{"gene":"PDE3B","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2013,"finding":"IKKε and TBK1 phosphorylate and activate PDE3B in adipocytes, thereby reducing cAMP levels and attenuating β-adrenergic/catecholamine signaling and lipolysis; specific inhibition of these kinases with amlexanox reversed obesity-induced catecholamine resistance and restored PKA signaling in vivo.","method":"Overexpression and inhibitor studies in 3T3-L1 adipocytes; in vivo treatment of obese mice with amlexanox; measurement of cAMP, lipolysis, HSL phosphorylation, and UCP1 induction","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain- and loss-of-function with pharmacological and genetic tools, replicated in vitro and in vivo with multiple orthogonal readouts","pmids":["24368730"],"is_preprint":false},{"year":2015,"finding":"PDE3B is required for insulin's anti-lipolytic action in adipocytes, as PDE3B knockout adipocytes fail to suppress β-adrenergic receptor-stimulated glycerol release in response to insulin; however, reexpression of a PDE3B mutant ablating the major Akt phosphorylation site (S273) still rescues insulin's anti-lipolytic effect, demonstrating that direct Akt phosphorylation of PDE3B at S273 is not required for this action.","method":"PDE3B knockout brown adipocytes; adenoviral reexpression of wild-type and S273A mutant PDE3B; glycerol release assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — genetic KO with reconstitution using wild-type and phosphosite mutant, multiple orthogonal controls","pmids":["26031333"],"is_preprint":false},{"year":2006,"finding":"The novel PI3Kγ regulatory subunit p87PIKAP physically interacts with PDE3B, suggesting p87PIKAP participates in the noncatalytic scaffolding interaction of PI3Kγ p110γ with PDE3B; however, coexpression of PDE3B with PI3Kγ subunits alone was not sufficient to reconstitute the regulatory effect of PI3Kγ on PDE3B activity observed in heart.","method":"Co-immunoprecipitation; heterologous expression in HEK293 cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP demonstrating physical interaction, single lab, but functional reconstitution was negative","pmids":["16476736"],"is_preprint":false},{"year":1998,"finding":"PDE3B (135 kDa) is exclusively localized to the particulate (membrane) fraction in all rat tissues and cultured vascular smooth muscle cells examined, in contrast to PDE3A which is cytosolic; prolonged cAMP elevation increases PDE3B protein and particulate PDE3 activity.","method":"Subcellular fractionation; immunoblotting with PDE3B-selective antisera; RT-PCR","journal":"British journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical fractionation with isoform-selective antibodies, multiple tissues, single lab","pmids":["9884079"],"is_preprint":false},{"year":2000,"finding":"Phosphatidylinositol 3-kinase serine kinase activity associated with the insulin receptor phosphorylates PDE3B (the 135-kDa protein) in human adipocytes, and this phosphorylation is associated with PDE3B activation and the antilipolytic effect of insulin.","method":"PI3K activity assay; immunoprecipitation with anti-PDE3B; serine phosphorylation measurement; PI3K inhibitor wortmannin","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical identification of PI3K-PDE3B phosphorylation in human primary adipocytes, single lab, two orthogonal methods","pmids":["10744689"],"is_preprint":false},{"year":1999,"finding":"Protein phosphatase 2A (PP2A) dephosphorylates and deactivates PDE3B in rat adipocytes; PP2A co-purifies with PDE3B phosphatase activity, and okadaic acid (which selectively inhibits PP2A over PP1 at 1 µM) activates PDE3B in vivo, while tautomycin (PP1-selective) does not.","method":"Phosphatase inhibitor treatment in adipocytes; MonoQ chromatography co-purification; 32P phosphorylation assays; in vitro dephosphorylation assay","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro dephosphorylation assay plus in vivo pharmacological evidence with selective inhibitors, single lab","pmids":["10417351"],"is_preprint":false},{"year":2007,"finding":"Insulin induces formation of large macromolecular complexes at ER/Golgi and plasma membrane fractions of adipocytes containing phosphorylated/activated PDE3B together with IRS-1, IRS-2, PI3K p85, PKB/Akt, HSP90, and 14-3-3; the N-terminal region of PDE3B (first 604 amino acids) is required for insulin-induced activation and recruitment into these complexes; PDE3B co-immunoprecipitates preferentially with phosphorylated/activated PKB.","method":"Subcellular fractionation; Superose 6 gel filtration; co-immunoprecipitation; siRNA knockdown; recombinant truncation mutants; confocal microscopy; PI3K inhibitors","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (fractionation, gel filtration, co-IP, mutagenesis, confocal), single lab but rigorous","pmids":["17324123"],"is_preprint":false},{"year":2009,"finding":"Insulin preferentially phosphorylates/activates PDE3B in internal membrane (ER/Golgi) compartments, whereas the β3-adrenergic agonist CL316243 preferentially activates PDE3B in caveolae; caveolin-1 knockdown abolishes CL316243-mediated PDE3B activation and lipolysis signaling, implicating cav-1 as a chaperone/scaffold for PDE3B in lipid raft microdomains.","method":"Subcellular fractionation; siRNA knockdown of caveolin-1; Cav-1 KO mouse adipocytes; Superose 6 gel filtration; 32P phosphorylation; HSL and perilipin phosphorylation","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic (KO mice + siRNA) and biochemical fractionation with multiple signaling readouts, single lab but multiple orthogonal approaches","pmids":["19747167"],"is_preprint":false},{"year":2006,"finding":"Plasma membrane PDE3B in adipocytes is associated with caveolae, co-eluting with caveolin-1, flotillin-1, and cholesterol; disruption of caveolae (by methyl-β-cyclodextrin or caveolin-1 deficiency) reduces membrane-associated PDE3B activity; PDE3B co-immunoprecipitates with caveolin-1.","method":"Subcellular fractionation; detergent-resistance assay; Superose-6 chromatography; sucrose density gradient; co-immunoprecipitation; caveolin-1 KO mice; methyl-β-cyclodextrin treatment","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple complementary biochemical approaches and genetic KO model, single lab","pmids":["16503395"],"is_preprint":false},{"year":2005,"finding":"PDE3B (but not PDE4) contributes to insulin-induced glucose uptake, GLUT-4 translocation to the plasma membrane, and lipogenesis in rat primary adipocytes; PDE3 inhibition reduces GLUT-4 translocation to caveolae; this regulation appears to involve a cAMP/Epac (not PKA) signaling mechanism, as H89 (PKA inhibitor) did not reverse the effect but an Epac agonist mimicked it.","method":"PDE3 and PDE4 selective inhibitors (OPC3911, milrinone, RO 20-1724); glucose uptake assays; GLUT-4 translocation measurement; PKA activity; lipolysis assay; Epac agonist; H89","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological dissection with isoform-selective inhibitors and signaling pathway probes, single lab","pmids":["15961276"],"is_preprint":false},{"year":2007,"finding":"Insulin regulates adiponectin and leptin secretion and expression through a PI3K-PDE3B-cAMP pathway; PDE3 inhibition (milrinone) or PI3K inhibitors block the ability of insulin to restore β-agonist/cAMP-suppressed adiponectin and leptin production in primary rat adipocytes.","method":"PDE3 inhibitor (milrinone); PI3K inhibitors; cAMP analogues; adiponectin/leptin ELISA in primary rat adipocytes","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological pathway dissection, single lab, consistent with established PI3K-PDE3B pathway","pmids":["17286556"],"is_preprint":false},{"year":2007,"finding":"PDE3B localizes to insulin secretory granules and plasma membrane in pancreatic β-cells; overexpression of PDE3B reduces first-phase Ca2+-triggered exocytosis and granule mobilization, while PDE3B KO increases K+-stimulated insulin secretion, establishing PDE3B as a regulator of depolarization-induced insulin secretion via cAMP hydrolysis.","method":"Transgenic RIP-PDE3B/7 mice; PDE3B KO mice; adenoviral PDE3B overexpression in INS-1 cells; subcellular fractionation; confocal microscopy; transmission electron microscopy; voltage-clamp capacitance measurements","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic gain- and loss-of-function combined with electrophysiology and imaging, single lab but multiple orthogonal approaches","pmids":["17368848"],"is_preprint":false},{"year":2015,"finding":"Targeted disruption of PDE3B (but not PDE3A) protects mouse heart from ischemia/reperfusion injury, reducing infarct size and improving cardiac function; the cardioprotective effect requires cAMP/PKA signaling and mitochondrial calcium-activated K channel opening; PDE3B KO mitochondria are enriched in Bcl-2, produce less ROS, and accumulate cardioprotective proteins in caveolin-3-enriched fractions (ICEFs) in a PKA-dependent manner; PDE3B was localized with caveolin-3 at transverse tubules.","method":"PDE3B and PDE3A KO mice; in vivo and in vitro I/R models; infarct size measurement; PKA inhibitor; paxilline (mito K-channel blocker); proteomics; mitochondrial fractionation; ROS measurement; mitochondrial permeability transition pore assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — isoform-specific KO with multiple mechanistic readouts, in vivo and in vitro validation, proteomics confirmation","pmids":["25877153"],"is_preprint":false},{"year":2018,"finding":"ABHD15 associates with and stabilizes PDE3B protein; loss of ABHD15 decreases PDE3B expression in white adipose tissue, resulting in elevated PKA activity, increased HSL phosphorylation, and failure of insulin to suppress lipolysis, leading to insulin resistance.","method":"Abhd15 global and conditional KO mice; in vitro co-immunoprecipitation; PDE3B protein quantification; AKT phosphorylation; glucose uptake; lipolysis assay; HSL phosphorylation","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO in vivo and in vitro co-IP with multiple mechanistic readouts, single lab but orthogonal approaches","pmids":["29768196"],"is_preprint":false},{"year":2003,"finding":"Tryptophan 1072 in the catalytic domain of human PDE3B is critical for inhibitor binding but not substrate hydrolysis; W1072A mutation caused 158-fold decrease in cilostamide affinity and 740-fold decrease in cGMP affinity, but only ~7-fold increase in cAMP Km, demonstrating that the inhibitor binding region is distinct from but overlapping with the substrate binding region.","method":"Recombinant PDE3B expression in E. coli; active-site mutagenesis (W1072A, W1072Y); enzyme kinetic assays; inhibitor binding assays; homology modeling based on PDE4B crystal structure","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro mutagenesis with quantitative enzyme kinetics, single lab, two mutations tested","pmids":["12878217"],"is_preprint":false},{"year":2018,"finding":"PDE3B hydrolyzes cUMP with low affinity (Km ~550 µM) and high velocity (Vmax ~76 µmol/min/mg) in a milrinone-sensitive manner; docking studies using the PDE3B crystal structure show uracil 3-NH forms one hydrogen bond with Q988, whereas cAMP forms two hydrogen bonds; the milrinone-sensitive cUMP-hydrolytic activity previously observed in rat adipose tissue is attributable to PDE3B.","method":"Recombinant PDE3B enzyme kinetics; HPLC-tandem MS substrate/product quantitation; milrinone inhibition assay; molecular docking with crystal structure PDB 1SO2; adipocyte lysate and rat adipose tissue membrane assays","journal":"Naunyn-Schmiedeberg's archives of pharmacology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzyme assay with structural docking, single lab, validates activity in native tissue","pmids":["29808231"],"is_preprint":false},{"year":2006,"finding":"CREB and phospho-CREB bind to cAMP-response elements in both distal and proximal promoter regions of the Pde3b gene and are required for IBMX-induced transcriptional upregulation of PDE3B during 3T3-L1 preadipocyte differentiation; dominant-negative CREB markedly inhibits Pde3b mRNA and protein induction.","method":"Luciferase reporter assays with Pde3b promoter fragments; dominant-negative CREB; chromatin immunoprecipitation (ChIP) with anti-CREB, anti-phospho-CREB, anti-CBP/p300; real-time PCR; immunoblotting","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — promoter mapping with luciferase, ChIP, and dominant-negative genetic approach, multiple orthogonal methods, single lab","pmids":["16702214"],"is_preprint":false},{"year":2015,"finding":"G-CSF activates a JAK2/PI3K/PDE3B signaling pathway in adrenal cortical cells, leading to cAMP degradation and inhibition of corticosterone synthesis; PDE3B inhibition in vivo reverses the neuroprotective effects of G-CSF in a neonatal hypoxic-ischemic brain injury rat model.","method":"Western blot for JAK2/PI3K/Akt/PDE3B in Y1 adrenal cells; cAMP and corticosterone ELISA; PDE3B inhibitor in vivo; neonatal HI rat model with TTC staining","journal":"Experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and biochemical pathway dissection in cells and in vivo, single lab","pmids":["25816736"],"is_preprint":false},{"year":2017,"finding":"PDE3B knockout in mouse WAT leads to activation of cAMP/PKA and AMPK signaling pathways, resulting in white-to-beige adipocyte conversion ('browning') with increased β-oxidation and oxygen consumption under high-fat diet conditions.","method":"Targeted Pde3b gene inactivation (KO mice); cAMP/PKA and AMPK pathway analysis; metabolic phenotyping; β-oxidation assay; oxygen consumption measurement","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with metabolic and signaling readouts, single lab","pmids":["28084425"],"is_preprint":false},{"year":2016,"finding":"PDE3B ablation in white adipose tissue prevents NLRP3 inflammasome activation by reducing expression of NLRP3, caspase-1, ASC, AIM2, TNFα, and IL-1β; signaling cascades including SMAD, NFAT, NFκB, and MAP kinases are modulated in PDE3B KO WAT; PDE3B KO also reduces atherosclerotic plaque formation in apoE-/- and LDL-R-/- backgrounds.","method":"PDE3B KO mice; LPS injection model; serum cytokine measurement; gene expression analysis; double KO mice (apoE-/-/PDE3B-/-; LDL-R-/-/PDE3B-/-); aortic plaque quantification","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple inflammatory and cardiovascular readouts, single lab","pmids":["27321128"],"is_preprint":false},{"year":2019,"finding":"PDE3B (but not PDE3A) silencing impairs endothelial cell angiogenic sprouting; PDE3B and PKA co-localize in a perinuclear region in human endothelial cells and can be co-immunoprecipitated; PDE3B silencing activates the perinuclear pool of PKA; PDE3B antagonizes anti-angiogenic PKA actions by controlling cAMP levels that regulate podosome rosette biogenesis, matrix degradation, and cdc42 activity.","method":"siRNA silencing of PDE3B vs. PDE3A; in vitro and ex vivo angiogenesis sprouting assays; cilostamide pharmacology; PKA inhibitor; co-immunoprecipitation; subcellular PKA activity imaging; cdc42 activity assay","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific siRNA with multiple functional assays and co-IP, single lab","pmids":["31176020"],"is_preprint":false},{"year":2024,"finding":"PDE3B elevation during supercooling liver preservation promotes cAMP reduction, triggering AMPK-dependent autophagy that leads to liver injury; cilostamide (PDE3B inhibitor) blocks this pathway, inhibits autophagy, and substantially ameliorates liver injury in rat, pig, and human liver models.","method":"Integrative metabolomics, transcriptomics, and proteomics; cilostamide treatment in rat, pig, and human liver SLP models; cAMP measurement; AMPK-autophagy pathway analysis","journal":"Science translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-omic identification plus pharmacological intervention validated across three species, single study","pmids":["39602509"],"is_preprint":false},{"year":2024,"finding":"Crystal structure re-analysis of PDE3B complexed with boronic acid inhibitor GSK4394835A reveals that H737 undergoes nucleophilic addition to the boronic acid moiety, generating a tetrahedral boronate anion covalently bound in the PDE3B active site, establishing GSK4394835A as a reversible covalent inhibitor.","method":"Re-refinement of X-ray crystal structure (PDB 8SYC) with reprocessed structure factor amplitudes; electron density map analysis; crystallographic refinement","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure re-analysis with rigorous electron density, single preprint, not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"In adipocytes, insulin-activated PDE3B predominantly regulates cytoplasmic cAMP pools, while FGF1/PDE4D primarily regulates plasma membrane cAMP; neither pathway affects a distinct lipid droplet-associated cAMP pool detected by a novel perilipin-1-EPAC1-FRET biosensor.","method":"EPAC1-based FRET cAMP biosensors targeted to cytoplasm, plasma membrane, or lipid droplets (perilipin-1 fusion); PDE inhibitor pharmacology; live-cell imaging in 3T3-L1 adipocytes","journal":"British journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — novel biosensor tool with subcellular resolution, pharmacological dissection, single lab","pmids":["41082906"],"is_preprint":false},{"year":2025,"finding":"Esrrg (estrogen-related receptor-γ) binds directly to the Pde3b promoter and transcriptionally activates Pde3b expression in airway epithelial cells; Esrrg inhibition reduces PDE3B expression and ameliorates PM2.5-aggravated airway inflammation.","method":"Dual luciferase reporter assay; chromatin immunoprecipitation PCR (ChIP-PCR); AAV-shEsrrg silencing in vivo; pharmacological Esrrg inhibition (GSK5182); mRNA sequencing","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding shown by luciferase reporter and ChIP, supported by genetic and pharmacological knockdown, single lab","pmids":["40153608"],"is_preprint":false}],"current_model":"PDE3B is a membrane-associated cAMP/cGMP phosphodiesterase that is activated by insulin (via PI3K/Akt-mediated phosphorylation and macromolecular complex assembly at ER/Golgi membranes) and by β-adrenergic signaling (via PKA at caveolae), and is also phosphorylated and activated by the inflammatory kinases IKKε/TBK1; it localizes to ER/Golgi, caveolae, and insulin secretory granule membranes in a caveolin-1-dependent manner, and in each compartment it hydrolyzes local cAMP pools to control lipolysis, glucose uptake/GLUT-4 translocation, insulin secretion, catecholamine sensitivity, angiogenic sprouting, and inflammasome activation, while PP2A serves as its dephosphorylating/deactivating phosphatase and ABHD15 stabilizes its protein expression."},"narrative":{"mechanistic_narrative":"PDE3B is a membrane-associated cyclic nucleotide phosphodiesterase that hydrolyzes compartmentalized cAMP pools to integrate hormonal and inflammatory signals controlling lipolysis, glucose handling, insulin secretion, and cardiovascular function [PMID:26031333, PMID:17324123]. Unlike the cytosolic PDE3A, PDE3B partitions exclusively to membrane fractions and is enriched in caveolae through association with caveolin-1, which acts as a scaffold for its localization and activation in lipid raft microdomains [PMID:9884079, PMID:16503395]. Insulin activates PDE3B downstream of the insulin receptor/PI3K axis: PI3K-associated serine kinase activity phosphorylates and activates PDE3B [PMID:10744689], and insulin drives assembly of large macromolecular complexes at ER/Golgi membranes containing PDE3B together with IRS-1/2, PI3K p85, PKB/Akt, HSP90, and 14-3-3, requiring the PDE3B N-terminal region for recruitment [PMID:17324123]. This activation underlies insulin's anti-lipolytic action through PDE3B-dependent cAMP hydrolysis, although direct Akt phosphorylation of PDE3B at S273 is dispensable for this effect [PMID:26031333]. Different stimuli target distinct pools: insulin preferentially activates ER/Golgi-resident PDE3B while β3-adrenergic signaling activates caveolar PDE3B in a caveolin-1-dependent manner [PMID:19747167], and biosensor measurements place insulin-activated PDE3B as the dominant controller of cytoplasmic cAMP [PMID:41082906]. PDE3B activity is reversed by PP2A, which dephosphorylates and deactivates the enzyme [PMID:10417351], and its protein level is stabilized by ABHD15, loss of which lowers PDE3B and produces insulin resistance [PMID:29768196]. The inflammatory kinases IKKε and TBK1 also phosphorylate and activate PDE3B in adipocytes to attenuate β-adrenergic catecholamine signaling [PMID:24368730]. Beyond adipose, PDE3B localizes to pancreatic β-cell secretory granules where it restrains depolarization-induced insulin secretion [PMID:17368848], and isoform-specific knockout studies establish roles in cardioprotection against ischemia/reperfusion injury via cAMP/PKA and mitochondrial K-channel signaling [PMID:25877153], endothelial angiogenic sprouting through a perinuclear PKA pool [PMID:31176020], and NLRP3 inflammasome and atherosclerosis control [PMID:27321128]. Pde3b transcription is driven by CREB during adipocyte differentiation [PMID:16702214] and by ESRRG in airway epithelium [PMID:40153608]. Structurally, the catalytic domain residue W1072 governs inhibitor binding distinct from substrate hydrolysis [PMID:12878217], and PDE3B also hydrolyzes cUMP in a milrinone-sensitive manner [PMID:29808231].","teleology":[{"year":1998,"claim":"Established that PDE3B is distinguished from its paralog PDE3A by exclusive membrane localization, defining it as a particulate enzyme positioned to control local cAMP.","evidence":"Subcellular fractionation and isoform-selective immunoblotting across rat tissues and vascular smooth muscle cells","pmids":["9884079"],"confidence":"Medium","gaps":["Did not identify the membrane anchor or microdomain","Single lab, antibody-based"]},{"year":1999,"claim":"Identified the phosphatase arm of PDE3B regulation by showing PP2A deactivates the enzyme, framing PDE3B activity as a reversible phosphorylation switch.","evidence":"Phosphatase inhibitor pharmacology, MonoQ co-purification, and in vitro dephosphorylation assays in rat adipocytes","pmids":["10417351"],"confidence":"Medium","gaps":["Did not map the dephosphorylated residues","PP2A targeting/recruitment mechanism unknown"]},{"year":2000,"claim":"Linked insulin receptor signaling to PDE3B by showing PI3K-associated serine kinase activity phosphorylates and activates PDE3B, providing a biochemical basis for insulin's anti-lipolytic effect.","evidence":"PI3K activity assays, anti-PDE3B immunoprecipitation, serine phosphorylation measurement, and wortmannin in human adipocytes","pmids":["10744689"],"confidence":"Medium","gaps":["Did not identify the terminal kinase or phosphosites","Correlative link between phosphorylation and activation"]},{"year":2003,"claim":"Defined the catalytic-domain determinant W1072 that separates inhibitor binding from substrate hydrolysis, informing the pharmacology of PDE3B-selective compounds.","evidence":"Recombinant active-site mutagenesis, enzyme kinetics, and homology modeling","pmids":["12878217"],"confidence":"High","gaps":["Only two mutations tested","No full crystal structure in this study"]},{"year":2006,"claim":"Localized plasma-membrane PDE3B to caveolae via caveolin-1 association, identifying the structural basis for its membrane targeting.","evidence":"Detergent-resistance, sucrose gradients, co-IP with caveolin-1, and caveolin-1 KO mice in adipocytes","pmids":["16503395"],"confidence":"High","gaps":["Did not resolve whether caveolin-1 binding is direct","Role in non-adipose tissues untested here"]},{"year":2006,"claim":"Tested whether PI3Kγ scaffolding subunit p87PIKAP couples PI3Kγ to PDE3B, establishing a physical interaction but not functional reconstitution.","evidence":"Co-immunoprecipitation and heterologous expression in HEK293 cells","pmids":["16476736"],"confidence":"Medium","gaps":["Functional reconstitution was negative","Single-lab co-IP without reciprocal in vivo validation"]},{"year":2006,"claim":"Identified CREB as the transcription factor driving Pde3b induction during adipocyte differentiation, connecting cAMP signaling to PDE3B gene expression.","evidence":"Pde3b promoter luciferase reporters, ChIP, and dominant-negative CREB in 3T3-L1 cells","pmids":["16702214"],"confidence":"High","gaps":["Did not address regulation in mature adipocytes","Other promoter inputs not excluded"]},{"year":2007,"claim":"Resolved the molecular architecture of insulin activation by showing PDE3B is recruited into Akt/IRS/PI3K macromolecular complexes at ER/Golgi membranes via its N-terminal region.","evidence":"Subcellular fractionation, gel filtration, co-IP, siRNA, truncation mutants, and confocal microscopy in adipocytes","pmids":["17324123"],"confidence":"High","gaps":["Did not pinpoint the direct binding partner within the complex","Stoichiometry and assembly order unresolved"]},{"year":2007,"claim":"Extended PDE3B function to pancreatic β-cells, establishing it as a brake on depolarization-induced insulin secretion via cAMP hydrolysis at secretory granules.","evidence":"Transgenic and KO mice, adenoviral overexpression in INS-1 cells, electron microscopy, and capacitance electrophysiology","pmids":["17368848"],"confidence":"High","gaps":["Granule-targeting mechanism not defined","Relationship to caveolar pool unclear"]},{"year":2009,"claim":"Demonstrated stimulus-specific compartmentalization: insulin activates ER/Golgi PDE3B while β3-adrenergic signaling activates caveolar PDE3B in a caveolin-1-dependent manner.","evidence":"Fractionation, caveolin-1 siRNA and KO mice, gel filtration, and phosphorylation/lipolysis readouts in adipocytes","pmids":["19747167"],"confidence":"High","gaps":["How a single enzyme is differentially routed remains unresolved","Kinetics of inter-pool exchange unknown"]},{"year":2013,"claim":"Identified IKKε/TBK1 as inflammatory kinases that phosphorylate and activate PDE3B, linking obesity-associated inflammation to catecholamine resistance.","evidence":"Overexpression/inhibitor studies in 3T3-L1 cells and amlexanox treatment of obese mice with cAMP and lipolysis readouts","pmids":["24368730"],"confidence":"High","gaps":["Direct phosphosites not mapped in this study","Whether activation is direct vs. via intermediaries"]},{"year":2015,"claim":"Showed PDE3B is required for insulin's anti-lipolytic action but that the major Akt site S273 is dispensable, refining the phosphorylation model.","evidence":"PDE3B KO brown adipocytes reconstituted with wild-type and S273A mutant; glycerol release assays","pmids":["26031333"],"confidence":"High","gaps":["The functionally critical phosphosite(s) remain unidentified","Did not test combinatorial mutants"]},{"year":2015,"claim":"Established an isoform-specific cardioprotective role for PDE3B in ischemia/reperfusion, acting through cAMP/PKA and mitochondrial K-channel signaling.","evidence":"PDE3B vs PDE3A KO mice, in vivo/in vitro I/R models, proteomics, and mitochondrial assays","pmids":["25877153"],"confidence":"High","gaps":["Mechanism linking PDE3B to mitochondrial protein enrichment not fully defined","Caveolin-3 dependence not directly tested"]},{"year":2017,"claim":"Showed PDE3B loss drives white-to-beige adipocyte conversion via cAMP/PKA and AMPK activation, connecting the enzyme to whole-body energy expenditure.","evidence":"Pde3b KO mice with metabolic phenotyping, β-oxidation, and oxygen consumption measurements","pmids":["28084425"],"confidence":"Medium","gaps":["Adipocyte-autonomous vs systemic effects not separated","Direct PKA/AMPK targets not mapped"]},{"year":2016,"claim":"Linked PDE3B to innate immunity and atherosclerosis by showing its ablation suppresses NLRP3 inflammasome activation and plaque formation.","evidence":"PDE3B KO and double-KO mice (apoE-/-, LDL-R-/-) with cytokine, gene expression, and plaque readouts","pmids":["27321128"],"confidence":"Medium","gaps":["Cell type driving the inflammasome effect unresolved","Mechanistic link from cAMP to NLRP3 not defined"]},{"year":2018,"claim":"Identified ABHD15 as a binding partner that stabilizes PDE3B protein, establishing post-translational control of PDE3B abundance as a node in insulin sensitivity.","evidence":"Abhd15 KO mice, co-IP, and PDE3B/lipolysis/HSL readouts","pmids":["29768196"],"confidence":"High","gaps":["Structural basis of stabilization unknown","Whether ABHD15 binding is direct vs complex-mediated"]},{"year":2018,"claim":"Demonstrated PDE3B hydrolyzes cUMP in a milrinone-sensitive manner, broadening its substrate repertoire beyond cAMP/cGMP.","evidence":"Recombinant enzyme kinetics, HPLC-MS substrate quantitation, and docking on PDB 1SO2","pmids":["29808231"],"confidence":"Medium","gaps":["Physiological role of cUMP hydrolysis untested","Low affinity questions in vivo relevance"]},{"year":2019,"claim":"Established an isoform-specific role for PDE3B in endothelial angiogenic sprouting by antagonizing a perinuclear PKA pool that controls podosome biogenesis and cdc42 activity.","evidence":"PDE3B vs PDE3A siRNA, sprouting assays, co-IP with PKA, and subcellular PKA activity imaging","pmids":["31176020"],"confidence":"Medium","gaps":["Mechanism of perinuclear targeting unresolved","Whether PDE3B-PKA interaction is direct"]},{"year":2024,"claim":"Implicated PDE3B in organ preservation injury, where its elevation triggers AMPK-dependent autophagy and liver damage reversible by pharmacological inhibition.","evidence":"Multi-omics and cilostamide treatment across rat, pig, and human supercooled liver preservation models","pmids":["39602509"],"confidence":"Medium","gaps":["Upstream driver of PDE3B elevation unknown","Single study"]},{"year":2025,"claim":"Defined the cAMP pool controlled by PDE3B at subcellular resolution, placing insulin-activated PDE3B as the dominant regulator of cytoplasmic cAMP distinct from plasma-membrane and lipid-droplet pools.","evidence":"Compartment-targeted EPAC1-FRET biosensors and PDE inhibitor pharmacology in 3T3-L1 adipocytes","pmids":["41082906"],"confidence":"Medium","gaps":["Does not explain how compartment specificity is achieved","Single lab"]},{"year":2025,"claim":"Identified ESRRG as a direct transcriptional activator of Pde3b in airway epithelium, extending PDE3B transcriptional control to inflammatory airway disease.","evidence":"Luciferase reporter, ChIP-PCR, AAV-shEsrrg silencing, and pharmacological inhibition in vivo","pmids":["40153608"],"confidence":"Medium","gaps":["Generality beyond airway epithelium untested","Interaction with CREB-driven regulation unclear"]},{"year":null,"claim":"The functionally critical phosphosite(s) and the direct kinase(s)/binding partners that mediate compartment-specific activation of PDE3B remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["S273-independent activating phosphorylation not mapped","Direct interactor within the insulin macromolecular complex unidentified","Mechanism routing one enzyme to distinct membrane pools unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[14,15]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[14,15]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,8,11]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[6,7]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[6,7]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,6,7,0]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,9,18]},{"term_id":"R-HSA-168256","term_label":"Immune 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specific inhibition of these kinases with amlexanox reversed obesity-induced catecholamine resistance and restored PKA signaling in vivo.\",\n      \"method\": \"Overexpression and inhibitor studies in 3T3-L1 adipocytes; in vivo treatment of obese mice with amlexanox; measurement of cAMP, lipolysis, HSL phosphorylation, and UCP1 induction\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain- and loss-of-function with pharmacological and genetic tools, replicated in vitro and in vivo with multiple orthogonal readouts\",\n      \"pmids\": [\"24368730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PDE3B is required for insulin's anti-lipolytic action in adipocytes, as PDE3B knockout adipocytes fail to suppress β-adrenergic receptor-stimulated glycerol release in response to insulin; however, reexpression of a PDE3B mutant ablating the major Akt phosphorylation site (S273) still rescues insulin's anti-lipolytic effect, demonstrating that direct Akt phosphorylation of PDE3B at S273 is not required for this action.\",\n      \"method\": \"PDE3B knockout brown adipocytes; adenoviral reexpression of wild-type and S273A mutant PDE3B; glycerol release assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — genetic KO with reconstitution using wild-type and phosphosite mutant, multiple orthogonal controls\",\n      \"pmids\": [\"26031333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The novel PI3Kγ regulatory subunit p87PIKAP physically interacts with PDE3B, suggesting p87PIKAP participates in the noncatalytic scaffolding interaction of PI3Kγ p110γ with PDE3B; however, coexpression of PDE3B with PI3Kγ subunits alone was not sufficient to reconstitute the regulatory effect of PI3Kγ on PDE3B activity observed in heart.\",\n      \"method\": \"Co-immunoprecipitation; heterologous expression in HEK293 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP demonstrating physical interaction, single lab, but functional reconstitution was negative\",\n      \"pmids\": [\"16476736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"PDE3B (135 kDa) is exclusively localized to the particulate (membrane) fraction in all rat tissues and cultured vascular smooth muscle cells examined, in contrast to PDE3A which is cytosolic; prolonged cAMP elevation increases PDE3B protein and particulate PDE3 activity.\",\n      \"method\": \"Subcellular fractionation; immunoblotting with PDE3B-selective antisera; RT-PCR\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical fractionation with isoform-selective antibodies, multiple tissues, single lab\",\n      \"pmids\": [\"9884079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Phosphatidylinositol 3-kinase serine kinase activity associated with the insulin receptor phosphorylates PDE3B (the 135-kDa protein) in human adipocytes, and this phosphorylation is associated with PDE3B activation and the antilipolytic effect of insulin.\",\n      \"method\": \"PI3K activity assay; immunoprecipitation with anti-PDE3B; serine phosphorylation measurement; PI3K inhibitor wortmannin\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical identification of PI3K-PDE3B phosphorylation in human primary adipocytes, single lab, two orthogonal methods\",\n      \"pmids\": [\"10744689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Protein phosphatase 2A (PP2A) dephosphorylates and deactivates PDE3B in rat adipocytes; PP2A co-purifies with PDE3B phosphatase activity, and okadaic acid (which selectively inhibits PP2A over PP1 at 1 µM) activates PDE3B in vivo, while tautomycin (PP1-selective) does not.\",\n      \"method\": \"Phosphatase inhibitor treatment in adipocytes; MonoQ chromatography co-purification; 32P phosphorylation assays; in vitro dephosphorylation assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro dephosphorylation assay plus in vivo pharmacological evidence with selective inhibitors, single lab\",\n      \"pmids\": [\"10417351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Insulin induces formation of large macromolecular complexes at ER/Golgi and plasma membrane fractions of adipocytes containing phosphorylated/activated PDE3B together with IRS-1, IRS-2, PI3K p85, PKB/Akt, HSP90, and 14-3-3; the N-terminal region of PDE3B (first 604 amino acids) is required for insulin-induced activation and recruitment into these complexes; PDE3B co-immunoprecipitates preferentially with phosphorylated/activated PKB.\",\n      \"method\": \"Subcellular fractionation; Superose 6 gel filtration; co-immunoprecipitation; siRNA knockdown; recombinant truncation mutants; confocal microscopy; PI3K inhibitors\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (fractionation, gel filtration, co-IP, mutagenesis, confocal), single lab but rigorous\",\n      \"pmids\": [\"17324123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Insulin preferentially phosphorylates/activates PDE3B in internal membrane (ER/Golgi) compartments, whereas the β3-adrenergic agonist CL316243 preferentially activates PDE3B in caveolae; caveolin-1 knockdown abolishes CL316243-mediated PDE3B activation and lipolysis signaling, implicating cav-1 as a chaperone/scaffold for PDE3B in lipid raft microdomains.\",\n      \"method\": \"Subcellular fractionation; siRNA knockdown of caveolin-1; Cav-1 KO mouse adipocytes; Superose 6 gel filtration; 32P phosphorylation; HSL and perilipin phosphorylation\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic (KO mice + siRNA) and biochemical fractionation with multiple signaling readouts, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"19747167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Plasma membrane PDE3B in adipocytes is associated with caveolae, co-eluting with caveolin-1, flotillin-1, and cholesterol; disruption of caveolae (by methyl-β-cyclodextrin or caveolin-1 deficiency) reduces membrane-associated PDE3B activity; PDE3B co-immunoprecipitates with caveolin-1.\",\n      \"method\": \"Subcellular fractionation; detergent-resistance assay; Superose-6 chromatography; sucrose density gradient; co-immunoprecipitation; caveolin-1 KO mice; methyl-β-cyclodextrin treatment\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple complementary biochemical approaches and genetic KO model, single lab\",\n      \"pmids\": [\"16503395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PDE3B (but not PDE4) contributes to insulin-induced glucose uptake, GLUT-4 translocation to the plasma membrane, and lipogenesis in rat primary adipocytes; PDE3 inhibition reduces GLUT-4 translocation to caveolae; this regulation appears to involve a cAMP/Epac (not PKA) signaling mechanism, as H89 (PKA inhibitor) did not reverse the effect but an Epac agonist mimicked it.\",\n      \"method\": \"PDE3 and PDE4 selective inhibitors (OPC3911, milrinone, RO 20-1724); glucose uptake assays; GLUT-4 translocation measurement; PKA activity; lipolysis assay; Epac agonist; H89\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological dissection with isoform-selective inhibitors and signaling pathway probes, single lab\",\n      \"pmids\": [\"15961276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Insulin regulates adiponectin and leptin secretion and expression through a PI3K-PDE3B-cAMP pathway; PDE3 inhibition (milrinone) or PI3K inhibitors block the ability of insulin to restore β-agonist/cAMP-suppressed adiponectin and leptin production in primary rat adipocytes.\",\n      \"method\": \"PDE3 inhibitor (milrinone); PI3K inhibitors; cAMP analogues; adiponectin/leptin ELISA in primary rat adipocytes\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological pathway dissection, single lab, consistent with established PI3K-PDE3B pathway\",\n      \"pmids\": [\"17286556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PDE3B localizes to insulin secretory granules and plasma membrane in pancreatic β-cells; overexpression of PDE3B reduces first-phase Ca2+-triggered exocytosis and granule mobilization, while PDE3B KO increases K+-stimulated insulin secretion, establishing PDE3B as a regulator of depolarization-induced insulin secretion via cAMP hydrolysis.\",\n      \"method\": \"Transgenic RIP-PDE3B/7 mice; PDE3B KO mice; adenoviral PDE3B overexpression in INS-1 cells; subcellular fractionation; confocal microscopy; transmission electron microscopy; voltage-clamp capacitance measurements\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic gain- and loss-of-function combined with electrophysiology and imaging, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"17368848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Targeted disruption of PDE3B (but not PDE3A) protects mouse heart from ischemia/reperfusion injury, reducing infarct size and improving cardiac function; the cardioprotective effect requires cAMP/PKA signaling and mitochondrial calcium-activated K channel opening; PDE3B KO mitochondria are enriched in Bcl-2, produce less ROS, and accumulate cardioprotective proteins in caveolin-3-enriched fractions (ICEFs) in a PKA-dependent manner; PDE3B was localized with caveolin-3 at transverse tubules.\",\n      \"method\": \"PDE3B and PDE3A KO mice; in vivo and in vitro I/R models; infarct size measurement; PKA inhibitor; paxilline (mito K-channel blocker); proteomics; mitochondrial fractionation; ROS measurement; mitochondrial permeability transition pore assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isoform-specific KO with multiple mechanistic readouts, in vivo and in vitro validation, proteomics confirmation\",\n      \"pmids\": [\"25877153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ABHD15 associates with and stabilizes PDE3B protein; loss of ABHD15 decreases PDE3B expression in white adipose tissue, resulting in elevated PKA activity, increased HSL phosphorylation, and failure of insulin to suppress lipolysis, leading to insulin resistance.\",\n      \"method\": \"Abhd15 global and conditional KO mice; in vitro co-immunoprecipitation; PDE3B protein quantification; AKT phosphorylation; glucose uptake; lipolysis assay; HSL phosphorylation\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO in vivo and in vitro co-IP with multiple mechanistic readouts, single lab but orthogonal approaches\",\n      \"pmids\": [\"29768196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Tryptophan 1072 in the catalytic domain of human PDE3B is critical for inhibitor binding but not substrate hydrolysis; W1072A mutation caused 158-fold decrease in cilostamide affinity and 740-fold decrease in cGMP affinity, but only ~7-fold increase in cAMP Km, demonstrating that the inhibitor binding region is distinct from but overlapping with the substrate binding region.\",\n      \"method\": \"Recombinant PDE3B expression in E. coli; active-site mutagenesis (W1072A, W1072Y); enzyme kinetic assays; inhibitor binding assays; homology modeling based on PDE4B crystal structure\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro mutagenesis with quantitative enzyme kinetics, single lab, two mutations tested\",\n      \"pmids\": [\"12878217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PDE3B hydrolyzes cUMP with low affinity (Km ~550 µM) and high velocity (Vmax ~76 µmol/min/mg) in a milrinone-sensitive manner; docking studies using the PDE3B crystal structure show uracil 3-NH forms one hydrogen bond with Q988, whereas cAMP forms two hydrogen bonds; the milrinone-sensitive cUMP-hydrolytic activity previously observed in rat adipose tissue is attributable to PDE3B.\",\n      \"method\": \"Recombinant PDE3B enzyme kinetics; HPLC-tandem MS substrate/product quantitation; milrinone inhibition assay; molecular docking with crystal structure PDB 1SO2; adipocyte lysate and rat adipose tissue membrane assays\",\n      \"journal\": \"Naunyn-Schmiedeberg's archives of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzyme assay with structural docking, single lab, validates activity in native tissue\",\n      \"pmids\": [\"29808231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CREB and phospho-CREB bind to cAMP-response elements in both distal and proximal promoter regions of the Pde3b gene and are required for IBMX-induced transcriptional upregulation of PDE3B during 3T3-L1 preadipocyte differentiation; dominant-negative CREB markedly inhibits Pde3b mRNA and protein induction.\",\n      \"method\": \"Luciferase reporter assays with Pde3b promoter fragments; dominant-negative CREB; chromatin immunoprecipitation (ChIP) with anti-CREB, anti-phospho-CREB, anti-CBP/p300; real-time PCR; immunoblotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — promoter mapping with luciferase, ChIP, and dominant-negative genetic approach, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"16702214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"G-CSF activates a JAK2/PI3K/PDE3B signaling pathway in adrenal cortical cells, leading to cAMP degradation and inhibition of corticosterone synthesis; PDE3B inhibition in vivo reverses the neuroprotective effects of G-CSF in a neonatal hypoxic-ischemic brain injury rat model.\",\n      \"method\": \"Western blot for JAK2/PI3K/Akt/PDE3B in Y1 adrenal cells; cAMP and corticosterone ELISA; PDE3B inhibitor in vivo; neonatal HI rat model with TTC staining\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and biochemical pathway dissection in cells and in vivo, single lab\",\n      \"pmids\": [\"25816736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PDE3B knockout in mouse WAT leads to activation of cAMP/PKA and AMPK signaling pathways, resulting in white-to-beige adipocyte conversion ('browning') with increased β-oxidation and oxygen consumption under high-fat diet conditions.\",\n      \"method\": \"Targeted Pde3b gene inactivation (KO mice); cAMP/PKA and AMPK pathway analysis; metabolic phenotyping; β-oxidation assay; oxygen consumption measurement\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with metabolic and signaling readouts, single lab\",\n      \"pmids\": [\"28084425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PDE3B ablation in white adipose tissue prevents NLRP3 inflammasome activation by reducing expression of NLRP3, caspase-1, ASC, AIM2, TNFα, and IL-1β; signaling cascades including SMAD, NFAT, NFκB, and MAP kinases are modulated in PDE3B KO WAT; PDE3B KO also reduces atherosclerotic plaque formation in apoE-/- and LDL-R-/- backgrounds.\",\n      \"method\": \"PDE3B KO mice; LPS injection model; serum cytokine measurement; gene expression analysis; double KO mice (apoE-/-/PDE3B-/-; LDL-R-/-/PDE3B-/-); aortic plaque quantification\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple inflammatory and cardiovascular readouts, single lab\",\n      \"pmids\": [\"27321128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PDE3B (but not PDE3A) silencing impairs endothelial cell angiogenic sprouting; PDE3B and PKA co-localize in a perinuclear region in human endothelial cells and can be co-immunoprecipitated; PDE3B silencing activates the perinuclear pool of PKA; PDE3B antagonizes anti-angiogenic PKA actions by controlling cAMP levels that regulate podosome rosette biogenesis, matrix degradation, and cdc42 activity.\",\n      \"method\": \"siRNA silencing of PDE3B vs. PDE3A; in vitro and ex vivo angiogenesis sprouting assays; cilostamide pharmacology; PKA inhibitor; co-immunoprecipitation; subcellular PKA activity imaging; cdc42 activity assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific siRNA with multiple functional assays and co-IP, single lab\",\n      \"pmids\": [\"31176020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PDE3B elevation during supercooling liver preservation promotes cAMP reduction, triggering AMPK-dependent autophagy that leads to liver injury; cilostamide (PDE3B inhibitor) blocks this pathway, inhibits autophagy, and substantially ameliorates liver injury in rat, pig, and human liver models.\",\n      \"method\": \"Integrative metabolomics, transcriptomics, and proteomics; cilostamide treatment in rat, pig, and human liver SLP models; cAMP measurement; AMPK-autophagy pathway analysis\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omic identification plus pharmacological intervention validated across three species, single study\",\n      \"pmids\": [\"39602509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Crystal structure re-analysis of PDE3B complexed with boronic acid inhibitor GSK4394835A reveals that H737 undergoes nucleophilic addition to the boronic acid moiety, generating a tetrahedral boronate anion covalently bound in the PDE3B active site, establishing GSK4394835A as a reversible covalent inhibitor.\",\n      \"method\": \"Re-refinement of X-ray crystal structure (PDB 8SYC) with reprocessed structure factor amplitudes; electron density map analysis; crystallographic refinement\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure re-analysis with rigorous electron density, single preprint, not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In adipocytes, insulin-activated PDE3B predominantly regulates cytoplasmic cAMP pools, while FGF1/PDE4D primarily regulates plasma membrane cAMP; neither pathway affects a distinct lipid droplet-associated cAMP pool detected by a novel perilipin-1-EPAC1-FRET biosensor.\",\n      \"method\": \"EPAC1-based FRET cAMP biosensors targeted to cytoplasm, plasma membrane, or lipid droplets (perilipin-1 fusion); PDE inhibitor pharmacology; live-cell imaging in 3T3-L1 adipocytes\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — novel biosensor tool with subcellular resolution, pharmacological dissection, single lab\",\n      \"pmids\": [\"41082906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Esrrg (estrogen-related receptor-γ) binds directly to the Pde3b promoter and transcriptionally activates Pde3b expression in airway epithelial cells; Esrrg inhibition reduces PDE3B expression and ameliorates PM2.5-aggravated airway inflammation.\",\n      \"method\": \"Dual luciferase reporter assay; chromatin immunoprecipitation PCR (ChIP-PCR); AAV-shEsrrg silencing in vivo; pharmacological Esrrg inhibition (GSK5182); mRNA sequencing\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding shown by luciferase reporter and ChIP, supported by genetic and pharmacological knockdown, single lab\",\n      \"pmids\": [\"40153608\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PDE3B is a membrane-associated cAMP/cGMP phosphodiesterase that is activated by insulin (via PI3K/Akt-mediated phosphorylation and macromolecular complex assembly at ER/Golgi membranes) and by β-adrenergic signaling (via PKA at caveolae), and is also phosphorylated and activated by the inflammatory kinases IKKε/TBK1; it localizes to ER/Golgi, caveolae, and insulin secretory granule membranes in a caveolin-1-dependent manner, and in each compartment it hydrolyzes local cAMP pools to control lipolysis, glucose uptake/GLUT-4 translocation, insulin secretion, catecholamine sensitivity, angiogenic sprouting, and inflammasome activation, while PP2A serves as its dephosphorylating/deactivating phosphatase and ABHD15 stabilizes its protein expression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PDE3B is a membrane-associated cyclic nucleotide phosphodiesterase that hydrolyzes compartmentalized cAMP pools to integrate hormonal and inflammatory signals controlling lipolysis, glucose handling, insulin secretion, and cardiovascular function [#1, #6]. Unlike the cytosolic PDE3A, PDE3B partitions exclusively to membrane fractions and is enriched in caveolae through association with caveolin-1, which acts as a scaffold for its localization and activation in lipid raft microdomains [#3, #8]. Insulin activates PDE3B downstream of the insulin receptor/PI3K axis: PI3K-associated serine kinase activity phosphorylates and activates PDE3B [#4], and insulin drives assembly of large macromolecular complexes at ER/Golgi membranes containing PDE3B together with IRS-1/2, PI3K p85, PKB/Akt, HSP90, and 14-3-3, requiring the PDE3B N-terminal region for recruitment [#6]. This activation underlies insulin's anti-lipolytic action through PDE3B-dependent cAMP hydrolysis, although direct Akt phosphorylation of PDE3B at S273 is dispensable for this effect [#1]. Different stimuli target distinct pools: insulin preferentially activates ER/Golgi-resident PDE3B while β3-adrenergic signaling activates caveolar PDE3B in a caveolin-1-dependent manner [#7], and biosensor measurements place insulin-activated PDE3B as the dominant controller of cytoplasmic cAMP [#23]. PDE3B activity is reversed by PP2A, which dephosphorylates and deactivates the enzyme [#5], and its protein level is stabilized by ABHD15, loss of which lowers PDE3B and produces insulin resistance [#13]. The inflammatory kinases IKKε and TBK1 also phosphorylate and activate PDE3B in adipocytes to attenuate β-adrenergic catecholamine signaling [#0]. Beyond adipose, PDE3B localizes to pancreatic β-cell secretory granules where it restrains depolarization-induced insulin secretion [#11], and isoform-specific knockout studies establish roles in cardioprotection against ischemia/reperfusion injury via cAMP/PKA and mitochondrial K-channel signaling [#12], endothelial angiogenic sprouting through a perinuclear PKA pool [#20], and NLRP3 inflammasome and atherosclerosis control [#19]. Pde3b transcription is driven by CREB during adipocyte differentiation [#16] and by ESRRG in airway epithelium [#24]. Structurally, the catalytic domain residue W1072 governs inhibitor binding distinct from substrate hydrolysis [#14], and PDE3B also hydrolyzes cUMP in a milrinone-sensitive manner [#15].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established that PDE3B is distinguished from its paralog PDE3A by exclusive membrane localization, defining it as a particulate enzyme positioned to control local cAMP.\",\n      \"evidence\": \"Subcellular fractionation and isoform-selective immunoblotting across rat tissues and vascular smooth muscle cells\",\n      \"pmids\": [\"9884079\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the membrane anchor or microdomain\", \"Single lab, antibody-based\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identified the phosphatase arm of PDE3B regulation by showing PP2A deactivates the enzyme, framing PDE3B activity as a reversible phosphorylation switch.\",\n      \"evidence\": \"Phosphatase inhibitor pharmacology, MonoQ co-purification, and in vitro dephosphorylation assays in rat adipocytes\",\n      \"pmids\": [\"10417351\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not map the dephosphorylated residues\", \"PP2A targeting/recruitment mechanism unknown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Linked insulin receptor signaling to PDE3B by showing PI3K-associated serine kinase activity phosphorylates and activates PDE3B, providing a biochemical basis for insulin's anti-lipolytic effect.\",\n      \"evidence\": \"PI3K activity assays, anti-PDE3B immunoprecipitation, serine phosphorylation measurement, and wortmannin in human adipocytes\",\n      \"pmids\": [\"10744689\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the terminal kinase or phosphosites\", \"Correlative link between phosphorylation and activation\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined the catalytic-domain determinant W1072 that separates inhibitor binding from substrate hydrolysis, informing the pharmacology of PDE3B-selective compounds.\",\n      \"evidence\": \"Recombinant active-site mutagenesis, enzyme kinetics, and homology modeling\",\n      \"pmids\": [\"12878217\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Only two mutations tested\", \"No full crystal structure in this study\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Localized plasma-membrane PDE3B to caveolae via caveolin-1 association, identifying the structural basis for its membrane targeting.\",\n      \"evidence\": \"Detergent-resistance, sucrose gradients, co-IP with caveolin-1, and caveolin-1 KO mice in adipocytes\",\n      \"pmids\": [\"16503395\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether caveolin-1 binding is direct\", \"Role in non-adipose tissues untested here\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Tested whether PI3Kγ scaffolding subunit p87PIKAP couples PI3Kγ to PDE3B, establishing a physical interaction but not functional reconstitution.\",\n      \"evidence\": \"Co-immunoprecipitation and heterologous expression in HEK293 cells\",\n      \"pmids\": [\"16476736\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional reconstitution was negative\", \"Single-lab co-IP without reciprocal in vivo validation\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified CREB as the transcription factor driving Pde3b induction during adipocyte differentiation, connecting cAMP signaling to PDE3B gene expression.\",\n      \"evidence\": \"Pde3b promoter luciferase reporters, ChIP, and dominant-negative CREB in 3T3-L1 cells\",\n      \"pmids\": [\"16702214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address regulation in mature adipocytes\", \"Other promoter inputs not excluded\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolved the molecular architecture of insulin activation by showing PDE3B is recruited into Akt/IRS/PI3K macromolecular complexes at ER/Golgi membranes via its N-terminal region.\",\n      \"evidence\": \"Subcellular fractionation, gel filtration, co-IP, siRNA, truncation mutants, and confocal microscopy in adipocytes\",\n      \"pmids\": [\"17324123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not pinpoint the direct binding partner within the complex\", \"Stoichiometry and assembly order unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extended PDE3B function to pancreatic β-cells, establishing it as a brake on depolarization-induced insulin secretion via cAMP hydrolysis at secretory granules.\",\n      \"evidence\": \"Transgenic and KO mice, adenoviral overexpression in INS-1 cells, electron microscopy, and capacitance electrophysiology\",\n      \"pmids\": [\"17368848\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Granule-targeting mechanism not defined\", \"Relationship to caveolar pool unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated stimulus-specific compartmentalization: insulin activates ER/Golgi PDE3B while β3-adrenergic signaling activates caveolar PDE3B in a caveolin-1-dependent manner.\",\n      \"evidence\": \"Fractionation, caveolin-1 siRNA and KO mice, gel filtration, and phosphorylation/lipolysis readouts in adipocytes\",\n      \"pmids\": [\"19747167\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single enzyme is differentially routed remains unresolved\", \"Kinetics of inter-pool exchange unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified IKKε/TBK1 as inflammatory kinases that phosphorylate and activate PDE3B, linking obesity-associated inflammation to catecholamine resistance.\",\n      \"evidence\": \"Overexpression/inhibitor studies in 3T3-L1 cells and amlexanox treatment of obese mice with cAMP and lipolysis readouts\",\n      \"pmids\": [\"24368730\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct phosphosites not mapped in this study\", \"Whether activation is direct vs. via intermediaries\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed PDE3B is required for insulin's anti-lipolytic action but that the major Akt site S273 is dispensable, refining the phosphorylation model.\",\n      \"evidence\": \"PDE3B KO brown adipocytes reconstituted with wild-type and S273A mutant; glycerol release assays\",\n      \"pmids\": [\"26031333\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The functionally critical phosphosite(s) remain unidentified\", \"Did not test combinatorial mutants\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established an isoform-specific cardioprotective role for PDE3B in ischemia/reperfusion, acting through cAMP/PKA and mitochondrial K-channel signaling.\",\n      \"evidence\": \"PDE3B vs PDE3A KO mice, in vivo/in vitro I/R models, proteomics, and mitochondrial assays\",\n      \"pmids\": [\"25877153\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking PDE3B to mitochondrial protein enrichment not fully defined\", \"Caveolin-3 dependence not directly tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed PDE3B loss drives white-to-beige adipocyte conversion via cAMP/PKA and AMPK activation, connecting the enzyme to whole-body energy expenditure.\",\n      \"evidence\": \"Pde3b KO mice with metabolic phenotyping, β-oxidation, and oxygen consumption measurements\",\n      \"pmids\": [\"28084425\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Adipocyte-autonomous vs systemic effects not separated\", \"Direct PKA/AMPK targets not mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked PDE3B to innate immunity and atherosclerosis by showing its ablation suppresses NLRP3 inflammasome activation and plaque formation.\",\n      \"evidence\": \"PDE3B KO and double-KO mice (apoE-/-, LDL-R-/-) with cytokine, gene expression, and plaque readouts\",\n      \"pmids\": [\"27321128\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell type driving the inflammasome effect unresolved\", \"Mechanistic link from cAMP to NLRP3 not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified ABHD15 as a binding partner that stabilizes PDE3B protein, establishing post-translational control of PDE3B abundance as a node in insulin sensitivity.\",\n      \"evidence\": \"Abhd15 KO mice, co-IP, and PDE3B/lipolysis/HSL readouts\",\n      \"pmids\": [\"29768196\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of stabilization unknown\", \"Whether ABHD15 binding is direct vs complex-mediated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated PDE3B hydrolyzes cUMP in a milrinone-sensitive manner, broadening its substrate repertoire beyond cAMP/cGMP.\",\n      \"evidence\": \"Recombinant enzyme kinetics, HPLC-MS substrate quantitation, and docking on PDB 1SO2\",\n      \"pmids\": [\"29808231\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological role of cUMP hydrolysis untested\", \"Low affinity questions in vivo relevance\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established an isoform-specific role for PDE3B in endothelial angiogenic sprouting by antagonizing a perinuclear PKA pool that controls podosome biogenesis and cdc42 activity.\",\n      \"evidence\": \"PDE3B vs PDE3A siRNA, sprouting assays, co-IP with PKA, and subcellular PKA activity imaging\",\n      \"pmids\": [\"31176020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of perinuclear targeting unresolved\", \"Whether PDE3B-PKA interaction is direct\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated PDE3B in organ preservation injury, where its elevation triggers AMPK-dependent autophagy and liver damage reversible by pharmacological inhibition.\",\n      \"evidence\": \"Multi-omics and cilostamide treatment across rat, pig, and human supercooled liver preservation models\",\n      \"pmids\": [\"39602509\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream driver of PDE3B elevation unknown\", \"Single study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the cAMP pool controlled by PDE3B at subcellular resolution, placing insulin-activated PDE3B as the dominant regulator of cytoplasmic cAMP distinct from plasma-membrane and lipid-droplet pools.\",\n      \"evidence\": \"Compartment-targeted EPAC1-FRET biosensors and PDE inhibitor pharmacology in 3T3-L1 adipocytes\",\n      \"pmids\": [\"41082906\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not explain how compartment specificity is achieved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified ESRRG as a direct transcriptional activator of Pde3b in airway epithelium, extending PDE3B transcriptional control to inflammatory airway disease.\",\n      \"evidence\": \"Luciferase reporter, ChIP-PCR, AAV-shEsrrg silencing, and pharmacological inhibition in vivo\",\n      \"pmids\": [\"40153608\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality beyond airway epithelium untested\", \"Interaction with CREB-driven regulation unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The functionally critical phosphosite(s) and the direct kinase(s)/binding partners that mediate compartment-specific activation of PDE3B remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"S273-independent activating phosphorylation not mapped\", \"Direct interactor within the insulin macromolecular complex unidentified\", \"Mechanism routing one enzyme to distinct membrane pools unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [14, 15]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [14, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 8, 11]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 6, 7, 0]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 9, 18]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"complexes\": [\"caveolae\", \"insulin-induced ER/Golgi macromolecular signaling complex (PDE3B/IRS/PI3K/Akt/HSP90/14-3-3)\"],\n    \"partners\": [\"CAV1\", \"AKT1\", \"ABHD15\", \"PRKACA\", \"PIK3R1\", \"IRS1\", \"IRS2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":10,"faith_total":10,"faith_pct":100.0}}