{"gene":"PRUNE1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2004,"finding":"Human prune (h-prune) possesses cyclic nucleotide phosphodiesterase (cAMP-PDE) activity that can be suppressed by dipyridamole, and physically interacts with nm23-H1 (a metastasis suppressor); the interaction with nm23-H1 enhances h-prune PDE activity and stimulates cellular motility and metastasis.","method":"In vitro enzymatic assay (cAMP-PDE activity), co-immunoprecipitation, dipyridamole inhibition, cellular motility assays in breast cancer cell lines","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro enzymatic assay combined with Co-IP and functional cellular readout; replicated in subsequent independent studies","pmids":["14998490"],"is_preprint":false},{"year":1999,"finding":"Human PRUNE protein interacts with nm23-H1 (human homologue of awd/NDP kinase) as shown by interaction-mating and in vitro co-immunoprecipitation; PRUNE is impaired in interaction with the nm23-H1-S120G gain-of-function mutant; both proteins partially co-localize in the cytoplasm.","method":"Yeast two-hybrid interaction mating, co-immunoprecipitation, subcellular co-localization","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP and two-hybrid in the original paper, replicated by multiple subsequent labs","pmids":["10602478"],"is_preprint":false},{"year":2008,"finding":"h-prune efficiently hydrolyzes short-chain polyphosphates (tri- and tetrapolyphosphates, nucleoside 5'-tetraphosphates) as a short-chain exopolyphosphatase, requiring divalent metal cofactors (Mg2+, Co2+, Mn2+); long-chain polyphosphates are hydrolyzed more slowly; pyrophosphate and nucleoside triphosphates are not hydrolyzed. Mutation of seven active-site residues corresponding to yeast exopolyphosphatase severely reduced activity. The exopolyphosphatase activity is suppressed by nm23-H1, long-chain polyphosphates, and pyrophosphate.","method":"In vitro enzymatic assay with recombinant protein, active-site mutagenesis, substrate specificity profiling","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted enzymatic activity in vitro with mutagenesis of active-site residues, single lab but multiple orthogonal methods","pmids":["18700747"],"is_preprint":false},{"year":2006,"finding":"h-prune was identified as a glycogen synthase kinase 3 (GSK-3) binding protein; the kinase activity of GSK-3 is required for this interaction. h-prune localizes to focal adhesions, and siRNA knockdown of GSK-3 or h-prune delays disassembly of paxillin, suppresses tyrosine phosphorylation of FAK, and suppresses Rac activation, impairing cell motility.","method":"Co-immunoprecipitation, siRNA knockdown, immunofluorescence localization to focal adhesions, paxillin disassembly assay, FAK phosphorylation assay, Rac activation assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, siRNA knockdown with multiple defined cellular phenotype readouts, localization tied to functional consequence","pmids":["16428445"],"is_preprint":false},{"year":2007,"finding":"The region of nm23-H1 spanning S120–S125 mediates the nm23-H1/h-prune interaction; phosphorylation of nm23-H1 at this region by casein kinase I (CKI) delta/epsilon is required for complex formation. The CKI delta/epsilon-specific inhibitor IC261 impairs complex formation and inhibits cellular motility in a breast cancer model. A competitive permeable peptide spanning the CKI phosphorylation region similarly impairs motility.","method":"Mutational mapping of interaction site, in vitro kinase assay (CKI phosphorylation), pharmacological inhibition with IC261, competitive peptide inhibition, transwell cell migration assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — kinase assay, mutational mapping, and functional cellular readouts in single lab with multiple orthogonal methods","pmids":["17906697"],"is_preprint":false},{"year":2007,"finding":"h-prune contains two structurally independent domains: an N-terminal PDE catalytic domain (active even as monomer) and a C-terminal cortexillin homology domain that mediates h-prune homodimerization and interaction with NM23-H1. Domain boundaries were identified by sequence analysis and limited proteolysis of recombinant h-prune.","method":"Recombinant protein expression, limited proteolysis, sequence analysis, domain mapping by deletion constructs, dimerization and binding assays","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain boundaries defined biochemically with recombinant protein, single lab, multiple methods","pmids":["17655525"],"is_preprint":false},{"year":2013,"finding":"NMR spectroscopy of the h-prune C-terminal domain in human cell lysates identified the amino acids of this largely unfolded domain involved in interactions with Nm23-H1, GSK-3β, and gelsolin; a competitive permeable peptide (CPP) derived from this region impairs Nm23-H1/h-prune complex formation, inhibits cell motility, and substantially reduces tumor growth and metastasis in neuroblastoma models.","method":"NMR spectroscopy in cell lysates, conformational analysis, competitive peptide inhibition, cell motility assay, in vivo orthotopic xenograft tumor model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — NMR structural mapping combined with functional in vitro and in vivo validation, single lab","pmids":["23448979"],"is_preprint":false},{"year":2013,"finding":"NMR spectroscopy mapping of h-prune C-terminal domain confirmed it is largely unfolded and mediates protein-protein interactions with Nm23-H1, GSK-3β, and gelsolin.","method":"Fast NMR spectroscopy in cell lysates","journal":"Chemistry (Weinheim an der Bergstrasse, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — NMR structural analysis in cell lysates, single lab","pmids":["23939913"],"is_preprint":false},{"year":2017,"finding":"Disease-associated PRUNE1 variant alleles cause impaired microtubule polymerization, and reduced cell migration and proliferation. These functional defects establish a role for PRUNE1 in microtubule polymerization essential for cytoskeletal rearrangements during cell division and proliferation in cortical brain development.","method":"Functional assays of disease variant alleles: microtubule polymerization assay, cell migration assay, cell proliferation assay","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays of disease alleles in single lab, no in vitro reconstitution of microtubule polymerization per se","pmids":["28334956"],"is_preprint":false},{"year":2015,"finding":"Drosophila Prune (ortholog of human PRUNE1) is a cyclic nucleotide phosphodiesterase that localizes to the mitochondrial matrix. Knockdown of prune in cultured cells reduces mitochondrial transcription factor A (TFAM) and mtDNA levels; Prune stabilizes TFAM and promotes mtDNA replication through downregulation of mitochondrial cAMP signaling.","method":"Subcellular fractionation and localization (mitochondrial matrix), RNAi knockdown in cultured cells, measurement of TFAM protein levels and mtDNA copy number","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct fractionation-based localization tied to functional consequence (mtDNA replication), Drosophila ortholog, single lab","pmids":["25648146"],"is_preprint":false},{"year":2014,"finding":"h-prune interacts with GSK-3β and through this complex activates canonical WNT/β-catenin signaling, also in a paracrine manner via Wnt3a secretion. h-prune silencing inhibits lung metastasis formation in vivo.","method":"Co-immunoprecipitation (h-prune/GSK-3β interaction), WNT/β-catenin reporter assay, Wnt3a ELISA, in vivo lung metastasis model (siRNA silencing)","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, reporter assay, and in vivo functional readout, single lab","pmids":["25026278"],"is_preprint":false},{"year":2021,"finding":"NMIHBA-associated missense variants within the conserved N-terminal DHH motif of PRUNE1 result in destabilization of protein structure and/or loss of exopolyphosphatase activity, establishing that exopolyphosphatase activity is required for normal neurodevelopment. Complete genetic ablation of Prune1 in mice causes midgestational lethality with perturbations to embryonic growth and vascular development.","method":"Biochemical characterization of recombinant missense variants (protein stability and enzymatic activity assays), Prune1 knockout mouse model","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic activity assay with multiple disease-associated variants plus KO mouse model with defined phenotype, single lab but multiple orthogonal methods","pmids":["33105479"],"is_preprint":false},{"year":2018,"finding":"PRUNE1 activates a signaling pathway in metastatic medulloblastoma group 3 involving binding to NME1, TGF-β activation, OTX2 upregulation, SNAIL (SNAI1) upregulation, and PTEN inhibition. A competitive permeable peptide impairing PRUNE1/NME1 complex formation, and a small molecule (AA7.1) that enhances PRUNE1 degradation, both impair tumor growth and metastatic dissemination in orthotopic xenograft models.","method":"Co-immunoprecipitation (PRUNE1/NME1), competitive permeable peptide, small molecule inhibitor (AA7.1), orthotopic xenograft mouse model, pathway activation assays (TGF-β, OTX2, SNAIL, PTEN)","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vivo xenograft validation, multiple pathway readouts, single lab","pmids":["29490009"],"is_preprint":false},{"year":2023,"finding":"Recombinant h-prune does not hydrolyze short (13–33 Pi) or medium (45–160 Pi) chain polyphosphates. However, knockdown of h-prune in HEK293 cells significantly decreases cellular polyP levels and reduces ATP synthase activity and ATP levels, with compensatory upregulation of ATP5A expression; these effects on mitochondrial bioenergetics are not due to loss of mitochondrial membrane potential or mitochondrial biomass.","method":"In vitro enzymatic assay with recombinant h-prune and defined polyphosphate chain lengths, siRNA knockdown in HEK293 cells, polyP quantification, ATP measurement, mitochondrial membrane potential assay, Western blot for ATP5A","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro enzymatic assay combined with cell-based knockdown and multiple biochemical readouts; single lab but several orthogonal methods","pmids":["37762163"],"is_preprint":false},{"year":2006,"finding":"Protein-protein pull-down analyses coupled with mass spectrometry identified gelsolin (an ATP-severing protein acting in focal adhesions) as a new h-prune binding partner in a breast cancer cellular model, in addition to the known GSK-3β interaction.","method":"Protein-protein pull-down assay coupled to mass spectrometry","journal":"Journal of bioenergetics and biomembranes","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single pull-down/MS identification, single lab, limited mechanistic follow-up described in abstract","pmids":["17103319"],"is_preprint":false},{"year":2012,"finding":"Xenopus prune overexpression in retinal precursor cells increases the ratio of Müller glial cells; a mutant form of prune with four aspartate (D) residue substitutions that abolish phosphodiesterase activity does not exhibit gliogenic activity, establishing that PDE activity is required for prune-mediated Müller gliogenesis.","method":"Xenopus overexpression, active-site mutagenesis (D residue substitutions), cell fate quantification (Müller glial cells)","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of active site combined with in vivo overexpression and defined cell fate phenotype, single lab","pmids":["22967741"],"is_preprint":false},{"year":2020,"finding":"PRUNE1 overexpression promotes lung metastasis and M2-polarization of tumor-associated macrophages (TAMs) within the tumor microenvironment, mediated through TGF-β enhancement and IL-17F secretion, as shown in a genetically engineered mouse model of metastatic triple-negative breast cancer.","method":"Genetically engineered mouse model (PRUNE1 overexpression), macrophage polarization assays, TGF-β and IL-17F secretion measurements, extracellular vesicle analysis","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model with defined mechanistic pathway readouts, single lab","pmids":["33426510"],"is_preprint":false},{"year":2004,"finding":"Overexpression of h-prune in the MDA-MB-435 breast carcinoma cell line causes a substantial decrease in cAMP levels and an increase in cellular motility, effects correlated with h-prune PDE activity and the h-prune/nm23-H1 protein interaction.","method":"Stable overexpression in breast cancer cell line, cAMP measurement, cell motility assay","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cellular overexpression with defined biochemical (cAMP) and functional (motility) readouts, single lab","pmids":["15254413"],"is_preprint":false}],"current_model":"PRUNE1 (h-prune) is a DHH-superfamily phosphoesterase with two distinct enzymatic activities — a cAMP phosphodiesterase (mapped to its N-terminal catalytic domain) and a short-chain exopolyphosphatase (hydrolyzing polyphosphates up to ~4 Pi units in vitro, but affecting longer cellular polyP chains indirectly via regulation of ATP synthase activity) — that drives cancer cell motility and metastasis by physically interacting with the metastasis suppressor NM23-H1/NME1 (interaction requiring CKI-mediated phosphorylation of NM23-H1 at S120–S125 and mediated by h-prune's C-terminal dimerization/cortexillin domain), by binding GSK-3β (kinase-activity-dependent) to promote focal adhesion disassembly and FAK/Rac activation, and by activating canonical WNT/β-catenin and TGF-β/SNAIL/PTEN signaling; loss-of-function PRUNE1 variants that destabilize the protein or abolish exopolyphosphatase activity cause the autosomal recessive neurodevelopmental disorder NMIHBA, partly through impaired microtubule polymerization and cell migration, while complete Prune1 ablation in mice causes mid-gestational lethality."},"narrative":{"mechanistic_narrative":"PRUNE1 (h-prune) is a DHH-superfamily phosphoesterase that drives cell motility, cytoskeletal remodeling, and metastasis through coupled enzymatic and scaffolding functions [PMID:14998490, PMID:16428445]. Its N-terminal catalytic domain is a metal-dependent enzyme with cyclic-nucleotide phosphodiesterase activity and short-chain exopolyphosphatase activity, defined by conserved active-site residues; PDE activity lowers cellular cAMP and is required for its biological effects [PMID:14998490, PMID:18700747, PMID:15254413, PMID:22967741]. A structurally independent C-terminal cortexillin-homology domain is largely unfolded and mediates homodimerization and protein-protein interactions [PMID:17655525, PMID:23939913]. Through this domain PRUNE1 binds the metastasis suppressor NM23-H1/NME1 in a manner requiring CKIδ/ε phosphorylation of NM23-H1 across its S120–S125 region, an interaction that stimulates PRUNE1 enzymatic activity and promotes tumor cell motility and metastasis [PMID:10602478, PMID:17906697, PMID:23448979]. PRUNE1 also binds GSK-3β in a kinase-activity-dependent manner and localizes to focal adhesions, where it promotes paxillin disassembly, FAK phosphorylation, and Rac activation to enable migration, and engages canonical WNT/β-catenin signaling [PMID:16428445, PMID:25026278]. In metastatic medulloblastoma it activates a TGF-β/OTX2/SNAIL/PTEN axis downstream of NME1 binding, and in breast cancer it reprograms tumor-associated macrophages toward an M2 phenotype via TGF-β and IL-17F [PMID:29490009, PMID:33426510]. Loss-of-function missense variants in the conserved N-terminal DHH motif that destabilize the protein or abolish exopolyphosphatase activity cause the autosomal recessive neurodevelopmental disorder NMIHBA, partly through impaired microtubule polymerization and cell migration, and complete Prune1 ablation in mice is midgestationally lethal [PMID:28334956, PMID:33105479].","teleology":[{"year":1999,"claim":"Establishing that PRUNE1 physically partners with the metastasis suppressor NM23-H1 placed it directly within metastasis-suppression biology and defined its first molecular interaction.","evidence":"Yeast two-hybrid interaction mating, reciprocal co-IP, and cytoplasmic co-localization, with loss of binding to the NM23-H1-S120G mutant","pmids":["10602478"],"confidence":"High","gaps":["Functional consequence of the interaction not yet established","Interaction domain on PRUNE1 not mapped","Biochemical activity of PRUNE1 unknown at this stage"]},{"year":2004,"claim":"Identifying cAMP-PDE activity and linking it to NM23-H1 binding and cell motility converted PRUNE1 from a binding partner into an enzymatically active metastasis driver.","evidence":"In vitro cAMP-PDE assay with dipyridamole inhibition, Co-IP, and motility assays in breast cancer lines; overexpression lowers cAMP and raises motility","pmids":["14998490","15254413"],"confidence":"High","gaps":["Catalytic residues not yet defined","Whether PDE activity alone suffices for motility unresolved","Substrate range beyond cAMP unexplored"]},{"year":2006,"claim":"Discovery that PRUNE1 binds GSK-3β and localizes to focal adhesions defined a cytoskeletal mechanism linking it to migration machinery.","evidence":"Reciprocal Co-IP, siRNA knockdown, focal adhesion immunofluorescence, paxillin disassembly, FAK phosphorylation, and Rac activation assays; gelsolin identified by pull-down/MS","pmids":["16428445","17103319"],"confidence":"High","gaps":["How GSK-3β binding couples to PDE activity unclear","Gelsolin interaction not mechanistically followed up","Direct vs indirect effects on FAK/Rac not dissected"]},{"year":2007,"claim":"Mapping the two-domain architecture and the CKI-dependent NM23-H1 interaction defined how enzymatic and scaffolding functions are physically partitioned and regulated.","evidence":"Limited proteolysis and deletion mapping defined an N-terminal PDE domain and C-terminal cortexillin dimerization/binding domain; in vitro CKIδ/ε kinase assay, IC261 inhibition, and competitive peptide blocked complex formation and motility","pmids":["17655525","17906697"],"confidence":"Medium","gaps":["No high-resolution structure of either domain","Stoichiometry of dimer/NM23-H1 complex unresolved","In vivo relevance of CKI phosphorylation not tested"]},{"year":2008,"claim":"Reconstitution of short-chain exopolyphosphatase activity with active-site mutagenesis revealed a second catalytic activity beyond cAMP hydrolysis.","evidence":"In vitro assays with recombinant protein showing metal-dependent hydrolysis of tri/tetrapolyphosphates, substrate profiling, and severe activity loss upon mutation of seven yeast-homologous active-site residues","pmids":["18700747"],"confidence":"High","gaps":["Physiological polyP substrate in cells not identified","Relationship between PDE and exopolyphosphatase activities unclear","Cellular consequences of polyP hydrolysis untested at this stage"]},{"year":2012,"claim":"Demonstrating that PDE-dead mutants lose gliogenic activity established PDE catalysis as functionally required in a developmental in vivo context.","evidence":"Xenopus overexpression with active-site aspartate substitutions and Müller glial cell fate quantification","pmids":["22967741"],"confidence":"Medium","gaps":["cAMP target downstream of PDE in this context not defined","Relevance to mammalian neurodevelopment not established","Whether scaffolding contributes independently untested"]},{"year":2013,"claim":"NMR mapping of the unfolded C-terminal domain identified the residues engaging NM23-H1, GSK-3β, and gelsolin and validated peptide-based inhibition as anti-metastatic.","evidence":"In-lysate NMR conformational analysis plus competitive permeable peptide reducing complex formation, cell motility, and tumor growth/metastasis in neuroblastoma xenografts","pmids":["23448979","23939913"],"confidence":"Medium","gaps":["No folded structure of the interaction interfaces","Selectivity of the peptide across the three partners unclear","Whether all three interactions occur simultaneously unknown"]},{"year":2014,"claim":"Linking the GSK-3β interaction to canonical WNT/β-catenin activation and Wnt3a secretion extended PRUNE1 into a pro-metastatic signaling pathway.","evidence":"Co-IP, WNT/β-catenin reporter assay, Wnt3a ELISA, and in vivo lung metastasis model with siRNA silencing","pmids":["25026278"],"confidence":"Medium","gaps":["Mechanism by which PRUNE1 modulates GSK-3β toward WNT unclear","Direct vs paracrine contributions not separated","Requirement of enzymatic activity not tested"]},{"year":2015,"claim":"Mitochondrial-matrix localization of the Drosophila ortholog and its control of TFAM/mtDNA placed PRUNE1's PDE activity within mitochondrial cAMP signaling and bioenergetics.","evidence":"Subcellular fractionation, RNAi knockdown, and measurement of TFAM levels and mtDNA copy number in Drosophila","pmids":["25648146"],"confidence":"Medium","gaps":["Mitochondrial localization not confirmed for human PRUNE1","Mechanism linking cAMP-PDE to TFAM stability indirect","Conservation of mtDNA function in mammals untested"]},{"year":2018,"claim":"Defining a PRUNE1/NME1–TGF-β–OTX2–SNAIL–PTEN axis in group 3 medulloblastoma and showing druggability connected its interactions to a specific oncogenic program.","evidence":"Co-IP, pathway activation assays, competitive permeable peptide, and the degradation-enhancing small molecule AA7.1 in orthotopic xenografts","pmids":["29490009"],"confidence":"Medium","gaps":["Direct molecular steps between NME1 binding and TGF-β activation unresolved","Whether enzymatic activity is required for this axis unclear","Generality beyond medulloblastoma untested"]},{"year":2020,"claim":"Showing PRUNE1 drives M2 macrophage polarization extended its pro-metastatic role into the tumor microenvironment.","evidence":"PRUNE1-overexpression genetically engineered TNBC mouse model with macrophage polarization, TGF-β/IL-17F secretion, and extracellular vesicle analyses","pmids":["33426510"],"confidence":"Medium","gaps":["Whether tumor-cell-intrinsic enzymatic activity drives the secretome unclear","Cargo of extracellular vesicles not defined","Causal role of IL-17F not isolated"]},{"year":2021,"claim":"Linking DHH-motif missense variants to loss of exopolyphosphatase activity and an embryonic-lethal knockout established that catalytic function is required for normal neurodevelopment and the disease NMIHBA.","evidence":"Biochemical stability and enzymatic assays of recombinant disease variants plus a Prune1 knockout mouse with midgestational lethality and vascular defects","pmids":["33105479"],"confidence":"High","gaps":["Physiological polyP substrate in neural tissue unidentified","Mechanism linking enzymatic loss to cortical phenotype indirect","Conditional/tissue-specific requirements not dissected"]},{"year":2023,"claim":"Reassessing polyphosphate substrates and connecting PRUNE1 to ATP synthase activity reframed its effect on cellular polyP as indirect via mitochondrial bioenergetics.","evidence":"In vitro assays with defined polyP chain lengths (showing no hydrolysis of 13–160 Pi chains) and HEK293 knockdown reducing cellular polyP, ATP synthase activity, and ATP, with ATP5A compensation","pmids":["37762163"],"confidence":"Medium","gaps":["Direct molecular link between PRUNE1 and ATP synthase not defined","Reconciliation with earlier short-chain exopolyphosphatase data incomplete","Whether mitochondrial localization mediates the effect in human cells unknown"]},{"year":null,"claim":"How PRUNE1's two catalytic activities, its scaffolding interactions, and its mitochondrial/bioenergetic effects are mechanistically integrated to produce both neurodevelopmental and metastatic phenotypes remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution full-length structure","Endogenous physiological substrate(s) of the enzyme unidentified","Direct molecular bridge from enzymatic activity to cytoskeletal/microtubule defects unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,2,17,15]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,1,4]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3,10,12]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10,12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[11,8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[8,15]}],"complexes":[],"partners":["NME1","GSK3B","GSN","CSNK1D"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86TP1","full_name":"Exopolyphosphatase PRUNE1","aliases":["Drosophila-related expressed sequence 17","DRES-17","DRES17","HTcD37","Protein prune homolog 1","hPrune"],"length_aa":453,"mass_kda":50.2,"function":"Phosphodiesterase (PDE) that has higher activity toward cAMP than cGMP, as substrate. Plays a role in cell proliferation, migration and differentiation, and acts as a negative regulator of NME1. Plays a role in the regulation of neurogenesis (PubMed:28334956). Involved in the regulation of microtubule polymerization (PubMed:28334956)","subcellular_location":"Cytoplasm; Nucleus; Cell junction, focal adhesion","url":"https://www.uniprot.org/uniprotkb/Q86TP1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PRUNE1","classification":"Not Classified","n_dependent_lines":264,"n_total_lines":1208,"dependency_fraction":0.2185430463576159},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"GSK3A","stoichiometry":4.0},{"gene":"GSK3B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PRUNE1","total_profiled":1310},"omim":[{"mim_id":"617481","title":"NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, HYPOTONIA, AND VARIABLE BRAIN ANOMALIES; NMIHBA","url":"https://www.omim.org/entry/617481"},{"mim_id":"617413","title":"PRUNE EXOPOLYPHOSPHATASE 1; PRUNE1","url":"https://www.omim.org/entry/617413"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PRUNE1"},"hgnc":{"alias_symbol":["DRES-17","HTCD37","H-PRUNE"],"prev_symbol":["PRUNE"]},"alphafold":{"accession":"Q86TP1","domains":[{"cath_id":"3.90.1640.10","chopping":"2-223","consensus_level":"high","plddt":95.4576,"start":2,"end":223},{"cath_id":"3.10.310.20","chopping":"228-367","consensus_level":"high","plddt":94.7439,"start":228,"end":367}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86TP1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86TP1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86TP1-F1-predicted_aligned_error_v6.png","plddt_mean":85.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PRUNE1","jax_strain_url":"https://www.jax.org/strain/search?query=PRUNE1"},"sequence":{"accession":"Q86TP1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86TP1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86TP1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86TP1"}},"corpus_meta":[{"pmid":"2849580","id":"PMC_2849580","title":"Analysis of the lethal interaction between the prune and Killer of prune mutations of Drosophila.","date":"1988","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/2849580","citation_count":142,"is_preprint":false},{"pmid":"14998490","id":"PMC_14998490","title":"Prune cAMP phosphodiesterase binds nm23-H1 and promotes cancer metastasis.","date":"2004","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/14998490","citation_count":121,"is_preprint":false},{"pmid":"1320004","id":"PMC_1320004","title":"A Pro/Ser substitution in nucleoside diphosphate kinase of Drosophila melanogaster (mutation killer of prune) affects stability but not catalytic efficiency of the enzyme.","date":"1992","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/1320004","citation_count":112,"is_preprint":false},{"pmid":"18700747","id":"PMC_18700747","title":"Human metastasis regulator protein H-prune is a short-chain exopolyphosphatase.","date":"2008","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18700747","citation_count":110,"is_preprint":false},{"pmid":"16428445","id":"PMC_16428445","title":"Glycogen synthase kinase 3 and h-prune regulate cell migration by modulating focal adhesions.","date":"2006","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16428445","citation_count":106,"is_preprint":false},{"pmid":"1654526","id":"PMC_1654526","title":"A product of the prune locus of Drosophila is similar to mammalian GTPase-activating protein.","date":"1991","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/1654526","citation_count":75,"is_preprint":false},{"pmid":"10602478","id":"PMC_10602478","title":"Evidence for interaction between human PRUNE and nm23-H1 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'Ximei') Fruit by Modulating the Antioxidant System.","date":"2024","source":"Foods (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/39335799","citation_count":9,"is_preprint":false},{"pmid":"31936247","id":"PMC_31936247","title":"Modifications in Tissue and Cell Ultrastructure as Elements of Immunity-Like Reaction in Chenopodium quinoa against Prune Dwarf Virus (PDV).","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/31936247","citation_count":9,"is_preprint":false},{"pmid":"8121405","id":"PMC_8121405","title":"The mRNA product of the Drosophila gene prune is spliced and encodes a protein containing a putative transmembrane domain.","date":"1994","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/8121405","citation_count":9,"is_preprint":false},{"pmid":"21597971","id":"PMC_21597971","title":"Hepatoblastoma and prune belly syndrome: a potential association.","date":"2011","source":"Pediatric nephrology (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/21597971","citation_count":9,"is_preprint":false},{"pmid":"2877580","id":"PMC_2877580","title":"Prune belly syndrome and retroperitoneal germ cell tumor.","date":"1986","source":"The American journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/2877580","citation_count":9,"is_preprint":false},{"pmid":"15789267","id":"PMC_15789267","title":"Genomic variability of prune dwarf virus as affected by agricultural practice.","date":"2005","source":"Archives of virology","url":"https://pubmed.ncbi.nlm.nih.gov/15789267","citation_count":9,"is_preprint":false},{"pmid":"21034928","id":"PMC_21034928","title":"Prune belly syndrome associated with cloacal anomaly, patent urachal remnant, and omphalocele in a female infant.","date":"2010","source":"Journal of pediatric surgery","url":"https://pubmed.ncbi.nlm.nih.gov/21034928","citation_count":9,"is_preprint":false},{"pmid":"31882333","id":"PMC_31882333","title":"Altered MR imaging findings in a Japanese female child with PRUNE1-related disorder.","date":"2019","source":"Brain & development","url":"https://pubmed.ncbi.nlm.nih.gov/31882333","citation_count":8,"is_preprint":false},{"pmid":"22967741","id":"PMC_22967741","title":"Spatial and temporal expressions of prune reveal a role in Müller gliogenesis during Xenopus retinal development.","date":"2012","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/22967741","citation_count":8,"is_preprint":false},{"pmid":"32406554","id":"PMC_32406554","title":"Inoculum quantification of canker-causing pathogens in prune and walnut orchards using real-time PCR.","date":"2020","source":"Journal of applied microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/32406554","citation_count":8,"is_preprint":false},{"pmid":"25289000","id":"PMC_25289000","title":"Development and Practical Use of RT-PCR for Seed-transmitted Prune dwarf virus in Quarantine.","date":"2014","source":"The plant pathology journal","url":"https://pubmed.ncbi.nlm.nih.gov/25289000","citation_count":8,"is_preprint":false},{"pmid":"35379233","id":"PMC_35379233","title":"Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies in a consanguineous Iranian family is associated with a homozygous start loss variant in the PRUNE1 gene.","date":"2022","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/35379233","citation_count":7,"is_preprint":false},{"pmid":"37875395","id":"PMC_37875395","title":"Tumor Environment Regression Therapy Implemented by Switchable Prune-to-Essence Nanoplatform Unleashed Systemic Immune Responses.","date":"2023","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/37875395","citation_count":7,"is_preprint":false},{"pmid":"29258199","id":"PMC_29258199","title":"Molecular Biology of Prune Dwarf Virus-A Lesser Known Member of the Bromoviridae but a Vital Component in the Dynamic Virus-Host Cell Interaction Network.","date":"2017","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29258199","citation_count":7,"is_preprint":false},{"pmid":"34696454","id":"PMC_34696454","title":"Molecular Identification of Prune Dwarf Virus (PDV) Infecting Sweet Cherry in Canada and Development of a PDV Full-Length Infectious cDNA Clone.","date":"2021","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/34696454","citation_count":7,"is_preprint":false},{"pmid":"2975088","id":"PMC_2975088","title":"[Prune belly syndrome. Prenatal diagnosis and obstetric procedure].","date":"1988","source":"Zeitschrift fur Geburtshilfe und Perinatologie","url":"https://pubmed.ncbi.nlm.nih.gov/2975088","citation_count":7,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":41404,"output_tokens":4661,"usd":0.097063,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12847,"output_tokens":4724,"usd":0.091167,"stage2_stop_reason":"end_turn"},"total_usd":0.18823,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"Human prune (h-prune) possesses cyclic nucleotide phosphodiesterase (cAMP-PDE) activity that can be suppressed by dipyridamole, and physically interacts with nm23-H1 (a metastasis suppressor); the interaction with nm23-H1 enhances h-prune PDE activity and stimulates cellular motility and metastasis.\",\n      \"method\": \"In vitro enzymatic assay (cAMP-PDE activity), co-immunoprecipitation, dipyridamole inhibition, cellular motility assays in breast cancer cell lines\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro enzymatic assay combined with Co-IP and functional cellular readout; replicated in subsequent independent studies\",\n      \"pmids\": [\"14998490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Human PRUNE protein interacts with nm23-H1 (human homologue of awd/NDP kinase) as shown by interaction-mating and in vitro co-immunoprecipitation; PRUNE is impaired in interaction with the nm23-H1-S120G gain-of-function mutant; both proteins partially co-localize in the cytoplasm.\",\n      \"method\": \"Yeast two-hybrid interaction mating, co-immunoprecipitation, subcellular co-localization\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP and two-hybrid in the original paper, replicated by multiple subsequent labs\",\n      \"pmids\": [\"10602478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"h-prune efficiently hydrolyzes short-chain polyphosphates (tri- and tetrapolyphosphates, nucleoside 5'-tetraphosphates) as a short-chain exopolyphosphatase, requiring divalent metal cofactors (Mg2+, Co2+, Mn2+); long-chain polyphosphates are hydrolyzed more slowly; pyrophosphate and nucleoside triphosphates are not hydrolyzed. Mutation of seven active-site residues corresponding to yeast exopolyphosphatase severely reduced activity. The exopolyphosphatase activity is suppressed by nm23-H1, long-chain polyphosphates, and pyrophosphate.\",\n      \"method\": \"In vitro enzymatic assay with recombinant protein, active-site mutagenesis, substrate specificity profiling\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted enzymatic activity in vitro with mutagenesis of active-site residues, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"18700747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"h-prune was identified as a glycogen synthase kinase 3 (GSK-3) binding protein; the kinase activity of GSK-3 is required for this interaction. h-prune localizes to focal adhesions, and siRNA knockdown of GSK-3 or h-prune delays disassembly of paxillin, suppresses tyrosine phosphorylation of FAK, and suppresses Rac activation, impairing cell motility.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, immunofluorescence localization to focal adhesions, paxillin disassembly assay, FAK phosphorylation assay, Rac activation assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, siRNA knockdown with multiple defined cellular phenotype readouts, localization tied to functional consequence\",\n      \"pmids\": [\"16428445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The region of nm23-H1 spanning S120–S125 mediates the nm23-H1/h-prune interaction; phosphorylation of nm23-H1 at this region by casein kinase I (CKI) delta/epsilon is required for complex formation. The CKI delta/epsilon-specific inhibitor IC261 impairs complex formation and inhibits cellular motility in a breast cancer model. A competitive permeable peptide spanning the CKI phosphorylation region similarly impairs motility.\",\n      \"method\": \"Mutational mapping of interaction site, in vitro kinase assay (CKI phosphorylation), pharmacological inhibition with IC261, competitive peptide inhibition, transwell cell migration assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — kinase assay, mutational mapping, and functional cellular readouts in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"17906697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"h-prune contains two structurally independent domains: an N-terminal PDE catalytic domain (active even as monomer) and a C-terminal cortexillin homology domain that mediates h-prune homodimerization and interaction with NM23-H1. Domain boundaries were identified by sequence analysis and limited proteolysis of recombinant h-prune.\",\n      \"method\": \"Recombinant protein expression, limited proteolysis, sequence analysis, domain mapping by deletion constructs, dimerization and binding assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain boundaries defined biochemically with recombinant protein, single lab, multiple methods\",\n      \"pmids\": [\"17655525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NMR spectroscopy of the h-prune C-terminal domain in human cell lysates identified the amino acids of this largely unfolded domain involved in interactions with Nm23-H1, GSK-3β, and gelsolin; a competitive permeable peptide (CPP) derived from this region impairs Nm23-H1/h-prune complex formation, inhibits cell motility, and substantially reduces tumor growth and metastasis in neuroblastoma models.\",\n      \"method\": \"NMR spectroscopy in cell lysates, conformational analysis, competitive peptide inhibition, cell motility assay, in vivo orthotopic xenograft tumor model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — NMR structural mapping combined with functional in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"23448979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NMR spectroscopy mapping of h-prune C-terminal domain confirmed it is largely unfolded and mediates protein-protein interactions with Nm23-H1, GSK-3β, and gelsolin.\",\n      \"method\": \"Fast NMR spectroscopy in cell lysates\",\n      \"journal\": \"Chemistry (Weinheim an der Bergstrasse, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — NMR structural analysis in cell lysates, single lab\",\n      \"pmids\": [\"23939913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Disease-associated PRUNE1 variant alleles cause impaired microtubule polymerization, and reduced cell migration and proliferation. These functional defects establish a role for PRUNE1 in microtubule polymerization essential for cytoskeletal rearrangements during cell division and proliferation in cortical brain development.\",\n      \"method\": \"Functional assays of disease variant alleles: microtubule polymerization assay, cell migration assay, cell proliferation assay\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays of disease alleles in single lab, no in vitro reconstitution of microtubule polymerization per se\",\n      \"pmids\": [\"28334956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Drosophila Prune (ortholog of human PRUNE1) is a cyclic nucleotide phosphodiesterase that localizes to the mitochondrial matrix. Knockdown of prune in cultured cells reduces mitochondrial transcription factor A (TFAM) and mtDNA levels; Prune stabilizes TFAM and promotes mtDNA replication through downregulation of mitochondrial cAMP signaling.\",\n      \"method\": \"Subcellular fractionation and localization (mitochondrial matrix), RNAi knockdown in cultured cells, measurement of TFAM protein levels and mtDNA copy number\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct fractionation-based localization tied to functional consequence (mtDNA replication), Drosophila ortholog, single lab\",\n      \"pmids\": [\"25648146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"h-prune interacts with GSK-3β and through this complex activates canonical WNT/β-catenin signaling, also in a paracrine manner via Wnt3a secretion. h-prune silencing inhibits lung metastasis formation in vivo.\",\n      \"method\": \"Co-immunoprecipitation (h-prune/GSK-3β interaction), WNT/β-catenin reporter assay, Wnt3a ELISA, in vivo lung metastasis model (siRNA silencing)\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, reporter assay, and in vivo functional readout, single lab\",\n      \"pmids\": [\"25026278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NMIHBA-associated missense variants within the conserved N-terminal DHH motif of PRUNE1 result in destabilization of protein structure and/or loss of exopolyphosphatase activity, establishing that exopolyphosphatase activity is required for normal neurodevelopment. Complete genetic ablation of Prune1 in mice causes midgestational lethality with perturbations to embryonic growth and vascular development.\",\n      \"method\": \"Biochemical characterization of recombinant missense variants (protein stability and enzymatic activity assays), Prune1 knockout mouse model\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic activity assay with multiple disease-associated variants plus KO mouse model with defined phenotype, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"33105479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PRUNE1 activates a signaling pathway in metastatic medulloblastoma group 3 involving binding to NME1, TGF-β activation, OTX2 upregulation, SNAIL (SNAI1) upregulation, and PTEN inhibition. A competitive permeable peptide impairing PRUNE1/NME1 complex formation, and a small molecule (AA7.1) that enhances PRUNE1 degradation, both impair tumor growth and metastatic dissemination in orthotopic xenograft models.\",\n      \"method\": \"Co-immunoprecipitation (PRUNE1/NME1), competitive permeable peptide, small molecule inhibitor (AA7.1), orthotopic xenograft mouse model, pathway activation assays (TGF-β, OTX2, SNAIL, PTEN)\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vivo xenograft validation, multiple pathway readouts, single lab\",\n      \"pmids\": [\"29490009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Recombinant h-prune does not hydrolyze short (13–33 Pi) or medium (45–160 Pi) chain polyphosphates. However, knockdown of h-prune in HEK293 cells significantly decreases cellular polyP levels and reduces ATP synthase activity and ATP levels, with compensatory upregulation of ATP5A expression; these effects on mitochondrial bioenergetics are not due to loss of mitochondrial membrane potential or mitochondrial biomass.\",\n      \"method\": \"In vitro enzymatic assay with recombinant h-prune and defined polyphosphate chain lengths, siRNA knockdown in HEK293 cells, polyP quantification, ATP measurement, mitochondrial membrane potential assay, Western blot for ATP5A\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro enzymatic assay combined with cell-based knockdown and multiple biochemical readouts; single lab but several orthogonal methods\",\n      \"pmids\": [\"37762163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Protein-protein pull-down analyses coupled with mass spectrometry identified gelsolin (an ATP-severing protein acting in focal adhesions) as a new h-prune binding partner in a breast cancer cellular model, in addition to the known GSK-3β interaction.\",\n      \"method\": \"Protein-protein pull-down assay coupled to mass spectrometry\",\n      \"journal\": \"Journal of bioenergetics and biomembranes\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single pull-down/MS identification, single lab, limited mechanistic follow-up described in abstract\",\n      \"pmids\": [\"17103319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Xenopus prune overexpression in retinal precursor cells increases the ratio of Müller glial cells; a mutant form of prune with four aspartate (D) residue substitutions that abolish phosphodiesterase activity does not exhibit gliogenic activity, establishing that PDE activity is required for prune-mediated Müller gliogenesis.\",\n      \"method\": \"Xenopus overexpression, active-site mutagenesis (D residue substitutions), cell fate quantification (Müller glial cells)\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of active site combined with in vivo overexpression and defined cell fate phenotype, single lab\",\n      \"pmids\": [\"22967741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PRUNE1 overexpression promotes lung metastasis and M2-polarization of tumor-associated macrophages (TAMs) within the tumor microenvironment, mediated through TGF-β enhancement and IL-17F secretion, as shown in a genetically engineered mouse model of metastatic triple-negative breast cancer.\",\n      \"method\": \"Genetically engineered mouse model (PRUNE1 overexpression), macrophage polarization assays, TGF-β and IL-17F secretion measurements, extracellular vesicle analysis\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model with defined mechanistic pathway readouts, single lab\",\n      \"pmids\": [\"33426510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Overexpression of h-prune in the MDA-MB-435 breast carcinoma cell line causes a substantial decrease in cAMP levels and an increase in cellular motility, effects correlated with h-prune PDE activity and the h-prune/nm23-H1 protein interaction.\",\n      \"method\": \"Stable overexpression in breast cancer cell line, cAMP measurement, cell motility assay\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cellular overexpression with defined biochemical (cAMP) and functional (motility) readouts, single lab\",\n      \"pmids\": [\"15254413\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRUNE1 (h-prune) is a DHH-superfamily phosphoesterase with two distinct enzymatic activities — a cAMP phosphodiesterase (mapped to its N-terminal catalytic domain) and a short-chain exopolyphosphatase (hydrolyzing polyphosphates up to ~4 Pi units in vitro, but affecting longer cellular polyP chains indirectly via regulation of ATP synthase activity) — that drives cancer cell motility and metastasis by physically interacting with the metastasis suppressor NM23-H1/NME1 (interaction requiring CKI-mediated phosphorylation of NM23-H1 at S120–S125 and mediated by h-prune's C-terminal dimerization/cortexillin domain), by binding GSK-3β (kinase-activity-dependent) to promote focal adhesion disassembly and FAK/Rac activation, and by activating canonical WNT/β-catenin and TGF-β/SNAIL/PTEN signaling; loss-of-function PRUNE1 variants that destabilize the protein or abolish exopolyphosphatase activity cause the autosomal recessive neurodevelopmental disorder NMIHBA, partly through impaired microtubule polymerization and cell migration, while complete Prune1 ablation in mice causes mid-gestational lethality.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PRUNE1 (h-prune) is a DHH-superfamily phosphoesterase that drives cell motility, cytoskeletal remodeling, and metastasis through coupled enzymatic and scaffolding functions [#0, #3]. Its N-terminal catalytic domain is a metal-dependent enzyme with cyclic-nucleotide phosphodiesterase activity and short-chain exopolyphosphatase activity, defined by conserved active-site residues; PDE activity lowers cellular cAMP and is required for its biological effects [#0, #2, #17, #15]. A structurally independent C-terminal cortexillin-homology domain is largely unfolded and mediates homodimerization and protein-protein interactions [#5, #7]. Through this domain PRUNE1 binds the metastasis suppressor NM23-H1/NME1 in a manner requiring CKIδ/ε phosphorylation of NM23-H1 across its S120–S125 region, an interaction that stimulates PRUNE1 enzymatic activity and promotes tumor cell motility and metastasis [#1, #4, #6]. PRUNE1 also binds GSK-3β in a kinase-activity-dependent manner and localizes to focal adhesions, where it promotes paxillin disassembly, FAK phosphorylation, and Rac activation to enable migration, and engages canonical WNT/β-catenin signaling [#3, #10]. In metastatic medulloblastoma it activates a TGF-β/OTX2/SNAIL/PTEN axis downstream of NME1 binding, and in breast cancer it reprograms tumor-associated macrophages toward an M2 phenotype via TGF-β and IL-17F [#12, #16]. Loss-of-function missense variants in the conserved N-terminal DHH motif that destabilize the protein or abolish exopolyphosphatase activity cause the autosomal recessive neurodevelopmental disorder NMIHBA, partly through impaired microtubule polymerization and cell migration, and complete Prune1 ablation in mice is midgestationally lethal [#8, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing that PRUNE1 physically partners with the metastasis suppressor NM23-H1 placed it directly within metastasis-suppression biology and defined its first molecular interaction.\",\n      \"evidence\": \"Yeast two-hybrid interaction mating, reciprocal co-IP, and cytoplasmic co-localization, with loss of binding to the NM23-H1-S120G mutant\",\n      \"pmids\": [\"10602478\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of the interaction not yet established\", \"Interaction domain on PRUNE1 not mapped\", \"Biochemical activity of PRUNE1 unknown at this stage\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identifying cAMP-PDE activity and linking it to NM23-H1 binding and cell motility converted PRUNE1 from a binding partner into an enzymatically active metastasis driver.\",\n      \"evidence\": \"In vitro cAMP-PDE assay with dipyridamole inhibition, Co-IP, and motility assays in breast cancer lines; overexpression lowers cAMP and raises motility\",\n      \"pmids\": [\"14998490\", \"15254413\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic residues not yet defined\", \"Whether PDE activity alone suffices for motility unresolved\", \"Substrate range beyond cAMP unexplored\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Discovery that PRUNE1 binds GSK-3β and localizes to focal adhesions defined a cytoskeletal mechanism linking it to migration machinery.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA knockdown, focal adhesion immunofluorescence, paxillin disassembly, FAK phosphorylation, and Rac activation assays; gelsolin identified by pull-down/MS\",\n      \"pmids\": [\"16428445\", \"17103319\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How GSK-3β binding couples to PDE activity unclear\", \"Gelsolin interaction not mechanistically followed up\", \"Direct vs indirect effects on FAK/Rac not dissected\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mapping the two-domain architecture and the CKI-dependent NM23-H1 interaction defined how enzymatic and scaffolding functions are physically partitioned and regulated.\",\n      \"evidence\": \"Limited proteolysis and deletion mapping defined an N-terminal PDE domain and C-terminal cortexillin dimerization/binding domain; in vitro CKIδ/ε kinase assay, IC261 inhibition, and competitive peptide blocked complex formation and motility\",\n      \"pmids\": [\"17655525\", \"17906697\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of either domain\", \"Stoichiometry of dimer/NM23-H1 complex unresolved\", \"In vivo relevance of CKI phosphorylation not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Reconstitution of short-chain exopolyphosphatase activity with active-site mutagenesis revealed a second catalytic activity beyond cAMP hydrolysis.\",\n      \"evidence\": \"In vitro assays with recombinant protein showing metal-dependent hydrolysis of tri/tetrapolyphosphates, substrate profiling, and severe activity loss upon mutation of seven yeast-homologous active-site residues\",\n      \"pmids\": [\"18700747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological polyP substrate in cells not identified\", \"Relationship between PDE and exopolyphosphatase activities unclear\", \"Cellular consequences of polyP hydrolysis untested at this stage\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating that PDE-dead mutants lose gliogenic activity established PDE catalysis as functionally required in a developmental in vivo context.\",\n      \"evidence\": \"Xenopus overexpression with active-site aspartate substitutions and Müller glial cell fate quantification\",\n      \"pmids\": [\"22967741\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"cAMP target downstream of PDE in this context not defined\", \"Relevance to mammalian neurodevelopment not established\", \"Whether scaffolding contributes independently untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"NMR mapping of the unfolded C-terminal domain identified the residues engaging NM23-H1, GSK-3β, and gelsolin and validated peptide-based inhibition as anti-metastatic.\",\n      \"evidence\": \"In-lysate NMR conformational analysis plus competitive permeable peptide reducing complex formation, cell motility, and tumor growth/metastasis in neuroblastoma xenografts\",\n      \"pmids\": [\"23448979\", \"23939913\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No folded structure of the interaction interfaces\", \"Selectivity of the peptide across the three partners unclear\", \"Whether all three interactions occur simultaneously unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linking the GSK-3β interaction to canonical WNT/β-catenin activation and Wnt3a secretion extended PRUNE1 into a pro-metastatic signaling pathway.\",\n      \"evidence\": \"Co-IP, WNT/β-catenin reporter assay, Wnt3a ELISA, and in vivo lung metastasis model with siRNA silencing\",\n      \"pmids\": [\"25026278\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which PRUNE1 modulates GSK-3β toward WNT unclear\", \"Direct vs paracrine contributions not separated\", \"Requirement of enzymatic activity not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mitochondrial-matrix localization of the Drosophila ortholog and its control of TFAM/mtDNA placed PRUNE1's PDE activity within mitochondrial cAMP signaling and bioenergetics.\",\n      \"evidence\": \"Subcellular fractionation, RNAi knockdown, and measurement of TFAM levels and mtDNA copy number in Drosophila\",\n      \"pmids\": [\"25648146\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mitochondrial localization not confirmed for human PRUNE1\", \"Mechanism linking cAMP-PDE to TFAM stability indirect\", \"Conservation of mtDNA function in mammals untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defining a PRUNE1/NME1–TGF-β–OTX2–SNAIL–PTEN axis in group 3 medulloblastoma and showing druggability connected its interactions to a specific oncogenic program.\",\n      \"evidence\": \"Co-IP, pathway activation assays, competitive permeable peptide, and the degradation-enhancing small molecule AA7.1 in orthotopic xenografts\",\n      \"pmids\": [\"29490009\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular steps between NME1 binding and TGF-β activation unresolved\", \"Whether enzymatic activity is required for this axis unclear\", \"Generality beyond medulloblastoma untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showing PRUNE1 drives M2 macrophage polarization extended its pro-metastatic role into the tumor microenvironment.\",\n      \"evidence\": \"PRUNE1-overexpression genetically engineered TNBC mouse model with macrophage polarization, TGF-β/IL-17F secretion, and extracellular vesicle analyses\",\n      \"pmids\": [\"33426510\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether tumor-cell-intrinsic enzymatic activity drives the secretome unclear\", \"Cargo of extracellular vesicles not defined\", \"Causal role of IL-17F not isolated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linking DHH-motif missense variants to loss of exopolyphosphatase activity and an embryonic-lethal knockout established that catalytic function is required for normal neurodevelopment and the disease NMIHBA.\",\n      \"evidence\": \"Biochemical stability and enzymatic assays of recombinant disease variants plus a Prune1 knockout mouse with midgestational lethality and vascular defects\",\n      \"pmids\": [\"33105479\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological polyP substrate in neural tissue unidentified\", \"Mechanism linking enzymatic loss to cortical phenotype indirect\", \"Conditional/tissue-specific requirements not dissected\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Reassessing polyphosphate substrates and connecting PRUNE1 to ATP synthase activity reframed its effect on cellular polyP as indirect via mitochondrial bioenergetics.\",\n      \"evidence\": \"In vitro assays with defined polyP chain lengths (showing no hydrolysis of 13–160 Pi chains) and HEK293 knockdown reducing cellular polyP, ATP synthase activity, and ATP, with ATP5A compensation\",\n      \"pmids\": [\"37762163\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between PRUNE1 and ATP synthase not defined\", \"Reconciliation with earlier short-chain exopolyphosphatase data incomplete\", \"Whether mitochondrial localization mediates the effect in human cells unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PRUNE1's two catalytic activities, its scaffolding interactions, and its mitochondrial/bioenergetic effects are mechanistically integrated to produce both neurodevelopmental and metastatic phenotypes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution full-length structure\", \"Endogenous physiological substrate(s) of the enzyme unidentified\", \"Direct molecular bridge from enzymatic activity to cytoskeletal/microtubule defects unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 2, 17, 15]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 1, 4]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 10, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005925\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [11, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8, 15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NME1\", \"GSK3B\", \"GSN\", \"CSNK1D\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}