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Showing CXADR — CAR is a alias.

CXADR

Coxsackievirus and adenovirus receptor · UniProt P78310

Length
365 aa
Mass
40.0 kDa
Annotated
2026-06-09
18 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2015 Medium

    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

    PMID:26076477

    Open questions at the time
    • Negative result does not identify the compensating molecules
    • Does not address CXADR function in other epithelial cell types
  2. 2016 Medium

    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

    PMID:26729920

    Open questions at the time
    • Molecular mechanism connecting CXADR to occludin/TJP1 recruitment not defined
    • Single-species embryonic model
  3. 2018 High

    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

    PMID:30385615

    Open questions at the time
    • Structural basis of PTEN/PHLPP2 stabilization unresolved
    • Direct versus indirect binding to phosphatases not distinguished
  4. 2019 Medium

    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

    PMID:31373105

    Open questions at the time
    • Complex inferred from co-localization and functional interaction, not direct co-IP
    • Whether ADAM10 cleaves CXADR is not established
  5. 2019 High

    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

    PMID:30679679

    Open questions at the time
    • Receptor-virus binding interface not mapped
    • Does not address co-receptor requirements
  6. 2019 Medium

    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

    PMID:31338035

    Open questions at the time
    • Primary embryonic/yolk-sac driver of placental defects not molecularly resolved
    • Signaling pathway in placenta not connected to AKT mechanism
  7. 2022 Medium

    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

    PMID:36470861

    Open questions at the time
    • Mechanism linking CXADR levels to migratory machinery unknown
    • Single stem-cell model
  8. 2023 Medium

    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

    PMID:37243239

    Open questions at the time
    • How PTTG1 increases CXADR surface expression is not defined
    • Single tumor type
  9. 2023 Medium

    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)

    PMID:36674801

    Open questions at the time
    • Evidence grounded in review summary
    • Signaling versus purely structural contribution not separated
  10. 2025 Medium

    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

    PMID:39747179

    Open questions at the time
    • Specific functional assays underdescribed
    • Molecular signal driving SynT-I/SynT-II fate choice not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0001618 virus receptor activity 2 GO:0098631 cell adhesion mediator activity 2 GO:0098772 molecular function regulator activity 2 GO:0060090 molecular adaptor activity 1
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 2 R-HSA-1643685 Disease 2
Partners
ADAM10PHLPP2PTEN
Complex memberships
CXADR-PTEN-PHLPP2 AKT-inhibitory signalosome

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 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. Loss-of-function and restoration experiments in breast cancer cell lines; Co-IP/signalosome assembly assays; functional AKT activity measurements; TGFβ1-induced EMT assays Cancer research High 30385615
2024 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. In vitro loss-of-function and overexpression experiments in Ishikawa cells; immunohistochemistry; phosphorylation assays for AKT and GSK-3β; EMT marker assessment Cell cycle (Georgetown, Tex.) Medium 38146657
2019 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. CXADR-knockout cell lines (CRISPR or equivalent); CXADR addback/transduction rescue experiments; viral replication assays Scientific reports High 30679679
2016 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. siRNA knockdown (dsRNA microinjection); qRT-PCR; immunocytochemistry; FITC-dextran TJ permeability assay Reproduction (Cambridge, England) Medium 26729920
2019 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. siRNA knockdown; ADAM10-specific inhibitor (GI254023X); immunofluorescence localization; in vitro embryo outgrowth assay; TJ assembly assessment Molecular reproduction and development Medium 31373105
2022 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. Down syndrome hiPSC differentiation model; CXADR knockdown by siRNA/shRNA; migration assays; quantification of post-migratory NCSCs Cell death & disease Medium 36470861
2023 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. CXADR overexpression and knockdown; flow cytometry for CXADR surface expression; GFP-OAd5 transduction assay; CCK-8 cell viability Viruses Medium 37243239
2023 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. 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 Gastroenterology High 37716376
2019 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. Cxadr mutant mouse model; tissue-restricted conditional deletions; immunofluorescence localization; placental transport assays; analysis of trophoblast and endothelial subpopulations Frontiers in physiology Medium 31338035
2025 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. Single-cell RNA sequencing of mouse trophoblast stem cells; functional CXADR loss-of-function analysis; trophoblast differentiation assays Nature communications Medium 39747179
2015 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. Conditional podocyte-specific Cxadr knockout mice; histological and ultrastructural analysis; injury models (toxic, genetic, immunologic) PloS one Medium 26076477
2023 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. Sertoli cell-specific Cxadr conditional knockout mice; barrier function assay; apoptosis assays; immunofluorescence localization (review summarizing primary experimental findings) International journal of molecular sciences Medium 36674801

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 IGSF11 gene, frequently up-regulated in intestinal-type gastric cancer, encodes adhesion molecule homologous to CXADR, FLJ22415 and ESAM. International journal of oncology 88 12851705
2018 CXADR-Mediated Formation of an AKT Inhibitory Signalosome at Tight Junctions Controls Epithelial-Mesenchymal Plasticity in Breast Cancer. Cancer research 36 30385615
2020 CXADR-like membrane protein protects against heart injury by preventing excessive pyroptosis after myocardial infarction. Journal of cellular and molecular medicine 27 33084169
2012 Variants in CXADR and F2RL1 are associated with blood pressure and obesity in African-Americans in regions identified through admixture mapping. Journal of hypertension 26 22914544
2019 Characterization of a novel species of adenovirus from Japanese microbat and role of CXADR as its entry factor. Scientific reports 16 30679679
2016 CXADR is required for AJ and TJ assembly during porcine blastocyst formation. Reproduction (Cambridge, England) 12 26729920
2023 PTTG1 Enhances Oncolytic Adenovirus 5 Entry into Pancreatic Adenocarcinoma Cells by Increasing CXADR Expression. Viruses 9 37243239
2019 Secondary Placental Defects in Cxadr Mutant Mice. Frontiers in physiology 9 31338035
2023 CXADR-Like Membrane Protein Regulates Colonic Epithelial Cell Proliferation and Prevents Tumor Growth. Gastroenterology 8 37716376
2019 The Cxadr-Adam10 complex plays pivotal roles in tight junction integrity and early trophoblast development in mice. Molecular reproduction and development 8 31373105
2015 Podocyte-Specific Deletion of Murine CXADR Does Not Impair Podocyte Development, Function or Stress Response. PloS one 7 26076477
2025 Single-cell RNA sequencing identifies CXADR as a fate determinant of the placental exchange surface. Nature communications 6 39747179
2022 Migration deficits of the neural crest caused by CXADR triplication in a human Down syndrome stem cell model. Cell death & disease 6 36470861
2024 CXADR promote epithelial-mesenchymal transition in endometriosis by modulating AKT/GSK-3β signaling. Cell cycle (Georgetown, Tex.) 3 38146657
2023 CXADR: From an Essential Structural Component to a Vital Signaling Mediator in Spermatogenesis. International journal of molecular sciences 3 36674801
2021 Coxsackievirus and Adenovirus Receptor (CXADR): Recent Findings and Its Role and Regulation in Spermatogenesis. Advances in experimental medicine and biology 3 34453733
2016 CXADR-like membrane protein (CLMP) in the rat ovary: stimulation by human chorionic gonadotrophin during the periovulatory period. Reproduction, fertility, and development 2 25400132
2023 CXADR polymorphism rs6517774 modifies islet autoimmunity characteristics and exhibits sex disparity. Frontiers in genetics 0 38028613

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