{"gene":"CXADR","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2018,"finding":"CXADR forms an AKT-inhibitory signalosome at tight junctions by stabilizing the phosphatases PTEN and PHLPP2; loss of CXADR leads to hyperactivation of AKT and sensitizes cells to TGFβ1-induced epithelial-mesenchymal transition (EMT), while restoration of CXADR stabilizes PHLPP2 and PTEN, inhibits AKT, and promotes epithelial differentiation.","method":"Loss-of-function and restoration experiments in breast cancer cell lines; Co-IP/signalosome assembly assays; functional AKT activity measurements; TGFβ1-induced EMT assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal functional rescue experiments, multiple orthogonal methods (loss-of-function, gain-of-function, AKT activity, EMT phenotype) in a single focused study","pmids":["30385615"],"is_preprint":false},{"year":2024,"finding":"CXADR regulates the stability and function of AKT inhibitors PHLPP2 and PTEN; loss of CXADR leads to phosphorylation of AKT and GSK-3β, which stabilizes the EMT transcription factor SNAIL1, thereby inducing EMT and enhancing proliferation, migration, and invasion of endometrial cells.","method":"In vitro loss-of-function and overexpression experiments in Ishikawa cells; immunohistochemistry; phosphorylation assays for AKT and GSK-3β; EMT marker assessment","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, multiple cellular assays but no structural or in vitro reconstitution; mechanistic pathway placement via phosphorylation assays","pmids":["38146657"],"is_preprint":false},{"year":2019,"finding":"CXADR functions as an entry receptor for bat adenoviruses (BtAdVs); CXADR-knockout canine kidney cells showed significantly hampered BtAdV replication, and replication was rescued by re-addition of canine, human, or bat CXADR, demonstrating that multiple mammalian CXADRs support viral entry.","method":"CXADR-knockout cell lines (CRISPR or equivalent); CXADR addback/transduction rescue experiments; viral replication assays","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — knockout plus multiple species addback rescue, orthogonal confirmation of CXADR as functional entry factor across mammalian species","pmids":["30679679"],"is_preprint":false},{"year":2016,"finding":"CXADR is required for adherens junction (AJ) and tight junction (TJ) assembly during porcine blastocyst formation; CXADR knockdown caused failure to develop to blastocyst stage and defects in TJ assembly (reduced occludin, TJP1, increased FITC-dextran permeability), with CXADR localizing to cell-cell contact edges from the 8-cell stage onwards.","method":"siRNA knockdown (dsRNA microinjection); qRT-PCR; immunocytochemistry; FITC-dextran TJ permeability assay","journal":"Reproduction (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular phenotype (TJ markers, permeability), multiple assays in a single lab","pmids":["26729920"],"is_preprint":false},{"year":2019,"finding":"CXADR forms a complex with ADAM10 at tight junctions; ADAM10 knockdown or chemical inhibition (GI254023X) disrupted subcellular localization of CXADR and TJP1, leading to disrupted TJ assembly; CXADR knockdown also resulted in reduced trophoblast outgrowth and aberrant expression of the trophoblast marker AP-2γ.","method":"siRNA knockdown; ADAM10-specific inhibitor (GI254023X); immunofluorescence localization; in vitro embryo outgrowth assay; TJ assembly assessment","journal":"Molecular reproduction and development","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — complex inferred from co-localization and functional interaction rather than direct co-IP; multiple functional assays support the interaction","pmids":["31373105"],"is_preprint":false},{"year":2022,"finding":"Triplication of CXADR (an adhesion protein) in Down syndrome impairs neural crest cell migration; knockdown of CXADR in Down syndrome hiPSC-derived neural crest cells substantially recovered migratory ability and the generation of post-migratory cranial neural crest stem cells, indicating that excess CXADR inhibits cell migration.","method":"Down syndrome hiPSC differentiation model; CXADR knockdown by siRNA/shRNA; migration assays; quantification of post-migratory NCSCs","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — loss-of-function rescue experiment with defined migration phenotype; single lab, stem cell model","pmids":["36470861"],"is_preprint":false},{"year":2023,"finding":"PTTG1 enhances oncolytic adenovirus 5 (OAd5) entry into pancreatic cancer cells by increasing CXADR expression on the cell surface; CXADR knockdown abolished the PTTG1-dependent enhancement of OAd5 transduction, placing CXADR downstream of PTTG1 in this pathway.","method":"CXADR overexpression and knockdown; flow cytometry for CXADR surface expression; GFP-OAd5 transduction assay; CCK-8 cell viability","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — epistasis established by CXADR knockdown abolishing PTTG1 effect; single lab, multiple assays","pmids":["37243239"],"is_preprint":false},{"year":2023,"finding":"CLMP (CXADR-like membrane protein) regulates colonic epithelial cell proliferation and acts as a tumor suppressor; loss of CLMP enhanced IEC proliferation and tumor growth, while CLMP overexpression reduced proliferation; mechanistically, CLMP-dependent regulation is linked to mTOR-AKT-β-catenin signaling.","method":"Conditional intestinal epithelial-specific CLMP knockout mice (ClmpΔIEC); intestinal organoids; xenograft experiments; azoxymethane/DSS colonic tumorigenesis model; RNA sequencing; overexpression and loss-of-function in IECs","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vivo and in vitro approaches (conditional KO, organoids, xenograft, carcinogenesis model), pathway placement via mTOR-AKT-β-catenin","pmids":["37716376"],"is_preprint":false},{"year":2019,"finding":"CXADR is expressed specifically by trophoblast labyrinth progenitors and visceral yolk sac cells; in Cxadr-null placentas, there is altered expression of angiogenic factors, poor expansion of trophoblast and fetal endothelial cell subpopulations, and diminished placental transport; conditional preservation of trophoblast Cxadr revealed placental defects are secondary to primary embryonic/yolk sac phenotypes.","method":"Cxadr mutant mouse model; tissue-restricted conditional deletions; immunofluorescence localization; placental transport assays; analysis of trophoblast and endothelial subpopulations","journal":"Frontiers in physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional genetic approaches plus functional transport assays, single lab","pmids":["31338035"],"is_preprint":false},{"year":2025,"finding":"CXADR is a fate determinant of the placental exchange surface; functional analysis in mouse trophoblast stem cells showed that CXADR regulates the differentiation dynamics between the two syncytial layers of the mouse labyrinth (SynT-I and SynT-II lineages), ensuring correct establishment of the placental exchange surface.","method":"Single-cell RNA sequencing of mouse trophoblast stem cells; functional CXADR loss-of-function analysis; trophoblast differentiation assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional analysis reported but abstract provides limited detail on specific assay methods; single study","pmids":["39747179"],"is_preprint":false},{"year":2015,"finding":"Podocyte-specific deletion of Cxadr in mice did not impair podocyte development, foot process architecture, or stress response to toxic, genetic, or immunologic injury, indicating that mammalian podocytes have acquired compensatory mechanisms and that CXADR is dispensable in this cell type despite being upregulated during glomerular injury.","method":"Conditional podocyte-specific Cxadr knockout mice; histological and ultrastructural analysis; injury models (toxic, genetic, immunologic)","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — rigorous conditional KO with multiple injury paradigms, but all results are negative (no phenotype detected); single lab","pmids":["26076477"],"is_preprint":false},{"year":2023,"finding":"CXADR is localized at the Sertoli-Sertoli and Sertoli-germ cell interface in the testis; Sertoli cell-specific knockout of CXADR in mice impairs the blood-testis barrier, induces germ cell apoptosis, and causes premature loss of spermatids, demonstrating an essential structural and signaling role in spermatogenesis.","method":"Sertoli cell-specific Cxadr conditional knockout mice; barrier function assay; apoptosis assays; immunofluorescence localization (review summarizing primary experimental findings)","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — findings summarized in review citing primary KO studies; conditional KO with defined cellular phenotypes, but evidence grounded in review abstract","pmids":["36674801"],"is_preprint":false}],"current_model":"CXADR is a transmembrane immunoglobulin superfamily protein that functions at cell junctions as a viral entry receptor (for coxsackieviruses, adenoviruses, and bat adenoviruses), a structural component of tight and adherens junctions, and a signaling scaffold that assembles an AKT-inhibitory complex by stabilizing the phosphatases PTEN and PHLPP2, thereby suppressing AKT/GSK-3β signaling, restraining EMT, regulating epithelial proliferation via mTOR-AKT-β-catenin, and supporting tissue-specific processes including spermatogenesis, placental labyrinth fate determination, and neural crest cell migration."},"narrative":{"mechanistic_narrative":"CXADR is a junctional immunoglobulin-superfamily transmembrane protein that functions both as a structural component of epithelial cell-cell junctions and as a signaling scaffold restraining AKT-driven proliferation and epithelial-mesenchymal transition [PMID:30385615, PMID:26729920]. At tight junctions it assembles an AKT-inhibitory signalosome by stabilizing the phosphatases PTEN and PHLPP2; loss of CXADR releases this brake, driving phosphorylation of AKT and GSK-3β, stabilization of the EMT transcription factor SNAIL1, and enhanced proliferation, migration, and invasion in breast and endometrial epithelial cells [PMID:30385615, PMID:38146657]. Consistent with a junction-organizing role, CXADR localizes to cell-cell contacts and is required for tight- and adherens-junction assembly and barrier integrity during blastocyst formation, acting in concert with ADAM10 [PMID:26729920, PMID:31373105]. These activities underlie tissue-specific functions including spermatogenesis and blood-testis barrier maintenance [PMID:36674801], placental labyrinth progenitor fate determination and the differentiation of syncytiotrophoblast exchange-surface lineages [PMID:31338035, PMID:39747179], and the control of neural crest cell migration, where excess CXADR inhibits migration [PMID:36470861]. CXADR also serves as a cell-surface entry receptor for adenoviruses, including bat adenoviruses and oncolytic adenovirus 5, with its surface abundance limiting viral transduction [PMID:30679679, PMID:37243239]. CXADR is dispensable in mammalian podocytes, where compensatory mechanisms operate despite its upregulation during glomerular injury [PMID:26076477].","teleology":[{"year":2015,"claim":"Tested whether CXADR is functionally required in a specialized epithelial barrier cell, establishing tissue-specific dispensability.","evidence":"Podocyte-specific conditional Cxadr knockout mice across toxic, genetic, and immunologic injury models","pmids":["26076477"],"confidence":"Medium","gaps":["Negative result does not identify the compensating molecules","Does not address CXADR function in other epithelial cell types"]},{"year":2016,"claim":"Showed CXADR is needed to build epithelial junctions de novo, linking it to barrier formation rather than only viral entry.","evidence":"siRNA knockdown in porcine embryos with TJ marker analysis and FITC-dextran permeability assay","pmids":["26729920"],"confidence":"Medium","gaps":["Molecular mechanism connecting CXADR to occludin/TJP1 recruitment not defined","Single-species embryonic model"]},{"year":2018,"claim":"Defined the central signaling mechanism: CXADR scaffolds an AKT-inhibitory complex by stabilizing PTEN and PHLPP2, explaining how junctional CXADR restrains EMT.","evidence":"Loss-of-function/restoration, Co-IP signalosome assays, AKT activity and TGFβ1-EMT assays in breast cancer cells","pmids":["30385615"],"confidence":"High","gaps":["Structural basis of PTEN/PHLPP2 stabilization unresolved","Direct versus indirect binding to phosphatases not distinguished"]},{"year":2019,"claim":"Extended the junctional assembly mechanism by identifying a CXADR-ADAM10 functional partnership required for correct CXADR/TJP1 localization.","evidence":"siRNA knockdown plus ADAM10 inhibitor (GI254023X), immunofluorescence and embryo outgrowth assays","pmids":["31373105"],"confidence":"Medium","gaps":["Complex inferred from co-localization and functional interaction, not direct co-IP","Whether ADAM10 cleaves CXADR is not established"]},{"year":2019,"claim":"Demonstrated CXADR is a functional adenovirus entry receptor conserved across mammalian species, broadening its receptor role beyond human pathogens.","evidence":"CXADR-knockout cells with canine/human/bat CXADR addback rescue of bat adenovirus replication","pmids":["30679679"],"confidence":"High","gaps":["Receptor-virus binding interface not mapped","Does not address co-receptor requirements"]},{"year":2019,"claim":"Placed CXADR in placental development as a marker and functional regulator of labyrinth and yolk sac lineages.","evidence":"Cxadr mutant and tissue-restricted conditional knockout mice with placental transport assays","pmids":["31338035"],"confidence":"Medium","gaps":["Primary embryonic/yolk-sac driver of placental defects not molecularly resolved","Signaling pathway in placenta not connected to AKT mechanism"]},{"year":2022,"claim":"Showed CXADR dosage controls cell migration, with overexpression (as in Down syndrome triplication) inhibiting neural crest migration.","evidence":"Down syndrome hiPSC-derived neural crest cells with CXADR knockdown migration rescue","pmids":["36470861"],"confidence":"Medium","gaps":["Mechanism linking CXADR levels to migratory machinery unknown","Single stem-cell model"]},{"year":2023,"claim":"Established CXADR surface abundance as a rate-limiting entry factor exploited by oncolytic adenovirus, placing it downstream of PTTG1.","evidence":"CXADR overexpression/knockdown with surface flow cytometry and GFP-OAd5 transduction in pancreatic cancer cells","pmids":["37243239"],"confidence":"Medium","gaps":["How PTTG1 increases CXADR surface expression is not defined","Single tumor type"]},{"year":2023,"claim":"Demonstrated an essential structural and signaling role for CXADR in the blood-testis barrier and spermatogenesis.","evidence":"Sertoli cell-specific Cxadr conditional knockout mice with barrier and apoptosis assays (review summarizing primary findings)","pmids":["36674801"],"confidence":"Medium","gaps":["Evidence grounded in review summary","Signaling versus purely structural contribution not separated"]},{"year":2025,"claim":"Refined the placental role, showing CXADR determines the differentiation balance between syncytiotrophoblast lineages forming the exchange surface.","evidence":"Single-cell RNA-seq and CXADR loss-of-function in mouse trophoblast stem cells","pmids":["39747179"],"confidence":"Medium","gaps":["Specific functional assays underdescribed","Molecular signal driving SynT-I/SynT-II fate choice not identified"]},{"year":null,"claim":"How CXADR's junctional scaffolding, phosphatase-stabilizing signaling, and viral-receptor functions are mechanistically integrated, and whether the AKT-inhibitory mechanism operates across the developmental tissues where CXADR acts, remains open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of CXADR-PTEN/PHLPP2 assembly","Unknown whether placental, testis, and neural crest phenotypes depend on the AKT-PTEN/PHLPP2 axis","Direct adenovirus binding interface unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[2,6]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[3,4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,6]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,8,9,5]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,6]}],"complexes":["CXADR-PTEN-PHLPP2 AKT-inhibitory signalosome"],"partners":["PTEN","PHLPP2","ADAM10"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P78310","full_name":"Coxsackievirus and adenovirus receptor","aliases":["CVB3-binding protein","Coxsackievirus B-adenovirus receptor","HCVADR"],"length_aa":365,"mass_kda":40.0,"function":"Component of the epithelial apical junction complex that may function as a homophilic cell adhesion molecule and is essential for tight junction integrity. Also involved in transepithelial migration of leukocytes through adhesive interactions with JAML a transmembrane protein of the plasma membrane of leukocytes. The interaction between both receptors also mediates the activation of gamma-delta T-cells, a subpopulation of T-cells residing in epithelia and involved in tissue homeostasis and repair. Upon epithelial CXADR-binding, JAML induces downstream cell signaling events in gamma-delta T-cells through PI3-kinase and MAP kinases. It results in proliferation and production of cytokines and growth factors by T-cells that in turn stimulate epithelial tissues repair (Microbial infection) Acts as a receptor for adenovirus type C (Microbial infection) Acts as a receptor for Coxsackievirus B1 to B6","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P78310/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CXADR","classification":"Not Classified","n_dependent_lines":57,"n_total_lines":383,"dependency_fraction":0.14882506527415143},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CXADR","total_profiled":1310},"omim":[{"mim_id":"611693","title":"COXSACKIEVIRUS- AND ADENOVIRUS RECEPTOR-LIKE MEMBRANE PROTEIN; CLMP","url":"https://www.omim.org/entry/611693"},{"mim_id":"609770","title":"JUNCTIONAL ADHESION MOLECULE-LIKE; JAML","url":"https://www.omim.org/entry/609770"},{"mim_id":"608351","title":"IMMUNOGLOBULIN SUPERFAMILY, MEMBER 11; IGSF11","url":"https://www.omim.org/entry/608351"},{"mim_id":"603829","title":"VENTRICULAR FIBRILLATION, PAROXYSMAL FAMILIAL, 1; VF1","url":"https://www.omim.org/entry/603829"},{"mim_id":"602621","title":"COXSACKIEVIRUS AND ADENOVIRUS RECEPTOR; CXADR","url":"https://www.omim.org/entry/602621"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cell Junctions","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skin 1","ntpm":50.3}],"url":"https://www.proteinatlas.org/search/CXADR"},"hgnc":{"alias_symbol":["CAR"],"prev_symbol":[]},"alphafold":{"accession":"P78310","domains":[{"cath_id":"2.60.40.10","chopping":"20-137","consensus_level":"high","plddt":91.9762,"start":20,"end":137},{"cath_id":"2.60.40.10","chopping":"141-226","consensus_level":"high","plddt":95.0823,"start":141,"end":226}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P78310","model_url":"https://alphafold.ebi.ac.uk/files/AF-P78310-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P78310-F1-predicted_aligned_error_v6.png","plddt_mean":79.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CXADR","jax_strain_url":"https://www.jax.org/strain/search?query=CXADR"},"sequence":{"accession":"P78310","fasta_url":"https://rest.uniprot.org/uniprotkb/P78310.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P78310/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P78310"}},"corpus_meta":[{"pmid":"12851705","id":"PMC_12851705","title":"IGSF11 gene, frequently up-regulated in intestinal-type gastric cancer, encodes adhesion molecule homologous to CXADR, FLJ22415 and ESAM.","date":"2003","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/12851705","citation_count":88,"is_preprint":false},{"pmid":"30385615","id":"PMC_30385615","title":"CXADR-Mediated Formation of an AKT Inhibitory Signalosome at Tight Junctions Controls Epithelial-Mesenchymal Plasticity in Breast Cancer.","date":"2018","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/30385615","citation_count":36,"is_preprint":false},{"pmid":"33084169","id":"PMC_33084169","title":"CXADR-like membrane protein protects against heart injury by preventing excessive pyroptosis after myocardial infarction.","date":"2020","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33084169","citation_count":27,"is_preprint":false},{"pmid":"22914544","id":"PMC_22914544","title":"Variants in CXADR and F2RL1 are associated with blood pressure and obesity in African-Americans in regions identified through admixture mapping.","date":"2012","source":"Journal of hypertension","url":"https://pubmed.ncbi.nlm.nih.gov/22914544","citation_count":26,"is_preprint":false},{"pmid":"30679679","id":"PMC_30679679","title":"Characterization of a novel species of adenovirus from Japanese microbat and role of CXADR as its entry factor.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30679679","citation_count":16,"is_preprint":false},{"pmid":"26729920","id":"PMC_26729920","title":"CXADR is required for AJ and TJ assembly during porcine blastocyst formation.","date":"2016","source":"Reproduction (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/26729920","citation_count":12,"is_preprint":false},{"pmid":"31338035","id":"PMC_31338035","title":"Secondary Placental Defects in Cxadr Mutant Mice.","date":"2019","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31338035","citation_count":9,"is_preprint":false},{"pmid":"37243239","id":"PMC_37243239","title":"PTTG1 Enhances Oncolytic Adenovirus 5 Entry into Pancreatic Adenocarcinoma Cells by Increasing CXADR Expression.","date":"2023","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/37243239","citation_count":9,"is_preprint":false},{"pmid":"37716376","id":"PMC_37716376","title":"CXADR-Like Membrane Protein Regulates Colonic Epithelial Cell Proliferation and Prevents Tumor Growth.","date":"2023","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/37716376","citation_count":8,"is_preprint":false},{"pmid":"31373105","id":"PMC_31373105","title":"The Cxadr-Adam10 complex plays pivotal roles in tight junction integrity and early trophoblast development in mice.","date":"2019","source":"Molecular reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/31373105","citation_count":8,"is_preprint":false},{"pmid":"26076477","id":"PMC_26076477","title":"Podocyte-Specific Deletion of Murine CXADR Does Not Impair Podocyte Development, Function or Stress Response.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26076477","citation_count":7,"is_preprint":false},{"pmid":"39747179","id":"PMC_39747179","title":"Single-cell RNA sequencing identifies CXADR as a fate determinant of the placental exchange surface.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39747179","citation_count":6,"is_preprint":false},{"pmid":"36470861","id":"PMC_36470861","title":"Migration deficits of the neural crest caused by CXADR triplication in a human Down syndrome stem cell model.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36470861","citation_count":6,"is_preprint":false},{"pmid":"34453733","id":"PMC_34453733","title":"Coxsackievirus and Adenovirus Receptor (CXADR): Recent Findings and Its Role and Regulation in Spermatogenesis.","date":"2021","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/34453733","citation_count":3,"is_preprint":false},{"pmid":"36674801","id":"PMC_36674801","title":"CXADR: From an Essential Structural Component to a Vital Signaling Mediator in Spermatogenesis.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36674801","citation_count":3,"is_preprint":false},{"pmid":"38146657","id":"PMC_38146657","title":"CXADR promote epithelial-mesenchymal transition in endometriosis by modulating AKT/GSK-3β signaling.","date":"2024","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/38146657","citation_count":3,"is_preprint":false},{"pmid":"25400132","id":"PMC_25400132","title":"CXADR-like membrane protein (CLMP) in the rat ovary: stimulation by human chorionic gonadotrophin during the periovulatory period.","date":"2016","source":"Reproduction, fertility, and development","url":"https://pubmed.ncbi.nlm.nih.gov/25400132","citation_count":2,"is_preprint":false},{"pmid":"38028613","id":"PMC_38028613","title":"CXADR polymorphism rs6517774 modifies islet autoimmunity characteristics and exhibits sex disparity.","date":"2023","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38028613","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10813,"output_tokens":3158,"usd":0.039905,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10591,"output_tokens":3249,"usd":0.06709,"stage2_stop_reason":"end_turn"},"total_usd":0.106995,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"CXADR forms an AKT-inhibitory signalosome at tight junctions by stabilizing the phosphatases PTEN and PHLPP2; loss of CXADR leads to hyperactivation of AKT and sensitizes cells to TGFβ1-induced epithelial-mesenchymal transition (EMT), while restoration of CXADR stabilizes PHLPP2 and PTEN, inhibits AKT, and promotes epithelial differentiation.\",\n      \"method\": \"Loss-of-function and restoration experiments in breast cancer cell lines; Co-IP/signalosome assembly assays; functional AKT activity measurements; TGFβ1-induced EMT assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional rescue experiments, multiple orthogonal methods (loss-of-function, gain-of-function, AKT activity, EMT phenotype) in a single focused study\",\n      \"pmids\": [\"30385615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CXADR regulates the stability and function of AKT inhibitors PHLPP2 and PTEN; loss of CXADR leads to phosphorylation of AKT and GSK-3β, which stabilizes the EMT transcription factor SNAIL1, thereby inducing EMT and enhancing proliferation, migration, and invasion of endometrial cells.\",\n      \"method\": \"In vitro loss-of-function and overexpression experiments in Ishikawa cells; immunohistochemistry; phosphorylation assays for AKT and GSK-3β; EMT marker assessment\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, multiple cellular assays but no structural or in vitro reconstitution; mechanistic pathway placement via phosphorylation assays\",\n      \"pmids\": [\"38146657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CXADR functions as an entry receptor for bat adenoviruses (BtAdVs); CXADR-knockout canine kidney cells showed significantly hampered BtAdV replication, and replication was rescued by re-addition of canine, human, or bat CXADR, demonstrating that multiple mammalian CXADRs support viral entry.\",\n      \"method\": \"CXADR-knockout cell lines (CRISPR or equivalent); CXADR addback/transduction rescue experiments; viral replication assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout plus multiple species addback rescue, orthogonal confirmation of CXADR as functional entry factor across mammalian species\",\n      \"pmids\": [\"30679679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CXADR is required for adherens junction (AJ) and tight junction (TJ) assembly during porcine blastocyst formation; CXADR knockdown caused failure to develop to blastocyst stage and defects in TJ assembly (reduced occludin, TJP1, increased FITC-dextran permeability), with CXADR localizing to cell-cell contact edges from the 8-cell stage onwards.\",\n      \"method\": \"siRNA knockdown (dsRNA microinjection); qRT-PCR; immunocytochemistry; FITC-dextran TJ permeability assay\",\n      \"journal\": \"Reproduction (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular phenotype (TJ markers, permeability), multiple assays in a single lab\",\n      \"pmids\": [\"26729920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CXADR forms a complex with ADAM10 at tight junctions; ADAM10 knockdown or chemical inhibition (GI254023X) disrupted subcellular localization of CXADR and TJP1, leading to disrupted TJ assembly; CXADR knockdown also resulted in reduced trophoblast outgrowth and aberrant expression of the trophoblast marker AP-2γ.\",\n      \"method\": \"siRNA knockdown; ADAM10-specific inhibitor (GI254023X); immunofluorescence localization; in vitro embryo outgrowth assay; TJ assembly assessment\",\n      \"journal\": \"Molecular reproduction and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — complex inferred from co-localization and functional interaction rather than direct co-IP; multiple functional assays support the interaction\",\n      \"pmids\": [\"31373105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Triplication of CXADR (an adhesion protein) in Down syndrome impairs neural crest cell migration; knockdown of CXADR in Down syndrome hiPSC-derived neural crest cells substantially recovered migratory ability and the generation of post-migratory cranial neural crest stem cells, indicating that excess CXADR inhibits cell migration.\",\n      \"method\": \"Down syndrome hiPSC differentiation model; CXADR knockdown by siRNA/shRNA; migration assays; quantification of post-migratory NCSCs\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — loss-of-function rescue experiment with defined migration phenotype; single lab, stem cell model\",\n      \"pmids\": [\"36470861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PTTG1 enhances oncolytic adenovirus 5 (OAd5) entry into pancreatic cancer cells by increasing CXADR expression on the cell surface; CXADR knockdown abolished the PTTG1-dependent enhancement of OAd5 transduction, placing CXADR downstream of PTTG1 in this pathway.\",\n      \"method\": \"CXADR overexpression and knockdown; flow cytometry for CXADR surface expression; GFP-OAd5 transduction assay; CCK-8 cell viability\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — epistasis established by CXADR knockdown abolishing PTTG1 effect; single lab, multiple assays\",\n      \"pmids\": [\"37243239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CLMP (CXADR-like membrane protein) regulates colonic epithelial cell proliferation and acts as a tumor suppressor; loss of CLMP enhanced IEC proliferation and tumor growth, while CLMP overexpression reduced proliferation; mechanistically, CLMP-dependent regulation is linked to mTOR-AKT-β-catenin signaling.\",\n      \"method\": \"Conditional intestinal epithelial-specific CLMP knockout mice (ClmpΔIEC); intestinal organoids; xenograft experiments; azoxymethane/DSS colonic tumorigenesis model; RNA sequencing; overexpression and loss-of-function in IECs\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vivo and in vitro approaches (conditional KO, organoids, xenograft, carcinogenesis model), pathway placement via mTOR-AKT-β-catenin\",\n      \"pmids\": [\"37716376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CXADR is expressed specifically by trophoblast labyrinth progenitors and visceral yolk sac cells; in Cxadr-null placentas, there is altered expression of angiogenic factors, poor expansion of trophoblast and fetal endothelial cell subpopulations, and diminished placental transport; conditional preservation of trophoblast Cxadr revealed placental defects are secondary to primary embryonic/yolk sac phenotypes.\",\n      \"method\": \"Cxadr mutant mouse model; tissue-restricted conditional deletions; immunofluorescence localization; placental transport assays; analysis of trophoblast and endothelial subpopulations\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional genetic approaches plus functional transport assays, single lab\",\n      \"pmids\": [\"31338035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CXADR is a fate determinant of the placental exchange surface; functional analysis in mouse trophoblast stem cells showed that CXADR regulates the differentiation dynamics between the two syncytial layers of the mouse labyrinth (SynT-I and SynT-II lineages), ensuring correct establishment of the placental exchange surface.\",\n      \"method\": \"Single-cell RNA sequencing of mouse trophoblast stem cells; functional CXADR loss-of-function analysis; trophoblast differentiation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional analysis reported but abstract provides limited detail on specific assay methods; single study\",\n      \"pmids\": [\"39747179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Podocyte-specific deletion of Cxadr in mice did not impair podocyte development, foot process architecture, or stress response to toxic, genetic, or immunologic injury, indicating that mammalian podocytes have acquired compensatory mechanisms and that CXADR is dispensable in this cell type despite being upregulated during glomerular injury.\",\n      \"method\": \"Conditional podocyte-specific Cxadr knockout mice; histological and ultrastructural analysis; injury models (toxic, genetic, immunologic)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — rigorous conditional KO with multiple injury paradigms, but all results are negative (no phenotype detected); single lab\",\n      \"pmids\": [\"26076477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CXADR is localized at the Sertoli-Sertoli and Sertoli-germ cell interface in the testis; Sertoli cell-specific knockout of CXADR in mice impairs the blood-testis barrier, induces germ cell apoptosis, and causes premature loss of spermatids, demonstrating an essential structural and signaling role in spermatogenesis.\",\n      \"method\": \"Sertoli cell-specific Cxadr conditional knockout mice; barrier function assay; apoptosis assays; immunofluorescence localization (review summarizing primary experimental findings)\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — findings summarized in review citing primary KO studies; conditional KO with defined cellular phenotypes, but evidence grounded in review abstract\",\n      \"pmids\": [\"36674801\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CXADR is a transmembrane immunoglobulin superfamily protein that functions at cell junctions as a viral entry receptor (for coxsackieviruses, adenoviruses, and bat adenoviruses), a structural component of tight and adherens junctions, and a signaling scaffold that assembles an AKT-inhibitory complex by stabilizing the phosphatases PTEN and PHLPP2, thereby suppressing AKT/GSK-3β signaling, restraining EMT, regulating epithelial proliferation via mTOR-AKT-β-catenin, and supporting tissue-specific processes including spermatogenesis, placental labyrinth fate determination, and neural crest cell migration.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CXADR is a junctional immunoglobulin-superfamily transmembrane protein that functions both as a structural component of epithelial cell-cell junctions and as a signaling scaffold restraining AKT-driven proliferation and epithelial-mesenchymal transition [#0, #3]. At tight junctions it assembles an AKT-inhibitory signalosome by stabilizing the phosphatases PTEN and PHLPP2; loss of CXADR releases this brake, driving phosphorylation of AKT and GSK-3\\u03b2, stabilization of the EMT transcription factor SNAIL1, and enhanced proliferation, migration, and invasion in breast and endometrial epithelial cells [#0, #1]. Consistent with a junction-organizing role, CXADR localizes to cell-cell contacts and is required for tight- and adherens-junction assembly and barrier integrity during blastocyst formation, acting in concert with ADAM10 [#3, #4]. These activities underlie tissue-specific functions including spermatogenesis and blood-testis barrier maintenance [#11], placental labyrinth progenitor fate determination and the differentiation of syncytiotrophoblast exchange-surface lineages [#8, #9], and the control of neural crest cell migration, where excess CXADR inhibits migration [#5]. CXADR also serves as a cell-surface entry receptor for adenoviruses, including bat adenoviruses and oncolytic adenovirus 5, with its surface abundance limiting viral transduction [#2, #6]. CXADR is dispensable in mammalian podocytes, where compensatory mechanisms operate despite its upregulation during glomerular injury [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Tested whether CXADR is functionally required in a specialized epithelial barrier cell, establishing tissue-specific dispensability.\",\n      \"evidence\": \"Podocyte-specific conditional Cxadr knockout mice across toxic, genetic, and immunologic injury models\",\n      \"pmids\": [\"26076477\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result does not identify the compensating molecules\", \"Does not address CXADR function in other epithelial cell types\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed CXADR is needed to build epithelial junctions de novo, linking it to barrier formation rather than only viral entry.\",\n      \"evidence\": \"siRNA knockdown in porcine embryos with TJ marker analysis and FITC-dextran permeability assay\",\n      \"pmids\": [\"26729920\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism connecting CXADR to occludin/TJP1 recruitment not defined\", \"Single-species embryonic model\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the central signaling mechanism: CXADR scaffolds an AKT-inhibitory complex by stabilizing PTEN and PHLPP2, explaining how junctional CXADR restrains EMT.\",\n      \"evidence\": \"Loss-of-function/restoration, Co-IP signalosome assays, AKT activity and TGF\\u03b21-EMT assays in breast cancer cells\",\n      \"pmids\": [\"30385615\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of PTEN/PHLPP2 stabilization unresolved\", \"Direct versus indirect binding to phosphatases not distinguished\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended the junctional assembly mechanism by identifying a CXADR-ADAM10 functional partnership required for correct CXADR/TJP1 localization.\",\n      \"evidence\": \"siRNA knockdown plus ADAM10 inhibitor (GI254023X), immunofluorescence and embryo outgrowth assays\",\n      \"pmids\": [\"31373105\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Complex inferred from co-localization and functional interaction, not direct co-IP\", \"Whether ADAM10 cleaves CXADR is not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated CXADR is a functional adenovirus entry receptor conserved across mammalian species, broadening its receptor role beyond human pathogens.\",\n      \"evidence\": \"CXADR-knockout cells with canine/human/bat CXADR addback rescue of bat adenovirus replication\",\n      \"pmids\": [\"30679679\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor-virus binding interface not mapped\", \"Does not address co-receptor requirements\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed CXADR in placental development as a marker and functional regulator of labyrinth and yolk sac lineages.\",\n      \"evidence\": \"Cxadr mutant and tissue-restricted conditional knockout mice with placental transport assays\",\n      \"pmids\": [\"31338035\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Primary embryonic/yolk-sac driver of placental defects not molecularly resolved\", \"Signaling pathway in placenta not connected to AKT mechanism\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed CXADR dosage controls cell migration, with overexpression (as in Down syndrome triplication) inhibiting neural crest migration.\",\n      \"evidence\": \"Down syndrome hiPSC-derived neural crest cells with CXADR knockdown migration rescue\",\n      \"pmids\": [\"36470861\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking CXADR levels to migratory machinery unknown\", \"Single stem-cell model\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established CXADR surface abundance as a rate-limiting entry factor exploited by oncolytic adenovirus, placing it downstream of PTTG1.\",\n      \"evidence\": \"CXADR overexpression/knockdown with surface flow cytometry and GFP-OAd5 transduction in pancreatic cancer cells\",\n      \"pmids\": [\"37243239\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How PTTG1 increases CXADR surface expression is not defined\", \"Single tumor type\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated an essential structural and signaling role for CXADR in the blood-testis barrier and spermatogenesis.\",\n      \"evidence\": \"Sertoli cell-specific Cxadr conditional knockout mice with barrier and apoptosis assays (review summarizing primary findings)\",\n      \"pmids\": [\"36674801\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Evidence grounded in review summary\", \"Signaling versus purely structural contribution not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Refined the placental role, showing CXADR determines the differentiation balance between syncytiotrophoblast lineages forming the exchange surface.\",\n      \"evidence\": \"Single-cell RNA-seq and CXADR loss-of-function in mouse trophoblast stem cells\",\n      \"pmids\": [\"39747179\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific functional assays underdescribed\", \"Molecular signal driving SynT-I/SynT-II fate choice not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CXADR's junctional scaffolding, phosphatase-stabilizing signaling, and viral-receptor functions are mechanistically integrated, and whether the AKT-inhibitory mechanism operates across the developmental tissues where CXADR acts, remains open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of CXADR-PTEN/PHLPP2 assembly\", \"Unknown whether placental, testis, and neural crest phenotypes depend on the AKT-PTEN/PHLPP2 axis\", \"Direct adenovirus binding interface unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"GO:0005911\", \"supporting_discovery_ids\": [0, 3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 8, 9, 5]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 6]}\n    ],\n    \"complexes\": [\"CXADR-PTEN-PHLPP2 AKT-inhibitory signalosome\"],\n    \"partners\": [\"PTEN\", \"PHLPP2\", \"ADAM10\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}