{"gene":"INPP5A","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2001,"finding":"Inositol polyphosphate 5-phosphatase IV (INPP5A/5ptase IV) hydrolyzes PI(3,4,5)P3 with ~10-fold higher affinity (Km = 0.65 µM) than other 5-phosphatases including SHIP, OCRL, and 5ptase II. Overexpression in 293 cells depleted both PI(4,5)P2 and PI(3,4,5)P3, increased PI(4)P and PI(3,4)P2, inhibited Akt phosphorylation (correlated with PI(3,4,5)P3 levels, not PI(3,4)P2), and sensitized cells to FAS-induced apoptosis, placing 5ptase IV as a regulator of the PI3K/Akt pathway.","method":"In vitro enzyme kinetics; stable cell lines overexpressing 5ptase IV alone or combined with inositol polyphosphate 4-phosphatase; phosphoinositide mass measurement; Akt phosphorylation immunoblot; FAS-induced apoptosis assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinetics plus multiple orthogonal cellular assays with mechanistic controls","pmids":["11706019"],"is_preprint":false},{"year":2006,"finding":"Inositol polyphosphate 5-phosphatase IV (INPP5A/5ptase IV) is highly expressed in arcuate and lateral hypothalamic neurons, undergoes time-dependent tyrosine phosphorylation following intracerebroventricular insulin, and its antisense-mediated knockdown (~80% reduction) increases basal inositol phosphate accumulation in the hypothalamus, reduces food intake, and causes body weight loss, demonstrating that it regulates PI3K signaling downstream of insulin in the hypothalamus.","method":"Antisense oligonucleotide knockdown in rat hypothalamus; immunoblotting for tyrosine phosphorylation; inositol phosphate accumulation assay; food intake and body weight measurement","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo knockdown with defined biochemical and physiological phenotypes; single lab","pmids":["16916951"],"is_preprint":false},{"year":2007,"finding":"The 72-kDa inositol polyphosphate 5-phosphatase (72-5ptase, i.e., INPP5A) is dynamically recruited to FcγR-stimulated phagocytic cups, where it degrades PI(3,4,5)P3; dominant-negative 72-5ptase or siRNA knockdown amplifies and prolongs PI(3,4,5)P3 at the FcγR phagocytic cup but not the CR3 cup, inhibiting pseudopod extension and phagosome closure specifically in FcγR-mediated phagocytosis.","method":"Time-lapse imaging of PI(3,4,5)P3 biosensors; dominant-negative expression; siRNA knockdown; co-localization to phagocytic cup","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — live-cell imaging with biosensors, dominant-negative, and siRNA; multiple orthogonal methods","pmids":["17682126"],"is_preprint":false},{"year":2012,"finding":"AAV-mediated overexpression of Inpp5a (5PP) in Purkinje cells of SCA2 transgenic mice chronically reduces IP3 levels, alleviates age-dependent aberrant firing patterns of Purkinje cells, rescues motor incoordination, and prevents Purkinje cell death, demonstrating that INPP5A-mediated IP3 hydrolysis is neuroprotective against supranormal IP3R-driven calcium signaling in SCA2.","method":"AAV-mediated gene delivery; rotarod behavioral testing; electrophysiology of Purkinje cell firing; histological assessment of Purkinje cell survival","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — in vivo gain-of-function with multiple orthogonal phenotypic readouts in a disease model; replicated across behavioral, electrophysiological, and histological endpoints","pmids":["22973002"],"is_preprint":false},{"year":2015,"finding":"Gene-trap deletion of Inpp5a in mice causes early-onset, slowly progressive Purkinje cell degeneration and ataxia; homozygous mutants show reduced phosphatase activity toward phosphoinositol substrates, locomotor instability beginning at P16, and widespread Purkinje cell loss by P60, establishing a non-redundant, cell-autonomous requirement for INPP5A in Purkinje cell survival.","method":"Gene-trap mouse model; qRT-PCR; immunohistochemistry; Western blot; rotarod; β-galactosidase staining; phosphatase activity assay","journal":"Neurogenetics","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function mouse model with biochemical, histological, and behavioral phenotypes","pmids":["26051944"],"is_preprint":false},{"year":2020,"finding":"In SCA17 knock-in mice, mutant TBP inhibits SP1-mediated transcription to down-regulate INPP5A; CRISPR/Cas9-mediated deletion of Inpp5a in wild-type mouse cerebellum causes Purkinje cell degeneration, and Inpp5a overexpression decreases IP3 levels and ameliorates Purkinje cell degeneration in SCA17 mice, placing INPP5A as a downstream effector of TBP/SP1 transcription that protects Purkinje cells by hydrolyzing IP3.","method":"SCA17 knock-in mice; CRISPR/Cas9 cerebellar deletion; AAV-mediated Inpp5a overexpression; IP3 level measurement; Purkinje cell histology; SP1-mediated transcription assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 — multiple genetic manipulations (KO and overexpression) with biochemical and histological validation in vivo","pmids":["32107387"],"is_preprint":false},{"year":2021,"finding":"Loss of INPP5A causes IP3 accumulation and calcium efflux from ER stores, which triggers dissociation of oxysterol binding protein (OSBP) from the Golgi and from VAP-containing ER-Golgi membrane contact sites, resulting in depletion of cholesterol and Gb3 from the cell surface and blockade of clathrin-independent endocytosis of Shiga toxin.","method":"INPP5A loss-of-function; IP3 measurement; calcium imaging; OSBP localization by confocal microscopy; cholesterol and Gb3 surface staining; Shiga toxin uptake assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods linking INPP5A loss to IP3→Ca2+→OSBP dissociation→lipid transfer defect","pmids":["33976123"],"is_preprint":false},{"year":2024,"finding":"Genome-scale CRISPR screens identified INPP5A as a selective synthetic lethal dependency in GNAQ/GNA11-mutant uveal melanoma (UM) cells in vitro and in vivo. Suppression of INPP5A in mutant cells causes accumulation of IP3, hyperactivation of IP3 receptor signaling, increased cytosolic calcium, and p53-dependent apoptosis. GNAQ/GNA11-mutant cells and patient tumors exhibit elevated IP4 (a biomarker of enhanced IP3 production) that is abolished by GNAQ/GNA11 inhibition and correlates with sensitivity to INPP5A depletion.","method":"Genome-scale CRISPR screens; in vivo xenograft models; IP3/IP4 mass measurement; calcium imaging; p53-dependent apoptosis assays; GNAQ/GNA11 inhibitor experiments","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 1–2 — genome-scale genetic screen plus multiple biochemical and in vivo validations","pmids":["38233483"],"is_preprint":false},{"year":2025,"finding":"INPP5A is a farnesylated and reversibly palmitoylated membrane-bound IP3 5-phosphatase that is upregulated in and required by CA-GNAQ/11-driven UM cells. Palmitoylation targets INPP5A to the plasma membrane (mutation of palmitoylation site reduces PM localization), while mutation of the prenylation site results in purely nucleoplasmic localization. INPP5A regulates low-frequency Ca2+ oscillations in UM cells driven by constitutive Gq/11 activity, and acute pharmacological inhibition of INPP5A augments Ca2+ oscillation rate, demonstrating that it safeguards UM cells from Ca2+ overload by controlling IP3-evoked Ca2+ dynamics.","method":"GFP-tagged INPP5A localization imaging; palmitoylation and prenylation site mutagenesis; single-cell calcium imaging; pharmacological INPP5A inhibitor (YU144369); UM cell survival assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — structure-function mutagenesis combined with live-cell calcium imaging and pharmacological inhibition","pmids":["40812428"],"is_preprint":false},{"year":2024,"finding":"INPP5A is targeted to plasma membrane, nuclear envelope, ER, and lysosomes through C-terminal farnesylation and palmitoylation; mutation of the palmitoylation site significantly reduces plasma membrane localization, and these distinct localizations regulate IP3 metabolism and Ca2+ mobilization in uveal melanoma cells.","method":"GFP-INPP5A subcellular localization imaging; palmitoylation and prenylation site mutagenesis; calcium mobilization assays in UM cells","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization with functional mutagenesis; preprint not yet peer-reviewed","pmids":["bio_10.1101_2024.09.18.613756"],"is_preprint":true},{"year":2013,"finding":"In obese rodent models, 72k-5ptase (INPP5A) expression is increased in skeletal muscle and adipose tissue; antisense oligonucleotide reduction of 72k-5ptase catalytic activity in obese rats improves insulin signal transduction and restores glucose homeostasis, demonstrating its role as a negative regulator of peripheral insulin signaling.","method":"Antisense oligonucleotide knockdown; immunoblotting for insulin signaling components; hyperinsulinemic-euglycemic clamp; 72k-5ptase catalytic activity assay","journal":"The Journal of endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo knockdown with defined biochemical and physiological phenotypes; single lab","pmids":["23349329"],"is_preprint":false},{"year":2011,"finding":"In itpka-deficient neurons, the levels of Inpp5a protein are upregulated at synapses as a compensatory response, and this is associated with decreased duration of IP3 signals and shorter IP3-dependent Ca2+ transients, establishing that INPP5A is a synaptic regulator of IP3 and Ca2+ signal duration.","method":"siRNA knockdown of itpka; immunoblotting for Inpp5a at synaptoneurosomes; IP3 mass assay; dendritic Ca2+ imaging","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 3 — indirect evidence via compensatory upregulation; single lab","pmids":["22120525"],"is_preprint":false},{"year":2021,"finding":"TRIM32 deficiency in mice decreases INPP5A protein levels in the cerebellum, associated with impaired motor balance and Purkinje cell dendritic/synaptic deficits, suggesting TRIM32 regulates INPP5A abundance in cerebellar neurons.","method":"TRIM32 knockout mice; immunohistochemistry; Golgi staining; rotarod; immunoblotting for INPP5A","journal":"Frontiers in aging neuroscience","confidence":"Low","confidence_rationale":"Tier 3 — indirect association; no direct mechanistic link between TRIM32 and INPP5A established","pmids":["34421574"],"is_preprint":false},{"year":2026,"finding":"MBD2 directly binds the INPP5A promoter to repress its transcription; PKA-mediated phosphorylation of MBD2 at S99 recruits 14-3-3σ to stabilize MBD2, enhancing transcriptional repression of INPP5A; reduced INPP5A promotes IP3 accumulation and PI3K/Akt pathway activation, driving pituitary tumor malignant progression.","method":"ChIP assay (MBD2 binding to INPP5A promoter); PKA pharmacological activation; co-immunoprecipitation (MBD2/14-3-3σ); INPP5A overexpression and knockdown in pituitary tumor cells; IP3 measurement; PI3K/Akt pathway immunoblotting","journal":"CNS neuroscience & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 — direct promoter binding plus multiple biochemical validations; single lab, recently published","pmids":["41857481"],"is_preprint":false}],"current_model":"INPP5A is a farnesylated and palmitoylated membrane-associated type I inositol 1,4,5-trisphosphate 5-phosphatase that hydrolyzes IP3 (and PI(3,4,5)P3 with high affinity) to terminate IP3R-mediated calcium signaling; it is essential for Purkinje cell survival (loss causes ataxia and neurodegeneration in mice), acts as a synthetic lethal vulnerability in GNAQ/GNA11-mutant uveal melanoma by preventing IP3-driven calcium overload and p53-dependent apoptosis, negatively regulates PI3K/Akt signaling and peripheral insulin action, controls lipid exchange at ER-Golgi membrane contact sites via IP3-Ca2+-OSBP axis, and is transcriptionally repressed by MBD2/PKA in pituitary tumors, with its subcellular localization to the plasma membrane, ER, and lysosomes regulated by dual lipid modifications (farnesylation and palmitoylation)."},"narrative":{"teleology":[{"year":2001,"claim":"Establishing that INPP5A is not merely an IP3 phosphatase but also a high-affinity PI(3,4,5)P3 phosphatase that controls Akt signaling and apoptotic sensitivity answered the question of whether 5-phosphatases could directly regulate the PI3K/Akt axis.","evidence":"In vitro enzyme kinetics with purified substrates plus stable overexpression in HEK293 cells measuring phosphoinositide mass, Akt phosphorylation, and FAS-induced apoptosis","pmids":["11706019"],"confidence":"High","gaps":["Endogenous loss-of-function data for PI(3,4,5)P3 regulation were not provided","Relative contribution of IP3 vs PI(3,4,5)P3 hydrolysis in physiological contexts unclear","No structural basis for substrate selectivity"]},{"year":2006,"claim":"Demonstrating that INPP5A is an insulin-responsive phosphatase in hypothalamic neurons whose knockdown reduces food intake established a role for INPP5A in central metabolic regulation beyond its known IP3 phosphatase activity.","evidence":"Antisense oligonucleotide knockdown in rat hypothalamus with inositol phosphate accumulation, food intake, and body weight measurements","pmids":["16916951"],"confidence":"Medium","gaps":["Genetic loss-of-function model not used","Whether the metabolic effect is IP3- or PI(3,4,5)P3-dependent was not resolved","No independent replication"]},{"year":2007,"claim":"Showing that INPP5A is dynamically recruited to FcγR phagocytic cups to degrade PI(3,4,5)P3 and enable phagosome closure answered how PI(3,4,5)P3 is spatiotemporally resolved during receptor-specific phagocytosis.","evidence":"Live-cell PI(3,4,5)P3 biosensor imaging combined with dominant-negative expression and siRNA knockdown in macrophages","pmids":["17682126"],"confidence":"High","gaps":["Whether INPP5A recruitment mechanism involves direct lipid or protein interactions at the cup is unknown","In vivo phagocytosis phenotype not tested"]},{"year":2011,"claim":"Identification of compensatory INPP5A upregulation at synapses upon loss of ITPKA linked INPP5A to fine-tuning of synaptic IP3/Ca²⁺ signal duration, addressing which phosphatases shape postsynaptic IP3 dynamics.","evidence":"ITPKA siRNA knockdown in neurons with synaptoneurosome fractionation, IP3 mass assay, and dendritic calcium imaging","pmids":["22120525"],"confidence":"Medium","gaps":["Evidence is correlative from a compensatory context","Direct synaptic loss-of-function of INPP5A not performed","Mechanism of upregulation unknown"]},{"year":2012,"claim":"AAV-mediated Purkinje cell–specific overexpression of INPP5A rescuing SCA2 motor and electrophysiological phenotypes established INPP5A as a neuroprotective agent that counteracts IP3R-driven excitotoxic calcium signaling in cerebellar ataxia.","evidence":"AAV delivery to SCA2 transgenic mouse cerebellum with rotarod, Purkinje cell electrophysiology, and histological survival analysis","pmids":["22973002"],"confidence":"High","gaps":["Endogenous INPP5A loss-of-function in cerebellum had not yet been reported","Whether rescue reflects IP3 or PI(3,4,5)P3 hydrolysis not distinguished"]},{"year":2013,"claim":"Antisense reduction of INPP5A in obese rats improving insulin sensitivity and glucose homeostasis established it as a negative regulator of peripheral insulin signaling, complementing the central metabolic role described earlier.","evidence":"Antisense knockdown in obese rodents with hyperinsulinemic-euglycemic clamp and insulin signaling immunoblots","pmids":["23349329"],"confidence":"Medium","gaps":["Genetic knockout model for peripheral insulin action not available","Relative importance in muscle vs adipose not resolved"]},{"year":2015,"claim":"Gene-trap deletion of Inpp5a causing progressive Purkinje cell loss and ataxia in mice provided the first definitive loss-of-function genetic evidence that INPP5A is non-redundantly required for Purkinje cell survival.","evidence":"Gene-trap mouse model with rotarod, immunohistochemistry, and phosphatase activity assays","pmids":["26051944"],"confidence":"High","gaps":["Cell-autonomous vs non-cell-autonomous contributions not fully dissected","Downstream calcium and IP3 levels not directly measured in knockout cerebellum"]},{"year":2020,"claim":"Discovery that mutant TBP in SCA17 represses INPP5A transcription via SP1, and that CRISPR deletion of Inpp5a in wild-type cerebellum recapitulates Purkinje cell degeneration, linked INPP5A deficiency to transcriptionally driven cerebellar neurodegeneration and identified the upstream regulatory axis.","evidence":"SCA17 knock-in mice; CRISPR/Cas9 cerebellar deletion; AAV overexpression rescue; IP3 measurement; SP1 transcription assays","pmids":["32107387"],"confidence":"High","gaps":["Whether SP1-INPP5A axis is relevant in other polyglutamine ataxias beyond SCA2 and SCA17 not tested","Chromatin-level regulation of INPP5A promoter not fully characterized"]},{"year":2021,"claim":"Demonstration that INPP5A loss triggers an IP3→Ca²⁺→OSBP dissociation cascade that disrupts ER–Golgi membrane contact sites and depletes surface cholesterol/Gb3 revealed a previously unknown role for INPP5A in non-vesicular lipid transport.","evidence":"INPP5A loss-of-function with IP3 measurement, calcium imaging, OSBP localization, cholesterol/Gb3 staining, and Shiga toxin uptake","pmids":["33976123"],"confidence":"High","gaps":["Whether this lipid transfer defect contributes to Purkinje cell degeneration is unknown","Direct physical interaction between INPP5A and OSBP/VAP not assessed"]},{"year":2024,"claim":"Genome-scale CRISPR screens identifying INPP5A as a selective synthetic lethal dependency in GNAQ/GNA11-mutant uveal melanoma established that oncogenic Gq signaling creates a critical reliance on INPP5A to buffer IP3/Ca²⁺ overload, with p53 as the apoptotic executor upon INPP5A loss.","evidence":"Genome-scale CRISPR screens in UM cell panels; xenograft models; IP3/IP4 mass measurements; calcium imaging; p53-dependent apoptosis assays","pmids":["38233483"],"confidence":"High","gaps":["Therapeutic window for INPP5A inhibition in vivo not established","Whether other Gq-driven cancers share this dependency is untested"]},{"year":2025,"claim":"Structure-function analysis showing that farnesylation directs INPP5A away from the nucleus while palmitoylation targets it to the plasma membrane, where it controls Ca²⁺ oscillation frequency, resolved how dual lipid modifications govern INPP5A's subcellular localization and function in UM cells.","evidence":"GFP-tagged INPP5A with prenylation and palmitoylation site mutagenesis; single-cell calcium imaging; pharmacological inhibitor YU144369","pmids":["40812428"],"confidence":"High","gaps":["Identity of the palmitoyl acyltransferase(s) modifying INPP5A unknown","Structural basis for membrane orientation not determined","Whether lipid modification state changes in cerebellar neurons is untested"]},{"year":2026,"claim":"Identification of MBD2 as a direct transcriptional repressor of INPP5A, stabilized by PKA-mediated phosphorylation and 14-3-3σ binding, revealed a second transcriptional axis (beyond SP1/TBP) that silences INPP5A to promote IP3/Akt-driven tumorigenesis in pituitary tumors.","evidence":"ChIP for MBD2 at INPP5A promoter; co-IP of MBD2/14-3-3σ; PKA activation; INPP5A overexpression/knockdown in pituitary tumor cells","pmids":["41857481"],"confidence":"Medium","gaps":["Whether MBD2-mediated INPP5A repression occurs in other tumor types is unknown","Epigenetic context (DNA methylation state of INPP5A promoter) not fully characterized","Single-lab finding awaits independent confirmation"]},{"year":null,"claim":"Key unresolved questions include the structural basis for INPP5A's dual substrate specificity toward IP3 and PI(3,4,5)P3, the identity of the palmitoyl acyltransferase(s) modifying INPP5A, whether the ER–Golgi lipid transfer function contributes to neurodegeneration, and whether INPP5A inhibition is therapeutically viable in GNAQ/GNA11-mutant cancers.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal structure of INPP5A","Palmitoylation enzyme not identified","Causal link between lipid transfer defect and Purkinje cell death not tested","In vivo pharmacological INPP5A inhibition in cancer models not yet reported"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,3,4,5,6,7,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,7,10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[8,9]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[6,9]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[9]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,6,7,8,10,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,4,5,7,13]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,7]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[3,4,5,11]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[6]}],"complexes":[],"partners":["OSBP","GNAQ","GNA11","TP53","SP1","MBD2","YWHAS"],"other_free_text":[]},"mechanistic_narrative":"INPP5A is a type I inositol polyphosphate 5-phosphatase that hydrolyzes both IP3 and PI(3,4,5)P3, thereby terminating IP3 receptor–mediated calcium signaling and attenuating PI3K/Akt pathway activation [PMID:11706019, PMID:33976123]. In cerebellar Purkinje cells, INPP5A is essential for survival: genetic deletion causes progressive Purkinje cell degeneration and ataxia, while overexpression rescues neurodegeneration in SCA2 and SCA17 mouse models by reducing IP3 levels and normalizing calcium dynamics [PMID:26051944, PMID:22973002, PMID:32107387]. INPP5A is a farnesylated and palmitoylated protein whose dual lipid modifications direct it to the plasma membrane and endomembranes; loss of INPP5A triggers IP3-dependent calcium release from the ER that dissociates OSBP from ER–Golgi membrane contact sites, disrupting cholesterol and glycosphingolipid surface delivery [PMID:33976123, PMID:40812428]. In GNAQ/GNA11-mutant uveal melanoma, INPP5A is a synthetic lethal dependency that buffers constitutive Gq-driven IP3 production, and its depletion causes calcium overload and p53-dependent apoptosis [PMID:38233483, PMID:40812428]."},"prefetch_data":{"uniprot":{"accession":"Q14642","full_name":"Inositol polyphosphate-5-phosphatase A","aliases":["43 kDa inositol polyphosphate 5-phosphatase","Type I inositol 1,4,5-trisphosphate 5-phosphatase","5PTase"],"length_aa":412,"mass_kda":47.8,"function":"Phosphatase that specifically hydrolyzes the 5-phosphate of inositol 1,4,5-trisphosphate to inositol 1,4-bisphosphate, and inositol 1,3,4,5-tetrasphosphate to inositol 1,3,4-trisphosphate (PubMed:8013665, PubMed:8626616, PubMed:8769125). Plays a crucial role in the survival of cerebellar Purkinje cells (By similarity)","subcellular_location":"Cell membrane; Cell projection, dendrite","url":"https://www.uniprot.org/uniprotkb/Q14642/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/INPP5A","classification":"Not Classified","n_dependent_lines":28,"n_total_lines":1208,"dependency_fraction":0.023178807947019868},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/INPP5A","total_profiled":1310},"omim":[{"mim_id":"601582","title":"INOSITOL POLYPHOSPHATE-5-PHOSPHATASE, 145-KD; INPP5D","url":"https://www.omim.org/entry/601582"},{"mim_id":"600106","title":"INOSITOL POLYPHOSPHATE-5-PHOSPHATASE, 40-KD; INPP5A","url":"https://www.omim.org/entry/600106"},{"mim_id":"300163","title":"FOUR-AND-A-HALF LIM DOMAINS 1; FHL1","url":"https://www.omim.org/entry/300163"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/INPP5A"},"hgnc":{"alias_symbol":["5PTASE"],"prev_symbol":[]},"alphafold":{"accession":"Q14642","domains":[{"cath_id":"3.60.10.10","chopping":"9-236_290-393","consensus_level":"high","plddt":94.1585,"start":9,"end":393}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14642","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14642-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14642-F1-predicted_aligned_error_v6.png","plddt_mean":91.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=INPP5A","jax_strain_url":"https://www.jax.org/strain/search?query=INPP5A"},"sequence":{"accession":"Q14642","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14642.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14642/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14642"}},"corpus_meta":[{"pmid":"17088424","id":"PMC_17088424","title":"Rapidly inducible changes 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= 0.65 µM) than other 5-phosphatases including SHIP, OCRL, and 5ptase II. Overexpression in 293 cells depleted both PI(4,5)P2 and PI(3,4,5)P3, increased PI(4)P and PI(3,4)P2, inhibited Akt phosphorylation (correlated with PI(3,4,5)P3 levels, not PI(3,4)P2), and sensitized cells to FAS-induced apoptosis, placing 5ptase IV as a regulator of the PI3K/Akt pathway.\",\n      \"method\": \"In vitro enzyme kinetics; stable cell lines overexpressing 5ptase IV alone or combined with inositol polyphosphate 4-phosphatase; phosphoinositide mass measurement; Akt phosphorylation immunoblot; FAS-induced apoptosis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinetics plus multiple orthogonal cellular assays with mechanistic controls\",\n      \"pmids\": [\"11706019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Inositol polyphosphate 5-phosphatase IV (INPP5A/5ptase IV) is highly expressed in arcuate and lateral hypothalamic neurons, undergoes time-dependent tyrosine phosphorylation following intracerebroventricular insulin, and its antisense-mediated knockdown (~80% reduction) increases basal inositol phosphate accumulation in the hypothalamus, reduces food intake, and causes body weight loss, demonstrating that it regulates PI3K signaling downstream of insulin in the hypothalamus.\",\n      \"method\": \"Antisense oligonucleotide knockdown in rat hypothalamus; immunoblotting for tyrosine phosphorylation; inositol phosphate accumulation assay; food intake and body weight measurement\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo knockdown with defined biochemical and physiological phenotypes; single lab\",\n      \"pmids\": [\"16916951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The 72-kDa inositol polyphosphate 5-phosphatase (72-5ptase, i.e., INPP5A) is dynamically recruited to FcγR-stimulated phagocytic cups, where it degrades PI(3,4,5)P3; dominant-negative 72-5ptase or siRNA knockdown amplifies and prolongs PI(3,4,5)P3 at the FcγR phagocytic cup but not the CR3 cup, inhibiting pseudopod extension and phagosome closure specifically in FcγR-mediated phagocytosis.\",\n      \"method\": \"Time-lapse imaging of PI(3,4,5)P3 biosensors; dominant-negative expression; siRNA knockdown; co-localization to phagocytic cup\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — live-cell imaging with biosensors, dominant-negative, and siRNA; multiple orthogonal methods\",\n      \"pmids\": [\"17682126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"AAV-mediated overexpression of Inpp5a (5PP) in Purkinje cells of SCA2 transgenic mice chronically reduces IP3 levels, alleviates age-dependent aberrant firing patterns of Purkinje cells, rescues motor incoordination, and prevents Purkinje cell death, demonstrating that INPP5A-mediated IP3 hydrolysis is neuroprotective against supranormal IP3R-driven calcium signaling in SCA2.\",\n      \"method\": \"AAV-mediated gene delivery; rotarod behavioral testing; electrophysiology of Purkinje cell firing; histological assessment of Purkinje cell survival\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo gain-of-function with multiple orthogonal phenotypic readouts in a disease model; replicated across behavioral, electrophysiological, and histological endpoints\",\n      \"pmids\": [\"22973002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Gene-trap deletion of Inpp5a in mice causes early-onset, slowly progressive Purkinje cell degeneration and ataxia; homozygous mutants show reduced phosphatase activity toward phosphoinositol substrates, locomotor instability beginning at P16, and widespread Purkinje cell loss by P60, establishing a non-redundant, cell-autonomous requirement for INPP5A in Purkinje cell survival.\",\n      \"method\": \"Gene-trap mouse model; qRT-PCR; immunohistochemistry; Western blot; rotarod; β-galactosidase staining; phosphatase activity assay\",\n      \"journal\": \"Neurogenetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function mouse model with biochemical, histological, and behavioral phenotypes\",\n      \"pmids\": [\"26051944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In SCA17 knock-in mice, mutant TBP inhibits SP1-mediated transcription to down-regulate INPP5A; CRISPR/Cas9-mediated deletion of Inpp5a in wild-type mouse cerebellum causes Purkinje cell degeneration, and Inpp5a overexpression decreases IP3 levels and ameliorates Purkinje cell degeneration in SCA17 mice, placing INPP5A as a downstream effector of TBP/SP1 transcription that protects Purkinje cells by hydrolyzing IP3.\",\n      \"method\": \"SCA17 knock-in mice; CRISPR/Cas9 cerebellar deletion; AAV-mediated Inpp5a overexpression; IP3 level measurement; Purkinje cell histology; SP1-mediated transcription assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple genetic manipulations (KO and overexpression) with biochemical and histological validation in vivo\",\n      \"pmids\": [\"32107387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of INPP5A causes IP3 accumulation and calcium efflux from ER stores, which triggers dissociation of oxysterol binding protein (OSBP) from the Golgi and from VAP-containing ER-Golgi membrane contact sites, resulting in depletion of cholesterol and Gb3 from the cell surface and blockade of clathrin-independent endocytosis of Shiga toxin.\",\n      \"method\": \"INPP5A loss-of-function; IP3 measurement; calcium imaging; OSBP localization by confocal microscopy; cholesterol and Gb3 surface staining; Shiga toxin uptake assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods linking INPP5A loss to IP3→Ca2+→OSBP dissociation→lipid transfer defect\",\n      \"pmids\": [\"33976123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Genome-scale CRISPR screens identified INPP5A as a selective synthetic lethal dependency in GNAQ/GNA11-mutant uveal melanoma (UM) cells in vitro and in vivo. Suppression of INPP5A in mutant cells causes accumulation of IP3, hyperactivation of IP3 receptor signaling, increased cytosolic calcium, and p53-dependent apoptosis. GNAQ/GNA11-mutant cells and patient tumors exhibit elevated IP4 (a biomarker of enhanced IP3 production) that is abolished by GNAQ/GNA11 inhibition and correlates with sensitivity to INPP5A depletion.\",\n      \"method\": \"Genome-scale CRISPR screens; in vivo xenograft models; IP3/IP4 mass measurement; calcium imaging; p53-dependent apoptosis assays; GNAQ/GNA11 inhibitor experiments\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genome-scale genetic screen plus multiple biochemical and in vivo validations\",\n      \"pmids\": [\"38233483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"INPP5A is a farnesylated and reversibly palmitoylated membrane-bound IP3 5-phosphatase that is upregulated in and required by CA-GNAQ/11-driven UM cells. Palmitoylation targets INPP5A to the plasma membrane (mutation of palmitoylation site reduces PM localization), while mutation of the prenylation site results in purely nucleoplasmic localization. INPP5A regulates low-frequency Ca2+ oscillations in UM cells driven by constitutive Gq/11 activity, and acute pharmacological inhibition of INPP5A augments Ca2+ oscillation rate, demonstrating that it safeguards UM cells from Ca2+ overload by controlling IP3-evoked Ca2+ dynamics.\",\n      \"method\": \"GFP-tagged INPP5A localization imaging; palmitoylation and prenylation site mutagenesis; single-cell calcium imaging; pharmacological INPP5A inhibitor (YU144369); UM cell survival assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — structure-function mutagenesis combined with live-cell calcium imaging and pharmacological inhibition\",\n      \"pmids\": [\"40812428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"INPP5A is targeted to plasma membrane, nuclear envelope, ER, and lysosomes through C-terminal farnesylation and palmitoylation; mutation of the palmitoylation site significantly reduces plasma membrane localization, and these distinct localizations regulate IP3 metabolism and Ca2+ mobilization in uveal melanoma cells.\",\n      \"method\": \"GFP-INPP5A subcellular localization imaging; palmitoylation and prenylation site mutagenesis; calcium mobilization assays in UM cells\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional mutagenesis; preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.09.18.613756\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In obese rodent models, 72k-5ptase (INPP5A) expression is increased in skeletal muscle and adipose tissue; antisense oligonucleotide reduction of 72k-5ptase catalytic activity in obese rats improves insulin signal transduction and restores glucose homeostasis, demonstrating its role as a negative regulator of peripheral insulin signaling.\",\n      \"method\": \"Antisense oligonucleotide knockdown; immunoblotting for insulin signaling components; hyperinsulinemic-euglycemic clamp; 72k-5ptase catalytic activity assay\",\n      \"journal\": \"The Journal of endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo knockdown with defined biochemical and physiological phenotypes; single lab\",\n      \"pmids\": [\"23349329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In itpka-deficient neurons, the levels of Inpp5a protein are upregulated at synapses as a compensatory response, and this is associated with decreased duration of IP3 signals and shorter IP3-dependent Ca2+ transients, establishing that INPP5A is a synaptic regulator of IP3 and Ca2+ signal duration.\",\n      \"method\": \"siRNA knockdown of itpka; immunoblotting for Inpp5a at synaptoneurosomes; IP3 mass assay; dendritic Ca2+ imaging\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — indirect evidence via compensatory upregulation; single lab\",\n      \"pmids\": [\"22120525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM32 deficiency in mice decreases INPP5A protein levels in the cerebellum, associated with impaired motor balance and Purkinje cell dendritic/synaptic deficits, suggesting TRIM32 regulates INPP5A abundance in cerebellar neurons.\",\n      \"method\": \"TRIM32 knockout mice; immunohistochemistry; Golgi staining; rotarod; immunoblotting for INPP5A\",\n      \"journal\": \"Frontiers in aging neuroscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — indirect association; no direct mechanistic link between TRIM32 and INPP5A established\",\n      \"pmids\": [\"34421574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MBD2 directly binds the INPP5A promoter to repress its transcription; PKA-mediated phosphorylation of MBD2 at S99 recruits 14-3-3σ to stabilize MBD2, enhancing transcriptional repression of INPP5A; reduced INPP5A promotes IP3 accumulation and PI3K/Akt pathway activation, driving pituitary tumor malignant progression.\",\n      \"method\": \"ChIP assay (MBD2 binding to INPP5A promoter); PKA pharmacological activation; co-immunoprecipitation (MBD2/14-3-3σ); INPP5A overexpression and knockdown in pituitary tumor cells; IP3 measurement; PI3K/Akt pathway immunoblotting\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct promoter binding plus multiple biochemical validations; single lab, recently published\",\n      \"pmids\": [\"41857481\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"INPP5A is a farnesylated and palmitoylated membrane-associated type I inositol 1,4,5-trisphosphate 5-phosphatase that hydrolyzes IP3 (and PI(3,4,5)P3 with high affinity) to terminate IP3R-mediated calcium signaling; it is essential for Purkinje cell survival (loss causes ataxia and neurodegeneration in mice), acts as a synthetic lethal vulnerability in GNAQ/GNA11-mutant uveal melanoma by preventing IP3-driven calcium overload and p53-dependent apoptosis, negatively regulates PI3K/Akt signaling and peripheral insulin action, controls lipid exchange at ER-Golgi membrane contact sites via IP3-Ca2+-OSBP axis, and is transcriptionally repressed by MBD2/PKA in pituitary tumors, with its subcellular localization to the plasma membrane, ER, and lysosomes regulated by dual lipid modifications (farnesylation and palmitoylation).\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"INPP5A is a type I inositol polyphosphate 5-phosphatase that hydrolyzes both IP3 and PI(3,4,5)P3, thereby terminating IP3 receptor–mediated calcium signaling and attenuating PI3K/Akt pathway activation [PMID:11706019, PMID:33976123]. In cerebellar Purkinje cells, INPP5A is essential for survival: genetic deletion causes progressive Purkinje cell degeneration and ataxia, while overexpression rescues neurodegeneration in SCA2 and SCA17 mouse models by reducing IP3 levels and normalizing calcium dynamics [PMID:26051944, PMID:22973002, PMID:32107387]. INPP5A is a farnesylated and palmitoylated protein whose dual lipid modifications direct it to the plasma membrane and endomembranes; loss of INPP5A triggers IP3-dependent calcium release from the ER that dissociates OSBP from ER–Golgi membrane contact sites, disrupting cholesterol and glycosphingolipid surface delivery [PMID:33976123, PMID:40812428]. In GNAQ/GNA11-mutant uveal melanoma, INPP5A is a synthetic lethal dependency that buffers constitutive Gq-driven IP3 production, and its depletion causes calcium overload and p53-dependent apoptosis [PMID:38233483, PMID:40812428].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing that INPP5A is not merely an IP3 phosphatase but also a high-affinity PI(3,4,5)P3 phosphatase that controls Akt signaling and apoptotic sensitivity answered the question of whether 5-phosphatases could directly regulate the PI3K/Akt axis.\",\n      \"evidence\": \"In vitro enzyme kinetics with purified substrates plus stable overexpression in HEK293 cells measuring phosphoinositide mass, Akt phosphorylation, and FAS-induced apoptosis\",\n      \"pmids\": [\"11706019\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous loss-of-function data for PI(3,4,5)P3 regulation were not provided\", \"Relative contribution of IP3 vs PI(3,4,5)P3 hydrolysis in physiological contexts unclear\", \"No structural basis for substrate selectivity\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating that INPP5A is an insulin-responsive phosphatase in hypothalamic neurons whose knockdown reduces food intake established a role for INPP5A in central metabolic regulation beyond its known IP3 phosphatase activity.\",\n      \"evidence\": \"Antisense oligonucleotide knockdown in rat hypothalamus with inositol phosphate accumulation, food intake, and body weight measurements\",\n      \"pmids\": [\"16916951\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genetic loss-of-function model not used\", \"Whether the metabolic effect is IP3- or PI(3,4,5)P3-dependent was not resolved\", \"No independent replication\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showing that INPP5A is dynamically recruited to FcγR phagocytic cups to degrade PI(3,4,5)P3 and enable phagosome closure answered how PI(3,4,5)P3 is spatiotemporally resolved during receptor-specific phagocytosis.\",\n      \"evidence\": \"Live-cell PI(3,4,5)P3 biosensor imaging combined with dominant-negative expression and siRNA knockdown in macrophages\",\n      \"pmids\": [\"17682126\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether INPP5A recruitment mechanism involves direct lipid or protein interactions at the cup is unknown\", \"In vivo phagocytosis phenotype not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identification of compensatory INPP5A upregulation at synapses upon loss of ITPKA linked INPP5A to fine-tuning of synaptic IP3/Ca²⁺ signal duration, addressing which phosphatases shape postsynaptic IP3 dynamics.\",\n      \"evidence\": \"ITPKA siRNA knockdown in neurons with synaptoneurosome fractionation, IP3 mass assay, and dendritic calcium imaging\",\n      \"pmids\": [\"22120525\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Evidence is correlative from a compensatory context\", \"Direct synaptic loss-of-function of INPP5A not performed\", \"Mechanism of upregulation unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"AAV-mediated Purkinje cell–specific overexpression of INPP5A rescuing SCA2 motor and electrophysiological phenotypes established INPP5A as a neuroprotective agent that counteracts IP3R-driven excitotoxic calcium signaling in cerebellar ataxia.\",\n      \"evidence\": \"AAV delivery to SCA2 transgenic mouse cerebellum with rotarod, Purkinje cell electrophysiology, and histological survival analysis\",\n      \"pmids\": [\"22973002\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous INPP5A loss-of-function in cerebellum had not yet been reported\", \"Whether rescue reflects IP3 or PI(3,4,5)P3 hydrolysis not distinguished\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Antisense reduction of INPP5A in obese rats improving insulin sensitivity and glucose homeostasis established it as a negative regulator of peripheral insulin signaling, complementing the central metabolic role described earlier.\",\n      \"evidence\": \"Antisense knockdown in obese rodents with hyperinsulinemic-euglycemic clamp and insulin signaling immunoblots\",\n      \"pmids\": [\"23349329\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genetic knockout model for peripheral insulin action not available\", \"Relative importance in muscle vs adipose not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Gene-trap deletion of Inpp5a causing progressive Purkinje cell loss and ataxia in mice provided the first definitive loss-of-function genetic evidence that INPP5A is non-redundantly required for Purkinje cell survival.\",\n      \"evidence\": \"Gene-trap mouse model with rotarod, immunohistochemistry, and phosphatase activity assays\",\n      \"pmids\": [\"26051944\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-autonomous vs non-cell-autonomous contributions not fully dissected\", \"Downstream calcium and IP3 levels not directly measured in knockout cerebellum\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovery that mutant TBP in SCA17 represses INPP5A transcription via SP1, and that CRISPR deletion of Inpp5a in wild-type cerebellum recapitulates Purkinje cell degeneration, linked INPP5A deficiency to transcriptionally driven cerebellar neurodegeneration and identified the upstream regulatory axis.\",\n      \"evidence\": \"SCA17 knock-in mice; CRISPR/Cas9 cerebellar deletion; AAV overexpression rescue; IP3 measurement; SP1 transcription assays\",\n      \"pmids\": [\"32107387\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SP1-INPP5A axis is relevant in other polyglutamine ataxias beyond SCA2 and SCA17 not tested\", \"Chromatin-level regulation of INPP5A promoter not fully characterized\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstration that INPP5A loss triggers an IP3→Ca²⁺→OSBP dissociation cascade that disrupts ER–Golgi membrane contact sites and depletes surface cholesterol/Gb3 revealed a previously unknown role for INPP5A in non-vesicular lipid transport.\",\n      \"evidence\": \"INPP5A loss-of-function with IP3 measurement, calcium imaging, OSBP localization, cholesterol/Gb3 staining, and Shiga toxin uptake\",\n      \"pmids\": [\"33976123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this lipid transfer defect contributes to Purkinje cell degeneration is unknown\", \"Direct physical interaction between INPP5A and OSBP/VAP not assessed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Genome-scale CRISPR screens identifying INPP5A as a selective synthetic lethal dependency in GNAQ/GNA11-mutant uveal melanoma established that oncogenic Gq signaling creates a critical reliance on INPP5A to buffer IP3/Ca²⁺ overload, with p53 as the apoptotic executor upon INPP5A loss.\",\n      \"evidence\": \"Genome-scale CRISPR screens in UM cell panels; xenograft models; IP3/IP4 mass measurements; calcium imaging; p53-dependent apoptosis assays\",\n      \"pmids\": [\"38233483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Therapeutic window for INPP5A inhibition in vivo not established\", \"Whether other Gq-driven cancers share this dependency is untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Structure-function analysis showing that farnesylation directs INPP5A away from the nucleus while palmitoylation targets it to the plasma membrane, where it controls Ca²⁺ oscillation frequency, resolved how dual lipid modifications govern INPP5A's subcellular localization and function in UM cells.\",\n      \"evidence\": \"GFP-tagged INPP5A with prenylation and palmitoylation site mutagenesis; single-cell calcium imaging; pharmacological inhibitor YU144369\",\n      \"pmids\": [\"40812428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the palmitoyl acyltransferase(s) modifying INPP5A unknown\", \"Structural basis for membrane orientation not determined\", \"Whether lipid modification state changes in cerebellar neurons is untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identification of MBD2 as a direct transcriptional repressor of INPP5A, stabilized by PKA-mediated phosphorylation and 14-3-3σ binding, revealed a second transcriptional axis (beyond SP1/TBP) that silences INPP5A to promote IP3/Akt-driven tumorigenesis in pituitary tumors.\",\n      \"evidence\": \"ChIP for MBD2 at INPP5A promoter; co-IP of MBD2/14-3-3σ; PKA activation; INPP5A overexpression/knockdown in pituitary tumor cells\",\n      \"pmids\": [\"41857481\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MBD2-mediated INPP5A repression occurs in other tumor types is unknown\", \"Epigenetic context (DNA methylation state of INPP5A promoter) not fully characterized\", \"Single-lab finding awaits independent confirmation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for INPP5A's dual substrate specificity toward IP3 and PI(3,4,5)P3, the identity of the palmitoyl acyltransferase(s) modifying INPP5A, whether the ER–Golgi lipid transfer function contributes to neurodegeneration, and whether INPP5A inhibition is therapeutically viable in GNAQ/GNA11-mutant cancers.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal structure of INPP5A\", \"Palmitoylation enzyme not identified\", \"Causal link between lipid transfer defect and Purkinje cell death not tested\", \"In vivo pharmacological INPP5A inhibition in cancer models not yet reported\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 3, 4, 5, 6, 7, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 7, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [6, 9]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 6, 7, 8, 10, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 4, 5, 7, 13]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [3, 4, 5, 11]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"OSBP\",\n      \"GNAQ\",\n      \"GNA11\",\n      \"TP53\",\n      \"SP1\",\n      \"MBD2\",\n      \"YWHAS\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}