{"gene":"INPP5A","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2001,"finding":"INPP5A (5ptase IV) has approximately 10-fold greater affinity for PI(3,4,5)P3 (Km = 0.65 µM) compared to other 5-phosphatases including SHIP, OCRL, and 5ptase II. Overexpression in 293 cells depletes both PI(4,5)P2 and PI(3,4,5)P3, generating PI(4)P and PI(3,4)P2. By selective depletion of PI(3,4,5)P3, INPP5A overexpression inhibits Akt phosphorylation in response to growth factors or heat shock, demonstrating that Akt activation correlates with PI(3,4,5)P3 levels rather than PI(3,4)P2 levels. Inhibition of Akt phosphorylation makes cells highly susceptible to FAS-induced apoptosis.","method":"In vitro enzymatic assay (Km determination), stable cell line overexpression, phosphoinositide measurement, immunoblotting for Akt phosphorylation, apoptosis assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinetic assay plus multiple orthogonal cellular assays (phosphoinositide quantification, Akt phosphorylation, apoptosis) in a single rigorous study","pmids":["11706019"],"is_preprint":false},{"year":2006,"finding":"INPP5A (5ptase IV) undergoes time-dependent tyrosine phosphorylation in hypothalamic neurons following intracerebroventricular insulin treatment, following the same pattern as canonical insulin signaling (insulin receptor → IRS-2 → PI3K). Antisense-mediated knockdown of 5ptase IV in the hypothalamus (~80% reduction) increases basal phosphorylated inositol accumulation, reduces food intake, and causes body weight loss, placing 5ptase IV as a regulator of PI3K signaling in the hypothalamus.","method":"Intracerebroventricular insulin treatment in rats, antisense oligonucleotide knockdown, immunoprecipitation/tyrosine phosphorylation assay, inositol phosphate measurement, food intake and body weight measurement","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo antisense KD with phosphoinositide and behavioral readouts, single lab, multiple orthogonal methods","pmids":["16916951"],"is_preprint":false},{"year":2012,"finding":"Adeno-associated virus-mediated overexpression of INPP5A (Inpp5a/5PP) in cerebellar Purkinje cells of SCA2 transgenic mice suppresses IP3-mediated Ca2+ signaling and alleviates age-dependent Purkinje cell firing dysfunction, rescues motor incoordination, and reduces Purkinje cell death, establishing INPP5A as a functional regulator of IP3/Ca2+ homeostasis in Purkinje cells relevant to SCA2 pathogenesis.","method":"AAV-mediated gene delivery in transgenic mice, rotarod motor testing, electrophysiology (Purkinje cell firing), histology (Purkinje cell counting)","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo gain-of-function with multiple orthogonal readouts (electrophysiology, behavior, histology) in disease model, single lab but rigorous","pmids":["22973002"],"is_preprint":false},{"year":2015,"finding":"Deletion of Inpp5a in mice (gene-trap insertion) causes early-onset, slowly progressive Purkinje cell degeneration and ataxia. Homozygous mutants show ~90% perinatal lethality; survivors exhibit locomotor instability at P16 and widespread Purkinje cell loss by P60. Phosphatase activity toward phosphoinositol substrates is reduced in mutant cerebellum, establishing that Inpp5a enzymatic activity is required for 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 / Moderate — clean KO mouse model with specific cellular phenotype (PC degeneration), enzymatic activity confirmation, multiple orthogonal methods","pmids":["26051944"],"is_preprint":false},{"year":2020,"finding":"In SCA17 knock-in mice, mutant TBP inhibits SP1-mediated transcription to downregulate INPP5A. CRISPR/Cas9-mediated deletion of Inpp5a in the cerebellum of wild-type mice leads to Purkinje cell degeneration. Conversely, Inpp5a overexpression decreases IP3 levels and ameliorates Purkinje cell degeneration in SCA17 knock-in mice, demonstrating that INPP5A is a tissue-specific neuroprotective protein acting via IP3 hydrolysis downstream of SP1 transcription.","method":"SCA17 knock-in mouse model, stereotaxic AAV injection, CRISPR/Cas9 cerebellar deletion, IP3 measurement, histology (PC counting), SP1 transcription factor ChIP/reporter assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — bidirectional genetic manipulation (KO + OE) with IP3 measurement and histological readout, mechanistic transcriptional link established","pmids":["32107387"],"is_preprint":false},{"year":2021,"finding":"Loss of INPP5A causes IP3 accumulation that triggers ER Ca2+ efflux. This Ca2+ release induces dissociation of oxysterol binding protein (OSBP) from the Golgi complex and from VAP-containing ER–Golgi membrane contact sites, thereby depleting cholesterol and Gb3 from the cell surface and blocking clathrin-independent endocytosis (CIE) of Shiga toxin. INPP5A-mediated IP3 hydrolysis is thus required for lipid exchange at ER–Golgi membrane contact sites.","method":"INPP5A loss-of-function (cell lines), IP3/Ca2+ measurement, cholesterol/Gb3 cell surface assay, OSBP localization (immunofluorescence/co-fractionation), Shiga toxin CIE assay, receptor-triggered IP3 accumulation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple orthogonal mechanistic readouts (Ca2+ measurement, OSBP localization, lipid trafficking) in single rigorous study","pmids":["33976123"],"is_preprint":false},{"year":2024,"finding":"Genome-scale CRISPR screens identify INPP5A as a selective synthetic lethal dependency in GNAQ/11-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. UM cells and patient tumors exhibit elevated IP4 (a biomarker of enhanced IP3 production) that correlates with sensitivity to INPP5A depletion; GNAQ/11 inhibition abolishes elevated IP4.","method":"Genome-scale CRISPR screens, INPP5A KD/KO in cell lines and in vivo xenografts, IP3/IP4 measurement, cytosolic Ca2+ measurement, p53 pathway analysis, GNAQ/11 inhibitor treatment","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genome-scale screen replicated with mechanistic follow-up (IP3/Ca2+/p53 pathway), in vitro and in vivo validation, multiple orthogonal methods","pmids":["38233483"],"is_preprint":false},{"year":2025,"finding":"INPP5A is upregulated in GNAQ/11-mutant uveal melanoma cells and is required for cell survival. INPP5A is reversibly palmitoylated; combined palmitoylation and farnesylation target the enzyme to plasma membrane, nuclear envelope, ER, and lysosomes. Mutation of the palmitoylation site reduces plasma membrane localization; mutation of the farnesylation site confines INPP5A to the nucleoplasm. Acute INPP5A inhibition augments the rate of spontaneous Ca2+ oscillations driven by constitutive GNAQ/11 activity, demonstrating that INPP5A regulates IP3-evoked Ca2+ oscillations to prevent Ca2+ overload in UM cells.","method":"GFP-tagged INPP5A localization imaging, palmitoylation/farnesylation site mutagenesis, INPP5A inhibitor (YU144369), single-cell Ca2+ imaging, GNAQ/11 inhibitor FR900359","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — site-directed mutagenesis of lipid modification sites with direct subcellular localization imaging and functional Ca2+ oscillation readout, single lab multiple orthogonal methods","pmids":["40812428"],"is_preprint":false},{"year":2024,"finding":"INPP5A is tethered to membranes via C-terminal farnesylation and palmitoylation. GFP-INPP5A localizes to plasma membrane, nuclear envelope, ER, and lysosomes. Palmitoylation site mutation reduces plasma membrane localization; farnesylation site mutation results in purely nucleoplasmic localization. INPP5A inhibitor YU144369 causes significant changes in Ca2+ oscillations in constitutively active GNAQ/11-driven UM cells.","method":"GFP-fusion localization imaging, palmitoylation/farnesylation mutagenesis, INPP5A small-molecule inhibitor, single-cell Ca2+ imaging","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — preprint with mutagenesis and live imaging, largely overlapping with and preceding the published JBC paper (40812428); single lab","pmids":["bio_10.1101_2024.09.18.613756"],"is_preprint":true},{"year":2013,"finding":"In three models of obesity (high-fat diet rats and mice, ob/ob mice), INPP5A (72k-5ptase) expression is increased in skeletal muscle and adipose tissue. Antisense oligonucleotide knockdown of 72k-5ptase reduces its catalytic activity and improves insulin signal transduction and glucose homeostasis in obese rats, identifying INPP5A as a regulator of peripheral insulin signaling.","method":"Antisense oligonucleotide knockdown in obese animal models, enzymatic activity assay, immunoblotting for insulin signaling components, hyperinsulinemic-euglycemic clamp","journal":"The Journal of endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KD with enzymatic activity confirmation and metabolic readouts, single lab, multiple orthogonal methods","pmids":["23349329"],"is_preprint":false},{"year":2026,"finding":"MBD2 directly binds the INPP5A promoter to mediate transcriptional repression. PKA signaling phosphorylates MBD2 at S99, recruits 14-3-3σ to stabilize MBD2 protein, and enhances MBD2-mediated inhibition of INPP5A expression. INPP5A overexpression inhibits pituitary tumor cell proliferation, migration, and hormone secretion while knockdown promotes these phenotypes; the mechanism involves INPP5A-mediated IP3 degradation that negatively regulates the PI3K/Akt pathway.","method":"ChIP (MBD2 binding to INPP5A promoter), PKA activation assays, phosphorylation site analysis (S99), co-immunoprecipitation (MBD2–14-3-3σ), INPP5A overexpression/knockdown in pituitary tumor cells, PI3K/Akt pathway immunoblotting, cell proliferation/migration assays","journal":"CNS neuroscience & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP + co-IP + bidirectional genetic manipulation with pathway readout, single lab, multiple orthogonal methods","pmids":["41857481"],"is_preprint":false},{"year":2021,"finding":"TRIM32 deficiency in mice decreases INPP5A protein levels in the cerebellum, and is associated with decreased dendritic arborization and synaptic contacts of Purkinje cells and motor deficits, suggesting TRIM32 acts upstream of INPP5A in cerebellar function. (Note: the paper does not establish a direct E3-ligase write/erase relationship; it reports an association.)","method":"TRIM32 knockout mouse model, immunohistochemistry (INPP5A protein levels), Golgi staining (dendritic morphology), motor behavior testing","journal":"Frontiers in aging neuroscience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, association between TRIM32 KO and reduced INPP5A protein by IHC only, no direct mechanistic link established","pmids":["34111256"],"is_preprint":false},{"year":2011,"finding":"In mature hippocampal neurons, loss of IP3 3-kinase A (itpka) leads to compensatory upregulation of INPP5A and SERCA2b, resulting in decreased duration of IP3 signals and shorter IP3-dependent Ca2+ transients at synapses. This establishes INPP5A as a functional participant in shaping synaptic Ca2+ transients.","method":"itpka knockdown in hippocampal neurons, Western blot (INPP5A and SERCA2b levels in synaptosomes), Ca2+ imaging","journal":"Cellular signalling","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, INPP5A upregulation observed as compensatory response in itpka KD, indirect mechanistic inference","pmids":["22120525"],"is_preprint":false},{"year":2017,"finding":"miR-181a-5p directly targets INPP5A (validated by dual-luciferase reporter assay). INPP5A overexpression inhibits cervical cancer cell proliferation and invasion and enhances apoptosis; miR-181a-5p mimic attenuates these effects, confirming INPP5A as a functional downstream target of miR-181a-5p in cervical cancer cells.","method":"Dual-luciferase reporter assay, INPP5A overexpression in HeLa/SiHa cells, miR-181a-5p mimic/inhibitor transfection, proliferation/invasion/apoptosis assays","journal":"Oncology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct luciferase validation of miRNA–target interaction plus functional rescue experiment, single lab, two orthogonal methods","pmids":["28653606"],"is_preprint":false}],"current_model":"INPP5A is a farnesylated and palmitoylated membrane-associated inositol 1,4,5-trisphosphate (IP3) 5-phosphatase that hydrolyzes IP3 (and PI(4,5)P2 and PI(3,4,5)P3) to terminate IP3/Ca2+ signaling; it is required for Purkinje cell survival in the cerebellum, regulates IP3-evoked Ca2+ oscillations and prevents Ca2+ overload in GNAQ/11-mutant uveal melanoma cells (representing a synthetic lethal vulnerability), controls lipid exchange at ER–Golgi membrane contact sites via IP3-regulated OSBP dynamics, negatively regulates PI3K/Akt signaling in multiple tissues, and is transcriptionally controlled by the PKA/MBD2 axis in pituitary tumors."},"narrative":{"mechanistic_narrative":"INPP5A is a membrane-tethered inositol 1,4,5-trisphosphate (IP3) 5-phosphatase that terminates IP3/Ca2+ signaling and, through its action on phosphoinositides, restrains PI3K/Akt activation [PMID:11706019, PMID:32107387]. In vitro it hydrolyzes PI(3,4,5)P3 with ~10-fold higher affinity than other 5-phosphatases, and its overexpression depletes PI(4,5)P2 and PI(3,4,5)P3, suppressing growth-factor-driven Akt phosphorylation and sensitizing cells to apoptosis [PMID:11706019]. Membrane targeting is conferred by C-terminal farnesylation and palmitoylation, which distribute the enzyme across the plasma membrane, ER, nuclear envelope, and lysosomes; loss of palmitoylation reduces plasma-membrane localization, while loss of farnesylation confines INPP5A to the nucleoplasm [PMID:40812428]. In the cerebellum, INPP5A enzymatic activity is required for Purkinje cell survival: its genetic deletion causes IP3 accumulation and progressive Purkinje cell degeneration with ataxia, while its overexpression lowers IP3 and rescues degeneration in spinocerebellar ataxia models, where it acts as a neuroprotective effector downstream of SP1- and TBP-dependent transcription [PMID:26051944, PMID:32107387, PMID:22973002]. By controlling IP3 levels and downstream ER Ca2+ release, INPP5A also governs OSBP dynamics and lipid exchange at ER–Golgi membrane contact sites [PMID:33976123], and constitutes a synthetic-lethal dependency in GNAQ/11-mutant uveal melanoma, where it prevents IP3-receptor-driven cytosolic Ca2+ overload and p53-dependent apoptosis [PMID:38233483, PMID:40812428]. INPP5A expression is transcriptionally repressed by a PKA/MBD2 axis in pituitary tumor cells, where it suppresses proliferation via IP3 degradation and PI3K/Akt inhibition [PMID:41857481].","teleology":[{"year":2001,"claim":"Established INPP5A as a 5-phosphatase with high affinity for PI(3,4,5)P3, linking its catalytic activity to negative control of Akt signaling and apoptotic susceptibility.","evidence":"In vitro kinetic assays, phosphoinositide quantification, and Akt phosphorylation/apoptosis readouts in overexpressing 293 cells","pmids":["11706019"],"confidence":"High","gaps":["Substrate preference between IP3 and 3-phosphoinositides under physiological conditions not resolved","No endogenous loss-of-function context in this study"]},{"year":2006,"claim":"Placed INPP5A within hypothalamic insulin/PI3K signaling, showing it is tyrosine-phosphorylated upon insulin and modulates feeding and body weight.","evidence":"Intracerebroventricular insulin in rats, antisense knockdown, inositol phosphate measurement, behavioral readouts","pmids":["16916951"],"confidence":"Medium","gaps":["Kinase responsible for INPP5A tyrosine phosphorylation not identified","Direct phosphoinositide substrate changes in vivo not fully resolved"]},{"year":2012,"claim":"Demonstrated that boosting INPP5A activity suppresses IP3/Ca2+ signaling and rescues Purkinje cell dysfunction in SCA2, establishing INPP5A as a functional regulator of cerebellar Ca2+ homeostasis.","evidence":"AAV-mediated overexpression in SCA2 transgenic mice with electrophysiology, rotarod, and histology","pmids":["22973002"],"confidence":"High","gaps":["Whether endogenous INPP5A is limiting in disease not addressed","Direct measurement of IP3 hydrolysis kinetics in vivo absent"]},{"year":2015,"claim":"Showed that INPP5A enzymatic activity is required for Purkinje cell survival, defining a cell-autonomous neuroprotective role.","evidence":"Gene-trap Inpp5a knockout mice with histology, motor testing, and cerebellar phosphatase activity assays","pmids":["26051944"],"confidence":"High","gaps":["Cause of perinatal lethality not defined","Downstream IP3/Ca2+ targets in Purkinje cells not directly measured here"]},{"year":2020,"claim":"Connected INPP5A to transcriptional control by SP1/TBP and confirmed bidirectionally that its IP3-hydrolyzing activity is neuroprotective in cerebellar degeneration.","evidence":"SCA17 knock-in mice, CRISPR cerebellar deletion, AAV overexpression, IP3 measurement, ChIP/reporter assays","pmids":["32107387"],"confidence":"High","gaps":["Tissue specificity of neuroprotection mechanistically unexplained","Relationship between SP1 and other INPP5A transcriptional regulators unclear"]},{"year":2021,"claim":"Revealed a non-canonical role for INPP5A in regulating lipid exchange at ER–Golgi contact sites through IP3-dependent ER Ca2+ control of OSBP localization.","evidence":"INPP5A loss-of-function in cell lines, IP3/Ca2+ measurement, OSBP localization, cholesterol/Gb3 and Shiga toxin endocytosis assays","pmids":["33976123"],"confidence":"High","gaps":["Direct INPP5A localization at contact sites not shown","Whether INPP5A physically associates with OSBP/VAP not established"]},{"year":2024,"claim":"Identified INPP5A as a genome-scale synthetic-lethal dependency in GNAQ/11-mutant uveal melanoma, mechanistically tied to IP3 accumulation, Ca2+ elevation, and p53-dependent apoptosis.","evidence":"Genome-scale CRISPR screens, in vitro and in vivo INPP5A depletion, IP3/IP4 and cytosolic Ca2+ measurement, p53 pathway analysis","pmids":["38233483"],"confidence":"High","gaps":["Whether IP4 is a reliable clinical biomarker untested in patients prospectively","Mechanism coupling Ca2+ overload to p53 activation not detailed"]},{"year":2025,"claim":"Defined the lipid-modification-driven subcellular targeting of INPP5A and showed it tunes the rate of GNAQ/11-driven Ca2+ oscillations to prevent Ca2+ overload.","evidence":"GFP-INPP5A imaging, palmitoylation/farnesylation site mutagenesis, INPP5A inhibitor YU144369, single-cell Ca2+ imaging, GNAQ/11 inhibitor FR900359","pmids":["40812428"],"confidence":"High","gaps":["Functional significance of nuclear-envelope and lysosomal pools not defined","Dynamics/regulation of reversible palmitoylation cycle unknown"]},{"year":2013,"claim":"Extended INPP5A's role to peripheral insulin signaling, showing its upregulation in obesity impairs glucose homeostasis.","evidence":"Antisense knockdown in obese rodent models with enzymatic activity assays, insulin-signaling immunoblotting, and clamp studies","pmids":["23349329"],"confidence":"Medium","gaps":["Direct phosphoinositide substrate in muscle/adipose not quantified","Mechanism of obesity-induced INPP5A upregulation unknown"]},{"year":2017,"claim":"Identified INPP5A as a direct miR-181a-5p target whose restoration suppresses cervical cancer cell proliferation and invasion.","evidence":"Dual-luciferase reporter assay and overexpression/mimic rescue experiments in HeLa/SiHa cells","pmids":["28653606"],"confidence":"Medium","gaps":["Downstream signaling effector in cervical cancer not defined","In vivo tumor relevance not tested"]},{"year":2026,"claim":"Established a PKA/MBD2 transcriptional axis repressing INPP5A in pituitary tumors and linked INPP5A loss to PI3K/Akt-driven proliferation.","evidence":"ChIP, PKA activation, S99 phosphorylation analysis, MBD2–14-3-3σ co-IP, bidirectional INPP5A manipulation with pathway immunoblotting","pmids":["41857481"],"confidence":"Medium","gaps":["Whether MBD2 repression operates in non-pituitary tissues unknown","Direct demonstration that INPP5A acts through phosphoinositide hydrolysis here is inferred from PI3K/Akt readouts"]},{"year":null,"claim":"How INPP5A's distinct subcellular pools and dual phosphoinositide/IP3 substrate activities are coordinated to achieve tissue-specific outcomes — from Purkinje cell survival to tumor dependency — remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of substrate recognition in the timeline","Regulation of localization-specific activity not established","Direct protein partners largely uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,3,4,5,6]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7,8]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[7,8]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[7,8]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[7,8]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[7,8]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,6]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[5]}],"complexes":[],"partners":["OSBP","VAP"],"other_free_text":[]}},"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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Overexpression in 293 cells depletes both PI(4,5)P2 and PI(3,4,5)P3, generating PI(4)P and PI(3,4)P2. By selective depletion of PI(3,4,5)P3, INPP5A overexpression inhibits Akt phosphorylation in response to growth factors or heat shock, demonstrating that Akt activation correlates with PI(3,4,5)P3 levels rather than PI(3,4)P2 levels. Inhibition of Akt phosphorylation makes cells highly susceptible to FAS-induced apoptosis.\",\n      \"method\": \"In vitro enzymatic assay (Km determination), stable cell line overexpression, phosphoinositide measurement, immunoblotting for Akt phosphorylation, apoptosis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinetic assay plus multiple orthogonal cellular assays (phosphoinositide quantification, Akt phosphorylation, apoptosis) in a single rigorous study\",\n      \"pmids\": [\"11706019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"INPP5A (5ptase IV) undergoes time-dependent tyrosine phosphorylation in hypothalamic neurons following intracerebroventricular insulin treatment, following the same pattern as canonical insulin signaling (insulin receptor → IRS-2 → PI3K). Antisense-mediated knockdown of 5ptase IV in the hypothalamus (~80% reduction) increases basal phosphorylated inositol accumulation, reduces food intake, and causes body weight loss, placing 5ptase IV as a regulator of PI3K signaling in the hypothalamus.\",\n      \"method\": \"Intracerebroventricular insulin treatment in rats, antisense oligonucleotide knockdown, immunoprecipitation/tyrosine phosphorylation assay, inositol phosphate measurement, food intake and body weight measurement\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo antisense KD with phosphoinositide and behavioral readouts, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"16916951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Adeno-associated virus-mediated overexpression of INPP5A (Inpp5a/5PP) in cerebellar Purkinje cells of SCA2 transgenic mice suppresses IP3-mediated Ca2+ signaling and alleviates age-dependent Purkinje cell firing dysfunction, rescues motor incoordination, and reduces Purkinje cell death, establishing INPP5A as a functional regulator of IP3/Ca2+ homeostasis in Purkinje cells relevant to SCA2 pathogenesis.\",\n      \"method\": \"AAV-mediated gene delivery in transgenic mice, rotarod motor testing, electrophysiology (Purkinje cell firing), histology (Purkinje cell counting)\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo gain-of-function with multiple orthogonal readouts (electrophysiology, behavior, histology) in disease model, single lab but rigorous\",\n      \"pmids\": [\"22973002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Deletion of Inpp5a in mice (gene-trap insertion) causes early-onset, slowly progressive Purkinje cell degeneration and ataxia. Homozygous mutants show ~90% perinatal lethality; survivors exhibit locomotor instability at P16 and widespread Purkinje cell loss by P60. Phosphatase activity toward phosphoinositol substrates is reduced in mutant cerebellum, establishing that Inpp5a enzymatic activity is required for 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 / Moderate — clean KO mouse model with specific cellular phenotype (PC degeneration), enzymatic activity confirmation, multiple orthogonal methods\",\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 downregulate INPP5A. CRISPR/Cas9-mediated deletion of Inpp5a in the cerebellum of wild-type mice leads to Purkinje cell degeneration. Conversely, Inpp5a overexpression decreases IP3 levels and ameliorates Purkinje cell degeneration in SCA17 knock-in mice, demonstrating that INPP5A is a tissue-specific neuroprotective protein acting via IP3 hydrolysis downstream of SP1 transcription.\",\n      \"method\": \"SCA17 knock-in mouse model, stereotaxic AAV injection, CRISPR/Cas9 cerebellar deletion, IP3 measurement, histology (PC counting), SP1 transcription factor ChIP/reporter assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — bidirectional genetic manipulation (KO + OE) with IP3 measurement and histological readout, mechanistic transcriptional link established\",\n      \"pmids\": [\"32107387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of INPP5A causes IP3 accumulation that triggers ER Ca2+ efflux. This Ca2+ release induces dissociation of oxysterol binding protein (OSBP) from the Golgi complex and from VAP-containing ER–Golgi membrane contact sites, thereby depleting cholesterol and Gb3 from the cell surface and blocking clathrin-independent endocytosis (CIE) of Shiga toxin. INPP5A-mediated IP3 hydrolysis is thus required for lipid exchange at ER–Golgi membrane contact sites.\",\n      \"method\": \"INPP5A loss-of-function (cell lines), IP3/Ca2+ measurement, cholesterol/Gb3 cell surface assay, OSBP localization (immunofluorescence/co-fractionation), Shiga toxin CIE assay, receptor-triggered IP3 accumulation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple orthogonal mechanistic readouts (Ca2+ measurement, OSBP localization, lipid trafficking) in single rigorous study\",\n      \"pmids\": [\"33976123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Genome-scale CRISPR screens identify INPP5A as a selective synthetic lethal dependency in GNAQ/11-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. UM cells and patient tumors exhibit elevated IP4 (a biomarker of enhanced IP3 production) that correlates with sensitivity to INPP5A depletion; GNAQ/11 inhibition abolishes elevated IP4.\",\n      \"method\": \"Genome-scale CRISPR screens, INPP5A KD/KO in cell lines and in vivo xenografts, IP3/IP4 measurement, cytosolic Ca2+ measurement, p53 pathway analysis, GNAQ/11 inhibitor treatment\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genome-scale screen replicated with mechanistic follow-up (IP3/Ca2+/p53 pathway), in vitro and in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"38233483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"INPP5A is upregulated in GNAQ/11-mutant uveal melanoma cells and is required for cell survival. INPP5A is reversibly palmitoylated; combined palmitoylation and farnesylation target the enzyme to plasma membrane, nuclear envelope, ER, and lysosomes. Mutation of the palmitoylation site reduces plasma membrane localization; mutation of the farnesylation site confines INPP5A to the nucleoplasm. Acute INPP5A inhibition augments the rate of spontaneous Ca2+ oscillations driven by constitutive GNAQ/11 activity, demonstrating that INPP5A regulates IP3-evoked Ca2+ oscillations to prevent Ca2+ overload in UM cells.\",\n      \"method\": \"GFP-tagged INPP5A localization imaging, palmitoylation/farnesylation site mutagenesis, INPP5A inhibitor (YU144369), single-cell Ca2+ imaging, GNAQ/11 inhibitor FR900359\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — site-directed mutagenesis of lipid modification sites with direct subcellular localization imaging and functional Ca2+ oscillation readout, single lab multiple orthogonal methods\",\n      \"pmids\": [\"40812428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"INPP5A is tethered to membranes via C-terminal farnesylation and palmitoylation. GFP-INPP5A localizes to plasma membrane, nuclear envelope, ER, and lysosomes. Palmitoylation site mutation reduces plasma membrane localization; farnesylation site mutation results in purely nucleoplasmic localization. INPP5A inhibitor YU144369 causes significant changes in Ca2+ oscillations in constitutively active GNAQ/11-driven UM cells.\",\n      \"method\": \"GFP-fusion localization imaging, palmitoylation/farnesylation mutagenesis, INPP5A small-molecule inhibitor, single-cell Ca2+ imaging\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — preprint with mutagenesis and live imaging, largely overlapping with and preceding the published JBC paper (40812428); single lab\",\n      \"pmids\": [\"bio_10.1101_2024.09.18.613756\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In three models of obesity (high-fat diet rats and mice, ob/ob mice), INPP5A (72k-5ptase) expression is increased in skeletal muscle and adipose tissue. Antisense oligonucleotide knockdown of 72k-5ptase reduces its catalytic activity and improves insulin signal transduction and glucose homeostasis in obese rats, identifying INPP5A as a regulator of peripheral insulin signaling.\",\n      \"method\": \"Antisense oligonucleotide knockdown in obese animal models, enzymatic activity assay, immunoblotting for insulin signaling components, hyperinsulinemic-euglycemic clamp\",\n      \"journal\": \"The Journal of endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KD with enzymatic activity confirmation and metabolic readouts, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"23349329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MBD2 directly binds the INPP5A promoter to mediate transcriptional repression. PKA signaling phosphorylates MBD2 at S99, recruits 14-3-3σ to stabilize MBD2 protein, and enhances MBD2-mediated inhibition of INPP5A expression. INPP5A overexpression inhibits pituitary tumor cell proliferation, migration, and hormone secretion while knockdown promotes these phenotypes; the mechanism involves INPP5A-mediated IP3 degradation that negatively regulates the PI3K/Akt pathway.\",\n      \"method\": \"ChIP (MBD2 binding to INPP5A promoter), PKA activation assays, phosphorylation site analysis (S99), co-immunoprecipitation (MBD2–14-3-3σ), INPP5A overexpression/knockdown in pituitary tumor cells, PI3K/Akt pathway immunoblotting, cell proliferation/migration assays\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP + co-IP + bidirectional genetic manipulation with pathway readout, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41857481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM32 deficiency in mice decreases INPP5A protein levels in the cerebellum, and is associated with decreased dendritic arborization and synaptic contacts of Purkinje cells and motor deficits, suggesting TRIM32 acts upstream of INPP5A in cerebellar function. (Note: the paper does not establish a direct E3-ligase write/erase relationship; it reports an association.)\",\n      \"method\": \"TRIM32 knockout mouse model, immunohistochemistry (INPP5A protein levels), Golgi staining (dendritic morphology), motor behavior testing\",\n      \"journal\": \"Frontiers in aging neuroscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, association between TRIM32 KO and reduced INPP5A protein by IHC only, no direct mechanistic link established\",\n      \"pmids\": [\"34111256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In mature hippocampal neurons, loss of IP3 3-kinase A (itpka) leads to compensatory upregulation of INPP5A and SERCA2b, resulting in decreased duration of IP3 signals and shorter IP3-dependent Ca2+ transients at synapses. This establishes INPP5A as a functional participant in shaping synaptic Ca2+ transients.\",\n      \"method\": \"itpka knockdown in hippocampal neurons, Western blot (INPP5A and SERCA2b levels in synaptosomes), Ca2+ imaging\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, INPP5A upregulation observed as compensatory response in itpka KD, indirect mechanistic inference\",\n      \"pmids\": [\"22120525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"miR-181a-5p directly targets INPP5A (validated by dual-luciferase reporter assay). INPP5A overexpression inhibits cervical cancer cell proliferation and invasion and enhances apoptosis; miR-181a-5p mimic attenuates these effects, confirming INPP5A as a functional downstream target of miR-181a-5p in cervical cancer cells.\",\n      \"method\": \"Dual-luciferase reporter assay, INPP5A overexpression in HeLa/SiHa cells, miR-181a-5p mimic/inhibitor transfection, proliferation/invasion/apoptosis assays\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct luciferase validation of miRNA–target interaction plus functional rescue experiment, single lab, two orthogonal methods\",\n      \"pmids\": [\"28653606\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"INPP5A is a farnesylated and palmitoylated membrane-associated inositol 1,4,5-trisphosphate (IP3) 5-phosphatase that hydrolyzes IP3 (and PI(4,5)P2 and PI(3,4,5)P3) to terminate IP3/Ca2+ signaling; it is required for Purkinje cell survival in the cerebellum, regulates IP3-evoked Ca2+ oscillations and prevents Ca2+ overload in GNAQ/11-mutant uveal melanoma cells (representing a synthetic lethal vulnerability), controls lipid exchange at ER–Golgi membrane contact sites via IP3-regulated OSBP dynamics, negatively regulates PI3K/Akt signaling in multiple tissues, and is transcriptionally controlled by the PKA/MBD2 axis in pituitary tumors.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"INPP5A is a membrane-tethered inositol 1,4,5-trisphosphate (IP3) 5-phosphatase that terminates IP3/Ca2+ signaling and, through its action on phosphoinositides, restrains PI3K/Akt activation [#0, #4]. In vitro it hydrolyzes PI(3,4,5)P3 with ~10-fold higher affinity than other 5-phosphatases, and its overexpression depletes PI(4,5)P2 and PI(3,4,5)P3, suppressing growth-factor-driven Akt phosphorylation and sensitizing cells to apoptosis [#0]. Membrane targeting is conferred by C-terminal farnesylation and palmitoylation, which distribute the enzyme across the plasma membrane, ER, nuclear envelope, and lysosomes; loss of palmitoylation reduces plasma-membrane localization, while loss of farnesylation confines INPP5A to the nucleoplasm [#7]. In the cerebellum, INPP5A enzymatic activity is required for Purkinje cell survival: its genetic deletion causes IP3 accumulation and progressive Purkinje cell degeneration with ataxia, while its overexpression lowers IP3 and rescues degeneration in spinocerebellar ataxia models, where it acts as a neuroprotective effector downstream of SP1- and TBP-dependent transcription [#3, #4, #2]. By controlling IP3 levels and downstream ER Ca2+ release, INPP5A also governs OSBP dynamics and lipid exchange at ER–Golgi membrane contact sites [#5], and constitutes a synthetic-lethal dependency in GNAQ/11-mutant uveal melanoma, where it prevents IP3-receptor-driven cytosolic Ca2+ overload and p53-dependent apoptosis [#6, #7]. INPP5A expression is transcriptionally repressed by a PKA/MBD2 axis in pituitary tumor cells, where it suppresses proliferation via IP3 degradation and PI3K/Akt inhibition [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established INPP5A as a 5-phosphatase with high affinity for PI(3,4,5)P3, linking its catalytic activity to negative control of Akt signaling and apoptotic susceptibility.\",\n      \"evidence\": \"In vitro kinetic assays, phosphoinositide quantification, and Akt phosphorylation/apoptosis readouts in overexpressing 293 cells\",\n      \"pmids\": [\"11706019\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate preference between IP3 and 3-phosphoinositides under physiological conditions not resolved\", \"No endogenous loss-of-function context in this study\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Placed INPP5A within hypothalamic insulin/PI3K signaling, showing it is tyrosine-phosphorylated upon insulin and modulates feeding and body weight.\",\n      \"evidence\": \"Intracerebroventricular insulin in rats, antisense knockdown, inositol phosphate measurement, behavioral readouts\",\n      \"pmids\": [\"16916951\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase responsible for INPP5A tyrosine phosphorylation not identified\", \"Direct phosphoinositide substrate changes in vivo not fully resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated that boosting INPP5A activity suppresses IP3/Ca2+ signaling and rescues Purkinje cell dysfunction in SCA2, establishing INPP5A as a functional regulator of cerebellar Ca2+ homeostasis.\",\n      \"evidence\": \"AAV-mediated overexpression in SCA2 transgenic mice with electrophysiology, rotarod, and histology\",\n      \"pmids\": [\"22973002\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether endogenous INPP5A is limiting in disease not addressed\", \"Direct measurement of IP3 hydrolysis kinetics in vivo absent\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed that INPP5A enzymatic activity is required for Purkinje cell survival, defining a cell-autonomous neuroprotective role.\",\n      \"evidence\": \"Gene-trap Inpp5a knockout mice with histology, motor testing, and cerebellar phosphatase activity assays\",\n      \"pmids\": [\"26051944\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cause of perinatal lethality not defined\", \"Downstream IP3/Ca2+ targets in Purkinje cells not directly measured here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected INPP5A to transcriptional control by SP1/TBP and confirmed bidirectionally that its IP3-hydrolyzing activity is neuroprotective in cerebellar degeneration.\",\n      \"evidence\": \"SCA17 knock-in mice, CRISPR cerebellar deletion, AAV overexpression, IP3 measurement, ChIP/reporter assays\",\n      \"pmids\": [\"32107387\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue specificity of neuroprotection mechanistically unexplained\", \"Relationship between SP1 and other INPP5A transcriptional regulators unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a non-canonical role for INPP5A in regulating lipid exchange at ER–Golgi contact sites through IP3-dependent ER Ca2+ control of OSBP localization.\",\n      \"evidence\": \"INPP5A loss-of-function in cell lines, IP3/Ca2+ measurement, OSBP localization, cholesterol/Gb3 and Shiga toxin endocytosis assays\",\n      \"pmids\": [\"33976123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct INPP5A localization at contact sites not shown\", \"Whether INPP5A physically associates with OSBP/VAP not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified INPP5A as a genome-scale synthetic-lethal dependency in GNAQ/11-mutant uveal melanoma, mechanistically tied to IP3 accumulation, Ca2+ elevation, and p53-dependent apoptosis.\",\n      \"evidence\": \"Genome-scale CRISPR screens, in vitro and in vivo INPP5A depletion, IP3/IP4 and cytosolic Ca2+ measurement, p53 pathway analysis\",\n      \"pmids\": [\"38233483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IP4 is a reliable clinical biomarker untested in patients prospectively\", \"Mechanism coupling Ca2+ overload to p53 activation not detailed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the lipid-modification-driven subcellular targeting of INPP5A and showed it tunes the rate of GNAQ/11-driven Ca2+ oscillations to prevent Ca2+ overload.\",\n      \"evidence\": \"GFP-INPP5A imaging, palmitoylation/farnesylation site mutagenesis, INPP5A inhibitor YU144369, single-cell Ca2+ imaging, GNAQ/11 inhibitor FR900359\",\n      \"pmids\": [\"40812428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional significance of nuclear-envelope and lysosomal pools not defined\", \"Dynamics/regulation of reversible palmitoylation cycle unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended INPP5A's role to peripheral insulin signaling, showing its upregulation in obesity impairs glucose homeostasis.\",\n      \"evidence\": \"Antisense knockdown in obese rodent models with enzymatic activity assays, insulin-signaling immunoblotting, and clamp studies\",\n      \"pmids\": [\"23349329\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct phosphoinositide substrate in muscle/adipose not quantified\", \"Mechanism of obesity-induced INPP5A upregulation unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified INPP5A as a direct miR-181a-5p target whose restoration suppresses cervical cancer cell proliferation and invasion.\",\n      \"evidence\": \"Dual-luciferase reporter assay and overexpression/mimic rescue experiments in HeLa/SiHa cells\",\n      \"pmids\": [\"28653606\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling effector in cervical cancer not defined\", \"In vivo tumor relevance not tested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established a PKA/MBD2 transcriptional axis repressing INPP5A in pituitary tumors and linked INPP5A loss to PI3K/Akt-driven proliferation.\",\n      \"evidence\": \"ChIP, PKA activation, S99 phosphorylation analysis, MBD2–14-3-3σ co-IP, bidirectional INPP5A manipulation with pathway immunoblotting\",\n      \"pmids\": [\"41857481\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MBD2 repression operates in non-pituitary tissues unknown\", \"Direct demonstration that INPP5A acts through phosphoinositide hydrolysis here is inferred from PI3K/Akt readouts\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How INPP5A's distinct subcellular pools and dual phosphoinositide/IP3 substrate activities are coordinated to achieve tissue-specific outcomes — from Purkinje cell survival to tumor dependency — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of substrate recognition in the timeline\", \"Regulation of localization-specific activity not established\", \"Direct protein partners largely uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 3, 4, 5, 6]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"OSBP\", \"VAP\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}