{"gene":"XIRP1","run_date":"2026-04-28T23:00:23","timeline":{"discoveries":[{"year":1999,"finding":"Chick Xin (cXin) is required for cardiac morphogenesis and looping; antisense knockdown causes thickened myocardium with abnormal invaginations. cXin expression is induced by BMP signaling downstream of Nkx2.5 and MEF2C transcription factors, and both MEF2C and Nkx2.5 can transactivate the mXin promoter.","method":"Antisense oligonucleotide knockdown in chick embryos; luciferase reporter assays; BMP explant induction; in situ hybridization; immunofluorescence","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function with specific morphological phenotype plus transcriptional pathway placement with reporter assays, replicated across multiple experimental approaches","pmids":["10021346"],"is_preprint":false},{"year":2002,"finding":"Mouse Xin (mXin) protein colocalizes with N-cadherin and β-catenin at intercalated discs throughout embryogenesis and adulthood, and is found associated with β-catenin within the N-cadherin complex in embryonic chick hearts by co-immunoprecipitation. Xin is a component of the adherens junction complex in cardiac muscle and the myotendon junction in skeletal muscle.","method":"Immunofluorescence of whole-mount mouse embryos and frozen sections; co-immunoprecipitation from embryonic chick hearts; immunostaining of C2C12 myotubes","journal":"Developmental dynamics : an official publication of the American Association of Anatomists","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP demonstrating complex membership plus direct localization with functional context","pmids":["12203715"],"is_preprint":false},{"year":2005,"finding":"mXinα (XIRP1) directly interacts with β-catenin; the Xin repeats bind to actin filaments and can organize microfilaments into networks. mXinα expression is regulated by Nkx2.5 and MEF2C transcription factors (drastically reduced in their knockout embryos).","method":"Actin-binding assay; β-catenin interaction assay; analysis of Nkx2.5 and MEF2C knockout mouse embryos by expression profiling","journal":"Journal of medical sciences (Taipei, Taiwan)","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct actin-binding and β-catenin interaction established; genetic epistasis from knockout mice; single review-style paper consolidating multiple experiments","pmids":["16708114"],"is_preprint":false},{"year":2006,"finding":"Human Xin (XIRP1/CMYA1) is a direct binding partner of filamin c at intercalated discs and myotendinous junctions. Xin also directly binds the EVH1 domain proteins Mena and VASP. Unusual intraexonic splicing produces three Xin isoforms that associate differentially with filamin c and Mena/VASP. The filamin c–Xin–Mena/VASP complex is identified at intercalated discs.","method":"Co-immunoprecipitation; direct binding assays; immunofluorescence colocalization; RT-PCR characterization of splice isoforms","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP and direct binding assays identifying novel binding partners with isoform specificity, Moderate evidence strength","pmids":["16631741"],"is_preprint":false},{"year":2006,"finding":"Myomaxin (mouse ortholog of CMYA3/XIRP2, a Xin-related protein) is a direct downstream transcriptional target of MEF2A and interacts with the sarcomeric Z-disc protein alpha-actinin-2, localizing to the Z-disc/costameric region in striated muscle.","method":"mef2a knockout mice expression analysis; promoter reporter assays; co-immunoprecipitation; immunofluorescence","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis (MEF2A KO) plus direct interaction assay; note this describes XIRP2 ortholog (myomaxin/CMYA3), not XIRP1 itself","pmids":["17046827"],"is_preprint":false},{"year":2007,"finding":"Xin mRNA is robustly upregulated (>16-fold) within 12 h of skeletal muscle injury and is localized to muscle satellite cells. Reducing Xin expression via shRNA in C2C12 myoblasts increases proliferation by 26% and migration by 20%, demonstrating a role for Xin in regulating myoblast function.","method":"RT-PCR; immunohistochemistry of single myofibers; shRNA knockdown in C2C12 cells; proliferation and migration assays; promoter-reporter assays with MEF2, MyoD, Myf-5","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 2 — shRNA loss-of-function with specific quantitative phenotypic readouts in satellite cells and myoblasts, multiple orthogonal methods","pmids":["17855775"],"is_preprint":false},{"year":2008,"finding":"Xin proteins (mXinα and mXinβ) are able to bundle actin filaments and interact with β-catenin. All vertebrate Xins contain a conserved β-catenin-binding domain within the Xin repeat region. The Mena/VASP-binding domain is a derived trait found only in Xinα from placental mammals. Phylogenetic analysis places the origin of Xin at ~550 million years ago, coinciding with the emergence of chambered hearts.","method":"Phylogenetic analysis of 40 vertebrate Xins; actin-bundling assay; immunofluorescence colocalization with β-catenin in multiple vertebrate species","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 — actin-bundling and β-catenin interaction validated across species; domain conservation established by sequence analysis plus functional colocalization","pmids":["18682726"],"is_preprint":false},{"year":2009,"finding":"Complete loss of all murine Xin isoforms (XinABC−/−) leads to topographical alterations of intercalated disc (ID) localization in isolated cardiomyocytes, with a significantly increased number of non-terminally localized ID-like structures, altered sarcomere length and shortening parameters, and faster conduction velocity. XinC isoform is detected solely in human cardiac hypertrophy samples, suggesting it contributes to the stronger phenotype seen in XinAB−/− mice.","method":"Generation of XinABC−/− knockout mice; cardiomyocyte isolation; sarcomere length and contractility measurements; ECG; immunofluorescence; human cardiac tissue immunostaining","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 — genetic loss-of-function with multiple orthogonal functional readouts (contractility, electrophysiology, structural imaging) in a defined knockout model","pmids":["19843512"],"is_preprint":false},{"year":2011,"finding":"Reduction of Xin expression by shRNA adenovirus in mouse tibialis anterior muscle attenuates satellite cell (SC) activation after cardiotoxin injury, without affecting SC proliferation or G0-G1 cell cycle reentry, demonstrating a specific role for Xin in SC activation during skeletal muscle repair.","method":"In vivo shRNA adenoviral knockdown; single myofiber isolation; immunostaining for MyoD and Syndecan-4; cardiotoxin injury model; Myh3 expression and fiber area measurement; methylcellulose cell cycle reentry assay","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 2 — in vivo loss-of-function with specific SC activation phenotype distinguished from proliferation, multiple orthogonal readouts","pmids":["21975424"],"is_preprint":false},{"year":2012,"finding":"mXinβ (XIRP2) but not mXinα (XIRP1) is uniquely upregulated during postnatal redistribution of intercellular junctions from lateral membranes to cardiomyocyte termini. Loss of mXinβ causes failure of this junction redistribution at postnatal day 16.5, with mXinβ preferentially associating with forming ICDs by immunofluorescence and subcellular fractionation. mXinα is not essential for postnatal ICD formation.","method":"Quantitative Western blot; immunofluorescence; subcellular fractionation; mXinβ knockout mice; mXinα/mXinβ double knockout hearts","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — genetic loss-of-function with temporal correlation of expression and ICD formation, subcellular fractionation confirming localization, double-KO epistasis","pmids":["23261932"],"is_preprint":false},{"year":2014,"finding":"mXinα (XIRP1) acts as a scaffolding protein at ICDs, interacting with three classes of proteins: catenins (β-catenin), actin regulators/modulators, and ion-channel subunits. mXinα-null mice develop late-onset cardiomyopathy with conduction defects; mXinβ is upregulated in mXinα-null hearts, suggesting partial compensation. Xin expression is upregulated in early stressed hearts but downregulated in failing human hearts.","method":"mXinα knockout mouse model; co-immunoprecipitation for interacting protein classes; cardiac function and conduction assessment; human cardiomyopathy tissue analysis","journal":"International review of cell and molecular biology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO model with defined cardiac phenotype, multiple interaction classes established by Co-IP, replicated across labs as reviewed","pmids":["24725425"],"is_preprint":false},{"year":2015,"finding":"Xin-deficient (Xin−/−) mice exhibit generalized skeletal muscle myopathy, increased fatigability with decreased force recovery, impaired muscle regeneration, more activated satellite cells that fail to proliferate normally (approx. 50% reduction in proliferative capacity), and increased apoptotic satellite cells, demonstrating that Xin is required for normal satellite cell function and muscle maintenance.","method":"Xin−/− knockout mice; histological and immunofluorescent staining; in situ muscle stimulation for force measurements; cardiotoxin injury; TUNEL staining for apoptosis; MyoD immunostaining; primary myoblast cultures","journal":"Acta physiologica (Oxford, England)","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with multiple orthogonal functional and cellular phenotypic readouts across muscle physiology and satellite cell biology","pmids":["25582411"],"is_preprint":false},{"year":2015,"finding":"A short splice form of XIRP2 (lacking Xin repeats) is expressed in inner ear hair cells and is required for maintenance of stereocilia morphology; XIRP2-null mice (generated by CRISPR/Cas9) show high-frequency hearing loss and stereocilia degeneration.","method":"Mass spectrometry proteomics of hair bundle; CRISPR/Cas9-mediated knockout mice; auditory brainstem response testing; scanning electron microscopy of stereocilia","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 1-2 — CRISPR KO with specific functional (hearing) and ultrastructural phenotype; mass spectrometry identification of splice variant; note this is XIRP2 not XIRP1","pmids":["25653358"],"is_preprint":false},{"year":2020,"finding":"XIRP1 interacts with heart disease-associated transmembrane proteins POPDC1 and POPDC2 in human skeletal myotubes and adult rat heart. The interaction was identified by pull-down proteomic analysis and confirmed by co-immunoprecipitation from adult rat heart extracts. XIRP1 and POPDC1/2 co-localize at intercalated discs and T-tubules in adult rat and human heart.","method":"Pull-down with bead-coupled POPDC1/2 followed by mass spectrometry proteomics; co-immunoprecipitation from adult rat heart; immunofluorescence with monoclonal antibodies; adult human skeletal muscle immunostaining","journal":"BMC molecular and cell biology","confidence":"High","confidence_rationale":"Tier 2 — interaction identified by unbiased proteomics and confirmed by reciprocal Co-IP from native cardiac tissue; colocalization by immunofluorescence; mutations in all three genes cause arrhythmias providing functional context","pmids":["33261556"],"is_preprint":false},{"year":2012,"finding":"Assessment of Cmya1-EST (embryonic stem cell test using luciferase reporter driven by Cmya1 promoter) shows that Cmya1 expression in ES cells is a reliable marker of cardiac differentiation toxicity, demonstrating that Cmya1/XIRP1 promoter activity is induced during cardiomyocyte differentiation from ES cells.","method":"Luciferase reporter gene assay in genetically engineered mouse ES cells; cross-laboratory reproducibility assessment with embryotoxic chemicals","journal":"The Journal of toxicological sciences","confidence":"Low","confidence_rationale":"Tier 3 — promoter-reporter assay demonstrating XIRP1 promoter activity during cardiac differentiation; indirect functional inference only","pmids":["22863864"],"is_preprint":false}],"current_model":"XIRP1 (mXinα) is a striated muscle-specific F-actin-binding and -bundling scaffolding protein that localizes to intercalated discs (ICDs) in cardiomyocytes and myotendinous junctions in skeletal muscle, where it forms a complex with N-cadherin/β-catenin (via direct β-catenin interaction), filamin c, and Mena/VASP to link the actin cytoskeleton to cell-cell adhesion; it also interacts with ion-channel subunits and the transmembrane proteins POPDC1/2, and is required for normal ICD stability, adult cardiac function (its loss causes late-onset cardiomyopathy with conduction defects), satellite cell activation during skeletal muscle regeneration, and normal muscle contractility."},"narrative":{"teleology":[{"year":1999,"claim":"Establishing that Xin is required for cardiac morphogenesis answered whether this novel gene had a developmental role, placing it downstream of BMP/Nkx2.5/MEF2C signaling in heart formation.","evidence":"Antisense oligonucleotide knockdown in chick embryos causing abnormal cardiac looping; promoter-reporter assays showing MEF2C and Nkx2.5 transactivation","pmids":["10021346"],"confidence":"High","gaps":["Mechanism by which Xin loss causes thickened myocardium not resolved","Downstream effectors of Xin during cardiac looping unknown","No mammalian loss-of-function at this stage"]},{"year":2002,"claim":"Demonstrating that Xin colocalizes with and co-immunoprecipitates with N-cadherin/β-catenin at intercalated discs established its identity as an adherens junction-associated protein in cardiac muscle.","evidence":"Co-immunoprecipitation from embryonic chick hearts; immunofluorescence of mouse embryonic and adult hearts and C2C12 myotubes","pmids":["12203715"],"confidence":"High","gaps":["Whether Xin binds β-catenin directly or through intermediary not yet resolved","Functional consequence of the interaction not tested"]},{"year":2006,"claim":"Identification of filamin c and Mena/VASP as direct binding partners of XIRP1, together with discovery of splice isoform-specific interactions, revealed XIRP1 as a multiprotein scaffold linking actin regulators at intercalated discs.","evidence":"Direct binding assays and co-immunoprecipitation; RT-PCR characterization of three human XIRP1 splice isoforms","pmids":["16631741"],"confidence":"High","gaps":["Functional significance of differential isoform-binding specificity not tested in vivo","No structural model of the filamin c–Xin–Mena/VASP complex"]},{"year":2008,"claim":"Demonstrating that Xin repeat regions directly bind β-catenin and bundle actin filaments across vertebrate species established these as ancestral, conserved molecular activities, while Mena/VASP binding was identified as a mammalian-derived feature.","evidence":"Phylogenetic analysis of 40 vertebrate Xin sequences; in vitro actin-bundling assays; colocalization across species","pmids":["18682726"],"confidence":"Medium","gaps":["Actin-bundling activity not demonstrated in a cellular context","No structure of Xin repeat–actin or Xin repeat–β-catenin interfaces"]},{"year":2009,"claim":"Complete loss of all murine Xin isoforms showed that Xin proteins maintain normal intercalated disc topology and sarcomere function, as knockout cardiomyocytes displayed mislocalized ICD structures and altered contractility.","evidence":"XinABC−/− knockout mice; cardiomyocyte isolation with sarcomere length, contractility, and conduction velocity measurements","pmids":["19843512"],"confidence":"High","gaps":["Individual contributions of Xinα versus Xinβ to phenotype not fully disentangled at this point","Molecular mechanism of ICD disorganization unknown"]},{"year":2012,"claim":"Demonstrating that mXinβ (XIRP2), not mXinα (XIRP1), is essential for postnatal junction redistribution to cardiomyocyte termini clarified the division of labor between the two paralogs at intercalated discs.","evidence":"mXinβ knockout and mXinα/β double-knockout mice; quantitative Western blot and subcellular fractionation at postnatal day 16.5","pmids":["23261932"],"confidence":"High","gaps":["Whether mXinα has any non-redundant role at ICDs during postnatal maturation unclear","Mechanism by which mXinβ drives junction redistribution not identified"]},{"year":2014,"claim":"The mXinα-null mouse developing late-onset cardiomyopathy with conduction defects established that XIRP1 is required for adult cardiac function and acts as a scaffold for catenins, actin regulators, and ion-channel subunits, with mXinβ providing partial compensation.","evidence":"mXinα knockout mouse model; co-immunoprecipitation identifying three interaction classes; cardiac functional assessment; human cardiomyopathy tissue analysis","pmids":["24725425"],"confidence":"High","gaps":["Specific ion-channel subunits interacting with XIRP1 not fully catalogued","Whether human XIRP1 mutations cause cardiomyopathy not directly shown","Mechanism by which XIRP1 loss leads to conduction defects unresolved"]},{"year":2015,"claim":"Xin-null mice exhibiting skeletal myopathy, increased fatigability, impaired regeneration, and satellite cell dysfunction demonstrated that XIRP1 is essential not only in the heart but broadly in skeletal muscle maintenance and repair.","evidence":"Xin−/− knockout mice; in situ muscle force measurement; cardiotoxin injury with satellite cell quantification; TUNEL apoptosis assay; primary myoblast cultures","pmids":["25582411"],"confidence":"High","gaps":["Molecular mechanism linking XIRP1 to satellite cell survival and proliferation unknown","Whether myopathy is cell-autonomous to satellite cells or involves other compartments untested"]},{"year":2020,"claim":"Identification of POPDC1 and POPDC2 as XIRP1 interaction partners at intercalated discs and T-tubules connected XIRP1 to cAMP-regulated transmembrane signaling associated with cardiac arrhythmias.","evidence":"Unbiased pull-down proteomics from human skeletal myotubes; reciprocal co-immunoprecipitation from adult rat heart; immunofluorescence colocalization","pmids":["33261556"],"confidence":"High","gaps":["Functional consequence of XIRP1–POPDC interaction not tested","Whether XIRP1 regulates POPDC membrane localization or signaling unknown","No genetic epistasis between XIRP1 and POPDC mutants"]},{"year":null,"claim":"The molecular mechanism by which XIRP1 scaffolding at intercalated discs translates into normal electrical conduction and contractile function remains unresolved, and whether human XIRP1 mutations directly cause cardiomyopathy or skeletal myopathy has not been established by family studies or rescue experiments.","evidence":"","pmids":[],"confidence":"High","gaps":["No causative human XIRP1 mutations identified through genetic studies","No structural model of XIRP1 or its Xin repeat domain","Mechanism of XIRP1-dependent satellite cell activation unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,3,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,10,13]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,3,7,10,13]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2,6]}],"pathway":[{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[1,3,10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,9]},{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[7,11]}],"complexes":["N-cadherin/β-catenin adherens junction complex","Filamin c–XIRP1–Mena/VASP complex"],"partners":["CTNNB1","FLNC","ENAH","VASP","POPDC1","POPDC2","XIRP2"],"other_free_text":[]},"mechanistic_narrative":"XIRP1 (mXinα/CMYA1) is a striated muscle-specific actin-binding and -bundling scaffolding protein that links the actin cytoskeleton to cell–cell adhesion complexes at intercalated discs in cardiomyocytes and myotendinous junctions in skeletal muscle. Through its conserved Xin repeat region, XIRP1 directly binds and bundles F-actin and interacts with β-catenin within the N-cadherin adherens junction complex, while also binding filamin c and the EVH1-domain proteins Mena/VASP to coordinate cytoskeletal remodeling at cell junctions [PMID:12203715, PMID:16631741, PMID:18682726]. XIRP1 additionally interacts with ion-channel subunits and the transmembrane proteins POPDC1/POPDC2 at intercalated discs, and its loss in mice causes late-onset cardiomyopathy with conduction defects, generalized skeletal myopathy with increased fatigability, and impaired satellite cell activation and proliferation during muscle regeneration [PMID:24725425, PMID:25582411, PMID:33261556]. Its transcription is regulated by the cardiac transcription factors Nkx2.5 and MEF2C, and it is required for normal cardiac morphogenesis and looping during embryonic development [PMID:10021346]."},"prefetch_data":{"uniprot":{"accession":"Q702N8","full_name":"Xin actin-binding repeat-containing protein 1","aliases":["Cardiomyopathy-associated protein 1"],"length_aa":1843,"mass_kda":198.6,"function":"Protects actin filaments from depolymerization (PubMed:15454575). Required for correct cardiac intercalated disk ultrastructure via maintenance of cell-cell adhesion stability, and as a result maintains cardiac organ morphology, conductance and heart beat rhythm (By similarity). Required for development of normal skeletal muscle morphology and muscle fiber type composition (By similarity). Plays a role in regulating muscle satellite cell activation and survival, as a result promotes muscle fiber recovery from injury and fatigue (By similarity)","subcellular_location":"Cell junction, adherens junction; Cell junction, desmosome","url":"https://www.uniprot.org/uniprotkb/Q702N8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/XIRP1","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/XIRP1","total_profiled":1310},"omim":[{"mim_id":"620775","title":"NEUROMUSCULAR DISORDER, CONGENITAL, WITH DYSMORPHIC FACIES; NMDF","url":"https://www.omim.org/entry/620775"},{"mim_id":"609777","title":"XIN ACTIN-BINDING REPEAT-CONTAINING PROTEIN 1; XIRP1","url":"https://www.omim.org/entry/609777"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Actin filaments","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"heart muscle","ntpm":602.7},{"tissue":"skeletal muscle","ntpm":376.1}],"url":"https://www.proteinatlas.org/search/XIRP1"},"hgnc":{"alias_symbol":["DKFZp451D042","Xin"],"prev_symbol":["CMYA1"]},"alphafold":{"accession":"Q702N8","domains":[{"cath_id":"-","chopping":"771-917","consensus_level":"high","plddt":79.2347,"start":771,"end":917}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q702N8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q702N8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q702N8-F1-predicted_aligned_error_v6.png","plddt_mean":43.66},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=XIRP1","jax_strain_url":"https://www.jax.org/strain/search?query=XIRP1"},"sequence":{"accession":"Q702N8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q702N8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q702N8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q702N8"}},"corpus_meta":[{"pmid":"26822146","id":"PMC_26822146","title":"Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer's disease.","date":"2016","source":"Alzheimer's research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/26822146","citation_count":161,"is_preprint":false},{"pmid":"26896572","id":"PMC_26896572","title":"Metabolomics approach to explore the effects of Kai-Xin-San on Alzheimer's disease using UPLC/ESI-Q-TOF mass spectrometry.","date":"2016","source":"Journal of chromatography. 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hypertensive rats by enhancing PPAR-gamma expression and suppressing NF-kappaB activity.","date":"2008","source":"Chinese medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/18272042","citation_count":11,"is_preprint":false},{"pmid":"29312939","id":"PMC_29312939","title":"A Modified Chinese Herbal Decoction (Kai-Xin-San) Promotes NGF-Induced Neuronal Differentiation in PC12 Cells via Up-Regulating Trk A Signaling.","date":"2017","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/29312939","citation_count":11,"is_preprint":false},{"pmid":"37454749","id":"PMC_37454749","title":"Yang-Xin-Shu-Mai granule alleviates atherosclerosis by regulating macrophage polarization via the TLR9/MyD88/NF-κB signaling pathway.","date":"2023","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37454749","citation_count":10,"is_preprint":false},{"pmid":"33261556","id":"PMC_33261556","title":"An interaction of heart disease-associated proteins POPDC1/2 with XIRP1 in transverse tubules and intercalated discs.","date":"2020","source":"BMC molecular and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/33261556","citation_count":10,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":63270,"output_tokens":4097,"usd":0.125633},"stage2":{"model":"claude-opus-4-6","input_tokens":7666,"output_tokens":2654,"usd":0.15702},"total_usd":0.282653,"stage1_batch_id":"msgbatch_01BparvgRZ9S2LMidvaoo86K","stage2_batch_id":"msgbatch_01NkBfv9SVZWthhS7j6mU6G3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"Chick Xin (cXin) is required for cardiac morphogenesis and looping; antisense knockdown causes thickened myocardium with abnormal invaginations. cXin expression is induced by BMP signaling downstream of Nkx2.5 and MEF2C transcription factors, and both MEF2C and Nkx2.5 can transactivate the mXin promoter.\",\n      \"method\": \"Antisense oligonucleotide knockdown in chick embryos; luciferase reporter assays; BMP explant induction; in situ hybridization; immunofluorescence\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific morphological phenotype plus transcriptional pathway placement with reporter assays, replicated across multiple experimental approaches\",\n      \"pmids\": [\"10021346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Mouse Xin (mXin) protein colocalizes with N-cadherin and β-catenin at intercalated discs throughout embryogenesis and adulthood, and is found associated with β-catenin within the N-cadherin complex in embryonic chick hearts by co-immunoprecipitation. Xin is a component of the adherens junction complex in cardiac muscle and the myotendon junction in skeletal muscle.\",\n      \"method\": \"Immunofluorescence of whole-mount mouse embryos and frozen sections; co-immunoprecipitation from embryonic chick hearts; immunostaining of C2C12 myotubes\",\n      \"journal\": \"Developmental dynamics : an official publication of the American Association of Anatomists\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP demonstrating complex membership plus direct localization with functional context\",\n      \"pmids\": [\"12203715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"mXinα (XIRP1) directly interacts with β-catenin; the Xin repeats bind to actin filaments and can organize microfilaments into networks. mXinα expression is regulated by Nkx2.5 and MEF2C transcription factors (drastically reduced in their knockout embryos).\",\n      \"method\": \"Actin-binding assay; β-catenin interaction assay; analysis of Nkx2.5 and MEF2C knockout mouse embryos by expression profiling\",\n      \"journal\": \"Journal of medical sciences (Taipei, Taiwan)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct actin-binding and β-catenin interaction established; genetic epistasis from knockout mice; single review-style paper consolidating multiple experiments\",\n      \"pmids\": [\"16708114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Human Xin (XIRP1/CMYA1) is a direct binding partner of filamin c at intercalated discs and myotendinous junctions. Xin also directly binds the EVH1 domain proteins Mena and VASP. Unusual intraexonic splicing produces three Xin isoforms that associate differentially with filamin c and Mena/VASP. The filamin c–Xin–Mena/VASP complex is identified at intercalated discs.\",\n      \"method\": \"Co-immunoprecipitation; direct binding assays; immunofluorescence colocalization; RT-PCR characterization of splice isoforms\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and direct binding assays identifying novel binding partners with isoform specificity, Moderate evidence strength\",\n      \"pmids\": [\"16631741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Myomaxin (mouse ortholog of CMYA3/XIRP2, a Xin-related protein) is a direct downstream transcriptional target of MEF2A and interacts with the sarcomeric Z-disc protein alpha-actinin-2, localizing to the Z-disc/costameric region in striated muscle.\",\n      \"method\": \"mef2a knockout mice expression analysis; promoter reporter assays; co-immunoprecipitation; immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (MEF2A KO) plus direct interaction assay; note this describes XIRP2 ortholog (myomaxin/CMYA3), not XIRP1 itself\",\n      \"pmids\": [\"17046827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Xin mRNA is robustly upregulated (>16-fold) within 12 h of skeletal muscle injury and is localized to muscle satellite cells. Reducing Xin expression via shRNA in C2C12 myoblasts increases proliferation by 26% and migration by 20%, demonstrating a role for Xin in regulating myoblast function.\",\n      \"method\": \"RT-PCR; immunohistochemistry of single myofibers; shRNA knockdown in C2C12 cells; proliferation and migration assays; promoter-reporter assays with MEF2, MyoD, Myf-5\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — shRNA loss-of-function with specific quantitative phenotypic readouts in satellite cells and myoblasts, multiple orthogonal methods\",\n      \"pmids\": [\"17855775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Xin proteins (mXinα and mXinβ) are able to bundle actin filaments and interact with β-catenin. All vertebrate Xins contain a conserved β-catenin-binding domain within the Xin repeat region. The Mena/VASP-binding domain is a derived trait found only in Xinα from placental mammals. Phylogenetic analysis places the origin of Xin at ~550 million years ago, coinciding with the emergence of chambered hearts.\",\n      \"method\": \"Phylogenetic analysis of 40 vertebrate Xins; actin-bundling assay; immunofluorescence colocalization with β-catenin in multiple vertebrate species\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — actin-bundling and β-catenin interaction validated across species; domain conservation established by sequence analysis plus functional colocalization\",\n      \"pmids\": [\"18682726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Complete loss of all murine Xin isoforms (XinABC−/−) leads to topographical alterations of intercalated disc (ID) localization in isolated cardiomyocytes, with a significantly increased number of non-terminally localized ID-like structures, altered sarcomere length and shortening parameters, and faster conduction velocity. XinC isoform is detected solely in human cardiac hypertrophy samples, suggesting it contributes to the stronger phenotype seen in XinAB−/− mice.\",\n      \"method\": \"Generation of XinABC−/− knockout mice; cardiomyocyte isolation; sarcomere length and contractility measurements; ECG; immunofluorescence; human cardiac tissue immunostaining\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with multiple orthogonal functional readouts (contractility, electrophysiology, structural imaging) in a defined knockout model\",\n      \"pmids\": [\"19843512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Reduction of Xin expression by shRNA adenovirus in mouse tibialis anterior muscle attenuates satellite cell (SC) activation after cardiotoxin injury, without affecting SC proliferation or G0-G1 cell cycle reentry, demonstrating a specific role for Xin in SC activation during skeletal muscle repair.\",\n      \"method\": \"In vivo shRNA adenoviral knockdown; single myofiber isolation; immunostaining for MyoD and Syndecan-4; cardiotoxin injury model; Myh3 expression and fiber area measurement; methylcellulose cell cycle reentry assay\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo loss-of-function with specific SC activation phenotype distinguished from proliferation, multiple orthogonal readouts\",\n      \"pmids\": [\"21975424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"mXinβ (XIRP2) but not mXinα (XIRP1) is uniquely upregulated during postnatal redistribution of intercellular junctions from lateral membranes to cardiomyocyte termini. Loss of mXinβ causes failure of this junction redistribution at postnatal day 16.5, with mXinβ preferentially associating with forming ICDs by immunofluorescence and subcellular fractionation. mXinα is not essential for postnatal ICD formation.\",\n      \"method\": \"Quantitative Western blot; immunofluorescence; subcellular fractionation; mXinβ knockout mice; mXinα/mXinβ double knockout hearts\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with temporal correlation of expression and ICD formation, subcellular fractionation confirming localization, double-KO epistasis\",\n      \"pmids\": [\"23261932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"mXinα (XIRP1) acts as a scaffolding protein at ICDs, interacting with three classes of proteins: catenins (β-catenin), actin regulators/modulators, and ion-channel subunits. mXinα-null mice develop late-onset cardiomyopathy with conduction defects; mXinβ is upregulated in mXinα-null hearts, suggesting partial compensation. Xin expression is upregulated in early stressed hearts but downregulated in failing human hearts.\",\n      \"method\": \"mXinα knockout mouse model; co-immunoprecipitation for interacting protein classes; cardiac function and conduction assessment; human cardiomyopathy tissue analysis\",\n      \"journal\": \"International review of cell and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO model with defined cardiac phenotype, multiple interaction classes established by Co-IP, replicated across labs as reviewed\",\n      \"pmids\": [\"24725425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Xin-deficient (Xin−/−) mice exhibit generalized skeletal muscle myopathy, increased fatigability with decreased force recovery, impaired muscle regeneration, more activated satellite cells that fail to proliferate normally (approx. 50% reduction in proliferative capacity), and increased apoptotic satellite cells, demonstrating that Xin is required for normal satellite cell function and muscle maintenance.\",\n      \"method\": \"Xin−/− knockout mice; histological and immunofluorescent staining; in situ muscle stimulation for force measurements; cardiotoxin injury; TUNEL staining for apoptosis; MyoD immunostaining; primary myoblast cultures\",\n      \"journal\": \"Acta physiologica (Oxford, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with multiple orthogonal functional and cellular phenotypic readouts across muscle physiology and satellite cell biology\",\n      \"pmids\": [\"25582411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A short splice form of XIRP2 (lacking Xin repeats) is expressed in inner ear hair cells and is required for maintenance of stereocilia morphology; XIRP2-null mice (generated by CRISPR/Cas9) show high-frequency hearing loss and stereocilia degeneration.\",\n      \"method\": \"Mass spectrometry proteomics of hair bundle; CRISPR/Cas9-mediated knockout mice; auditory brainstem response testing; scanning electron microscopy of stereocilia\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — CRISPR KO with specific functional (hearing) and ultrastructural phenotype; mass spectrometry identification of splice variant; note this is XIRP2 not XIRP1\",\n      \"pmids\": [\"25653358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"XIRP1 interacts with heart disease-associated transmembrane proteins POPDC1 and POPDC2 in human skeletal myotubes and adult rat heart. The interaction was identified by pull-down proteomic analysis and confirmed by co-immunoprecipitation from adult rat heart extracts. XIRP1 and POPDC1/2 co-localize at intercalated discs and T-tubules in adult rat and human heart.\",\n      \"method\": \"Pull-down with bead-coupled POPDC1/2 followed by mass spectrometry proteomics; co-immunoprecipitation from adult rat heart; immunofluorescence with monoclonal antibodies; adult human skeletal muscle immunostaining\",\n      \"journal\": \"BMC molecular and cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — interaction identified by unbiased proteomics and confirmed by reciprocal Co-IP from native cardiac tissue; colocalization by immunofluorescence; mutations in all three genes cause arrhythmias providing functional context\",\n      \"pmids\": [\"33261556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Assessment of Cmya1-EST (embryonic stem cell test using luciferase reporter driven by Cmya1 promoter) shows that Cmya1 expression in ES cells is a reliable marker of cardiac differentiation toxicity, demonstrating that Cmya1/XIRP1 promoter activity is induced during cardiomyocyte differentiation from ES cells.\",\n      \"method\": \"Luciferase reporter gene assay in genetically engineered mouse ES cells; cross-laboratory reproducibility assessment with embryotoxic chemicals\",\n      \"journal\": \"The Journal of toxicological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — promoter-reporter assay demonstrating XIRP1 promoter activity during cardiac differentiation; indirect functional inference only\",\n      \"pmids\": [\"22863864\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"XIRP1 (mXinα) is a striated muscle-specific F-actin-binding and -bundling scaffolding protein that localizes to intercalated discs (ICDs) in cardiomyocytes and myotendinous junctions in skeletal muscle, where it forms a complex with N-cadherin/β-catenin (via direct β-catenin interaction), filamin c, and Mena/VASP to link the actin cytoskeleton to cell-cell adhesion; it also interacts with ion-channel subunits and the transmembrane proteins POPDC1/2, and is required for normal ICD stability, adult cardiac function (its loss causes late-onset cardiomyopathy with conduction defects), satellite cell activation during skeletal muscle regeneration, and normal muscle contractility.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"XIRP1 (mXinα/CMYA1) is a striated muscle-specific actin-binding and -bundling scaffolding protein that links the actin cytoskeleton to cell–cell adhesion complexes at intercalated discs in cardiomyocytes and myotendinous junctions in skeletal muscle. Through its conserved Xin repeat region, XIRP1 directly binds and bundles F-actin and interacts with β-catenin within the N-cadherin adherens junction complex, while also binding filamin c and the EVH1-domain proteins Mena/VASP to coordinate cytoskeletal remodeling at cell junctions [PMID:12203715, PMID:16631741, PMID:18682726]. XIRP1 additionally interacts with ion-channel subunits and the transmembrane proteins POPDC1/POPDC2 at intercalated discs, and its loss in mice causes late-onset cardiomyopathy with conduction defects, generalized skeletal myopathy with increased fatigability, and impaired satellite cell activation and proliferation during muscle regeneration [PMID:24725425, PMID:25582411, PMID:33261556]. Its transcription is regulated by the cardiac transcription factors Nkx2.5 and MEF2C, and it is required for normal cardiac morphogenesis and looping during embryonic development [PMID:10021346].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing that Xin is required for cardiac morphogenesis answered whether this novel gene had a developmental role, placing it downstream of BMP/Nkx2.5/MEF2C signaling in heart formation.\",\n      \"evidence\": \"Antisense oligonucleotide knockdown in chick embryos causing abnormal cardiac looping; promoter-reporter assays showing MEF2C and Nkx2.5 transactivation\",\n      \"pmids\": [\"10021346\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Xin loss causes thickened myocardium not resolved\", \"Downstream effectors of Xin during cardiac looping unknown\", \"No mammalian loss-of-function at this stage\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrating that Xin colocalizes with and co-immunoprecipitates with N-cadherin/β-catenin at intercalated discs established its identity as an adherens junction-associated protein in cardiac muscle.\",\n      \"evidence\": \"Co-immunoprecipitation from embryonic chick hearts; immunofluorescence of mouse embryonic and adult hearts and C2C12 myotubes\",\n      \"pmids\": [\"12203715\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Xin binds β-catenin directly or through intermediary not yet resolved\", \"Functional consequence of the interaction not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of filamin c and Mena/VASP as direct binding partners of XIRP1, together with discovery of splice isoform-specific interactions, revealed XIRP1 as a multiprotein scaffold linking actin regulators at intercalated discs.\",\n      \"evidence\": \"Direct binding assays and co-immunoprecipitation; RT-PCR characterization of three human XIRP1 splice isoforms\",\n      \"pmids\": [\"16631741\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional significance of differential isoform-binding specificity not tested in vivo\", \"No structural model of the filamin c–Xin–Mena/VASP complex\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating that Xin repeat regions directly bind β-catenin and bundle actin filaments across vertebrate species established these as ancestral, conserved molecular activities, while Mena/VASP binding was identified as a mammalian-derived feature.\",\n      \"evidence\": \"Phylogenetic analysis of 40 vertebrate Xin sequences; in vitro actin-bundling assays; colocalization across species\",\n      \"pmids\": [\"18682726\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Actin-bundling activity not demonstrated in a cellular context\", \"No structure of Xin repeat–actin or Xin repeat–β-catenin interfaces\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Complete loss of all murine Xin isoforms showed that Xin proteins maintain normal intercalated disc topology and sarcomere function, as knockout cardiomyocytes displayed mislocalized ICD structures and altered contractility.\",\n      \"evidence\": \"XinABC−/− knockout mice; cardiomyocyte isolation with sarcomere length, contractility, and conduction velocity measurements\",\n      \"pmids\": [\"19843512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Individual contributions of Xinα versus Xinβ to phenotype not fully disentangled at this point\", \"Molecular mechanism of ICD disorganization unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating that mXinβ (XIRP2), not mXinα (XIRP1), is essential for postnatal junction redistribution to cardiomyocyte termini clarified the division of labor between the two paralogs at intercalated discs.\",\n      \"evidence\": \"mXinβ knockout and mXinα/β double-knockout mice; quantitative Western blot and subcellular fractionation at postnatal day 16.5\",\n      \"pmids\": [\"23261932\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mXinα has any non-redundant role at ICDs during postnatal maturation unclear\", \"Mechanism by which mXinβ drives junction redistribution not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The mXinα-null mouse developing late-onset cardiomyopathy with conduction defects established that XIRP1 is required for adult cardiac function and acts as a scaffold for catenins, actin regulators, and ion-channel subunits, with mXinβ providing partial compensation.\",\n      \"evidence\": \"mXinα knockout mouse model; co-immunoprecipitation identifying three interaction classes; cardiac functional assessment; human cardiomyopathy tissue analysis\",\n      \"pmids\": [\"24725425\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific ion-channel subunits interacting with XIRP1 not fully catalogued\", \"Whether human XIRP1 mutations cause cardiomyopathy not directly shown\", \"Mechanism by which XIRP1 loss leads to conduction defects unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Xin-null mice exhibiting skeletal myopathy, increased fatigability, impaired regeneration, and satellite cell dysfunction demonstrated that XIRP1 is essential not only in the heart but broadly in skeletal muscle maintenance and repair.\",\n      \"evidence\": \"Xin−/− knockout mice; in situ muscle force measurement; cardiotoxin injury with satellite cell quantification; TUNEL apoptosis assay; primary myoblast cultures\",\n      \"pmids\": [\"25582411\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism linking XIRP1 to satellite cell survival and proliferation unknown\", \"Whether myopathy is cell-autonomous to satellite cells or involves other compartments untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of POPDC1 and POPDC2 as XIRP1 interaction partners at intercalated discs and T-tubules connected XIRP1 to cAMP-regulated transmembrane signaling associated with cardiac arrhythmias.\",\n      \"evidence\": \"Unbiased pull-down proteomics from human skeletal myotubes; reciprocal co-immunoprecipitation from adult rat heart; immunofluorescence colocalization\",\n      \"pmids\": [\"33261556\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of XIRP1–POPDC interaction not tested\", \"Whether XIRP1 regulates POPDC membrane localization or signaling unknown\", \"No genetic epistasis between XIRP1 and POPDC mutants\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular mechanism by which XIRP1 scaffolding at intercalated discs translates into normal electrical conduction and contractile function remains unresolved, and whether human XIRP1 mutations directly cause cardiomyopathy or skeletal myopathy has not been established by family studies or rescue experiments.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No causative human XIRP1 mutations identified through genetic studies\", \"No structural model of XIRP1 or its Xin repeat domain\", \"Mechanism of XIRP1-dependent satellite cell activation unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 3, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 10, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 3, 7, 10, 13]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [1, 3, 10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [7, 11]}\n    ],\n    \"complexes\": [\n      \"N-cadherin/β-catenin adherens junction complex\",\n      \"Filamin c–XIRP1–Mena/VASP complex\"\n    ],\n    \"partners\": [\n      \"CTNNB1\",\n      \"FLNC\",\n      \"ENAH\",\n      \"VASP\",\n      \"POPDC1\",\n      \"POPDC2\",\n      \"XIRP2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}