{"gene":"ADCY6","run_date":"2026-06-09T22:02:41","timeline":{"discoveries":[{"year":2006,"finding":"AC6 (together with AC5) mediates calcium-dependent inhibition of renin release from juxtaglomerular cells by suppressing intracellular cAMP levels; siRNA knockdown of AC5 and/or AC6 prevented calcium-liberator-induced suppression of cAMP and renin release, establishing AC6 as the enzymatic link between elevated intracellular calcium and reduced cAMP in renin-producing cells.","method":"siRNA knockdown in primary juxtaglomerular cells and As4.1 renin-producing cell line; cAMP measurements; renin release assays; permeable cAMP analog rescue experiments","journal":"Circulation Research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal siRNA knockdown with cAMP clamping rescue, replicated across primary cells and cell line, multiple orthogonal methods","pmids":["17068292"],"is_preprint":false},{"year":2010,"finding":"AC6 is required for vasopressin V2 receptor-stimulated adenylyl cyclase activity in kidney tubules and collecting ducts, and AC6 knockout mice show impaired water reabsorption, establishing AC6 as a critical component of renal water homeostasis via cAMP production.","method":"AC6 knockout mouse lines; immunohistochemistry; adenylyl cyclase activity assays (forskolin and V2R-selective agonist stimulation); metabolic cage assay; DCE-MRI","journal":"FEBS Letters","confidence":"High","confidence_rationale":"Tier 2 / Moderate — epithelium-specific KO with multiple orthogonal functional readouts (biochemical + physiological), single lab","pmids":["20466003"],"is_preprint":false},{"year":2010,"finding":"Fibroblast-specific overexpression of AC6 enhances beta-adrenergic (isoproterenol) and prostacyclin (beraprost) but not PGE2- or butaprost-stimulated cAMP production and inhibits collagen synthesis; in transgenic FTS1-AC6 mice, this blunts bleomycin-induced pulmonary fibrosis and collagen deposition, placing AC6 in a pathway that specifically amplifies catecholamine/prostacyclin anti-fibrotic signaling.","method":"AC6 overexpression in pulmonary fibroblasts; cAMP production assays; collagen synthesis assays; transgenic mice with fibroblast-specific AC6 expression (FTS1 promoter); bleomycin lung fibrosis model; histopathological scoring","journal":"American Journal of Physiology – Lung Cellular and Molecular Physiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vitro gain-of-function combined with in vivo transgenic model, multiple functional readouts, single lab","pmids":["20348281"],"is_preprint":false},{"year":2010,"finding":"A catalytically inactive AC6 mutant (D426A in the C1 catalytic domain), which has markedly reduced cAMP-generating capacity, replicates many biological effects of wild-type AC6 in cardiac myocytes — including reduction of phenylephrine-induced hypertrophy and apoptosis, reduction of cardiac ankyrin repeat protein and phospholamban expression, and enhancement of Ca2+ transients — demonstrating that these effects do not require increased cAMP production.","method":"Adenovirus-mediated gene transfer of AC6 and AC6 D426A mutant in adult rat cardiac myocytes; cAMP production assays; cell hypertrophy and apoptosis assays; Western blotting; Ca2+ transient measurements","journal":"Molecular Pharmacology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — active-site mutagenesis with multiple cellular phenotypic readouts, cAMP generation directly measured, single lab but multiple orthogonal methods","pmids":["21127130"],"is_preprint":false},{"year":2013,"finding":"A homozygous missense mutation in ADCY6 causes loss of peripheral nervous system myelination in humans, and morpholino knockdown of the zebrafish ADCY6 ortholog produces severe and specific peripheral myelin defects despite presence of Schwann cells, establishing ADCY6 as essential for PNS myelination, likely through the cAMP pathway.","method":"Whole exome sequencing; transmission electron microscopy of sciatic nerve; morpholino knockdown in zebrafish","journal":"Human Molecular Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetics plus zebrafish morpholino KD with structural phenotypic readout, but mechanistic pathway (cAMP) is inferred, not directly demonstrated","pmids":["24319099"],"is_preprint":false},{"year":2018,"finding":"AC6 physically and functionally associates with CFTR at the apical surface of intestinal epithelial cells, forming the principal cAMP-generating complex driving cholera toxin-induced CFTR-dependent fluid secretion; epithelium-specific AC6 knockout nearly abolishes CTX-induced fluid secretion in mouse ileal loops and impairs CFTR activation in intestinal spheroids.","method":"RNA-Seq (AC isoform identification); co-immunoprecipitation/biochemical interaction assays; epithelium-specific AC6 knockout mice; ligated ileal loop CTX challenge assay; intestinal spheroid CFTR activation assays","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — physical interaction plus epithelium-specific KO with functional rescue experiments, multiple orthogonal methods, replicated in mouse and human systems","pmids":["29903911"],"is_preprint":false},{"year":2019,"finding":"Purβ directly binds to the ADCY6 gene promoter (shown by chromatin immunoprecipitation and luciferase reporter assays) and promotes its transcription, thereby activating the glucagon/ADCY6/cAMP/PKA/CREB signaling pathway to drive hepatic glucose production; liver-specific Purβ knockdown in db/db mice ameliorates hyperglycemia by suppressing this pathway.","method":"Chromatin immunoprecipitation (ChIP); luciferase reporter assays; adenovirus-mediated Purβ knockdown/overexpression in primary hepatocytes and db/db mice; glucose/insulin/lactate tolerance tests; RNA-seq; Western blotting of p-CREB, p-Akt","journal":"Molecular Metabolism","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct promoter binding shown by ChIP and reporter assay, in vivo KD with metabolic phenotype, multiple orthogonal methods, single lab","pmids":["31918924"],"is_preprint":false},{"year":2020,"finding":"AC6 controls ciliary length in airway epithelial cells by inhibiting autophagy-mediated degradation of the microtubule-depolymerizing kinesin KIF19A: AC6 inhibits AMPK, which prevents AMPK from binding KIF19A and shuttling it to autophagosomes; epithelium-specific AC6 KO mice have longer cilia due to decreased KIF19A at cilia tips.","method":"Epithelium-specific AC6 knockout mice; ciliary length measurements; in vitro AMPK activity assays; KIF19A protein level measurements; autophagosome localization assays; pharmacological AMPK activation","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — epithelium-specific KO with mechanistic dissection of AMPK-KIF19A-autophagy axis, in vitro and in vivo, multiple orthogonal methods, single lab","pmids":["32683324"],"is_preprint":false},{"year":2016,"finding":"HSF1 positively regulates AC6 mRNA expression in pressure-overload heart failure; HSF1 transgenic mice show increased AC6 mRNA, cAMP, and PKA compared to WT, while HSF1 knockout mice show decreased AC6 mRNA and worse cardiac function, placing AC6 downstream of HSF1 in the AC6/cAMP/PKA pathway that ameliorates heart failure.","method":"Transverse aortic constriction (TAC) mouse model; HSF1 transgenic and knockout mice; RT-qPCR for AC6 mRNA; Western blotting for HSF1 and PKA; ELISA for cAMP; echocardiography; Masson staining","journal":"Environmental Toxicology and Pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic gain/loss of HSF1 with multiple downstream readouts including AC6 mRNA, cAMP, PKA; single lab, correlation-based pathway placement","pmids":["27643574"],"is_preprint":false},{"year":2021,"finding":"GPSM1 knockdown in B-ALL cells suppresses ADCY6 and RAPGEF3 expression and reduces JNK activity, placing ADCY6 downstream of GPSM1 in a GPSM1-ADCY6-RAPGEF3-JNK signaling pathway that promotes leukemia cell proliferation.","method":"siRNA knockdown of GPSM1 in BALL-1 and Reh cells; Western blotting for ADCY6, RAPGEF3, JNK; cell proliferation, apoptosis, and cell cycle assays","journal":"Pathology Oncology Research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single knockdown experiment with expression-level readout for ADCY6, no direct enzymatic or interaction assay, single lab","pmids":["34257610"],"is_preprint":false},{"year":2022,"finding":"TET1-mediated DNA demethylation of the ADCY6 locus activates ADCY6 expression; miR-27a-3p negatively regulates TET1, thereby increasing ADCY6 methylation and reducing its expression, which promotes EMT in breast cancer cells.","method":"DNA methylation-specific PCR; bisulfite Sanger sequencing; lentiviral miRNA stable transfection; luciferase and gene expression assays; cell invasion/migration assays","journal":"Frontiers in Oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct DNA methylation assays with functional cell biology validation, miRNA overexpression with target validation, single lab","pmids":["35978806"],"is_preprint":false},{"year":2023,"finding":"Quantitative phosphoproteomics reveals that AC6 (localized in lipid raft membranes) generates a cAMP signaling pool in human airway smooth muscle cells distinct from AC2 (non-raft): AC6-derived cAMP preferentially phosphorylates proteins involved in autophagy, Ca2+/CaM signaling, Rho GTPase regulation, and cytoskeletal regulation, while AC2-derived cAMP targets RNA/DNA binding and microtubule proteins; OFD1 Ser899 is phosphorylated in opposite directions by AC6 vs. AC2.","method":"AC2 and AC6 overexpression in human airway smooth muscle cells; forskolin stimulation; quantitative phosphoproteomics (LC-MS/MS); STRING protein interaction analysis","journal":"Frontiers in Physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative phosphoproteomics with AC isoform-specific overexpression, single lab, novel downstream signaling network characterized","pmids":["36926196"],"is_preprint":false},{"year":2024,"finding":"Forskolin alleviates hypertrophic cardiomyopathy in two HCM mouse models (Myh6R404Q and Tnnt2R109Q) and in NE-induced cardiomyocyte hypertrophy in vitro by activating ADCY6, which drives the ADCY6/cAMP/PKA pathway to reduce cardiac hypertrophy.","method":"In vivo HCM mouse models (Myh6R404Q, Tnnt2R109Q); in vitro NE-induced cardiomyocyte hypertrophy; cardiac function assessment; cell size measurements; hypertrophy gene expression; pharmacological activation of ADCY6 by forskolin","journal":"European Journal of Pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological activation with no direct ADCY6 mutagenesis or KO control confirming specificity; mechanism inferred from pathway marker changes, single lab","pmids":["38925286"],"is_preprint":false}],"current_model":"ADCY6 is a transmembrane adenylyl cyclase that produces cAMP in response to G-protein-coupled receptor stimulation, with its catalytic activity subject to inhibition by elevated intracellular calcium; it localizes to lipid raft membrane domains and physically associates with CFTR at the apical intestinal surface, forming a diarrheagenic signaling complex; in addition to its canonical cAMP-generating role—driving renin secretion, renal water reabsorption, hepatic glucose production (via Purβ-dependent transcriptional upregulation), and PNS myelination—AC6 exerts cAMP-independent effects in cardiac myocytes (demonstrated by a D426A catalytically inactive mutant) that reduce hypertrophy and apoptosis, and it controls airway ciliary length by inhibiting AMPK-mediated autophagy of the kinesin KIF19A."},"narrative":{"mechanistic_narrative":"ADCY6 (AC6) is a transmembrane adenylyl cyclase that generates cAMP downstream of G-protein-coupled receptor stimulation and serves as a node where receptor signaling and intracellular calcium are integrated to control diverse epithelial, secretory, and cardiac processes [PMID:17068292, PMID:20466003]. In renin-producing juxtaglomerular cells, AC6 acts as the enzymatic link coupling elevated intracellular calcium to reduced cAMP and suppressed renin release [PMID:17068292], while in kidney collecting ducts it supplies the vasopressin V2 receptor-stimulated cAMP required for water reabsorption [PMID:20466003]. AC6-derived cAMP operates through PKA/CREB-dependent programs in multiple tissues: it is transcriptionally upregulated by direct Purβ binding to its promoter to drive hepatic glucose production [PMID:31918924], and is required for peripheral nervous system myelination, where a homozygous missense mutation causes loss of PNS myelin in humans [PMID:24319099]. AC6 generates a spatially distinct, lipid-raft-associated cAMP pool that preferentially phosphorylates autophagy, Ca2+/calmodulin, Rho GTPase, and cytoskeletal targets [PMID:36926196], and it physically associates with CFTR at the apical intestinal surface to form the principal cAMP-generating complex driving cholera toxin-induced fluid secretion [PMID:29903911]. Beyond canonical cAMP production, AC6 controls airway ciliary length by inhibiting AMPK-mediated autophagic degradation of the kinesin KIF19A [PMID:32683324], and exerts cAMP-independent protective effects in cardiac myocytes—reducing hypertrophy and apoptosis—demonstrated by a catalytically inactive D426A mutant that reproduces these phenotypes without increasing cAMP [PMID:21127130].","teleology":[{"year":2006,"claim":"Established AC6 as the enzymatic link translating elevated intracellular calcium into reduced cAMP and suppressed renin release, defining its calcium-inhibitable cyclase behavior in a physiological setting.","evidence":"siRNA knockdown of AC5/AC6 in primary juxtaglomerular cells and As4.1 cells with cAMP measurement and permeable cAMP analog rescue","pmids":["17068292"],"confidence":"High","gaps":["Does not resolve the relative contribution of AC5 versus AC6","Mechanism of calcium-mediated inhibition of AC6 not structurally defined"]},{"year":2010,"claim":"Showed AC6 is required for V2 receptor-stimulated cAMP in the kidney, placing it in renal water homeostasis and demonstrating a non-redundant GPCR-coupled role in vivo.","evidence":"AC6 knockout mice with adenylyl cyclase activity assays, metabolic cage, and DCE-MRI","pmids":["20466003"],"confidence":"High","gaps":["Does not identify the downstream aquaporin trafficking steps","Tissue-specific contributions within the nephron not dissected"]},{"year":2010,"claim":"Demonstrated that AC6 amplifies catecholamine/prostacyclin-stimulated cAMP to inhibit collagen synthesis, linking AC6 to anti-fibrotic signaling.","evidence":"Fibroblast AC6 overexpression with cAMP and collagen assays, plus FTS1-AC6 transgenic mice in bleomycin lung fibrosis","pmids":["20348281"],"confidence":"High","gaps":["Receptor selectivity (isoproterenol/beraprost but not PGE2/butaprost) mechanism unexplained","Endogenous AC6 contribution not tested by loss-of-function"]},{"year":2010,"claim":"Revealed a cAMP-independent function of AC6 in cardiac myocytes, since a catalytically dead D426A mutant still reduced hypertrophy and apoptosis, separating enzymatic from non-enzymatic roles.","evidence":"Adenoviral transfer of AC6 and D426A mutant in adult rat cardiac myocytes with cAMP, hypertrophy, apoptosis, and Ca2+ transient readouts","pmids":["21127130"],"confidence":"High","gaps":["Molecular effector of the cAMP-independent activity unidentified","Whether D426A retains residual cyclase output sufficient for some effects not fully excluded"]},{"year":2013,"claim":"Connected ADCY6 to peripheral nervous system myelination through human genetics and zebrafish knockdown, establishing an essential developmental role.","evidence":"Whole exome sequencing identifying a homozygous missense mutation, sciatic nerve electron microscopy, and zebrafish morpholino knockdown","pmids":["24319099"],"confidence":"Medium","gaps":["cAMP pathway involvement inferred, not directly demonstrated","Morpholino specificity limitations","Schwann-cell-autonomous versus axonal requirement unresolved"]},{"year":2016,"claim":"Placed AC6 downstream of HSF1 in a transcriptional axis ameliorating pressure-overload heart failure, linking stress-responsive transcription to AC6/cAMP/PKA output.","evidence":"TAC model with HSF1 transgenic and knockout mice, AC6 mRNA RT-qPCR, cAMP ELISA, PKA Western blot, echocardiography","pmids":["27643574"],"confidence":"Medium","gaps":["Correlation-based pathway placement without direct HSF1-ADCY6 promoter binding evidence","Causality of AC6 in the HSF1 cardioprotective phenotype not tested by AC6 manipulation"]},{"year":2018,"claim":"Identified AC6 as the CFTR-associated cAMP source driving cholera toxin-induced intestinal fluid secretion, defining a diarrheagenic signaling complex.","evidence":"RNA-Seq isoform identification, co-immunoprecipitation, epithelium-specific AC6 knockout mice, ileal loop CTX challenge, and intestinal spheroid CFTR activation assays","pmids":["29903911"],"confidence":"High","gaps":["Structural basis and stoichiometry of the AC6-CFTR interaction not defined","Whether the interaction is direct or scaffold-mediated unresolved"]},{"year":2019,"claim":"Showed direct transcriptional control of ADCY6 by Purβ binding its promoter, coupling glucagon signaling to hepatic glucose production via the ADCY6/cAMP/PKA/CREB pathway.","evidence":"ChIP and luciferase reporter assays, adenoviral Purβ knockdown/overexpression in hepatocytes and db/db mice with metabolic tolerance tests","pmids":["31918924"],"confidence":"High","gaps":["Does not establish whether Purβ regulation of ADCY6 occurs in non-hepatic tissues","Cis-element within the promoter not finely mapped"]},{"year":2020,"claim":"Defined a cAMP-effector mechanism by which AC6 controls ciliary length, inhibiting AMPK to prevent autophagic degradation of the kinesin KIF19A.","evidence":"Epithelium-specific AC6 knockout mice, ciliary length measurement, in vitro AMPK activity assays, KIF19A level and autophagosome localization assays, pharmacological AMPK activation","pmids":["32683324"],"confidence":"High","gaps":["Direct biochemical step from cAMP/PKA to AMPK inhibition not fully mapped","Generalizability beyond airway epithelium untested"]},{"year":2023,"claim":"Demonstrated that lipid-raft-localized AC6 generates a compartmentalized cAMP pool with substrate specificity distinct from non-raft AC2, explaining isoform-specific signaling outcomes.","evidence":"AC2 and AC6 overexpression in human airway smooth muscle cells with quantitative phosphoproteomics and STRING analysis","pmids":["36926196"],"confidence":"Medium","gaps":["Phosphoproteomic targets identified by overexpression, not endogenous loss-of-function","Functional consequences of individual phosphosites (e.g., OFD1 Ser899) not validated"]},{"year":2022,"claim":"Linked epigenetic regulation of ADCY6 (TET1-mediated demethylation, antagonized by miR-27a-3p) to suppression of EMT in breast cancer, implicating ADCY6 as a regulated tumor-relevant locus.","evidence":"DNA methylation-specific PCR, bisulfite sequencing, lentiviral miRNA transfection, luciferase target validation, and invasion/migration assays","pmids":["35978806"],"confidence":"Medium","gaps":["Causal contribution of ADCY6 cyclase activity to the EMT phenotype not directly tested","Downstream effectors of ADCY6 in this context unidentified"]},{"year":null,"claim":"The molecular basis distinguishing AC6's cAMP-dependent from cAMP-independent activities, and the structural determinants of its calcium inhibition and CFTR/raft compartmentalization, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the AC6-CFTR complex","Effector mediating cAMP-independent cardiac protection unknown","Mechanism of raft-restricted cAMP pool formation undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0009975","term_label":"cyclase activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,11]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,6]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[1,5]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7]}],"complexes":[],"partners":["CFTR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43306","full_name":"Adenylate cyclase type 6","aliases":["ATP pyrophosphate-lyase 6","Adenylate cyclase type VI","Adenylyl cyclase 6","Ca(2+)-inhibitable adenylyl cyclase"],"length_aa":1168,"mass_kda":130.6,"function":"Catalyzes the formation of the signaling molecule cAMP downstream of G protein-coupled receptors (PubMed:17110384, PubMed:17916776). Functions in signaling cascades downstream of beta-adrenergic receptors in the heart and in vascular smooth muscle cells (PubMed:17916776). Functions in signaling cascades downstream of the vasopressin receptor in the kidney and has a role in renal water reabsorption. Functions in signaling cascades downstream of PTH1R and plays a role in regulating renal phosphate excretion. Functions in signaling cascades downstream of the VIP and SCT receptors in pancreas and contributes to the regulation of pancreatic amylase and fluid secretion (By similarity). Signaling mediates cAMP-dependent activation of protein kinase PKA. This promotes increased phosphorylation of various proteins, including AKT. Plays a role in regulating cardiac sarcoplasmic reticulum Ca(2+) uptake and storage, and is required for normal heart ventricular contractibility. May contribute to normal heart function (By similarity). Mediates vasodilatation after activation of beta-adrenergic receptors by isoproterenol (PubMed:17916776). Contributes to bone cell responses to mechanical stimuli (By similarity)","subcellular_location":"Cell membrane; Cell projection, cilium; Cell projection, stereocilium","url":"https://www.uniprot.org/uniprotkb/O43306/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADCY6","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ADCY6","total_profiled":1310},"omim":[{"mim_id":"619749","title":"VEZATIN, ADHERENS JUNCTIONS TRANSMEMBRANE PROTEIN; VEZT","url":"https://www.omim.org/entry/619749"},{"mim_id":"618484","title":"ARTHROGRYPOSIS MULTIPLEX CONGENITA 3, MYOGENIC TYPE; AMC3","url":"https://www.omim.org/entry/618484"},{"mim_id":"616287","title":"LETHAL CONGENITAL CONTRACTURE SYNDROME 8; LCCS8","url":"https://www.omim.org/entry/616287"},{"mim_id":"616286","title":"LETHAL CONGENITAL CONTRACTURE SYNDROME 7; LCCS7","url":"https://www.omim.org/entry/616286"},{"mim_id":"611607","title":"MICRO RNA 182; MIR182","url":"https://www.omim.org/entry/611607"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ADCY6"},"hgnc":{"alias_symbol":["AC6"],"prev_symbol":[]},"alphafold":{"accession":"O43306","domains":[{"cath_id":"-","chopping":"231-325_660-931","consensus_level":"medium","plddt":83.8829,"start":231,"end":931},{"cath_id":"3.30.70.1230","chopping":"371-566","consensus_level":"high","plddt":85.913,"start":371,"end":566},{"cath_id":"3.30.70.1230","chopping":"958-1165","consensus_level":"high","plddt":87.0201,"start":958,"end":1165}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43306","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43306-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43306-F1-predicted_aligned_error_v6.png","plddt_mean":76.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADCY6","jax_strain_url":"https://www.jax.org/strain/search?query=ADCY6"},"sequence":{"accession":"O43306","fasta_url":"https://rest.uniprot.org/uniprotkb/O43306.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43306/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43306"}},"corpus_meta":[{"pmid":"24319099","id":"PMC_24319099","title":"Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex congenita with axoglial defects.","date":"2013","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24319099","citation_count":102,"is_preprint":false},{"pmid":"17068292","id":"PMC_17068292","title":"The calcium paradoxon of renin release: calcium suppresses renin exocytosis by inhibition of calcium-dependent adenylate cyclases AC5 and AC6.","date":"2006","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/17068292","citation_count":65,"is_preprint":false},{"pmid":"31595165","id":"PMC_31595165","title":"Circ-HIPK3 Strengthens the Effects of Adrenaline in Heart Failure by MiR-17-3p - ADCY6 Axis.","date":"2019","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31595165","citation_count":49,"is_preprint":false},{"pmid":"20466003","id":"PMC_20466003","title":"Impaired water reabsorption in mice deficient in the type VI adenylyl cyclase (AC6).","date":"2010","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/20466003","citation_count":32,"is_preprint":false},{"pmid":"31918924","id":"PMC_31918924","title":"Purβ promotes hepatic glucose production by increasing Adcy6 transcription.","date":"2019","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/31918924","citation_count":27,"is_preprint":false},{"pmid":"32683324","id":"PMC_32683324","title":"AC6 regulates the microtubule-depolymerizing kinesin KIF19A to control ciliary length in mammals.","date":"2020","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32683324","citation_count":19,"is_preprint":false},{"pmid":"20348281","id":"PMC_20348281","title":"Fibroblast-specific expression of AC6 enhances beta-adrenergic and prostacyclin signaling and blunts bleomycin-induced pulmonary fibrosis.","date":"2010","source":"American journal of physiology. 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siRNA knockdown of AC5 and/or AC6 prevented calcium-liberator-induced suppression of cAMP and renin release, establishing AC6 as the enzymatic link between elevated intracellular calcium and reduced cAMP in renin-producing cells.\",\n      \"method\": \"siRNA knockdown in primary juxtaglomerular cells and As4.1 renin-producing cell line; cAMP measurements; renin release assays; permeable cAMP analog rescue experiments\",\n      \"journal\": \"Circulation Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal siRNA knockdown with cAMP clamping rescue, replicated across primary cells and cell line, multiple orthogonal methods\",\n      \"pmids\": [\"17068292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"AC6 is required for vasopressin V2 receptor-stimulated adenylyl cyclase activity in kidney tubules and collecting ducts, and AC6 knockout mice show impaired water reabsorption, establishing AC6 as a critical component of renal water homeostasis via cAMP production.\",\n      \"method\": \"AC6 knockout mouse lines; immunohistochemistry; adenylyl cyclase activity assays (forskolin and V2R-selective agonist stimulation); metabolic cage assay; DCE-MRI\",\n      \"journal\": \"FEBS Letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epithelium-specific KO with multiple orthogonal functional readouts (biochemical + physiological), single lab\",\n      \"pmids\": [\"20466003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Fibroblast-specific overexpression of AC6 enhances beta-adrenergic (isoproterenol) and prostacyclin (beraprost) but not PGE2- or butaprost-stimulated cAMP production and inhibits collagen synthesis; in transgenic FTS1-AC6 mice, this blunts bleomycin-induced pulmonary fibrosis and collagen deposition, placing AC6 in a pathway that specifically amplifies catecholamine/prostacyclin anti-fibrotic signaling.\",\n      \"method\": \"AC6 overexpression in pulmonary fibroblasts; cAMP production assays; collagen synthesis assays; transgenic mice with fibroblast-specific AC6 expression (FTS1 promoter); bleomycin lung fibrosis model; histopathological scoring\",\n      \"journal\": \"American Journal of Physiology – Lung Cellular and Molecular Physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro gain-of-function combined with in vivo transgenic model, multiple functional readouts, single lab\",\n      \"pmids\": [\"20348281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"A catalytically inactive AC6 mutant (D426A in the C1 catalytic domain), which has markedly reduced cAMP-generating capacity, replicates many biological effects of wild-type AC6 in cardiac myocytes — including reduction of phenylephrine-induced hypertrophy and apoptosis, reduction of cardiac ankyrin repeat protein and phospholamban expression, and enhancement of Ca2+ transients — demonstrating that these effects do not require increased cAMP production.\",\n      \"method\": \"Adenovirus-mediated gene transfer of AC6 and AC6 D426A mutant in adult rat cardiac myocytes; cAMP production assays; cell hypertrophy and apoptosis assays; Western blotting; Ca2+ transient measurements\",\n      \"journal\": \"Molecular Pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site mutagenesis with multiple cellular phenotypic readouts, cAMP generation directly measured, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"21127130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A homozygous missense mutation in ADCY6 causes loss of peripheral nervous system myelination in humans, and morpholino knockdown of the zebrafish ADCY6 ortholog produces severe and specific peripheral myelin defects despite presence of Schwann cells, establishing ADCY6 as essential for PNS myelination, likely through the cAMP pathway.\",\n      \"method\": \"Whole exome sequencing; transmission electron microscopy of sciatic nerve; morpholino knockdown in zebrafish\",\n      \"journal\": \"Human Molecular Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetics plus zebrafish morpholino KD with structural phenotypic readout, but mechanistic pathway (cAMP) is inferred, not directly demonstrated\",\n      \"pmids\": [\"24319099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AC6 physically and functionally associates with CFTR at the apical surface of intestinal epithelial cells, forming the principal cAMP-generating complex driving cholera toxin-induced CFTR-dependent fluid secretion; epithelium-specific AC6 knockout nearly abolishes CTX-induced fluid secretion in mouse ileal loops and impairs CFTR activation in intestinal spheroids.\",\n      \"method\": \"RNA-Seq (AC isoform identification); co-immunoprecipitation/biochemical interaction assays; epithelium-specific AC6 knockout mice; ligated ileal loop CTX challenge assay; intestinal spheroid CFTR activation assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — physical interaction plus epithelium-specific KO with functional rescue experiments, multiple orthogonal methods, replicated in mouse and human systems\",\n      \"pmids\": [\"29903911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Purβ directly binds to the ADCY6 gene promoter (shown by chromatin immunoprecipitation and luciferase reporter assays) and promotes its transcription, thereby activating the glucagon/ADCY6/cAMP/PKA/CREB signaling pathway to drive hepatic glucose production; liver-specific Purβ knockdown in db/db mice ameliorates hyperglycemia by suppressing this pathway.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP); luciferase reporter assays; adenovirus-mediated Purβ knockdown/overexpression in primary hepatocytes and db/db mice; glucose/insulin/lactate tolerance tests; RNA-seq; Western blotting of p-CREB, p-Akt\",\n      \"journal\": \"Molecular Metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct promoter binding shown by ChIP and reporter assay, in vivo KD with metabolic phenotype, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"31918924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AC6 controls ciliary length in airway epithelial cells by inhibiting autophagy-mediated degradation of the microtubule-depolymerizing kinesin KIF19A: AC6 inhibits AMPK, which prevents AMPK from binding KIF19A and shuttling it to autophagosomes; epithelium-specific AC6 KO mice have longer cilia due to decreased KIF19A at cilia tips.\",\n      \"method\": \"Epithelium-specific AC6 knockout mice; ciliary length measurements; in vitro AMPK activity assays; KIF19A protein level measurements; autophagosome localization assays; pharmacological AMPK activation\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epithelium-specific KO with mechanistic dissection of AMPK-KIF19A-autophagy axis, in vitro and in vivo, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"32683324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HSF1 positively regulates AC6 mRNA expression in pressure-overload heart failure; HSF1 transgenic mice show increased AC6 mRNA, cAMP, and PKA compared to WT, while HSF1 knockout mice show decreased AC6 mRNA and worse cardiac function, placing AC6 downstream of HSF1 in the AC6/cAMP/PKA pathway that ameliorates heart failure.\",\n      \"method\": \"Transverse aortic constriction (TAC) mouse model; HSF1 transgenic and knockout mice; RT-qPCR for AC6 mRNA; Western blotting for HSF1 and PKA; ELISA for cAMP; echocardiography; Masson staining\",\n      \"journal\": \"Environmental Toxicology and Pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic gain/loss of HSF1 with multiple downstream readouts including AC6 mRNA, cAMP, PKA; single lab, correlation-based pathway placement\",\n      \"pmids\": [\"27643574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GPSM1 knockdown in B-ALL cells suppresses ADCY6 and RAPGEF3 expression and reduces JNK activity, placing ADCY6 downstream of GPSM1 in a GPSM1-ADCY6-RAPGEF3-JNK signaling pathway that promotes leukemia cell proliferation.\",\n      \"method\": \"siRNA knockdown of GPSM1 in BALL-1 and Reh cells; Western blotting for ADCY6, RAPGEF3, JNK; cell proliferation, apoptosis, and cell cycle assays\",\n      \"journal\": \"Pathology Oncology Research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single knockdown experiment with expression-level readout for ADCY6, no direct enzymatic or interaction assay, single lab\",\n      \"pmids\": [\"34257610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TET1-mediated DNA demethylation of the ADCY6 locus activates ADCY6 expression; miR-27a-3p negatively regulates TET1, thereby increasing ADCY6 methylation and reducing its expression, which promotes EMT in breast cancer cells.\",\n      \"method\": \"DNA methylation-specific PCR; bisulfite Sanger sequencing; lentiviral miRNA stable transfection; luciferase and gene expression assays; cell invasion/migration assays\",\n      \"journal\": \"Frontiers in Oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct DNA methylation assays with functional cell biology validation, miRNA overexpression with target validation, single lab\",\n      \"pmids\": [\"35978806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Quantitative phosphoproteomics reveals that AC6 (localized in lipid raft membranes) generates a cAMP signaling pool in human airway smooth muscle cells distinct from AC2 (non-raft): AC6-derived cAMP preferentially phosphorylates proteins involved in autophagy, Ca2+/CaM signaling, Rho GTPase regulation, and cytoskeletal regulation, while AC2-derived cAMP targets RNA/DNA binding and microtubule proteins; OFD1 Ser899 is phosphorylated in opposite directions by AC6 vs. AC2.\",\n      \"method\": \"AC2 and AC6 overexpression in human airway smooth muscle cells; forskolin stimulation; quantitative phosphoproteomics (LC-MS/MS); STRING protein interaction analysis\",\n      \"journal\": \"Frontiers in Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative phosphoproteomics with AC isoform-specific overexpression, single lab, novel downstream signaling network characterized\",\n      \"pmids\": [\"36926196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Forskolin alleviates hypertrophic cardiomyopathy in two HCM mouse models (Myh6R404Q and Tnnt2R109Q) and in NE-induced cardiomyocyte hypertrophy in vitro by activating ADCY6, which drives the ADCY6/cAMP/PKA pathway to reduce cardiac hypertrophy.\",\n      \"method\": \"In vivo HCM mouse models (Myh6R404Q, Tnnt2R109Q); in vitro NE-induced cardiomyocyte hypertrophy; cardiac function assessment; cell size measurements; hypertrophy gene expression; pharmacological activation of ADCY6 by forskolin\",\n      \"journal\": \"European Journal of Pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological activation with no direct ADCY6 mutagenesis or KO control confirming specificity; mechanism inferred from pathway marker changes, single lab\",\n      \"pmids\": [\"38925286\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADCY6 is a transmembrane adenylyl cyclase that produces cAMP in response to G-protein-coupled receptor stimulation, with its catalytic activity subject to inhibition by elevated intracellular calcium; it localizes to lipid raft membrane domains and physically associates with CFTR at the apical intestinal surface, forming a diarrheagenic signaling complex; in addition to its canonical cAMP-generating role—driving renin secretion, renal water reabsorption, hepatic glucose production (via Purβ-dependent transcriptional upregulation), and PNS myelination—AC6 exerts cAMP-independent effects in cardiac myocytes (demonstrated by a D426A catalytically inactive mutant) that reduce hypertrophy and apoptosis, and it controls airway ciliary length by inhibiting AMPK-mediated autophagy of the kinesin KIF19A.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ADCY6 (AC6) is a transmembrane adenylyl cyclase that generates cAMP downstream of G-protein-coupled receptor stimulation and serves as a node where receptor signaling and intracellular calcium are integrated to control diverse epithelial, secretory, and cardiac processes [#0, #1]. In renin-producing juxtaglomerular cells, AC6 acts as the enzymatic link coupling elevated intracellular calcium to reduced cAMP and suppressed renin release [#0], while in kidney collecting ducts it supplies the vasopressin V2 receptor-stimulated cAMP required for water reabsorption [#1]. AC6-derived cAMP operates through PKA/CREB-dependent programs in multiple tissues: it is transcriptionally upregulated by direct Purβ binding to its promoter to drive hepatic glucose production [#6], and is required for peripheral nervous system myelination, where a homozygous missense mutation causes loss of PNS myelin in humans [#4]. AC6 generates a spatially distinct, lipid-raft-associated cAMP pool that preferentially phosphorylates autophagy, Ca2+/calmodulin, Rho GTPase, and cytoskeletal targets [#11], and it physically associates with CFTR at the apical intestinal surface to form the principal cAMP-generating complex driving cholera toxin-induced fluid secretion [#5]. Beyond canonical cAMP production, AC6 controls airway ciliary length by inhibiting AMPK-mediated autophagic degradation of the kinesin KIF19A [#7], and exerts cAMP-independent protective effects in cardiac myocytes—reducing hypertrophy and apoptosis—demonstrated by a catalytically inactive D426A mutant that reproduces these phenotypes without increasing cAMP [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established AC6 as the enzymatic link translating elevated intracellular calcium into reduced cAMP and suppressed renin release, defining its calcium-inhibitable cyclase behavior in a physiological setting.\",\n      \"evidence\": \"siRNA knockdown of AC5/AC6 in primary juxtaglomerular cells and As4.1 cells with cAMP measurement and permeable cAMP analog rescue\",\n      \"pmids\": [\"17068292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve the relative contribution of AC5 versus AC6\", \"Mechanism of calcium-mediated inhibition of AC6 not structurally defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed AC6 is required for V2 receptor-stimulated cAMP in the kidney, placing it in renal water homeostasis and demonstrating a non-redundant GPCR-coupled role in vivo.\",\n      \"evidence\": \"AC6 knockout mice with adenylyl cyclase activity assays, metabolic cage, and DCE-MRI\",\n      \"pmids\": [\"20466003\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not identify the downstream aquaporin trafficking steps\", \"Tissue-specific contributions within the nephron not dissected\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated that AC6 amplifies catecholamine/prostacyclin-stimulated cAMP to inhibit collagen synthesis, linking AC6 to anti-fibrotic signaling.\",\n      \"evidence\": \"Fibroblast AC6 overexpression with cAMP and collagen assays, plus FTS1-AC6 transgenic mice in bleomycin lung fibrosis\",\n      \"pmids\": [\"20348281\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor selectivity (isoproterenol/beraprost but not PGE2/butaprost) mechanism unexplained\", \"Endogenous AC6 contribution not tested by loss-of-function\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed a cAMP-independent function of AC6 in cardiac myocytes, since a catalytically dead D426A mutant still reduced hypertrophy and apoptosis, separating enzymatic from non-enzymatic roles.\",\n      \"evidence\": \"Adenoviral transfer of AC6 and D426A mutant in adult rat cardiac myocytes with cAMP, hypertrophy, apoptosis, and Ca2+ transient readouts\",\n      \"pmids\": [\"21127130\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular effector of the cAMP-independent activity unidentified\", \"Whether D426A retains residual cyclase output sufficient for some effects not fully excluded\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected ADCY6 to peripheral nervous system myelination through human genetics and zebrafish knockdown, establishing an essential developmental role.\",\n      \"evidence\": \"Whole exome sequencing identifying a homozygous missense mutation, sciatic nerve electron microscopy, and zebrafish morpholino knockdown\",\n      \"pmids\": [\"24319099\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"cAMP pathway involvement inferred, not directly demonstrated\", \"Morpholino specificity limitations\", \"Schwann-cell-autonomous versus axonal requirement unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed AC6 downstream of HSF1 in a transcriptional axis ameliorating pressure-overload heart failure, linking stress-responsive transcription to AC6/cAMP/PKA output.\",\n      \"evidence\": \"TAC model with HSF1 transgenic and knockout mice, AC6 mRNA RT-qPCR, cAMP ELISA, PKA Western blot, echocardiography\",\n      \"pmids\": [\"27643574\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlation-based pathway placement without direct HSF1-ADCY6 promoter binding evidence\", \"Causality of AC6 in the HSF1 cardioprotective phenotype not tested by AC6 manipulation\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified AC6 as the CFTR-associated cAMP source driving cholera toxin-induced intestinal fluid secretion, defining a diarrheagenic signaling complex.\",\n      \"evidence\": \"RNA-Seq isoform identification, co-immunoprecipitation, epithelium-specific AC6 knockout mice, ileal loop CTX challenge, and intestinal spheroid CFTR activation assays\",\n      \"pmids\": [\"29903911\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis and stoichiometry of the AC6-CFTR interaction not defined\", \"Whether the interaction is direct or scaffold-mediated unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed direct transcriptional control of ADCY6 by Purβ binding its promoter, coupling glucagon signaling to hepatic glucose production via the ADCY6/cAMP/PKA/CREB pathway.\",\n      \"evidence\": \"ChIP and luciferase reporter assays, adenoviral Purβ knockdown/overexpression in hepatocytes and db/db mice with metabolic tolerance tests\",\n      \"pmids\": [\"31918924\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not establish whether Purβ regulation of ADCY6 occurs in non-hepatic tissues\", \"Cis-element within the promoter not finely mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a cAMP-effector mechanism by which AC6 controls ciliary length, inhibiting AMPK to prevent autophagic degradation of the kinesin KIF19A.\",\n      \"evidence\": \"Epithelium-specific AC6 knockout mice, ciliary length measurement, in vitro AMPK activity assays, KIF19A level and autophagosome localization assays, pharmacological AMPK activation\",\n      \"pmids\": [\"32683324\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical step from cAMP/PKA to AMPK inhibition not fully mapped\", \"Generalizability beyond airway epithelium untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated that lipid-raft-localized AC6 generates a compartmentalized cAMP pool with substrate specificity distinct from non-raft AC2, explaining isoform-specific signaling outcomes.\",\n      \"evidence\": \"AC2 and AC6 overexpression in human airway smooth muscle cells with quantitative phosphoproteomics and STRING analysis\",\n      \"pmids\": [\"36926196\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphoproteomic targets identified by overexpression, not endogenous loss-of-function\", \"Functional consequences of individual phosphosites (e.g., OFD1 Ser899) not validated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked epigenetic regulation of ADCY6 (TET1-mediated demethylation, antagonized by miR-27a-3p) to suppression of EMT in breast cancer, implicating ADCY6 as a regulated tumor-relevant locus.\",\n      \"evidence\": \"DNA methylation-specific PCR, bisulfite sequencing, lentiviral miRNA transfection, luciferase target validation, and invasion/migration assays\",\n      \"pmids\": [\"35978806\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal contribution of ADCY6 cyclase activity to the EMT phenotype not directly tested\", \"Downstream effectors of ADCY6 in this context unidentified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular basis distinguishing AC6's cAMP-dependent from cAMP-independent activities, and the structural determinants of its calcium inhibition and CFTR/raft compartmentalization, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the AC6-CFTR complex\", \"Effector mediating cAMP-independent cardiac protection unknown\", \"Mechanism of raft-restricted cAMP pool formation undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0009975\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CFTR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}