{"gene":"FXYD3","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":1995,"finding":"FXYD3 (Mat-8) expression in Xenopus oocytes induces hyperpolarization-activated chloride currents, indicating it functions as a Cl- channel or Cl- channel regulator. The protein contains extracellular and transmembrane domains homologous to phospholemman but a distinct cytoplasmic domain lacking cAMP-dependent PKA and PKC consensus phosphorylation sites.","method":"Xenopus oocyte expression system, electrophysiology, RNA blot analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct functional reconstitution in Xenopus oocytes with electrophysiological readout, single lab but robust functional assay","pmids":["7836447"],"is_preprint":false},{"year":2005,"finding":"FXYD3 (Mat-8) associates with Na,K-ATPase and modifies its transport properties, decreasing both the apparent affinity for Na+ and K+. Mouse FXYD3 may adopt a double-transmembrane topology due to a non-cleavable signal peptide. In Xenopus oocytes, FXYD3 can associate with both Na,K-ATPase and H,K-ATPase, but in stomach tissue it associates only with Na,K-ATPase because its expression is restricted to mucous cells lacking H,K-ATPase. FXYD3 also modulates glycosylation processing of the beta subunit of X,K-ATPase in a signal-peptide-dependent manner.","method":"Xenopus oocyte co-expression, electrophysiology, in situ analysis, biochemical assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — functional reconstitution in Xenopus oocytes with electrophysiology plus in situ tissue analysis, multiple orthogonal methods in one study","pmids":["15743908"],"is_preprint":false},{"year":2006,"finding":"Two human FXYD3 splice variants exist: short FXYD3 (with a cleavable signal peptide and type I topology) and long FXYD3 (with a 26-amino acid insertion after the transmembrane domain), differentially expressed during CaCo-2 cell differentiation. Both isoforms co-immunoprecipitate with Na,K-ATPase but associate stably only with Na,K-ATPase isozymes, not with H,K-ATPase or Ca-ATPase, in Xenopus oocytes. Short human FXYD3 decreases apparent K+ and Na+ affinity of Na,K-ATPase over a large range of membrane potentials, whereas long FXYD3 decreases K+ affinity only at slightly negative/positive potentials and increases apparent Na+ affinity. Both isoforms induce hyperpolarization-activated currents.","method":"Co-immunoprecipitation, Xenopus oocyte co-expression, electrophysiology, Western blot, CaCo-2 differentiation model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reconstitution in Xenopus oocytes + co-IP + electrophysiology with multiple isoforms and rigorous controls in one study","pmids":["17077088"],"is_preprint":false},{"year":2007,"finding":"Mat-8 (FXYD3) tagged with Myc localizes to the plasma membrane in colorectal cancer cells and co-immunoprecipitates with the Na+/K+-ATPase alpha subunit. A Gly41→Arg mutation in the transmembrane domain abolishes association with the Na+/K+-ATPase alpha subunit and prevents plasma membrane localization, identifying Gly41 as essential for this interaction and surface targeting. Cys44→Ala or Cys49→Ala substitutions did not affect these properties. In CHO-K1 cells, Mat-8 localizes predominantly to intracellular membranes (ER/nuclear envelope).","method":"Reciprocal co-immunoprecipitation, site-directed mutagenesis, fluorescent protein tagging, subcellular localization in colorectal cancer and CHO cells","journal":"Biological & pharmaceutical bulletin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with mutagenesis identifying key residue, single lab, two orthogonal methods","pmids":["17409496"],"is_preprint":false},{"year":2005,"finding":"Mat-8 (FXYD3) tagged with DsRed fluorescent protein localizes to intracellular membranes in CHO-K1 cells, specifically distributed in a distinct ER region and nuclear envelope, with partial overlap with ER markers; no colocalization with lysosomes, endosomes, or Golgi bodies was detected.","method":"Stable fluorescent protein tagging, subcellular fractionation by density gradient centrifugation, co-localization with organelle markers","journal":"Biotechnology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct subcellular localization with fractionation and co-markers, single lab, single cell type","pmids":["16132847"],"is_preprint":false},{"year":2008,"finding":"FXYD3 silencing in Caco-2 cells promotes apoptosis and prevents cell differentiation (reduced alkaline phosphatase, villin, decreased transepithelial resistance) without affecting proliferation. FXYD3 deficiency increases the apparent Na+ and K+ affinities of Na,K-ATPase (reflecting loss of FXYD3-mediated pump regulation) and decreases maximal Na,K-ATPase activity via reduced turnover number, correlating with a shift in Na,K-ATPase isozyme expression characteristic of cancer cells.","method":"siRNA silencing, transepithelial resistance measurement, alkaline phosphatase/villin expression, Na,K-ATPase activity assays in Caco-2 cells","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KD with multiple functional readouts (differentiation markers, pump activity, ion affinities), mechanistic link to Na,K-ATPase regulation established","pmids":["19109419"],"is_preprint":false},{"year":2009,"finding":"Forced expression of wild-type FXYD3, but not a somatic point mutant (D19H/g55c), restores well-demarcated cortical actin distribution in lung cancer cells that had lost FXYD3 expression, indicating FXYD3 plays a role in maintenance of cytoskeletal integrity through a mechanism dependent on its intact sequence.","method":"Forced expression of wild-type vs. mutant FXYD3 in lung cancer cells, actin cytoskeleton imaging","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — gain-of-function with mutant comparison providing mechanistic insight, single lab, single method for cytoskeletal readout","pmids":["19893046"],"is_preprint":false},{"year":2010,"finding":"Pseudomonas aeruginosa type III effector ExoS directly binds FXYD3 via its transmembrane domain (the same domain that interacts with Na,K-ATPase), as shown by bacterial two-hybrid screen and pulldown assay. FXYD3 colocalizes with and regulates Na,K-ATPase, which controls tight junction structure and barrier function; ExoS binding to FXYD3 is proposed to facilitate bacterial translocation through the intestinal epithelial barrier.","method":"Bacterial two-hybrid screen, pulldown assay, colocalization studies","journal":"Infection and immunity","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — pulldown and two-hybrid identifying direct binding to transmembrane domain, single lab, limited functional validation of the mechanism in mammalian cells","pmids":["20805335"],"is_preprint":false},{"year":2011,"finding":"TGF-β signaling represses FXYD3 mRNA expression in MCF-10A human mammary epithelial cells via a Smad3-dependent (but not Smad2-dependent) pathway, acting through the downstream transcriptional repressor ZEB1/δEF1. TβRI inhibitor or Smad3 inhibitor abolishes TGF-β-induced FXYD3 repression. FXYD3 knockdown does not change E-cadherin or N-cadherin expression, indicating FXYD3 is not directly required for EMT.","method":"siRNA knockdown, pharmacological inhibitors (TβRI inhibitor, Smad3 inhibitor), RT-PCR, immunofluorescence in MCF-10A cells","journal":"Biological & pharmaceutical bulletin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological dissection of pathway (Smad2 vs Smad3) combined with ZEB1 siRNA, multiple orthogonal approaches, single lab","pmids":["21372379"],"is_preprint":false},{"year":2014,"finding":"In pancreatic beta-cells, FXYD3 overexpression reduces glucose-induced insulin secretion by acting downstream of plasma membrane depolarization and Ca2+ influx. FXYD3 expression is controlled by methylation of CpGs in its proximal promoter region, with increased methylation reducing transcription (evidenced by lower H3K4me3 at the transcription start site). Gluco-incretin signaling establishes this epigenetic silencing perinatally.","method":"Beta-cell overexpression, insulin secretion assay, promoter methylation analysis, ChIP for H3K4me3, transcription reporter assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — functional overexpression assay with defined epistatic placement (downstream of Ca2+ influx), epigenetic mechanism via ChIP and reporter, single lab","pmids":["25058609"],"is_preprint":false},{"year":2016,"finding":"FXYD3 overexpression in MCF-7 breast cancer cells protects Na+/K+-ATPase from oxidative inhibition by facilitating reversal of glutathionylation of the β1 Na+/K+-ATPase subunit. ~50% siRNA-mediated reduction of FXYD3 increases β1 subunit glutathionylation and reduces Na+/K+-ATPase activity by ~50%. Suppression of FXYD3 amplifies doxorubicin- and γ-radiation-induced Na+/K+-ATPase inhibition, cell death, and apoptosis in MCF-7 but not in MDA-MB-468 cells.","method":"siRNA knockdown, Na+/K+-ATPase activity assay (colorimetric), glutathionylation measurement, caspase 3/7 apoptosis assay, cell viability assay","journal":"Breast cancer research and treatment","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays (enzyme activity, post-translational modification, apoptosis) in single lab, mechanistic link to glutathionylation reversal established","pmids":["26740212"],"is_preprint":false},{"year":2018,"finding":"FXYD3 interacts with Src and ERα to form an activated complex that triggers nongenomic estrogen signaling in ER+ breast cancer stem cells. SOX9 transcription factor directly promotes FXYD3 expression, and FXYD3 is required for SOX9 nuclear localization, forming a positive regulatory feedback loop. FXYD3 amplification mediates tamoxifen resistance.","method":"Co-immunoprecipitation (FXYD3-Src-ERα complex), SOX9 promoter binding assays, nuclear localization imaging, siRNA/overexpression functional assays","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP identifying complex, nuclear localization assay, multiple functional readouts; single lab with several orthogonal approaches","pmids":["30206184"],"is_preprint":false},{"year":2022,"finding":"FXYD3 localizes to the basolateral membrane of all airway epithelial cell types and functions as a γ subunit of the Na/K-ATPase to facilitate Na+ and liquid absorption. siRNA-mediated reduction of FXYD3 decreases ouabain-sensitive short-circuit current (after apical membrane permeabilization with nystatin) and reduces amiloride-sensitive short-circuit current and liquid absorption across intact airway epithelia.","method":"Single-cell RNA sequencing, immunohistochemistry, siRNA knockdown, Ussing chamber short-circuit current measurements, liquid absorption assay","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct functional assay (Ussing chamber) with pharmacological dissection, localization by IHC and scRNA-seq, multiple orthogonal methods in single study","pmids":["35993520"],"is_preprint":false},{"year":2023,"finding":"FXYD3 promotes IL-17A signaling in keratinocytes by competitively binding TRAF3, thereby promoting formation of the IL-17R-ACT1 complex (by displacing TRAF3 from IL-17R), which activates NF-κB and MAPK signaling pathways and drives proinflammatory cytokine expression. FXYD3 deletion in keratinocytes attenuates psoriasis-like phenotype in an IMQ-induced mouse model. IL-17A drives FXYD3 expression in keratinocytes, forming a positive regulatory loop.","method":"Co-immunoprecipitation (FXYD3-TRAF3-IL-17R-ACT1 complex), FXYD3 conditional knockout mouse model, IMQ-induced psoriasis model, NF-κB/MAPK signaling assays","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying molecular mechanism + in vivo KO model with defined phenotype, multiple orthogonal methods, single lab","pmids":["36693922"],"is_preprint":false},{"year":2025,"finding":"FXYD3 in intestinal goblet cells interacts with the ER Ca2+-ATPase SERCA2 to enhance its pump activity. FXYD3 deficiency causes ER Ca2+ homeostasis defects and impaired mucin glycosylation, leading to a damaged mucus barrier, intestinal dysbiosis, and increased susceptibility to colitis. Gut microbiota metabolites propionate and butyrate promote FXYD3 expression.","method":"Co-immunoprecipitation (FXYD3-SERCA2), FXYD3 conditional knockout (intestinal epithelial), SERCA2 activity assay, ER Ca2+ measurement, mucin glycosylation analysis, germ-free/colonization models","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying SERCA2 interaction, in vivo conditional KO with multiple mechanistic readouts (Ca2+ homeostasis, mucin glycosylation, barrier function), single lab but multiple orthogonal methods","pmids":["41187059"],"is_preprint":false},{"year":2025,"finding":"FXYD3 directly interacts with IRF7 via its 60–87 amino acid domain, initiating a positive feedback loop through the cGAS/STING pathway amplified by type I interferon, resulting in sustained JAK2/STAT5 signaling activation that drives malignant progression of intrahepatic cholangiocarcinoma.","method":"Co-immunoprecipitation, single-cell sequencing, spatial transcriptomics, domain mapping, in vitro and in vivo functional assays, nano-delivery siRNA system","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP with domain mapping and in vivo validation, single lab, novel finding not yet replicated","pmids":["41164952"],"is_preprint":false},{"year":2015,"finding":"Estrogen and tamoxifen upregulate FXYD3 expression in ERα-positive MCF-7 cells via ERα, but not in ERα-negative MDA-MB-231 cells, establishing ERα as required for this response. ERα associates with ZEB1 in MCF-7 cells, and siRNA knockdown of ZEB1 disrupts estrogen- (but not tamoxifen-) induced FXYD3 upregulation, indicating two distinct mechanisms both involving ERα, one requiring ZEB1.","method":"Flow cytometry (fluorochrome-tagged antibody), siRNA knockdown of ZEB1, comparison of ERα-positive vs ERα-negative cell lines","journal":"SpringerPlus","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — cell-based gene regulation assay with siRNA and ERα-negative controls, mechanistic dissection of two pathways, single lab","pmids":["26090296"],"is_preprint":false}],"current_model":"FXYD3 is a small transmembrane protein that primarily functions as a tissue-specific regulator of Na,K-ATPase (decreasing apparent Na+ and K+ affinities and modulating pump activity), with two human isoforms adopting type I topology; it also interacts with SERCA2 to regulate ER Ca2+ homeostasis in goblet cells, engages in protein–protein interactions with Src/ERα (nongenomic estrogen signaling), TRAF3 (IL-17A/NF-κB/MAPK signaling in keratinocytes), and IRF7 (cGAS/STING-JAK2/STAT5 axis), facilitates cortical actin integrity, protects Na,K-ATPase from oxidative glutathionylation, and is transcriptionally regulated by TGF-β/Smad3/ZEB1 signaling and by CpG promoter methylation downstream of gluco-incretin signaling."},"narrative":{"mechanistic_narrative":"FXYD3 (Mat-8) is a small single-pass transmembrane protein that functions primarily as a tissue-specific auxiliary subunit of P-type ATPases, tuning ion transport in epithelial cells [PMID:15743908, PMID:17077088, PMID:35993520]. It associates physically and selectively with the Na,K-ATPase α subunit — an interaction requiring Gly41 in its transmembrane domain for both complex formation and plasma membrane targeting — and decreases the apparent Na+ and K+ affinities of the pump while modulating its turnover [PMID:15743908, PMID:17077088, PMID:17409496, PMID:19109419]. Two human splice isoforms (a short type I form and a long form with a 26-residue post-transmembrane insertion) exert distinct effects on pump ion affinities and both induce hyperpolarization-activated currents [PMID:7836447, PMID:17077088]. As a Na,K-ATPase regulator FXYD3 supports vectorial Na+ and liquid absorption at the basolateral membrane of airway epithelia [PMID:35993520], is required for enterocyte differentiation and epithelial barrier integrity [PMID:19109419], and protects the pump from oxidative inhibition by promoting reversal of β1 subunit glutathionylation [PMID:26740212]. Beyond the Na,K-ATPase, FXYD3 interacts with the ER Ca2+-ATPase SERCA2 in intestinal goblet cells to enhance Ca2+ uptake, supporting mucin glycosylation and the mucus barrier [PMID:41187059]. FXYD3 additionally participates in signaling complexes: it competitively binds TRAF3 to promote IL-17R–ACT1 assembly and NF-κB/MAPK activation in keratinocytes [PMID:36693922], and forms a Src–ERα complex driving nongenomic estrogen signaling and tamoxifen resistance in breast cancer [PMID:30206184]. Its expression is tightly controlled by TGF-β/Smad3/ZEB1 repression [PMID:21372379], CpG promoter methylation downstream of gluco-incretin signaling [PMID:25058609], and induction by ERα, IL-17A, and microbial short-chain fatty acids [PMID:36693922, PMID:41187059, PMID:26090296].","teleology":[{"year":1995,"claim":"Established FXYD3 as an electrically active membrane protein, raising the first question of how a phospholemman-homologous protein influences transmembrane ion flux.","evidence":"Xenopus oocyte expression with electrophysiology and RNA blot","pmids":["7836447"],"confidence":"High","gaps":["Whether FXYD3 is a bona fide Cl- channel or a regulator of an endogenous current was not resolved","No direct binding partner identified at this stage"]},{"year":2005,"claim":"Reframed FXYD3 from a putative channel to a regulatory subunit of the Na,K-ATPase, showing it modifies pump ion affinities and β-subunit glycosylation.","evidence":"Xenopus oocyte co-expression, electrophysiology, in situ tissue analysis, biochemical assays","pmids":["15743908"],"confidence":"High","gaps":["Topology (single vs double transmembrane) left ambiguous","Physiological consequence of pump regulation in native tissue not tested"]},{"year":2006,"claim":"Defined two human splice isoforms with distinct topologies and showed both bind selectively to Na,K-ATPase but exert divergent effects on Na+/K+ affinity, explaining isoform-specific pump tuning.","evidence":"Co-IP, Xenopus oocyte co-expression, electrophysiology, CaCo-2 differentiation model","pmids":["17077088"],"confidence":"High","gaps":["Functional significance of the long-isoform-specific affinity changes in vivo unknown","Selectivity for Na,K-ATPase over H,K-/Ca-ATPase mechanism not structurally defined"]},{"year":2005,"claim":"Addressed where FXYD3 resides, finding intracellular ER/nuclear-envelope localization in CHO cells, hinting that surface targeting is context-dependent.","evidence":"DsRed tagging, density-gradient fractionation, organelle marker co-localization in CHO-K1","pmids":["16132847"],"confidence":"Medium","gaps":["Single cell type tested","Did not establish what controls ER retention versus plasma membrane delivery"]},{"year":2007,"claim":"Identified Gly41 in the transmembrane domain as essential for both Na,K-ATPase association and plasma membrane targeting, mechanistically coupling complex assembly to trafficking.","evidence":"Reciprocal Co-IP, site-directed mutagenesis, fluorescent tagging in colorectal cancer and CHO cells","pmids":["17409496"],"confidence":"Medium","gaps":["Single lab, two orthogonal methods","Why CHO cells retain FXYD3 intracellularly while cancer cells display it at the surface unresolved"]},{"year":2008,"claim":"Showed FXYD3 is required for epithelial differentiation and barrier formation, linking its pump-regulatory role to a cellular phenotype.","evidence":"siRNA silencing, transepithelial resistance, differentiation markers, Na,K-ATPase activity assays in Caco-2","pmids":["19109419"],"confidence":"High","gaps":["Causal chain from pump regulation to apoptosis/differentiation not dissected","Single cell model"]},{"year":2009,"claim":"Connected FXYD3 to cytoskeletal organization, showing wild-type but not a point-mutant restores cortical actin, implying a sequence-dependent structural role.","evidence":"Forced expression of WT vs mutant FXYD3 in lung cancer cells, actin imaging","pmids":["19893046"],"confidence":"Medium","gaps":["Mechanism linking FXYD3 to actin (direct vs pump-mediated) unknown","Single readout, single lab"]},{"year":2010,"claim":"Revealed that a bacterial effector (ExoS) hijacks the FXYD3 transmembrane domain, exploiting its Na,K-ATPase/barrier-regulating function for pathogen translocation.","evidence":"Bacterial two-hybrid screen, pulldown, colocalization","pmids":["20805335"],"confidence":"Medium","gaps":["Mechanistic validation in mammalian cells limited","Functional consequence on barrier inferred rather than directly demonstrated"]},{"year":2011,"claim":"Mapped upstream transcriptional control, showing TGF-β represses FXYD3 via Smad3 and the repressor ZEB1, while decoupling FXYD3 from EMT.","evidence":"siRNA, TβRI/Smad3 inhibitors, ZEB1 knockdown, RT-PCR in MCF-10A","pmids":["21372379"],"confidence":"Medium","gaps":["Direct ZEB1 binding to FXYD3 promoter not shown","Single cell line"]},{"year":2014,"claim":"Established epigenetic regulation of FXYD3 and a function in insulin secretion, placing FXYD3 downstream of Ca2+ influx in beta-cells and under CpG-methylation control.","evidence":"Beta-cell overexpression, insulin secretion assay, promoter methylation, H3K4me3 ChIP, reporter assay","pmids":["25058609"],"confidence":"Medium","gaps":["Molecular step at which FXYD3 inhibits secretion downstream of Ca2+ not defined","Single lab"]},{"year":2015,"claim":"Showed estrogen and tamoxifen induce FXYD3 through ERα via two routes (one ZEB1-dependent), linking hormone signaling to FXYD3 expression.","evidence":"Flow cytometry, ZEB1 siRNA, ERα-positive vs -negative cell comparison","pmids":["26090296"],"confidence":"Medium","gaps":["Direct vs indirect ERα transcriptional control not resolved","Mechanism distinguishing estrogen and tamoxifen routes incomplete"]},{"year":2016,"claim":"Defined a protective role against oxidative pump inhibition, showing FXYD3 facilitates reversal of β1 subunit glutathionylation and modulates chemo/radiotherapy sensitivity.","evidence":"siRNA, Na,K-ATPase activity and glutathionylation assays, caspase 3/7 and viability assays in MCF-7","pmids":["26740212"],"confidence":"Medium","gaps":["Biochemical mechanism of how FXYD3 promotes deglutathionylation unknown","Cell-line-dependent effect (MCF-7 vs MDA-MB-468) unexplained"]},{"year":2018,"claim":"Extended FXYD3 beyond ion transport into nongenomic estrogen signaling, identifying an FXYD3–Src–ERα complex and a SOX9 feedback loop driving tamoxifen resistance.","evidence":"Co-IP, SOX9 promoter binding, nuclear localization imaging, siRNA/overexpression in breast cancer stem cells","pmids":["30206184"],"confidence":"Medium","gaps":["Direct vs scaffolded interactions within the complex not distinguished","How a membrane protein supports SOX9 nuclear localization unresolved"]},{"year":2022,"claim":"Confirmed FXYD3 as a functional Na,K-ATPase γ subunit in airway epithelia, mechanistically tying it to Na+ and liquid absorption physiology.","evidence":"scRNA-seq, IHC, siRNA, Ussing chamber short-circuit current, liquid absorption assays","pmids":["35993520"],"confidence":"High","gaps":["Contribution relative to other FXYD subunits not quantified","Role in airway disease not tested"]},{"year":2023,"claim":"Uncovered an immune-signaling function: FXYD3 competitively displaces TRAF3 to promote IL-17R–ACT1 assembly and NF-κB/MAPK activation, validated by KO rescue of psoriasis-like disease.","evidence":"Co-IP, conditional keratinocyte knockout, IMQ psoriasis model, NF-κB/MAPK assays","pmids":["36693922"],"confidence":"High","gaps":["Whether the same protein pool serves pump and IL-17 functions unknown","Structural basis of TRAF3 competition undefined"]},{"year":2025,"claim":"Identified SERCA2 as a second P-type ATPase partner, showing FXYD3 enhances ER Ca2+ uptake to support goblet-cell mucin glycosylation and the mucus barrier.","evidence":"Co-IP, intestinal-epithelial conditional KO, SERCA2 activity and ER Ca2+ assays, mucin glycosylation analysis, germ-free/colonization models","pmids":["41187059"],"confidence":"High","gaps":["Structural determinants of SERCA2 vs Na,K-ATPase selectivity not defined","Whether SERCA2 regulation generalizes beyond goblet cells unknown"]},{"year":2025,"claim":"Mapped a domain-specific interaction with IRF7 linking FXYD3 to a cGAS/STING–JAK2/STAT5 feedback loop in cholangiocarcinoma progression.","evidence":"Co-IP, domain mapping, single-cell/spatial transcriptomics, in vivo siRNA nano-delivery","pmids":["41164952"],"confidence":"Medium","gaps":["Single lab, not independently replicated","How a transmembrane protein engages the cytoplasmic IRF7 axis mechanistically unclear"]},{"year":null,"claim":"It remains unresolved how a single small transmembrane protein partitions among its multiple functional pools — P-type ATPase regulation (Na,K-ATPase and SERCA2) versus scaffolding of signaling complexes (TRAF3, Src/ERα, IRF7) — and what structural features dictate partner selectivity and subcellular targeting.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of FXYD3 in complex with any partner","Determinants of plasma membrane vs ER localization not defined","Whether signaling functions require or are independent of ion-pump regulation untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2,5,12,14]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[11,13,15]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,12]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[4,14]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[3,4]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[1,2,12]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[11,15]}],"complexes":["Na,K-ATPase","IL-17R-ACT1 complex","FXYD3-Src-ERalpha complex"],"partners":["ATP1A1","SERCA2","TRAF3","SRC","ESR1","IRF7","SOX9"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14802","full_name":"FXYD domain-containing ion transport regulator 3","aliases":["Chloride conductance inducer protein Mat-8","Mammary tumor 8 kDa protein","Phospholemman-like","Sodium/potassium-transporting ATPase subunit FXYD3"],"length_aa":87,"mass_kda":9.3,"function":"Associates with and regulates the activity of the sodium/potassium-transporting ATPase (NKA) which transports Na(+) out of the cell and K(+) into the cell (PubMed:17077088). Reduces glutathionylation of the NKA beta-1 subunit ATP1B1, thus reversing glutathionylation-mediated inhibition of ATP1B1 (PubMed:21454534). Induces a hyperpolarization-activated chloride current when expressed in Xenopus oocytes (PubMed:7836447) Decreases the apparent K+ and Na+ affinity of the sodium/potassium-transporting ATPase over a large range of membrane potentials Decreases the apparent K+ affinity of the sodium/potassium-transporting ATPase only at slightly negative and positive membrane potentials and increases the apparent Na+ affinity over a large range of membrane potentials","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q14802/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FXYD3","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FXYD3","total_profiled":1310},"omim":[{"mim_id":"604996","title":"FXYD DOMAIN-CONTAINING ION TRANSPORT REGULATOR 3; FXYD3","url":"https://www.omim.org/entry/604996"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":1697.0}],"url":"https://www.proteinatlas.org/search/FXYD3"},"hgnc":{"alias_symbol":["MAT-8"],"prev_symbol":["PLML"]},"alphafold":{"accession":"Q14802","domains":[{"cath_id":"1.20.58","chopping":"2-63","consensus_level":"medium","plddt":76.9376,"start":2,"end":63}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14802","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14802-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14802-F1-predicted_aligned_error_v6.png","plddt_mean":68.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FXYD3","jax_strain_url":"https://www.jax.org/strain/search?query=FXYD3"},"sequence":{"accession":"Q14802","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14802.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14802/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14802"}},"corpus_meta":[{"pmid":"7836447","id":"PMC_7836447","title":"Mat-8, a novel phospholemman-like protein expressed in human breast tumors, induces a chloride conductance in Xenopus oocytes.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7836447","citation_count":138,"is_preprint":false},{"pmid":"14654946","id":"PMC_14654946","title":"Up-regulated expression of the MAT-8 gene in prostate cancer and its siRNA-mediated inhibition of expression induces a decrease in proliferation of human prostate carcinoma cells.","date":"2004","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/14654946","citation_count":82,"is_preprint":false},{"pmid":"20805335","id":"PMC_20805335","title":"Translocation of Pseudomonas aeruginosa from the intestinal tract is mediated by the binding of ExoS to an Na,K-ATPase regulator, FXYD3.","date":"2010","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/20805335","citation_count":70,"is_preprint":false},{"pmid":"16003754","id":"PMC_16003754","title":"FXYD3 is overexpressed in pancreatic ductal adenocarcinoma and influences pancreatic cancer cell growth.","date":"2006","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/16003754","citation_count":63,"is_preprint":false},{"pmid":"15743908","id":"PMC_15743908","title":"FXYD3 (Mat-8), a new regulator of Na,K-ATPase.","date":"2005","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/15743908","citation_count":61,"is_preprint":false},{"pmid":"30206184","id":"PMC_30206184","title":"SOX9/FXYD3/Src Axis Is Critical for ER+ Breast Cancer Stem Cell Function.","date":"2018","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/30206184","citation_count":46,"is_preprint":false},{"pmid":"33350586","id":"PMC_33350586","title":"Extracellular vesicles-encapsulated let-7i shed from bone mesenchymal stem cells suppress lung cancer via KDM3A/DCLK1/FXYD3 axis.","date":"2020","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33350586","citation_count":46,"is_preprint":false},{"pmid":"19893046","id":"PMC_19893046","title":"Down-regulation of FXYD3 expression in human lung cancers: its mechanism and potential role in carcinogenesis.","date":"2009","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/19893046","citation_count":36,"is_preprint":false},{"pmid":"36693922","id":"PMC_36693922","title":"FXYD3 enhances IL-17A signaling to promote psoriasis by competitively binding TRAF3 in keratinocytes.","date":"2023","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36693922","citation_count":33,"is_preprint":false},{"pmid":"33621431","id":"PMC_33621431","title":"KDM5A silencing transcriptionally suppresses the FXYD3-PI3K/AKT axis to inhibit angiogenesis in hepatocellular cancer via miR-433 up-regulation.","date":"2021","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33621431","citation_count":29,"is_preprint":false},{"pmid":"17077088","id":"PMC_17077088","title":"Structural and functional properties of two human FXYD3 (Mat-8) isoforms.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17077088","citation_count":26,"is_preprint":false},{"pmid":"19955746","id":"PMC_19955746","title":"Expression of FXYD3 protein in relation to biological and clinicopathological variables in colorectal cancers.","date":"2009","source":"Chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/19955746","citation_count":26,"is_preprint":false},{"pmid":"19571376","id":"PMC_19571376","title":"FXYD3 protein involved in tumor cell proliferation is overproduced in human breast cancer tissues.","date":"2009","source":"Biological & pharmaceutical 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cell","url":"https://pubmed.ncbi.nlm.nih.gov/19109419","citation_count":21,"is_preprint":false},{"pmid":"21499437","id":"PMC_21499437","title":"FXYD3: A Promising Biomarker for Urothelial Carcinoma.","date":"2011","source":"Biomarker insights","url":"https://pubmed.ncbi.nlm.nih.gov/21499437","citation_count":20,"is_preprint":false},{"pmid":"37966117","id":"PMC_37966117","title":"FXYD3 functionally demarcates an ancestral breast cancer stem cell subpopulation with features of drug-tolerant persisters.","date":"2023","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/37966117","citation_count":17,"is_preprint":false},{"pmid":"37535601","id":"PMC_37535601","title":"TGM2, HMGA2, FXYD3, and LGALS4 genes as biomarkers in acquired oxaliplatin resistance of human colorectal cancer: A systems biology approach.","date":"2023","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/37535601","citation_count":17,"is_preprint":false},{"pmid":"32432654","id":"PMC_32432654","title":"LncRNA LINC01503 aggravates the progression of cervical cancer through sponging miR-342-3p to mediate FXYD3 expression.","date":"2020","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/32432654","citation_count":17,"is_preprint":false},{"pmid":"20364041","id":"PMC_20364041","title":"Expression and significance of FXYD-3 protein in gastric adenocarcinoma.","date":"2010","source":"Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/20364041","citation_count":17,"is_preprint":false},{"pmid":"25013464","id":"PMC_25013464","title":"Expression and clinical significance of FXYD3 in endometrial cancer.","date":"2014","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/25013464","citation_count":16,"is_preprint":false},{"pmid":"26740212","id":"PMC_26740212","title":"Silencing overexpression of FXYD3 protein in breast cancer cells amplifies effects of doxorubicin and γ-radiation on Na(+)/K(+)-ATPase and cell survival.","date":"2016","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/26740212","citation_count":14,"is_preprint":false},{"pmid":"20112499","id":"PMC_20112499","title":"FXYD3 expression in gliomas and its clinicopathological significance.","date":"2009","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/20112499","citation_count":13,"is_preprint":false},{"pmid":"24167366","id":"PMC_24167366","title":"Overexpression of FXYD-3 is involved in the tumorigenesis and development of esophageal squamous cell carcinoma.","date":"2013","source":"Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/24167366","citation_count":13,"is_preprint":false},{"pmid":"25058609","id":"PMC_25058609","title":"Gluco-incretins regulate beta-cell glucose competence by epigenetic silencing of Fxyd3 expression.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25058609","citation_count":12,"is_preprint":false},{"pmid":"32162907","id":"PMC_32162907","title":"Instrument-Free Detection of FXYD3 Using Vial-Based Immunosensor for Earlier and Faster Urothelial Carcinoma Diagnosis.","date":"2020","source":"ACS sensors","url":"https://pubmed.ncbi.nlm.nih.gov/32162907","citation_count":12,"is_preprint":false},{"pmid":"14694902","id":"PMC_14694902","title":"Fxyd3 and Lgi4 expression in the adult mouse: a case of endogenous antisense expression.","date":"2003","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/14694902","citation_count":10,"is_preprint":false},{"pmid":"25920992","id":"PMC_25920992","title":"External validation of FXYD3 and KRT20 as predictive biomarkers for the presence of micrometastasis in muscle invasive bladder cancer lymph nodes.","date":"2015","source":"Actas urologicas espanolas","url":"https://pubmed.ncbi.nlm.nih.gov/25920992","citation_count":10,"is_preprint":false},{"pmid":"16132847","id":"PMC_16132847","title":"Stable expression and visualization of Mat-8 (FXYD-3) tagged with a fluorescent protein in Chinese hamster ovary (CHO)-K1 cells.","date":"2005","source":"Biotechnology letters","url":"https://pubmed.ncbi.nlm.nih.gov/16132847","citation_count":10,"is_preprint":false},{"pmid":"26090296","id":"PMC_26090296","title":"Estrogen and tamoxifen up-regulate FXYD3 on breast cancer cells: assessing the differential roles of ER α and ZEB1.","date":"2015","source":"SpringerPlus","url":"https://pubmed.ncbi.nlm.nih.gov/26090296","citation_count":9,"is_preprint":false},{"pmid":"27104167","id":"PMC_27104167","title":"FXYD-3 expression in relation to local recurrence of rectal cancer.","date":"2016","source":"Radiation oncology journal","url":"https://pubmed.ncbi.nlm.nih.gov/27104167","citation_count":6,"is_preprint":false},{"pmid":"41187059","id":"PMC_41187059","title":"Goblet cell-expressed microprotein FXYD3 determines gut homeostasis by maintaining mucus barrier integrity.","date":"2025","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/41187059","citation_count":4,"is_preprint":false},{"pmid":"35993520","id":"PMC_35993520","title":"FXYD3 facilitates Na+ and liquid absorption across human airway epithelia by increasing the transport capacity of the Na/K ATPase.","date":"2022","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/35993520","citation_count":4,"is_preprint":false},{"pmid":"39417182","id":"PMC_39417182","title":"Uncovering the role of FXYD3 as a potential oncogene and early biomarker in pancreatic cancer.","date":"2024","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/39417182","citation_count":4,"is_preprint":false},{"pmid":"41164952","id":"PMC_41164952","title":"FXYD3 Promotes Tumor Progression by Binding With IRF7 to Regulate JAK2/STAT5 Signaling in Intrahepatic Cholangiocarcinoma.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41164952","citation_count":2,"is_preprint":false},{"pmid":"39783776","id":"PMC_39783776","title":"FXYD3 Is Frequently Expressed in Pancreatic Ductal Adenocarcinoma but Does Not Predict Survival.","date":"2025","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39783776","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21023,"output_tokens":5035,"usd":0.069297,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13397,"output_tokens":5269,"usd":0.099355,"stage2_stop_reason":"end_turn"},"total_usd":0.168652,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"FXYD3 (Mat-8) expression in Xenopus oocytes induces hyperpolarization-activated chloride currents, indicating it functions as a Cl- channel or Cl- channel regulator. The protein contains extracellular and transmembrane domains homologous to phospholemman but a distinct cytoplasmic domain lacking cAMP-dependent PKA and PKC consensus phosphorylation sites.\",\n      \"method\": \"Xenopus oocyte expression system, electrophysiology, RNA blot analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct functional reconstitution in Xenopus oocytes with electrophysiological readout, single lab but robust functional assay\",\n      \"pmids\": [\"7836447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"FXYD3 (Mat-8) associates with Na,K-ATPase and modifies its transport properties, decreasing both the apparent affinity for Na+ and K+. Mouse FXYD3 may adopt a double-transmembrane topology due to a non-cleavable signal peptide. In Xenopus oocytes, FXYD3 can associate with both Na,K-ATPase and H,K-ATPase, but in stomach tissue it associates only with Na,K-ATPase because its expression is restricted to mucous cells lacking H,K-ATPase. FXYD3 also modulates glycosylation processing of the beta subunit of X,K-ATPase in a signal-peptide-dependent manner.\",\n      \"method\": \"Xenopus oocyte co-expression, electrophysiology, in situ analysis, biochemical assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — functional reconstitution in Xenopus oocytes with electrophysiology plus in situ tissue analysis, multiple orthogonal methods in one study\",\n      \"pmids\": [\"15743908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Two human FXYD3 splice variants exist: short FXYD3 (with a cleavable signal peptide and type I topology) and long FXYD3 (with a 26-amino acid insertion after the transmembrane domain), differentially expressed during CaCo-2 cell differentiation. Both isoforms co-immunoprecipitate with Na,K-ATPase but associate stably only with Na,K-ATPase isozymes, not with H,K-ATPase or Ca-ATPase, in Xenopus oocytes. Short human FXYD3 decreases apparent K+ and Na+ affinity of Na,K-ATPase over a large range of membrane potentials, whereas long FXYD3 decreases K+ affinity only at slightly negative/positive potentials and increases apparent Na+ affinity. Both isoforms induce hyperpolarization-activated currents.\",\n      \"method\": \"Co-immunoprecipitation, Xenopus oocyte co-expression, electrophysiology, Western blot, CaCo-2 differentiation model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reconstitution in Xenopus oocytes + co-IP + electrophysiology with multiple isoforms and rigorous controls in one study\",\n      \"pmids\": [\"17077088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Mat-8 (FXYD3) tagged with Myc localizes to the plasma membrane in colorectal cancer cells and co-immunoprecipitates with the Na+/K+-ATPase alpha subunit. A Gly41→Arg mutation in the transmembrane domain abolishes association with the Na+/K+-ATPase alpha subunit and prevents plasma membrane localization, identifying Gly41 as essential for this interaction and surface targeting. Cys44→Ala or Cys49→Ala substitutions did not affect these properties. In CHO-K1 cells, Mat-8 localizes predominantly to intracellular membranes (ER/nuclear envelope).\",\n      \"method\": \"Reciprocal co-immunoprecipitation, site-directed mutagenesis, fluorescent protein tagging, subcellular localization in colorectal cancer and CHO cells\",\n      \"journal\": \"Biological & pharmaceutical bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with mutagenesis identifying key residue, single lab, two orthogonal methods\",\n      \"pmids\": [\"17409496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Mat-8 (FXYD3) tagged with DsRed fluorescent protein localizes to intracellular membranes in CHO-K1 cells, specifically distributed in a distinct ER region and nuclear envelope, with partial overlap with ER markers; no colocalization with lysosomes, endosomes, or Golgi bodies was detected.\",\n      \"method\": \"Stable fluorescent protein tagging, subcellular fractionation by density gradient centrifugation, co-localization with organelle markers\",\n      \"journal\": \"Biotechnology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct subcellular localization with fractionation and co-markers, single lab, single cell type\",\n      \"pmids\": [\"16132847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"FXYD3 silencing in Caco-2 cells promotes apoptosis and prevents cell differentiation (reduced alkaline phosphatase, villin, decreased transepithelial resistance) without affecting proliferation. FXYD3 deficiency increases the apparent Na+ and K+ affinities of Na,K-ATPase (reflecting loss of FXYD3-mediated pump regulation) and decreases maximal Na,K-ATPase activity via reduced turnover number, correlating with a shift in Na,K-ATPase isozyme expression characteristic of cancer cells.\",\n      \"method\": \"siRNA silencing, transepithelial resistance measurement, alkaline phosphatase/villin expression, Na,K-ATPase activity assays in Caco-2 cells\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with multiple functional readouts (differentiation markers, pump activity, ion affinities), mechanistic link to Na,K-ATPase regulation established\",\n      \"pmids\": [\"19109419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Forced expression of wild-type FXYD3, but not a somatic point mutant (D19H/g55c), restores well-demarcated cortical actin distribution in lung cancer cells that had lost FXYD3 expression, indicating FXYD3 plays a role in maintenance of cytoskeletal integrity through a mechanism dependent on its intact sequence.\",\n      \"method\": \"Forced expression of wild-type vs. mutant FXYD3 in lung cancer cells, actin cytoskeleton imaging\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — gain-of-function with mutant comparison providing mechanistic insight, single lab, single method for cytoskeletal readout\",\n      \"pmids\": [\"19893046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Pseudomonas aeruginosa type III effector ExoS directly binds FXYD3 via its transmembrane domain (the same domain that interacts with Na,K-ATPase), as shown by bacterial two-hybrid screen and pulldown assay. FXYD3 colocalizes with and regulates Na,K-ATPase, which controls tight junction structure and barrier function; ExoS binding to FXYD3 is proposed to facilitate bacterial translocation through the intestinal epithelial barrier.\",\n      \"method\": \"Bacterial two-hybrid screen, pulldown assay, colocalization studies\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — pulldown and two-hybrid identifying direct binding to transmembrane domain, single lab, limited functional validation of the mechanism in mammalian cells\",\n      \"pmids\": [\"20805335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TGF-β signaling represses FXYD3 mRNA expression in MCF-10A human mammary epithelial cells via a Smad3-dependent (but not Smad2-dependent) pathway, acting through the downstream transcriptional repressor ZEB1/δEF1. TβRI inhibitor or Smad3 inhibitor abolishes TGF-β-induced FXYD3 repression. FXYD3 knockdown does not change E-cadherin or N-cadherin expression, indicating FXYD3 is not directly required for EMT.\",\n      \"method\": \"siRNA knockdown, pharmacological inhibitors (TβRI inhibitor, Smad3 inhibitor), RT-PCR, immunofluorescence in MCF-10A cells\",\n      \"journal\": \"Biological & pharmaceutical bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological dissection of pathway (Smad2 vs Smad3) combined with ZEB1 siRNA, multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"21372379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In pancreatic beta-cells, FXYD3 overexpression reduces glucose-induced insulin secretion by acting downstream of plasma membrane depolarization and Ca2+ influx. FXYD3 expression is controlled by methylation of CpGs in its proximal promoter region, with increased methylation reducing transcription (evidenced by lower H3K4me3 at the transcription start site). Gluco-incretin signaling establishes this epigenetic silencing perinatally.\",\n      \"method\": \"Beta-cell overexpression, insulin secretion assay, promoter methylation analysis, ChIP for H3K4me3, transcription reporter assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — functional overexpression assay with defined epistatic placement (downstream of Ca2+ influx), epigenetic mechanism via ChIP and reporter, single lab\",\n      \"pmids\": [\"25058609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FXYD3 overexpression in MCF-7 breast cancer cells protects Na+/K+-ATPase from oxidative inhibition by facilitating reversal of glutathionylation of the β1 Na+/K+-ATPase subunit. ~50% siRNA-mediated reduction of FXYD3 increases β1 subunit glutathionylation and reduces Na+/K+-ATPase activity by ~50%. Suppression of FXYD3 amplifies doxorubicin- and γ-radiation-induced Na+/K+-ATPase inhibition, cell death, and apoptosis in MCF-7 but not in MDA-MB-468 cells.\",\n      \"method\": \"siRNA knockdown, Na+/K+-ATPase activity assay (colorimetric), glutathionylation measurement, caspase 3/7 apoptosis assay, cell viability assay\",\n      \"journal\": \"Breast cancer research and treatment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays (enzyme activity, post-translational modification, apoptosis) in single lab, mechanistic link to glutathionylation reversal established\",\n      \"pmids\": [\"26740212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FXYD3 interacts with Src and ERα to form an activated complex that triggers nongenomic estrogen signaling in ER+ breast cancer stem cells. SOX9 transcription factor directly promotes FXYD3 expression, and FXYD3 is required for SOX9 nuclear localization, forming a positive regulatory feedback loop. FXYD3 amplification mediates tamoxifen resistance.\",\n      \"method\": \"Co-immunoprecipitation (FXYD3-Src-ERα complex), SOX9 promoter binding assays, nuclear localization imaging, siRNA/overexpression functional assays\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP identifying complex, nuclear localization assay, multiple functional readouts; single lab with several orthogonal approaches\",\n      \"pmids\": [\"30206184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FXYD3 localizes to the basolateral membrane of all airway epithelial cell types and functions as a γ subunit of the Na/K-ATPase to facilitate Na+ and liquid absorption. siRNA-mediated reduction of FXYD3 decreases ouabain-sensitive short-circuit current (after apical membrane permeabilization with nystatin) and reduces amiloride-sensitive short-circuit current and liquid absorption across intact airway epithelia.\",\n      \"method\": \"Single-cell RNA sequencing, immunohistochemistry, siRNA knockdown, Ussing chamber short-circuit current measurements, liquid absorption assay\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct functional assay (Ussing chamber) with pharmacological dissection, localization by IHC and scRNA-seq, multiple orthogonal methods in single study\",\n      \"pmids\": [\"35993520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FXYD3 promotes IL-17A signaling in keratinocytes by competitively binding TRAF3, thereby promoting formation of the IL-17R-ACT1 complex (by displacing TRAF3 from IL-17R), which activates NF-κB and MAPK signaling pathways and drives proinflammatory cytokine expression. FXYD3 deletion in keratinocytes attenuates psoriasis-like phenotype in an IMQ-induced mouse model. IL-17A drives FXYD3 expression in keratinocytes, forming a positive regulatory loop.\",\n      \"method\": \"Co-immunoprecipitation (FXYD3-TRAF3-IL-17R-ACT1 complex), FXYD3 conditional knockout mouse model, IMQ-induced psoriasis model, NF-κB/MAPK signaling assays\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying molecular mechanism + in vivo KO model with defined phenotype, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"36693922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FXYD3 in intestinal goblet cells interacts with the ER Ca2+-ATPase SERCA2 to enhance its pump activity. FXYD3 deficiency causes ER Ca2+ homeostasis defects and impaired mucin glycosylation, leading to a damaged mucus barrier, intestinal dysbiosis, and increased susceptibility to colitis. Gut microbiota metabolites propionate and butyrate promote FXYD3 expression.\",\n      \"method\": \"Co-immunoprecipitation (FXYD3-SERCA2), FXYD3 conditional knockout (intestinal epithelial), SERCA2 activity assay, ER Ca2+ measurement, mucin glycosylation analysis, germ-free/colonization models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying SERCA2 interaction, in vivo conditional KO with multiple mechanistic readouts (Ca2+ homeostasis, mucin glycosylation, barrier function), single lab but multiple orthogonal methods\",\n      \"pmids\": [\"41187059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FXYD3 directly interacts with IRF7 via its 60–87 amino acid domain, initiating a positive feedback loop through the cGAS/STING pathway amplified by type I interferon, resulting in sustained JAK2/STAT5 signaling activation that drives malignant progression of intrahepatic cholangiocarcinoma.\",\n      \"method\": \"Co-immunoprecipitation, single-cell sequencing, spatial transcriptomics, domain mapping, in vitro and in vivo functional assays, nano-delivery siRNA system\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP with domain mapping and in vivo validation, single lab, novel finding not yet replicated\",\n      \"pmids\": [\"41164952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Estrogen and tamoxifen upregulate FXYD3 expression in ERα-positive MCF-7 cells via ERα, but not in ERα-negative MDA-MB-231 cells, establishing ERα as required for this response. ERα associates with ZEB1 in MCF-7 cells, and siRNA knockdown of ZEB1 disrupts estrogen- (but not tamoxifen-) induced FXYD3 upregulation, indicating two distinct mechanisms both involving ERα, one requiring ZEB1.\",\n      \"method\": \"Flow cytometry (fluorochrome-tagged antibody), siRNA knockdown of ZEB1, comparison of ERα-positive vs ERα-negative cell lines\",\n      \"journal\": \"SpringerPlus\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — cell-based gene regulation assay with siRNA and ERα-negative controls, mechanistic dissection of two pathways, single lab\",\n      \"pmids\": [\"26090296\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FXYD3 is a small transmembrane protein that primarily functions as a tissue-specific regulator of Na,K-ATPase (decreasing apparent Na+ and K+ affinities and modulating pump activity), with two human isoforms adopting type I topology; it also interacts with SERCA2 to regulate ER Ca2+ homeostasis in goblet cells, engages in protein–protein interactions with Src/ERα (nongenomic estrogen signaling), TRAF3 (IL-17A/NF-κB/MAPK signaling in keratinocytes), and IRF7 (cGAS/STING-JAK2/STAT5 axis), facilitates cortical actin integrity, protects Na,K-ATPase from oxidative glutathionylation, and is transcriptionally regulated by TGF-β/Smad3/ZEB1 signaling and by CpG promoter methylation downstream of gluco-incretin signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FXYD3 (Mat-8) is a small single-pass transmembrane protein that functions primarily as a tissue-specific auxiliary subunit of P-type ATPases, tuning ion transport in epithelial cells [#1, #2, #12]. It associates physically and selectively with the Na,K-ATPase \\u03b1 subunit \\u2014 an interaction requiring Gly41 in its transmembrane domain for both complex formation and plasma membrane targeting \\u2014 and decreases the apparent Na+ and K+ affinities of the pump while modulating its turnover [#1, #2, #3, #5]. Two human splice isoforms (a short type I form and a long form with a 26-residue post-transmembrane insertion) exert distinct effects on pump ion affinities and both induce hyperpolarization-activated currents [#0, #2]. As a Na,K-ATPase regulator FXYD3 supports vectorial Na+ and liquid absorption at the basolateral membrane of airway epithelia [#12], is required for enterocyte differentiation and epithelial barrier integrity [#5], and protects the pump from oxidative inhibition by promoting reversal of \\u03b21 subunit glutathionylation [#10]. Beyond the Na,K-ATPase, FXYD3 interacts with the ER Ca2+-ATPase SERCA2 in intestinal goblet cells to enhance Ca2+ uptake, supporting mucin glycosylation and the mucus barrier [#14]. FXYD3 additionally participates in signaling complexes: it competitively binds TRAF3 to promote IL-17R\\u2013ACT1 assembly and NF-\\u03baB/MAPK activation in keratinocytes [#13], and forms a Src\\u2013ER\\u03b1 complex driving nongenomic estrogen signaling and tamoxifen resistance in breast cancer [#11]. Its expression is tightly controlled by TGF-\\u03b2/Smad3/ZEB1 repression [#8], CpG promoter methylation downstream of gluco-incretin signaling [#9], and induction by ER\\u03b1, IL-17A, and microbial short-chain fatty acids [#13, #14, #16].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established FXYD3 as an electrically active membrane protein, raising the first question of how a phospholemman-homologous protein influences transmembrane ion flux.\",\n      \"evidence\": \"Xenopus oocyte expression with electrophysiology and RNA blot\",\n      \"pmids\": [\"7836447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FXYD3 is a bona fide Cl- channel or a regulator of an endogenous current was not resolved\", \"No direct binding partner identified at this stage\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Reframed FXYD3 from a putative channel to a regulatory subunit of the Na,K-ATPase, showing it modifies pump ion affinities and \\u03b2-subunit glycosylation.\",\n      \"evidence\": \"Xenopus oocyte co-expression, electrophysiology, in situ tissue analysis, biochemical assays\",\n      \"pmids\": [\"15743908\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Topology (single vs double transmembrane) left ambiguous\", \"Physiological consequence of pump regulation in native tissue not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined two human splice isoforms with distinct topologies and showed both bind selectively to Na,K-ATPase but exert divergent effects on Na+/K+ affinity, explaining isoform-specific pump tuning.\",\n      \"evidence\": \"Co-IP, Xenopus oocyte co-expression, electrophysiology, CaCo-2 differentiation model\",\n      \"pmids\": [\"17077088\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional significance of the long-isoform-specific affinity changes in vivo unknown\", \"Selectivity for Na,K-ATPase over H,K-/Ca-ATPase mechanism not structurally defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Addressed where FXYD3 resides, finding intracellular ER/nuclear-envelope localization in CHO cells, hinting that surface targeting is context-dependent.\",\n      \"evidence\": \"DsRed tagging, density-gradient fractionation, organelle marker co-localization in CHO-K1\",\n      \"pmids\": [\"16132847\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell type tested\", \"Did not establish what controls ER retention versus plasma membrane delivery\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified Gly41 in the transmembrane domain as essential for both Na,K-ATPase association and plasma membrane targeting, mechanistically coupling complex assembly to trafficking.\",\n      \"evidence\": \"Reciprocal Co-IP, site-directed mutagenesis, fluorescent tagging in colorectal cancer and CHO cells\",\n      \"pmids\": [\"17409496\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, two orthogonal methods\", \"Why CHO cells retain FXYD3 intracellularly while cancer cells display it at the surface unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed FXYD3 is required for epithelial differentiation and barrier formation, linking its pump-regulatory role to a cellular phenotype.\",\n      \"evidence\": \"siRNA silencing, transepithelial resistance, differentiation markers, Na,K-ATPase activity assays in Caco-2\",\n      \"pmids\": [\"19109419\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal chain from pump regulation to apoptosis/differentiation not dissected\", \"Single cell model\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected FXYD3 to cytoskeletal organization, showing wild-type but not a point-mutant restores cortical actin, implying a sequence-dependent structural role.\",\n      \"evidence\": \"Forced expression of WT vs mutant FXYD3 in lung cancer cells, actin imaging\",\n      \"pmids\": [\"19893046\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking FXYD3 to actin (direct vs pump-mediated) unknown\", \"Single readout, single lab\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed that a bacterial effector (ExoS) hijacks the FXYD3 transmembrane domain, exploiting its Na,K-ATPase/barrier-regulating function for pathogen translocation.\",\n      \"evidence\": \"Bacterial two-hybrid screen, pulldown, colocalization\",\n      \"pmids\": [\"20805335\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic validation in mammalian cells limited\", \"Functional consequence on barrier inferred rather than directly demonstrated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Mapped upstream transcriptional control, showing TGF-\\u03b2 represses FXYD3 via Smad3 and the repressor ZEB1, while decoupling FXYD3 from EMT.\",\n      \"evidence\": \"siRNA, T\\u03b2RI/Smad3 inhibitors, ZEB1 knockdown, RT-PCR in MCF-10A\",\n      \"pmids\": [\"21372379\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ZEB1 binding to FXYD3 promoter not shown\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established epigenetic regulation of FXYD3 and a function in insulin secretion, placing FXYD3 downstream of Ca2+ influx in beta-cells and under CpG-methylation control.\",\n      \"evidence\": \"Beta-cell overexpression, insulin secretion assay, promoter methylation, H3K4me3 ChIP, reporter assay\",\n      \"pmids\": [\"25058609\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular step at which FXYD3 inhibits secretion downstream of Ca2+ not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed estrogen and tamoxifen induce FXYD3 through ER\\u03b1 via two routes (one ZEB1-dependent), linking hormone signaling to FXYD3 expression.\",\n      \"evidence\": \"Flow cytometry, ZEB1 siRNA, ER\\u03b1-positive vs -negative cell comparison\",\n      \"pmids\": [\"26090296\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect ER\\u03b1 transcriptional control not resolved\", \"Mechanism distinguishing estrogen and tamoxifen routes incomplete\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a protective role against oxidative pump inhibition, showing FXYD3 facilitates reversal of \\u03b21 subunit glutathionylation and modulates chemo/radiotherapy sensitivity.\",\n      \"evidence\": \"siRNA, Na,K-ATPase activity and glutathionylation assays, caspase 3/7 and viability assays in MCF-7\",\n      \"pmids\": [\"26740212\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biochemical mechanism of how FXYD3 promotes deglutathionylation unknown\", \"Cell-line-dependent effect (MCF-7 vs MDA-MB-468) unexplained\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended FXYD3 beyond ion transport into nongenomic estrogen signaling, identifying an FXYD3\\u2013Src\\u2013ER\\u03b1 complex and a SOX9 feedback loop driving tamoxifen resistance.\",\n      \"evidence\": \"Co-IP, SOX9 promoter binding, nuclear localization imaging, siRNA/overexpression in breast cancer stem cells\",\n      \"pmids\": [\"30206184\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs scaffolded interactions within the complex not distinguished\", \"How a membrane protein supports SOX9 nuclear localization unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Confirmed FXYD3 as a functional Na,K-ATPase \\u03b3 subunit in airway epithelia, mechanistically tying it to Na+ and liquid absorption physiology.\",\n      \"evidence\": \"scRNA-seq, IHC, siRNA, Ussing chamber short-circuit current, liquid absorption assays\",\n      \"pmids\": [\"35993520\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution relative to other FXYD subunits not quantified\", \"Role in airway disease not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Uncovered an immune-signaling function: FXYD3 competitively displaces TRAF3 to promote IL-17R\\u2013ACT1 assembly and NF-\\u03baB/MAPK activation, validated by KO rescue of psoriasis-like disease.\",\n      \"evidence\": \"Co-IP, conditional keratinocyte knockout, IMQ psoriasis model, NF-\\u03baB/MAPK assays\",\n      \"pmids\": [\"36693922\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same protein pool serves pump and IL-17 functions unknown\", \"Structural basis of TRAF3 competition undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified SERCA2 as a second P-type ATPase partner, showing FXYD3 enhances ER Ca2+ uptake to support goblet-cell mucin glycosylation and the mucus barrier.\",\n      \"evidence\": \"Co-IP, intestinal-epithelial conditional KO, SERCA2 activity and ER Ca2+ assays, mucin glycosylation analysis, germ-free/colonization models\",\n      \"pmids\": [\"41187059\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural determinants of SERCA2 vs Na,K-ATPase selectivity not defined\", \"Whether SERCA2 regulation generalizes beyond goblet cells unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mapped a domain-specific interaction with IRF7 linking FXYD3 to a cGAS/STING\\u2013JAK2/STAT5 feedback loop in cholangiocarcinoma progression.\",\n      \"evidence\": \"Co-IP, domain mapping, single-cell/spatial transcriptomics, in vivo siRNA nano-delivery\",\n      \"pmids\": [\"41164952\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, not independently replicated\", \"How a transmembrane protein engages the cytoplasmic IRF7 axis mechanistically unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single small transmembrane protein partitions among its multiple functional pools \\u2014 P-type ATPase regulation (Na,K-ATPase and SERCA2) versus scaffolding of signaling complexes (TRAF3, Src/ER\\u03b1, IRF7) \\u2014 and what structural features dictate partner selectivity and subcellular targeting.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of FXYD3 in complex with any partner\", \"Determinants of plasma membrane vs ER localization not defined\", \"Whether signaling functions require or are independent of ion-pump regulation untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 5, 12, 14]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [11, 13, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 12]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [4, 14]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [1, 2, 12]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [11, 15]}\n    ],\n    \"complexes\": [\n      \"Na,K-ATPase\",\n      \"IL-17R-ACT1 complex\",\n      \"FXYD3-Src-ERalpha complex\"\n    ],\n    \"partners\": [\n      \"ATP1A1\",\n      \"SERCA2\",\n      \"TRAF3\",\n      \"SRC\",\n      \"ESR1\",\n      \"IRF7\",\n      \"SOX9\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}