"],"is_preprint":false},{"year":2019,"finding":"IP6K1 and IP6K2 together control inositol pyrophosphate metabolism; double knockout of IP6K1/2 in human HCT116 cells eliminates IP7 and IP8, elevates intracellular ATP and free phosphate, decreases phosphate flux (both import and export), and reduces phosphate export via the XPR1 exporter, which is regulated by inositol pyrophosphates binding to its SPX domain.","method":"CRISPR KO (IP6K1/2 double KO), PAGE and HPLC inositol phosphate profiling, Malachite green phosphate assay, 32Pi pulse labeling, XPR1 functional assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genetic KO with multiple orthogonal biochemical assays, mechanistic link to XPR1-SPX domain binding established","pmids":["31186349"],"is_preprint":false},{"year":2021,"finding":"IP6K2 physically interacts with creatine kinase-B (CK-B); IP6K2-knockout mouse cerebella produce less phosphocreatine and ATP, show higher reactive oxygen species, protein oxidative damage, and impaired cytochrome-c1 subunit expression of mitochondrial complex III; combined N-acetylcysteine and phosphocreatine treatment reversed some effects, establishing IP6K2-CK-B interaction in energy homeostasis and neuroprotection.","method":"Protein interactome (IP6K2 KO mouse brain), co-immunoprecipitation, metabolite measurement (phosphocreatine, ATP), ROS assay, mitochondrial complex analysis, pharmacological rescue","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and KO mouse phenotype with multiple metabolic readouts, single lab","pmids":["33547244"],"is_preprint":false},{"year":2022,"finding":"IP6K2 attenuates PINK1-mediated mitophagy in the brain via a non-catalytic (kinase-independent) mechanism; both wild-type and kinase-dead IP6K2 reverse mitophagy marker expression in IP6K2-knockdown cells, whereas IP6K2 supplementation in IP6K2/PINK1 double-knockdown cells fails to reverse LC3-II levels, placing IP6K2's mitoprotective effect upstream of or dependent on PINK1.","method":"IP6K2 KO mice, siRNA knockdown, kinase-dead mutant overexpression, LC3-II western blot, Drp-1/PGC1-alpha/NRF-1 expression, double-knockdown epistasis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase-dead mutant distinguishes catalytic from non-catalytic function, epistasis with PINK1, single lab","pmids":["35353626"],"is_preprint":false},{"year":2023,"finding":"Wild-type IP6K2 expression (but not kinase-dead IP6K2 mutant) expands the outer nucleolar granular region, establishing that IP7 produced by IP6K2 acts as an 'electrostatic glue' mediating biomolecular condensate assembly of multiple nucleolar proteins.","method":"Quantitative confocal imaging, CRISPR KO (NUDT3, PPIP5Ks), heterologous IP6K2 and kinase-dead mutant expression, pan-IP6K inhibitor, siRNA knockdown","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase-dead mutant as internal control, multiple genetic/pharmacological perturbations, single lab","pmids":["36671538"],"is_preprint":false},{"year":2023,"finding":"IP6K2 is selectively expressed in enteric neurons of the gastrointestinal tract; IP6K2-knockout mice show significantly impaired IP7 metabolism in gut/duodenal muscularis externa; IP6K2 ablation alters expression of gene sets associated with mature neurons, neural progenitor/stem cells, and glial cells, indicating a critical role of the IP6K2-IP7 axis in developmental and functional regulation of the enteric nervous system.","method":"LC-MS inositol pyrophosphate profiling, IP6K2 KO mice, cell-type immunostaining, whole transcriptome analysis of duodenal muscularis externa","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mice with LC-MS profiling and transcriptomics, single lab; subcellular/cell-type localization functionally linked","pmids":["36681123"],"is_preprint":false},{"year":2024,"finding":"Renal IP6K1/2 double-knockout mice show downregulated expression and function of Na+/Pi cotransporters NaPi-IIa and NaPi-IIc, hypophosphatemia, reduced brush border membrane phosphate uptake, decreased FGF23, increased bone resorption, diuresis, albuminuria, and hypercalciuria; in vitro, Ip6k1/2 depletion reduces phosphate transport and blunts adaptation to ambient phosphate changes.","method":"Renal tubular-specific Ip6k1/2 KO mice, opossum kidney cell model, mRNA/protein expression of NaPi cotransporters, Malachite green phosphate uptake, plasma phosphate/FGF23 measurement, bone analysis","journal":"Journal of the American Society of Nephrology : JASN","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific double KO in vivo and in vitro with multiple physiological readouts, single lab","pmids":["38317282"],"is_preprint":false},{"year":2025,"finding":"IP6K2 is activated by a ROS-Src phosphorylation axis to generate 5-IP7 around adherens junctions; 5-IP7 inhibits inositol 5-phosphatases (OCRL) to promote PI(4,5)P2-mediated endocytic adaptor recruitment and E-cadherin endocytosis, leading to AJ disassembly and beta-catenin transcriptional activation; intestinal epithelium-specific IP6K2 deletion attenuates DSS-induced colitis/CRC.","method":"IP6K2 KO (intestinal epithelium-specific), Src phosphorylation assay, OCRL binding/activity assay, PI(4,5)P2 imaging, E-cadherin endocytosis assay, beta-catenin reporter, DSS colitis model, IP6K2 isoform-selective inhibitor","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (biochemical, cell biological, in vivo KO, pharmacological inhibitor) in a single rigorous study establishing a detailed molecular mechanism","pmids":["40858937"],"is_preprint":false}],"current_model":"IP6K2 is an inositol hexakisphosphate kinase that phosphorylates IP6 to generate the inositol pyrophosphate 5-IP7; its catalytic activity and protein-protein interactions mediate diverse cellular functions including: apoptosis via direct binding to p53 and activation of a DNA-PK/ATM-CK2-TTT signaling cascade; pro-survival inhibition by HSP90 (which binds and suppresses IP6K2 catalytically) and CK2-mediated phosphorylation at S347/S356 leading to ubiquitin-proteasomal degradation; NF-kappaB suppression through TRAF2 binding; IFN-beta-induced apoptosis requiring nuclear translocation; cancer cell migration/metastasis through LKB1 nuclear inactivation; phosphate homeostasis by regulating XPR1-mediated phosphate export and renal Na+/Pi cotransporter expression; a non-catalytic role in attenuating PINK1-mediated mitophagy; interaction with CK-B for mitochondrial energy homeostasis; interaction with 4.1N for cerebellar circuit function; modulation of nucleolar condensate assembly via IP7; and activation by a ROS-Src axis to generate junctional 5-IP7 that inhibits OCRL phosphatase, promoting E-cadherin endocytosis and beta-catenin signaling in colorectal cancer."},"narrative":{"mechanistic_narrative":"IP6K2 is an inositol hexakisphosphate kinase that phosphorylates IP6 to generate the inositol pyrophosphate 5-IP7, and through this catalytic output—together with non-catalytic protein interactions—it governs apoptosis, phosphate homeostasis, cell adhesion, and neuronal function [PMID:19430495, PMID:31186349]. A crystallographic and modelling analysis of a hybrid IP6K/IP3K defined an open clamshell substrate-binding pocket built from an alpha-helical pair and a two-turn 3-10 helix, and showed human IP6K2 retains vestigial IP3K activity [PMID:24956979]. The enzyme is a positive regulator of cell death: it is induced by IFN-beta and must translocate to the nucleus to drive apoptosis, and direct microinjection of its product 5-IP7 (but not the IP6 substrate) is itself sufficient to kill carcinoma cells, while IP6K2-null mice show increased carcinogen-induced squamous carcinoma [PMID:11337497, PMID:15634191, PMID:19430495]. Mechanistically, IP6K2 binds p53 to bias the p53 response toward apoptosis over cell-cycle arrest, and IP7 binds CK2 to potentiate phosphorylation of the TTT cochaperone complex (Tti1/Tel2), stabilizing DNA-PKcs and ATM and driving p53 serine-15 phosphorylation [PMID:21078964, PMID:24657168]. Its pro-death activity is held in check by HSP90, which binds and catalytically suppresses IP6K2, and by CK2-mediated phosphorylation at S347/S356 within a PEST motif that targets IP6K2 for ubiquitin-proteasomal degradation [PMID:18195352, PMID:21262846]. The same S347/S359 region mediates binding to TRAF2, blocking TAK1 phosphorylation to suppress NF-kappaB signaling [PMID:17379600]. Beyond apoptosis, IP6K2 (with IP6K1) controls cellular inositol pyrophosphate pools and phosphate flux, regulating XPR1-mediated phosphate export via its SPX domain and renal NaPi-IIa/IIc cotransporter expression and systemic phosphate handling [PMID:31186349, PMID:38317282]. In a colorectal cancer context, a ROS-Src axis activates IP6K2 to generate junctional 5-IP7 that inhibits the OCRL 5-phosphatase, promoting PI(4,5)P2-dependent E-cadherin endocytosis and beta-catenin signaling [PMID:40858937]. IP6K2 also has tissue-specific roles in cerebellar circuitry through binding protein 4.1N and in mitochondrial energy homeostasis through binding creatine kinase-B, and it attenuates PINK1-mediated mitophagy through a kinase-independent mechanism [PMID:30006360, PMID:33547244, PMID:35353626].","teleology":[{"year":2002,"claim":"Established IP6K2 as a positive, kinase-dependent regulator of apoptosis, answering whether this inositol kinase functioned in cell death and through which death pathway.","evidence":"Antisense knockout, dominant-negative inositol-binding mutant, and dominant-negative DR5/caspase-8 analyses in IFN-beta- and irradiation-treated ovarian carcinoma cells","pmids":["11337497","11896621"],"confidence":"Medium","gaps":["Did not identify the molecular target of IP6K2 catalytic output","Restricted to ovarian carcinoma in a single lab","Mechanism linking kinase activity to extrinsic apoptotic pathway components unresolved"]},{"year":2005,"claim":"Showed that subcellular relocation, not just expression, gates IP6K2 function, demonstrating nuclear translocation is required for IFN-beta-induced apoptosis.","evidence":"IP6K2-eGFP live imaging and NLS point mutants linked to apoptosis resistance in carcinoma cells","pmids":["15634191"],"confidence":"Medium","gaps":["Nuclear targets of IP6K2/IP7 not defined","Signal triggering translocation unknown"]},{"year":2007,"claim":"Identified a non-apoptotic signaling role by showing IP6K2 binds TRAF2 to suppress NF-kappaB, mapping the interaction to specific serine residues.","evidence":"Co-immunoprecipitation, S347A/S359A mutagenesis, TAK1 phosphorylation and NF-kappaB DNA-binding assays","pmids":["17379600"],"confidence":"Medium","gaps":["Whether catalytic activity contributes to NF-kappaB suppression unclear","Single lab, no in vivo confirmation"]},{"year":2008,"claim":"Defined how IP6K2 pro-death activity is restrained, showing HSP90 binds and catalytically inhibits IP6K2 as the basis of HSP90's pro-survival function.","evidence":"Co-IP, catalytic activity assays, mutagenesis, and pharmacological HSP90 inhibition with cell-death readouts","pmids":["18195352"],"confidence":"High","gaps":["Structural basis of HSP90-IP6K2 inhibition not resolved","Generality across cell types untested at this stage"]},{"year":2009,"claim":"Provided in vivo and biochemical proof that the enzymatic product 5-IP7, not substrate IP6, is the death-inducing agent and that IP6K2 suppresses carcinogenesis.","evidence":"IP6K2 knockout mice with 4-NQO carcinogen, direct microinjection of IP7 versus IP6, comet assay","pmids":["19430495"],"confidence":"High","gaps":["Direct intracellular targets of microinjected IP7 not identified","Tumor-suppressive mechanism in vivo not molecularly dissected"]},{"year":2010,"claim":"Connected IP6K2 to the p53 apoptotic decision and to Hedgehog signaling, broadening its functional placement.","evidence":"IP6K2 gene disruption in HCT116 with apoptosis-versus-arrest readouts and p53 Co-IP; zebrafish morpholino and mammalian Hh reporter epistasis","pmids":["21078964","20980661"],"confidence":"High","gaps":["How IP6K2-p53 binding biases target gene selection unresolved","Molecular target of IP6K2 within the Hh pathway between Smoothened and Gli1 unknown"]},{"year":2011,"claim":"Established a degradation switch controlling IP6K2 levels, showing CK2 phosphorylates a PEST-motif site to drive ubiquitin-proteasomal turnover.","evidence":"In vitro kinase assay, S347/S356 mutagenesis, ubiquitination and stability assays, CK2 inhibitor with cell-death rescue","pmids":["21262846"],"confidence":"High","gaps":["E3 ligase mediating IP6K2 ubiquitination not identified","Interplay between CK2 degradation and TRAF2 binding at overlapping residues not reconciled"]},{"year":2014,"claim":"Resolved the downstream apoptotic cascade by showing IP7 binds CK2 to potentiate TTT-complex phosphorylation, stabilizing DNA-PKcs/ATM and activating p53-S15.","evidence":"In vitro IP7-CK2 binding, CK2 kinase and TTT phosphorylation assays, p53-S15 readout, depletion/overexpression in cells and mouse B cells","pmids":["24657168"],"confidence":"High","gaps":["Stoichiometry and structural basis of IP7-CK2 interaction not defined","How this nuclear cascade integrates with cytoplasmic IP6K2 functions unclear"]},{"year":2014,"claim":"Provided structural insight into catalysis, defining the substrate-binding pocket geometry and confirming vestigial IP3K activity of human IP6K2.","evidence":"X-ray crystallography of an E. histolytica hybrid IP6K/IP3K, modelling, mutagenesis, and kinase assays extrapolated to human IP6K2","pmids":["24956979"],"confidence":"High","gaps":["No direct crystal structure of human IP6K2","Conformational changes during catalysis inferred, not directly observed"]},{"year":2015,"claim":"Identified a pro-metastatic function, showing IP7 drives nuclear sequestration and inactivation of LKB1 to alter adhesion and promote invasion.","evidence":"IP6K2 overexpression/knockdown, migration/invasion assays, mouse metastasis, LKB1 fractionation/imaging, IP6K inhibitor","pmids":["25617365"],"confidence":"Medium","gaps":["Mechanism by which IP7 controls LKB1 localization unresolved","Apparent contrast with tumor-suppressive apoptotic role not reconciled"]},{"year":2017,"claim":"Disentangled which inositol pyrophosphate regulates p53, showing IP6K-derived 5-IP7 (not 1,5-IP8) controls p53 expression.","evidence":"CRISPR KO of PPIP5K, IP6K RNAi and TNP inhibitor, inositol phosphate profiling, p53/p21 westerns","pmids":["29078269"],"confidence":"Medium","gaps":["IP6K2-specific contribution versus other IP6K isoforms not isolated","Direct link from 5-IP7 levels to p53 transcription not mapped"]},{"year":2018,"claim":"Revealed a neuronal scaffolding function, showing IP6K2 binds protein 4.1N to control its nuclear translocation and cerebellar circuit integrity.","evidence":"Co-IP, IP6K2 KO mice, immunofluorescence, synaptic morphology, and motor behavior assays","pmids":["30006360"],"confidence":"Medium","gaps":["Whether catalytic activity is required for 4.1N regulation untested","Molecular consequence of 4.1N nuclear translocation undefined"]},{"year":2019,"claim":"Established the metabolic core function, showing IP6K1/2 set cellular IP7/IP8 pools and regulate phosphate flux via XPR1-SPX domain binding.","evidence":"IP6K1/2 double-KO HCT116, PAGE/HPLC inositol phosphate profiling, malachite green and 32Pi flux assays, XPR1 functional assay","pmids":["31186349"],"confidence":"High","gaps":["IP6K2-specific (versus IP6K1) contribution to phosphate export not separated","Direct binding of inositol pyrophosphate to XPR1-SPX inferred from prior context"]},{"year":2021,"claim":"Linked IP6K2 to mitochondrial energy homeostasis through binding creatine kinase-B and protecting against oxidative damage in cerebellum.","evidence":"IP6K2 KO mouse brain interactome, Co-IP, phosphocreatine/ATP and ROS measurements, mitochondrial complex analysis, pharmacological rescue","pmids":["33547244"],"confidence":"Medium","gaps":["Catalytic versus structural contribution of IP6K2 to CK-B function unclear","Mechanism connecting CK-B binding to complex III deficits undefined"]},{"year":2022,"claim":"Demonstrated a kinase-independent role, showing IP6K2 attenuates PINK1-mediated mitophagy via a non-catalytic mechanism.","evidence":"IP6K2 KO mice, siRNA, kinase-dead mutant rescue, LC3-II and mitophagy marker analysis, IP6K2/PINK1 double-knockdown epistasis","pmids":["35353626"],"confidence":"Medium","gaps":["Protein partners mediating the non-catalytic mitophagy effect not identified","Relationship to PINK1 (upstream versus dependent) only partially resolved"]},{"year":2023,"claim":"Showed IP6K2-derived IP7 promotes nucleolar condensate assembly and that IP6K2 marks and shapes the enteric nervous system, extending its functions to biomolecular condensates and gut neurobiology.","evidence":"Confocal imaging with kinase-dead IP6K2 control and CRISPR/inhibitor perturbations; LC-MS profiling, IP6K2 KO mice, cell-type immunostaining and transcriptomics of duodenal muscularis externa","pmids":["36671538","36681123"],"confidence":"Medium","gaps":["Which nucleolar proteins are directly bridged by IP7 not enumerated","Causal mechanism linking IP6K2-IP7 axis to enteric neuron development undefined"]},{"year":2024,"claim":"Defined a systemic phosphate-handling role, showing renal IP6K1/2 controls NaPi cotransporter expression and whole-body phosphate/mineral balance.","evidence":"Renal tubular-specific Ip6k1/2 KO mice and opossum kidney cells with NaPi expression, phosphate uptake, plasma FGF23 and bone analyses","pmids":["38317282"],"confidence":"Medium","gaps":["IP6K2-specific contribution distinct from IP6K1 not isolated","Mechanism coupling inositol pyrophosphates to NaPi cotransporter regulation not resolved"]},{"year":2025,"claim":"Integrated upstream activation with a junctional output, showing a ROS-Src axis activates IP6K2 to make 5-IP7 that inhibits OCRL, driving E-cadherin endocytosis and beta-catenin signaling in colorectal cancer.","evidence":"Intestinal epithelium-specific IP6K2 KO, Src phosphorylation and OCRL binding/activity assays, PI(4,5)P2 imaging, E-cadherin endocytosis, beta-catenin reporter, DSS colitis model, isoform-selective inhibitor","pmids":["40858937"],"confidence":"High","gaps":["Src phosphorylation site(s) on IP6K2 not detailed here","How junctional 5-IP7 pools are spatially confined unresolved"]},{"year":null,"claim":"How IP6K2's pro-apoptotic/tumor-suppressive functions are reconciled with its pro-metastatic and pro-tumorigenic roles across tissues, and how catalytic versus non-catalytic activities are selected in each context, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model distinguishing context-specific outputs of IP6K2","Isoform-specific versus IP6K1-shared functions incompletely separated","No human IP6K2 crystal structure with bound substrate/product"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[5,10,14]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[6,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,4,16]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[17]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[20]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5,6,9]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[14,19]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[14,19]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,20]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[20]}],"complexes":[],"partners":["TP53","TRAF2","HSP90","CSNK2A1","EPB41L1","CKB","OCRL","PINK1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UHH9","full_name":"Inositol hexakisphosphate kinase 2","aliases":["P(i)-uptake stimulator","PiUS"],"length_aa":426,"mass_kda":49.2,"function":"Converts inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7/PP-InsP5)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9UHH9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IP6K2","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/IP6K2","total_profiled":1310},"omim":[{"mim_id":"606993","title":"INOSITOL HEXAPHOSPHATE KINASE 3; IP6K3","url":"https://www.omim.org/entry/606993"},{"mim_id":"606992","title":"INOSITOL HEXAPHOSPHATE KINASE 2; IP6K2","url":"https://www.omim.org/entry/606992"},{"mim_id":"606991","title":"INOSITOL HEXAPHOSPHATE KINASE 1; IP6K1","url":"https://www.omim.org/entry/606991"},{"mim_id":"140571","title":"HEAT-SHOCK PROTEIN, 90-KD, ALPHA, CLASS A, MEMBER 1; HSP90AA1","url":"https://www.omim.org/entry/140571"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli fibrillar center","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cell Junctions","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IP6K2"},"hgnc":{"alias_symbol":[],"prev_symbol":["IHPK2"]},"alphafold":{"accession":"Q9UHH9","domains":[{"cath_id":"3.30.470.160","chopping":"16-92_154-338_372-423","consensus_level":"medium","plddt":89.4318,"start":16,"end":423}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UHH9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UHH9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UHH9-F1-predicted_aligned_error_v6.png","plddt_mean":76.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IP6K2","jax_strain_url":"https://www.jax.org/strain/search?query=IP6K2"},"sequence":{"accession":"Q9UHH9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UHH9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UHH9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UHH9"}},"corpus_meta":[{"pmid":"23725456","id":"PMC_23725456","title":"Inositol pyrophosphates: between signalling and metabolism.","date":"2013","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/23725456","citation_count":213,"is_preprint":false},{"pmid":"18033884","id":"PMC_18033884","title":"Requirement of inositol pyrophosphates for full exocytotic capacity in pancreatic beta cells.","date":"2007","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/18033884","citation_count":158,"is_preprint":false},{"pmid":"11337497","id":"PMC_11337497","title":"Inositol hexakisphosphate kinase 2 mediates growth suppressive and apoptotic effects of interferon-beta in ovarian carcinoma cells.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11337497","citation_count":138,"is_preprint":false},{"pmid":"21878680","id":"PMC_21878680","title":"Inositol pyrophosphates as mammalian cell signals.","date":"2011","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/21878680","citation_count":137,"is_preprint":false},{"pmid":"24657168","id":"PMC_24657168","title":"Inositol pyrophosphates mediate the DNA-PK/ATM-p53 cell death pathway by regulating CK2 phosphorylation of Tti1/Tel2.","date":"2014","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/24657168","citation_count":105,"is_preprint":false},{"pmid":"31186349","id":"PMC_31186349","title":"The inositol hexakisphosphate kinases IP6K1 and -2 regulate human cellular phosphate homeostasis, including XPR1-mediated phosphate export.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31186349","citation_count":87,"is_preprint":false},{"pmid":"18195352","id":"PMC_18195352","title":"HSP90 regulates cell survival via inositol hexakisphosphate kinase-2.","date":"2008","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/18195352","citation_count":86,"is_preprint":false},{"pmid":"21078964","id":"PMC_21078964","title":"p53-mediated apoptosis requires inositol hexakisphosphate kinase-2.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/21078964","citation_count":83,"is_preprint":false},{"pmid":"25617365","id":"PMC_25617365","title":"Inositol pyrophosphates promote tumor growth and metastasis by antagonizing liver kinase B1.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25617365","citation_count":82,"is_preprint":false},{"pmid":"29078269","id":"PMC_29078269","title":"KO of 5-InsP7 kinase activity transforms the HCT116 colon cancer cell line into a hypermetabolic, growth-inhibited phenotype.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/29078269","citation_count":68,"is_preprint":false},{"pmid":"19430495","id":"PMC_19430495","title":"Gene deletion of inositol hexakisphosphate kinase 2 predisposes to aerodigestive tract carcinoma.","date":"2009","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/19430495","citation_count":61,"is_preprint":false},{"pmid":"24956979","id":"PMC_24956979","title":"IP6K structure and the molecular determinants of catalytic specificity in an inositol phosphate kinase family.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/24956979","citation_count":61,"is_preprint":false},{"pmid":"11896621","id":"PMC_11896621","title":"Inositol hexakisphosphate kinase 2 sensitizes ovarian carcinoma cells to multiple cancer therapeutics.","date":"2002","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/11896621","citation_count":58,"is_preprint":false},{"pmid":"21950602","id":"PMC_21950602","title":"Macrocycles that inhibit the binding between heat shock protein 90 and TPR-containing proteins.","date":"2011","source":"ACS chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/21950602","citation_count":53,"is_preprint":false},{"pmid":"27140681","id":"PMC_27140681","title":"Deletion of inositol hexakisphosphate kinase 1 (IP6K1) reduces cell migration and invasion, conferring protection from aerodigestive tract carcinoma in mice.","date":"2016","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/27140681","citation_count":51,"is_preprint":false},{"pmid":"26245967","id":"PMC_26245967","title":"Inositol Hexakisphosphate Kinase-3 Regulates the Morphology and Synapse Formation of Cerebellar Purkinje Cells via Spectrin/Adducin.","date":"2015","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/26245967","citation_count":46,"is_preprint":false},{"pmid":"21262846","id":"PMC_21262846","title":"Casein kinase-2 mediates cell survival through phosphorylation and degradation of inositol hexakisphosphate kinase-2.","date":"2011","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/21262846","citation_count":43,"is_preprint":false},{"pmid":"15634191","id":"PMC_15634191","title":"Apo2L/TRAIL induction and nuclear translocation of inositol hexakisphosphate kinase 2 during IFN-beta-induced apoptosis in ovarian carcinoma.","date":"2005","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/15634191","citation_count":31,"is_preprint":false},{"pmid":"23018034","id":"PMC_23018034","title":"Identification of novel Sp1 targets involved in proliferation and cancer by functional genomics.","date":"2012","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/23018034","citation_count":31,"is_preprint":false},{"pmid":"12370820","id":"PMC_12370820","title":"Oncogenic transformation by beta-catenin: deletion analysis and characterization of selected target genes.","date":"2002","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/12370820","citation_count":29,"is_preprint":false},{"pmid":"20980661","id":"PMC_20980661","title":"Inositol hexakisphosphate kinase-2 acts as an effector of the vertebrate Hedgehog pathway.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20980661","citation_count":24,"is_preprint":false},{"pmid":"35467861","id":"PMC_35467861","title":"Development of Novel IP6K Inhibitors for the Treatment of Obesity and Obesity-Induced Metabolic Dysfunctions.","date":"2022","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35467861","citation_count":24,"is_preprint":false},{"pmid":"17379600","id":"PMC_17379600","title":"Effect of inositol hexakisphosphate kinase 2 on transforming growth factor beta-activated kinase 1 and NF-kappaB activation.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17379600","citation_count":21,"is_preprint":false},{"pmid":"36681123","id":"PMC_36681123","title":"Inositol pyrophosphate profiling reveals regulatory roles of IP6K2-dependent enhanced IP7 metabolism in the enteric nervous system.","date":"2023","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36681123","citation_count":20,"is_preprint":false},{"pmid":"29842835","id":"PMC_29842835","title":"Use of Protein Kinase-Focused Compound Libraries for the Discovery of New Inositol Phosphate Kinase Inhibitors.","date":"2018","source":"SLAS discovery : advancing life sciences R & D","url":"https://pubmed.ncbi.nlm.nih.gov/29842835","citation_count":19,"is_preprint":false},{"pmid":"22085832","id":"PMC_22085832","title":"Nuclear receptor HNF4α binding sequences are widespread in Alu repeats.","date":"2011","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/22085832","citation_count":19,"is_preprint":false},{"pmid":"32176627","id":"PMC_32176627","title":"LINC00467 knockdown repressed cell proliferation but stimulated cell apoptosis in glioblastoma via miR-339-3p/IP6K2 axis.","date":"2020","source":"Cancer biomarkers : section A of Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/32176627","citation_count":18,"is_preprint":false},{"pmid":"35353626","id":"PMC_35353626","title":"Inositol hexakisphosphate kinase-2 non-catalytically regulates mitophagy by attenuating PINK1 signaling.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/35353626","citation_count":18,"is_preprint":false},{"pmid":"33547244","id":"PMC_33547244","title":"Inositol hexakisphosphate kinase-2 determines cellular energy dynamics by regulating creatine kinase-B.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/33547244","citation_count":17,"is_preprint":false},{"pmid":"31445853","id":"PMC_31445853","title":"Synthesis and characterization of novel isoform-selective IP6K1 inhibitors.","date":"2019","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/31445853","citation_count":17,"is_preprint":false},{"pmid":"30006360","id":"PMC_30006360","title":"Inositol Hexakisphosphate Kinase-2 in Cerebellar Granule Cells Regulates Purkinje Cells and Motor Coordination via Protein 4.1N.","date":"2018","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/30006360","citation_count":16,"is_preprint":false},{"pmid":"37804111","id":"PMC_37804111","title":"Machine learning nominates the inositol pathway and novel genes in Parkinson's disease.","date":"2024","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/37804111","citation_count":14,"is_preprint":false},{"pmid":"35156508","id":"PMC_35156508","title":"LINC00467 facilitates the proliferation, migration and invasion of glioma via promoting the expression of inositol hexakisphosphate kinase 2 by binding to miR-339-3p.","date":"2022","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/35156508","citation_count":13,"is_preprint":false},{"pmid":"38403246","id":"PMC_38403246","title":"Insights into the roles of inositol hexakisphosphate kinase 1 (IP6K1) in mammalian cellular processes.","date":"2024","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38403246","citation_count":13,"is_preprint":false},{"pmid":"31856847","id":"PMC_31856847","title":"Differential alternative splicing regulation among hepatocellular carcinoma with different risk factors.","date":"2019","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/31856847","citation_count":13,"is_preprint":false},{"pmid":"20872794","id":"PMC_20872794","title":"Screening and identification of differentially expressed genes in goose hepatocytes exposed to free fatty acid.","date":"2010","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20872794","citation_count":12,"is_preprint":false},{"pmid":"34602499","id":"PMC_34602499","title":"Axial Impairment Following Deep Brain Stimulation in Parkinson's Disease: A Surgicogenomic Approach.","date":"2022","source":"Journal of Parkinson's disease","url":"https://pubmed.ncbi.nlm.nih.gov/34602499","citation_count":12,"is_preprint":false},{"pmid":"37270558","id":"PMC_37270558","title":"Investigation of enzalutamide, docetaxel, and cabazitaxel resistance in the castration resistant prostate cancer cell line C4 using genome-wide CRISPR/Cas9 screening.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/37270558","citation_count":11,"is_preprint":false},{"pmid":"36671538","id":"PMC_36671538","title":"Nucleolar Architecture Is Modulated by a Small Molecule, the Inositol Pyrophosphate 5-InsP7.","date":"2023","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/36671538","citation_count":11,"is_preprint":false},{"pmid":"38317282","id":"PMC_38317282","title":"The Ip6k1 and Ip6k2 Kinases Are Critical for Normal Renal Tubular Function.","date":"2024","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/38317282","citation_count":10,"is_preprint":false},{"pmid":"34589518","id":"PMC_34589518","title":"4.1N-Mediated Interactions and Functions in Nerve System and Cancer.","date":"2021","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/34589518","citation_count":9,"is_preprint":false},{"pmid":"27107179","id":"PMC_27107179","title":"Sequence-based analysis of 5'UTR and coding regions of CASP3 in terms of miRSNPs and SNPs in targetting miRNAs.","date":"2016","source":"Computational biology and chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27107179","citation_count":9,"is_preprint":false},{"pmid":"37013838","id":"PMC_37013838","title":"Synthesis and biological evaluation of flavonoid-based IP6K2 inhibitors.","date":"2023","source":"Journal of enzyme inhibition and medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37013838","citation_count":8,"is_preprint":false},{"pmid":"31051014","id":"PMC_31051014","title":"PPIP5K1 Suppresses Etoposide-triggered Apoptosis.","date":"2016","source":"Journal of molecular signaling","url":"https://pubmed.ncbi.nlm.nih.gov/31051014","citation_count":8,"is_preprint":false},{"pmid":"36979316","id":"PMC_36979316","title":"Genetics of Neurogenic Orthostatic Hypotension in Parkinson's Disease, Results from a Cross-Sectional In Silico Study.","date":"2023","source":"Brain sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36979316","citation_count":8,"is_preprint":false},{"pmid":"40858937","id":"PMC_40858937","title":"Oncometabolite 5-IP7 inhibits inositol 5-phosphatase to license E-cadherin endocytosis.","date":"2025","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/40858937","citation_count":7,"is_preprint":false},{"pmid":"23591012","id":"PMC_23591012","title":"A kinome-wide siRNA screen identifies multiple roles for protein kinases in hypoxic stress adaptation, including roles for IRAK4 and GAK in protection against apoptosis in VHL-/- renal carcinoma cells, despite activation of the NF-κB pathway.","date":"2013","source":"Journal of biomolecular screening","url":"https://pubmed.ncbi.nlm.nih.gov/23591012","citation_count":7,"is_preprint":false},{"pmid":"34434651","id":"PMC_34434651","title":"Identification of a circRNA-miRNA-mRNA regulatory network for exploring novel therapeutic options for glioma.","date":"2021","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/34434651","citation_count":7,"is_preprint":false},{"pmid":"33767863","id":"PMC_33767863","title":"IP6K2 predicts favorable clinical outcome of primary breast cancer.","date":"2021","source":"Molecular and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33767863","citation_count":6,"is_preprint":false},{"pmid":"38116421","id":"PMC_38116421","title":"Fragment-Based Screening Identifies New Quinazolinone-Based Inositol Hexakisphosphate Kinase (IP6K) Inhibitors.","date":"2023","source":"ACS medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/38116421","citation_count":6,"is_preprint":false},{"pmid":"36817960","id":"PMC_36817960","title":"MAPKAPK2-centric transcriptome profiling reveals its major role in governing molecular crosstalk of IGFBP2, MUC4, and PRKAR2B during HNSCC pathogenesis.","date":"2023","source":"Computational and structural biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/36817960","citation_count":6,"is_preprint":false},{"pmid":"38429095","id":"PMC_38429095","title":"Novel and unusual USP6 fusion partners in aneurysmal bone cyst and their role in pathogenesis and histopathological evaluation of this disease.","date":"2025","source":"Journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/38429095","citation_count":4,"is_preprint":false},{"pmid":"32676038","id":"PMC_32676038","title":"Monitoring Phytate Hydrolysis Using Serial Blood Sampling and Feather Myo-Inositol Levels in Broilers.","date":"2020","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32676038","citation_count":4,"is_preprint":false},{"pmid":"38980439","id":"PMC_38980439","title":"Circ-IP6K2 suppresses tumor progression by modulating the miR-1292-5p/CAMK2N1 signal in clear cell renal cell carcinoma.","date":"2024","source":"Functional & integrative genomics","url":"https://pubmed.ncbi.nlm.nih.gov/38980439","citation_count":3,"is_preprint":false},{"pmid":"37843983","id":"PMC_37843983","title":"An unconventional gatekeeper mutation sensitizes inositol hexakisphosphate kinases to an allosteric inhibitor.","date":"2023","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/37843983","citation_count":3,"is_preprint":false},{"pmid":"35892236","id":"PMC_35892236","title":"Comparison of Skin Transcriptome between Responder and Non-Responder Vitiligo Lesions to Cell Transplantation: A Clinical Trial Study.","date":"2022","source":"Cell journal","url":"https://pubmed.ncbi.nlm.nih.gov/35892236","citation_count":3,"is_preprint":false},{"pmid":"40075351","id":"PMC_40075351","title":"IP6K2 mutations as a novel mechanism of resistance to oncolytic virus therapy.","date":"2025","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40075351","citation_count":2,"is_preprint":false},{"pmid":"40879991","id":"PMC_40879991","title":"Knockout Mice as an Experimental Model to Study the Biology of Inositol Pyrophosphates.","date":"2025","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/40879991","citation_count":2,"is_preprint":false},{"pmid":"27736936","id":"PMC_27736936","title":"A High-Throughput Screening-Compatible Strategy for the Identification of Inositol Pyrophosphate Kinase Inhibitors.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27736936","citation_count":2,"is_preprint":false},{"pmid":"41683831","id":"PMC_41683831","title":"Role of Inositol Hexakisphosphate Kinases in Vascular Smooth Muscle Cell Calcification.","date":"2026","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41683831","citation_count":0,"is_preprint":false},{"pmid":"41249827","id":"PMC_41249827","title":"Integrating machine learning and molecular dynamics simulation to decipher the molecular network of dioxin-associated liposarcoma.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41249827","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":33035,"output_tokens":5770,"usd":0.092827,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14312,"output_tokens":6107,"usd":0.112117,"stage2_stop_reason":"end_turn"},"total_usd":0.204944,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"IP6K2 (RID-2) is post-transcriptionally induced by IFN-beta in ovarian carcinoma cells and mediates IFN-beta-induced apoptosis; a mutant IP6K2 with substitutions in the putative inositol phosphate binding domain abrogates IFN-beta-induced apoptosis, demonstrating the kinase activity is required.\",\n      \"method\": \"Antisense technical knockout, mutant overexpression, apoptosis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and dominant-negative mutant with defined apoptotic phenotype, single lab, multiple methods\",\n      \"pmids\": [\"11337497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"IP6K2 overexpression enhances radiosensitivity and IFN-beta-induced apoptosis in ovarian carcinoma cells, associated with increased caspase-8 mRNA induction, and both IFN-beta and gamma-irradiation induce apoptosis through the extrinsic receptor-mediated pathway (TRAIL/DR4/caspase-8), positively regulated by IP6K2.\",\n      \"method\": \"Overexpression, colony forming assay, caspase-8 and TRAIL mRNA analysis, dominant negative DR5 mutant\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in single lab, defined pathway placement via dominant-negative and RNA analyses\",\n      \"pmids\": [\"11896621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"IP6K2 (IHPK2) translocates from the cytoplasm/perinuclear region to the nucleus upon IFN-beta treatment, and nuclear localization is required for IFN-beta-induced apoptosis; point mutations in the NLS trap IP6K2 in the cytoplasm and confer resistance to IFN-beta.\",\n      \"method\": \"IHPK2-eGFP live imaging, NLS point mutant overexpression, IC50 apoptosis assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with NLS mutant functionally linked to apoptosis resistance, single lab\",\n      \"pmids\": [\"15634191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IP6K2 binds directly to TRAF2 via residues Ser-347 and Ser-359, and this interaction interferes with TAK1 phosphorylation, thereby inhibiting NF-kappaB signaling downstream of TNF-alpha; mutations at S347A/S359A abolish TRAF2 binding and increase NF-kappaB activity 6-10-fold.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis, TAK1 phosphorylation assay, NF-kappaB DNA binding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding and mutagenesis with defined downstream signaling readout, single lab\",\n      \"pmids\": [\"17379600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HSP90 physically binds IP6K2 and inhibits its catalytic (IP7-synthesizing) activity; disruption of HSP90-IP6K2 binding (by drugs or selective mutations) activates IP6K2 and leads to cell death, establishing HSP90's pro-survival function as inhibition of IP6K2.\",\n      \"method\": \"Co-immunoprecipitation, catalytic activity assay, mutagenesis, pharmacological HSP90 inhibitors\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding demonstrated, enzymatic activity measured, both pharmacological and genetic disruption tested in single rigorous study\",\n      \"pmids\": [\"18195352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IP6K2 knockout mice develop normally but show 4-fold increased incidence of invasive squamous cell carcinoma upon carcinogen exposure; direct microinjection of 5-PP-Ins(1,2,3,4,6)P5 (the IP6K2 product) induces cell death in squamous carcinoma cells, whereas IP6 (the substrate) does not, establishing the enzymatic product as the death-inducing agent.\",\n      \"method\": \"IP6K2 knockout mice, 4-NQO carcinogen treatment, direct microinjection of IP7 vs IP6, comet assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO model replicated multiple phenotypes plus direct product microinjection distinguishing substrate from product\",\n      \"pmids\": [\"19430495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IP6K2 is required for p53-mediated apoptosis: gene disruption of IP6K2 in colorectal cancer cells selectively impairs p53-mediated apoptosis (shifting response toward cell-cycle arrest), and IP6K2 acts by binding directly to p53 and decreasing expression of pro-arrest targets such as p21.\",\n      \"method\": \"IP6K2 gene disruption (HCT116), apoptosis vs. cell cycle arrest assays, co-immunoprecipitation, p21/p53 target gene expression\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined apoptotic vs. arrest phenotype plus direct IP6K2-p53 binding by Co-IP, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"21078964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IP6K2 acts as an effector of the vertebrate Hedgehog (Hh) signaling pathway: IP6K2 depletion in zebrafish inhibited Hh target gene expression and caused craniofacial/somite defects; IP6K2 overexpression enhanced Hh pathway response in mammalian cells; IP6K2 acts at the level of or downstream of Smoothened but upstream of Gli1.\",\n      \"method\": \"Zebrafish morpholino knockdown, mammalian cell Hh reporter assays, mRNA rescue, epistasis with smoM2/gli1 overexpression\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in two model systems, rescue experiments, single lab\",\n      \"pmids\": [\"20980661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CK2 (casein kinase-2) phosphorylates IP6K2 at residues S347 and S356 within a PEST sequence, triggering its ubiquitination and proteasomal degradation; IP6K2 mutants at these sites are resistant to CK2-mediated phosphorylation and are metabolically stable; HCT116 cells depleted of IP6K2 are resistant to cell death elicited by CK2 inhibitors.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis, ubiquitination assay, protein stability analysis, CK2 inhibitor treatment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro phosphorylation, mutagenesis defining specific residues, ubiquitination assay, and functional KD rescue all in one study\",\n      \"pmids\": [\"21262846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IP7 generated by IP6K2 binds CK2 to enhance CK2 phosphorylation of the TTT cochaperone complex (Tti1/Tel2), thereby stabilizing DNA-PKcs and ATM; this leads to p53 phosphorylation at serine 15 and activation of the apoptotic program in human cancer cells and murine B cells.\",\n      \"method\": \"In vitro binding assay (IP7-CK2), CK2 kinase assay, TTT complex phosphorylation assay, p53-S15 phosphorylation, IP6K2 depletion/overexpression in cell lines and mouse B cells\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct IP7-CK2 binding, in vitro kinase assay, genetic depletion in two cell contexts with defined molecular cascade\",\n      \"pmids\": [\"24657168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of an Entamoeba histolytica hybrid IP6K/IP3K was determined; molecular modelling and mutagenesis extrapolated to human IP6K2 revealed two structural elements (an alpha-helical pair and a two-turn 310 helix) forming a substrate-binding pocket with open clamshell geometry; InsP6 contacts both elements while InsP3 rotates 55° relative to InsP6, closer to the alpha-helices. Human IP6K2 retains vestigial IP3K activity.\",\n      \"method\": \"X-ray crystallography, molecular modelling, mutagenesis, kinase activity assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mutagenesis and enzymatic validation; direct structural determination of catalytic mechanism\",\n      \"pmids\": [\"24956979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IP6K2, via IP7 synthesis, promotes cancer cell migration and tumor metastasis by enhancing cell-matrix adhesion and decreasing cell-cell adhesion; this is mediated by IP7-elicited nuclear sequestration and inactivation of the tumor suppressor LKB1.\",\n      \"method\": \"IP6K2 overexpression/knockdown, cell migration/invasion assays, tumor metastasis in mice, LKB1 localization by fractionation and imaging, IP6K2 inhibitor\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo migration/metastasis with proposed LKB1 mechanism, single lab\",\n      \"pmids\": [\"25617365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IP6K2 RNAi and pan-IP6K inhibitor (TNP) restore 5-IP7 levels in PPIP5K-knockout cells to wild-type without rescuing 1,5-IP8; this attenuation of IP6K reverses p53 upregulation, demonstrating that 5-IP7 (produced by IP6K2 among others) regulates p53 expression.\",\n      \"method\": \"CRISPR knockout, RNAi, IP6K inhibitor, inositol phosphate profiling, p53/p21 western blot\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological depletion of IP6K2 with specific molecular readout; single lab but multiple perturbation approaches\",\n      \"pmids\": [\"29078269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IP6K2 binds protein 4.1N with high affinity and specificity; nuclear translocation of 4.1N is dependent on IP6K2; both proteins are highly expressed in cerebellar granule cells where their interaction regulates Purkinje cell morphology, cerebellar synapses, and locomotor function; disruption of IP6K2-4.1N interactions impairs cell viability.\",\n      \"method\": \"Co-immunoprecipitation, IP6K2 KO mice, immunofluorescence/localization, synaptic morphology analysis, motor behavior assays\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding by Co-IP, KO mice with defined phenotype, localization experiments functionally linked, single lab\",\n      \"pmids\": [\"30006360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IP6K1 and IP6K2 together control inositol pyrophosphate metabolism; double knockout of IP6K1/2 in human HCT116 cells eliminates IP7 and IP8, elevates intracellular ATP and free phosphate, decreases phosphate flux (both import and export), and reduces phosphate export via the XPR1 exporter, which is regulated by inositol pyrophosphates binding to its SPX domain.\",\n      \"method\": \"CRISPR KO (IP6K1/2 double KO), PAGE and HPLC inositol phosphate profiling, Malachite green phosphate assay, 32Pi pulse labeling, XPR1 functional assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genetic KO with multiple orthogonal biochemical assays, mechanistic link to XPR1-SPX domain binding established\",\n      \"pmids\": [\"31186349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IP6K2 physically interacts with creatine kinase-B (CK-B); IP6K2-knockout mouse cerebella produce less phosphocreatine and ATP, show higher reactive oxygen species, protein oxidative damage, and impaired cytochrome-c1 subunit expression of mitochondrial complex III; combined N-acetylcysteine and phosphocreatine treatment reversed some effects, establishing IP6K2-CK-B interaction in energy homeostasis and neuroprotection.\",\n      \"method\": \"Protein interactome (IP6K2 KO mouse brain), co-immunoprecipitation, metabolite measurement (phosphocreatine, ATP), ROS assay, mitochondrial complex analysis, pharmacological rescue\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and KO mouse phenotype with multiple metabolic readouts, single lab\",\n      \"pmids\": [\"33547244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IP6K2 attenuates PINK1-mediated mitophagy in the brain via a non-catalytic (kinase-independent) mechanism; both wild-type and kinase-dead IP6K2 reverse mitophagy marker expression in IP6K2-knockdown cells, whereas IP6K2 supplementation in IP6K2/PINK1 double-knockdown cells fails to reverse LC3-II levels, placing IP6K2's mitoprotective effect upstream of or dependent on PINK1.\",\n      \"method\": \"IP6K2 KO mice, siRNA knockdown, kinase-dead mutant overexpression, LC3-II western blot, Drp-1/PGC1-alpha/NRF-1 expression, double-knockdown epistasis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase-dead mutant distinguishes catalytic from non-catalytic function, epistasis with PINK1, single lab\",\n      \"pmids\": [\"35353626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Wild-type IP6K2 expression (but not kinase-dead IP6K2 mutant) expands the outer nucleolar granular region, establishing that IP7 produced by IP6K2 acts as an 'electrostatic glue' mediating biomolecular condensate assembly of multiple nucleolar proteins.\",\n      \"method\": \"Quantitative confocal imaging, CRISPR KO (NUDT3, PPIP5Ks), heterologous IP6K2 and kinase-dead mutant expression, pan-IP6K inhibitor, siRNA knockdown\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase-dead mutant as internal control, multiple genetic/pharmacological perturbations, single lab\",\n      \"pmids\": [\"36671538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IP6K2 is selectively expressed in enteric neurons of the gastrointestinal tract; IP6K2-knockout mice show significantly impaired IP7 metabolism in gut/duodenal muscularis externa; IP6K2 ablation alters expression of gene sets associated with mature neurons, neural progenitor/stem cells, and glial cells, indicating a critical role of the IP6K2-IP7 axis in developmental and functional regulation of the enteric nervous system.\",\n      \"method\": \"LC-MS inositol pyrophosphate profiling, IP6K2 KO mice, cell-type immunostaining, whole transcriptome analysis of duodenal muscularis externa\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice with LC-MS profiling and transcriptomics, single lab; subcellular/cell-type localization functionally linked\",\n      \"pmids\": [\"36681123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Renal IP6K1/2 double-knockout mice show downregulated expression and function of Na+/Pi cotransporters NaPi-IIa and NaPi-IIc, hypophosphatemia, reduced brush border membrane phosphate uptake, decreased FGF23, increased bone resorption, diuresis, albuminuria, and hypercalciuria; in vitro, Ip6k1/2 depletion reduces phosphate transport and blunts adaptation to ambient phosphate changes.\",\n      \"method\": \"Renal tubular-specific Ip6k1/2 KO mice, opossum kidney cell model, mRNA/protein expression of NaPi cotransporters, Malachite green phosphate uptake, plasma phosphate/FGF23 measurement, bone analysis\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific double KO in vivo and in vitro with multiple physiological readouts, single lab\",\n      \"pmids\": [\"38317282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IP6K2 is activated by a ROS-Src phosphorylation axis to generate 5-IP7 around adherens junctions; 5-IP7 inhibits inositol 5-phosphatases (OCRL) to promote PI(4,5)P2-mediated endocytic adaptor recruitment and E-cadherin endocytosis, leading to AJ disassembly and beta-catenin transcriptional activation; intestinal epithelium-specific IP6K2 deletion attenuates DSS-induced colitis/CRC.\",\n      \"method\": \"IP6K2 KO (intestinal epithelium-specific), Src phosphorylation assay, OCRL binding/activity assay, PI(4,5)P2 imaging, E-cadherin endocytosis assay, beta-catenin reporter, DSS colitis model, IP6K2 isoform-selective inhibitor\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (biochemical, cell biological, in vivo KO, pharmacological inhibitor) in a single rigorous study establishing a detailed molecular mechanism\",\n      \"pmids\": [\"40858937\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IP6K2 is an inositol hexakisphosphate kinase that phosphorylates IP6 to generate the inositol pyrophosphate 5-IP7; its catalytic activity and protein-protein interactions mediate diverse cellular functions including: apoptosis via direct binding to p53 and activation of a DNA-PK/ATM-CK2-TTT signaling cascade; pro-survival inhibition by HSP90 (which binds and suppresses IP6K2 catalytically) and CK2-mediated phosphorylation at S347/S356 leading to ubiquitin-proteasomal degradation; NF-kappaB suppression through TRAF2 binding; IFN-beta-induced apoptosis requiring nuclear translocation; cancer cell migration/metastasis through LKB1 nuclear inactivation; phosphate homeostasis by regulating XPR1-mediated phosphate export and renal Na+/Pi cotransporter expression; a non-catalytic role in attenuating PINK1-mediated mitophagy; interaction with CK-B for mitochondrial energy homeostasis; interaction with 4.1N for cerebellar circuit function; modulation of nucleolar condensate assembly via IP7; and activation by a ROS-Src axis to generate junctional 5-IP7 that inhibits OCRL phosphatase, promoting E-cadherin endocytosis and beta-catenin signaling in colorectal cancer.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IP6K2 is an inositol hexakisphosphate kinase that phosphorylates IP6 to generate the inositol pyrophosphate 5-IP7, and through this catalytic output—together with non-catalytic protein interactions—it governs apoptosis, phosphate homeostasis, cell adhesion, and neuronal function [#5, #14]. A crystallographic and modelling analysis of a hybrid IP6K/IP3K defined an open clamshell substrate-binding pocket built from an alpha-helical pair and a two-turn 3-10 helix, and showed human IP6K2 retains vestigial IP3K activity [#10]. The enzyme is a positive regulator of cell death: it is induced by IFN-beta and must translocate to the nucleus to drive apoptosis, and direct microinjection of its product 5-IP7 (but not the IP6 substrate) is itself sufficient to kill carcinoma cells, while IP6K2-null mice show increased carcinogen-induced squamous carcinoma [#0, #2, #5]. Mechanistically, IP6K2 binds p53 to bias the p53 response toward apoptosis over cell-cycle arrest, and IP7 binds CK2 to potentiate phosphorylation of the TTT cochaperone complex (Tti1/Tel2), stabilizing DNA-PKcs and ATM and driving p53 serine-15 phosphorylation [#6, #9]. Its pro-death activity is held in check by HSP90, which binds and catalytically suppresses IP6K2, and by CK2-mediated phosphorylation at S347/S356 within a PEST motif that targets IP6K2 for ubiquitin-proteasomal degradation [#4, #8]. The same S347/S359 region mediates binding to TRAF2, blocking TAK1 phosphorylation to suppress NF-kappaB signaling [#3]. Beyond apoptosis, IP6K2 (with IP6K1) controls cellular inositol pyrophosphate pools and phosphate flux, regulating XPR1-mediated phosphate export via its SPX domain and renal NaPi-IIa/IIc cotransporter expression and systemic phosphate handling [#14, #19]. In a colorectal cancer context, a ROS-Src axis activates IP6K2 to generate junctional 5-IP7 that inhibits the OCRL 5-phosphatase, promoting PI(4,5)P2-dependent E-cadherin endocytosis and beta-catenin signaling [#20]. IP6K2 also has tissue-specific roles in cerebellar circuitry through binding protein 4.1N and in mitochondrial energy homeostasis through binding creatine kinase-B, and it attenuates PINK1-mediated mitophagy through a kinase-independent mechanism [#13, #15, #16].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established IP6K2 as a positive, kinase-dependent regulator of apoptosis, answering whether this inositol kinase functioned in cell death and through which death pathway.\",\n      \"evidence\": \"Antisense knockout, dominant-negative inositol-binding mutant, and dominant-negative DR5/caspase-8 analyses in IFN-beta- and irradiation-treated ovarian carcinoma cells\",\n      \"pmids\": [\"11337497\", \"11896621\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the molecular target of IP6K2 catalytic output\", \"Restricted to ovarian carcinoma in a single lab\", \"Mechanism linking kinase activity to extrinsic apoptotic pathway components unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed that subcellular relocation, not just expression, gates IP6K2 function, demonstrating nuclear translocation is required for IFN-beta-induced apoptosis.\",\n      \"evidence\": \"IP6K2-eGFP live imaging and NLS point mutants linked to apoptosis resistance in carcinoma cells\",\n      \"pmids\": [\"15634191\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nuclear targets of IP6K2/IP7 not defined\", \"Signal triggering translocation unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified a non-apoptotic signaling role by showing IP6K2 binds TRAF2 to suppress NF-kappaB, mapping the interaction to specific serine residues.\",\n      \"evidence\": \"Co-immunoprecipitation, S347A/S359A mutagenesis, TAK1 phosphorylation and NF-kappaB DNA-binding assays\",\n      \"pmids\": [\"17379600\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether catalytic activity contributes to NF-kappaB suppression unclear\", \"Single lab, no in vivo confirmation\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined how IP6K2 pro-death activity is restrained, showing HSP90 binds and catalytically inhibits IP6K2 as the basis of HSP90's pro-survival function.\",\n      \"evidence\": \"Co-IP, catalytic activity assays, mutagenesis, and pharmacological HSP90 inhibition with cell-death readouts\",\n      \"pmids\": [\"18195352\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of HSP90-IP6K2 inhibition not resolved\", \"Generality across cell types untested at this stage\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Provided in vivo and biochemical proof that the enzymatic product 5-IP7, not substrate IP6, is the death-inducing agent and that IP6K2 suppresses carcinogenesis.\",\n      \"evidence\": \"IP6K2 knockout mice with 4-NQO carcinogen, direct microinjection of IP7 versus IP6, comet assay\",\n      \"pmids\": [\"19430495\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct intracellular targets of microinjected IP7 not identified\", \"Tumor-suppressive mechanism in vivo not molecularly dissected\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected IP6K2 to the p53 apoptotic decision and to Hedgehog signaling, broadening its functional placement.\",\n      \"evidence\": \"IP6K2 gene disruption in HCT116 with apoptosis-versus-arrest readouts and p53 Co-IP; zebrafish morpholino and mammalian Hh reporter epistasis\",\n      \"pmids\": [\"21078964\", \"20980661\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How IP6K2-p53 binding biases target gene selection unresolved\", \"Molecular target of IP6K2 within the Hh pathway between Smoothened and Gli1 unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established a degradation switch controlling IP6K2 levels, showing CK2 phosphorylates a PEST-motif site to drive ubiquitin-proteasomal turnover.\",\n      \"evidence\": \"In vitro kinase assay, S347/S356 mutagenesis, ubiquitination and stability assays, CK2 inhibitor with cell-death rescue\",\n      \"pmids\": [\"21262846\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase mediating IP6K2 ubiquitination not identified\", \"Interplay between CK2 degradation and TRAF2 binding at overlapping residues not reconciled\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved the downstream apoptotic cascade by showing IP7 binds CK2 to potentiate TTT-complex phosphorylation, stabilizing DNA-PKcs/ATM and activating p53-S15.\",\n      \"evidence\": \"In vitro IP7-CK2 binding, CK2 kinase and TTT phosphorylation assays, p53-S15 readout, depletion/overexpression in cells and mouse B cells\",\n      \"pmids\": [\"24657168\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural basis of IP7-CK2 interaction not defined\", \"How this nuclear cascade integrates with cytoplasmic IP6K2 functions unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided structural insight into catalysis, defining the substrate-binding pocket geometry and confirming vestigial IP3K activity of human IP6K2.\",\n      \"evidence\": \"X-ray crystallography of an E. histolytica hybrid IP6K/IP3K, modelling, mutagenesis, and kinase assays extrapolated to human IP6K2\",\n      \"pmids\": [\"24956979\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No direct crystal structure of human IP6K2\", \"Conformational changes during catalysis inferred, not directly observed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified a pro-metastatic function, showing IP7 drives nuclear sequestration and inactivation of LKB1 to alter adhesion and promote invasion.\",\n      \"evidence\": \"IP6K2 overexpression/knockdown, migration/invasion assays, mouse metastasis, LKB1 fractionation/imaging, IP6K inhibitor\",\n      \"pmids\": [\"25617365\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which IP7 controls LKB1 localization unresolved\", \"Apparent contrast with tumor-suppressive apoptotic role not reconciled\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Disentangled which inositol pyrophosphate regulates p53, showing IP6K-derived 5-IP7 (not 1,5-IP8) controls p53 expression.\",\n      \"evidence\": \"CRISPR KO of PPIP5K, IP6K RNAi and TNP inhibitor, inositol phosphate profiling, p53/p21 westerns\",\n      \"pmids\": [\"29078269\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IP6K2-specific contribution versus other IP6K isoforms not isolated\", \"Direct link from 5-IP7 levels to p53 transcription not mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed a neuronal scaffolding function, showing IP6K2 binds protein 4.1N to control its nuclear translocation and cerebellar circuit integrity.\",\n      \"evidence\": \"Co-IP, IP6K2 KO mice, immunofluorescence, synaptic morphology, and motor behavior assays\",\n      \"pmids\": [\"30006360\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether catalytic activity is required for 4.1N regulation untested\", \"Molecular consequence of 4.1N nuclear translocation undefined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established the metabolic core function, showing IP6K1/2 set cellular IP7/IP8 pools and regulate phosphate flux via XPR1-SPX domain binding.\",\n      \"evidence\": \"IP6K1/2 double-KO HCT116, PAGE/HPLC inositol phosphate profiling, malachite green and 32Pi flux assays, XPR1 functional assay\",\n      \"pmids\": [\"31186349\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"IP6K2-specific (versus IP6K1) contribution to phosphate export not separated\", \"Direct binding of inositol pyrophosphate to XPR1-SPX inferred from prior context\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked IP6K2 to mitochondrial energy homeostasis through binding creatine kinase-B and protecting against oxidative damage in cerebellum.\",\n      \"evidence\": \"IP6K2 KO mouse brain interactome, Co-IP, phosphocreatine/ATP and ROS measurements, mitochondrial complex analysis, pharmacological rescue\",\n      \"pmids\": [\"33547244\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Catalytic versus structural contribution of IP6K2 to CK-B function unclear\", \"Mechanism connecting CK-B binding to complex III deficits undefined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated a kinase-independent role, showing IP6K2 attenuates PINK1-mediated mitophagy via a non-catalytic mechanism.\",\n      \"evidence\": \"IP6K2 KO mice, siRNA, kinase-dead mutant rescue, LC3-II and mitophagy marker analysis, IP6K2/PINK1 double-knockdown epistasis\",\n      \"pmids\": [\"35353626\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Protein partners mediating the non-catalytic mitophagy effect not identified\", \"Relationship to PINK1 (upstream versus dependent) only partially resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed IP6K2-derived IP7 promotes nucleolar condensate assembly and that IP6K2 marks and shapes the enteric nervous system, extending its functions to biomolecular condensates and gut neurobiology.\",\n      \"evidence\": \"Confocal imaging with kinase-dead IP6K2 control and CRISPR/inhibitor perturbations; LC-MS profiling, IP6K2 KO mice, cell-type immunostaining and transcriptomics of duodenal muscularis externa\",\n      \"pmids\": [\"36671538\", \"36681123\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which nucleolar proteins are directly bridged by IP7 not enumerated\", \"Causal mechanism linking IP6K2-IP7 axis to enteric neuron development undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a systemic phosphate-handling role, showing renal IP6K1/2 controls NaPi cotransporter expression and whole-body phosphate/mineral balance.\",\n      \"evidence\": \"Renal tubular-specific Ip6k1/2 KO mice and opossum kidney cells with NaPi expression, phosphate uptake, plasma FGF23 and bone analyses\",\n      \"pmids\": [\"38317282\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IP6K2-specific contribution distinct from IP6K1 not isolated\", \"Mechanism coupling inositol pyrophosphates to NaPi cotransporter regulation not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Integrated upstream activation with a junctional output, showing a ROS-Src axis activates IP6K2 to make 5-IP7 that inhibits OCRL, driving E-cadherin endocytosis and beta-catenin signaling in colorectal cancer.\",\n      \"evidence\": \"Intestinal epithelium-specific IP6K2 KO, Src phosphorylation and OCRL binding/activity assays, PI(4,5)P2 imaging, E-cadherin endocytosis, beta-catenin reporter, DSS colitis model, isoform-selective inhibitor\",\n      \"pmids\": [\"40858937\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Src phosphorylation site(s) on IP6K2 not detailed here\", \"How junctional 5-IP7 pools are spatially confined unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How IP6K2's pro-apoptotic/tumor-suppressive functions are reconciled with its pro-metastatic and pro-tumorigenic roles across tissues, and how catalytic versus non-catalytic activities are selected in each context, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model distinguishing context-specific outputs of IP6K2\", \"Isoform-specific versus IP6K1-shared functions incompletely separated\", \"No human IP6K2 crystal structure with bound substrate/product\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [5, 10, 14]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [6, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 4, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 6, 9]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [14, 19]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [14, 19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 20]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TP53\", \"TRAF2\", \"HSP90\", \"CSNK2A1\", \"EPB41L1\", \"CKB\", \"OCRL\", \"PINK1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}