{"gene":"LAYN","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2020,"finding":"Layilin (LAYN) colocalizes with integrin αLβ2 (LFA-1) on CD8+ T cells, and cross-linking layilin promotes the activated/extended state of LFA-1. LAYN deletion results in attenuated LFA-1-dependent cellular adhesion, and lineage-specific deletion of layilin on murine CD8+ T cells reduced their accumulation in tumors and increased tumor growth in vivo. Gene editing of LAYN in human CD8+ T cells reduced direct tumor cell killing ex vivo.","method":"Colocalization microscopy, cross-linking experiments, integrin activation assay, CRISPR gene editing in human T cells, conditional knockout in mice with tumor growth readout","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional experiments in both human and mouse systems, multiple orthogonal methods (colocalization, integrin activation assay, KO with defined cellular phenotype, ex vivo killing assay)","pmids":["32539073"],"is_preprint":false},{"year":2021,"finding":"Layilin expression on Tregs is induced by TCR-mediated activation in the presence of IL-2 or TGF-β. In vivo, layilin expression on Tregs exerts a cumulative anchoring/motility-limiting effect, reducing Treg dynamic motility in tissue. Conditional deletion of layilin in Tregs reduced their accumulation in tumors but paradoxically enhanced immune regulation (increased tumor growth), without affecting Treg activation or suppressive capacity in vitro.","method":"Conditional knockout mice (Treg-specific LAYN deletion), live in vivo motility imaging, in vitro Treg suppression assay, flow cytometry, TCR activation experiments with cytokine stimulation","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined in vivo phenotype, live imaging of motility, in vitro functional assay with multiple orthogonal methods in single lab","pmids":["34470859"],"is_preprint":false},{"year":2015,"finding":"Layilin (LAYN) is involved in TNF-α-induced epithelial-mesenchymal transformation (EMT) of renal tubular epithelial cells. TNF-α (but not TGF-β) upregulates LAYN expression, and knockdown of LAYN in KMRC-1 cells prevents TNF-α-induced vimentin upregulation, E-cadherin downregulation, and fibroblast-like morphological change. TGF-β-induced EMT was not affected by LAYN knockdown, indicating specificity to the TNF-α pathway.","method":"siRNA knockdown, qPCR, western blotting, immunocytochemistry, in vivo TNF-α administration in mice","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined cellular phenotype and specificity control (TGF-β negative result), single lab with multiple orthogonal methods","pmids":["26410531"],"is_preprint":false},{"year":2014,"finding":"Antibody-mediated cross-linking of the extracellular domain of layilin (LAYN) on chondrosarcoma cells enhances secretion of inflammatory factors IL-8 and complement C5/C5a. TNF-α upregulates LAYN expression in human articular chondrocytes. These findings establish LAYN as a receptor whose signaling promotes inflammatory mediator secretion in chondrocytes.","method":"Anti-LAYN antibody stimulation of extracellular domain, ELISA for cytokine secretion, qPCR, western blotting","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — antibody cross-linking functional assay and cytokine measurement, single lab, multiple readouts","pmids":["25150153"],"is_preprint":false},{"year":2012,"finding":"LAYN functions as a hyaluronan (HA) receptor in human articular chondrocytes. HA represses IL-1β-induced MMP-1 and MMP-13 production in chondrocytes, and this effect is significantly abrogated when LAYN is knocked down by siRNA, placing LAYN as a mediator of HA's anti-inflammatory/chondroprotective signaling. IL-1β suppresses LAYN expression in chondrocytes and synoviocytes.","method":"siRNA knockdown, ELISA for MMP-1 and MMP-13, IL-1β and TNFα stimulation experiments, in vitro cell culture","journal":"Modern rheumatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined molecular phenotype (MMP production), pathway placement (HA-LAYN-MMP axis), single lab with multiple orthogonal methods","pmids":["22722918"],"is_preprint":false},{"year":2023,"finding":"In colorectal cancer cells, hyaluronan oligosaccharides (oHA) activate LAYN by binding to the 60–68th amino acid region of its extracellular segment. oHA-induced LAYN activation promotes cancer cell metastasis and CCL20 secretion through the NF-κB pathway. A blocking antibody targeting LAYN prevents oHA-mediated tumor metastasis, tumor-associated macrophage (TAM) infiltration, and M2 macrophage polarization in vivo.","method":"Domain mapping (extracellular segment mutagenesis/binding assay), NF-κB pathway reporter, CCL20 ELISA, blocking antibody experiments, in vitro and in vivo metastasis assays","journal":"Matrix biology : journal of the International Society for Matrix Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding domain mapped, downstream pathway identified, blocking antibody with in vivo functional readout, single lab","pmids":["36805871"],"is_preprint":false},{"year":2024,"finding":"CREB1 binds to the LAYN promoter (validated by chromatin immunoprecipitation) and transcriptionally regulates LAYN expression. LAYN interacts with TLN1 (talin-1) as demonstrated by co-immunoprecipitation. The LAYN-TLN1 axis promotes β1 integrin signaling, including phosphorylation of c-Jun, p38 MAPK, and ERK, driving cholangiocarcinoma metastasis. Knockdown of LAYN suppressed EMT and metastasis in vivo in a nude mouse model.","method":"Chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP), western blot, KD/OE cell lines, CCK-8 and Transwell assays, nude mouse tail vein metastasis model, immunofluorescence","journal":"Heliyon","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for transcriptional regulation, Co-IP for protein interaction, KO with in vivo phenotype, single lab with multiple orthogonal methods","pmids":["39286102"],"is_preprint":false},{"year":2011,"finding":"LAYN was identified as a downstream effector of the p53-p21 and p16-pRB tumour suppressor pathways in mediating cellular senescence. Direct silencing of LAYN using lentiviral shRNAmirs bypassed senescence in conditionally immortalised human fibroblasts in which these pathways were activated.","method":"RNA interference screen, lentiviral shRNAmir knockdown, microarray expression profiling, conditional senescence induction system","journal":"BMC genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic epistasis via RNAi screen validated by direct knockdown with clear phenotypic readout (senescence bypass), single lab","pmids":["21740549"],"is_preprint":false},{"year":2015,"finding":"Knockdown of LAYN in human Tregs or overexpression in conventional T cells (Tconvs) affects Treg suppression activity in an in vitro human Treg suppression assay, implicating LAYN in the suppressive function of Tregs.","method":"siRNA knockdown in human Tregs, overexpression in Tconvs, in vitro suppression assay","journal":"Human immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single functional assay, limited mechanistic detail in abstract","pmids":["26686412"],"is_preprint":false},{"year":2022,"finding":"LAYN expression on CD8+ T cells is transcriptionally regulated by the upstream transcription factor NR4A1. Overexpression of LAYN in CD8+ T cells inhibited their killing function against tumor cells in co-culture. Low-dose anti-VEGFR2 antibody treatment downregulated LAYN expression on tumor-infiltrating CD8+ T cells, correlating with enhanced anti-tumor immunity.","method":"CD8+ T cell overexpression of LAYN, co-culture tumor killing assay, flow cytometry, in vivo anti-VEGFR2 treatment, NR4A1 transcription factor analysis","journal":"Cellular oncology (Dordrecht, Netherlands)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, overexpression + killing assay, NR4A1 regulatory link not fully mechanistically dissected in abstract","pmids":["36260222"],"is_preprint":false},{"year":2023,"finding":"Layilin/LAYN protein is expressed in the apical membrane regions or throughout motile cilia of multiciliated cells (MCCs), but is absent from primary cilia. LAYN silencing altered apical actin cap formation and multiciliogenesis in human, mouse, and pig MCC models, indicating a functional role in MCC formation.","method":"Single-cell RNA-seq, super-resolution microscopy, siRNA knockdown with multiciliogenesis phenotype readout","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by super-resolution microscopy tied to functional consequence (KD impairs multiciliogenesis and actin cap), multiple species, single lab","pmids":["37102425"],"is_preprint":false},{"year":2021,"finding":"Adhesion of invasive breast cancer cells (MDA-MB-231) to bone marrow-derived mesenchymal stem cells (bmMSCs) is facilitated by a tumor-cell-induced HA-rich matrix and is mediated by the HA receptor LAYN, as demonstrated in co-culture adhesion experiments.","method":"Co-culture adhesion assay, HA matrix manipulation, identification of LAYN as mediator of adhesion","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single adhesion assay, single lab, limited mechanistic dissection described in abstract","pmids":["34707175"],"is_preprint":false}],"current_model":"Layilin (LAYN) is a C-type lectin transmembrane receptor that functions as a hyaluronan receptor and cytoskeletal adaptor, promoting integrin activation (particularly LFA-1/αLβ2) to enhance cellular adhesion; in T cells it limits motility to anchor regulatory T cells in tissue and maintains cytotoxic CD8+ T cell killing potential; its expression is transcriptionally regulated by NR4A1 and CREB1, it interacts with talin-1 (TLN1) to activate β1 integrin/MAPK signaling driving cancer metastasis, and it acts downstream of the p53-p21 and p16-pRB pathways to mediate cellular senescence, with additional roles in TNF-α-induced EMT in renal epithelial cells, inflammatory cytokine secretion in chondrocytes, and multiciliated cell formation through apical actin cap organization."},"narrative":{"mechanistic_narrative":"Layilin (LAYN) is a transmembrane hyaluronan (HA) receptor that couples extracellular matrix sensing to integrin activation and cytoskeletal organization, governing cell adhesion, motility, and immune effector function [PMID:32539073, PMID:22722918, PMID:39286102]. In CD8+ T cells, LAYN colocalizes with integrin αLβ2 (LFA-1) and cross-linking drives LFA-1 into its activated extended state, so that LAYN loss attenuates LFA-1-dependent adhesion, reduces intratumoral T cell accumulation, and impairs direct tumor cell killing [PMID:32539073]; in regulatory T cells, activation-induced LAYN limits dynamic motility to anchor Tregs within tissue [PMID:34470859]. Intracellularly, LAYN interacts with talin-1 (TLN1) to drive β1 integrin signaling through c-Jun, p38 MAPK, and ERK phosphorylation, promoting EMT and cancer metastasis, with its expression controlled transcriptionally by CREB1 [PMID:39286102] and NR4A1 [PMID:36260222]. As an HA receptor, LAYN transduces matrix cues bidirectionally: HA signaling through LAYN represses IL-1β-induced MMP production in chondrocytes [PMID:22722918], whereas HA oligosaccharides binding the 60–68 amino acid region of its extracellular domain activate NF-κB-dependent CCL20 secretion and pro-metastatic macrophage recruitment [PMID:36805871]. LAYN additionally organizes the apical actin cap required for multiciliogenesis [PMID:37102425] and acts as a downstream effector of the p53-p21 and p16-pRB pathways in cellular senescence [PMID:21740549].","teleology":[{"year":2011,"claim":"Established LAYN as a functional output of tumor-suppressor pathways rather than a passive marker, by showing it is required to execute senescence.","evidence":"RNAi screen and lentiviral shRNAmir knockdown in conditionally immortalized human fibroblasts with senescence-bypass readout","pmids":["21740549"],"confidence":"Medium","gaps":["Mechanism linking LAYN to p53-p21/p16-pRB outputs not defined","No molecular partners identified in the senescence context"]},{"year":2012,"claim":"Identified LAYN as a hyaluronan receptor mediating HA's chondroprotective signaling, connecting matrix sensing to suppression of matrix-degrading enzymes.","evidence":"siRNA knockdown in human articular chondrocytes with ELISA readout of IL-1β-induced MMP-1/MMP-13","pmids":["22722918"],"confidence":"Medium","gaps":["Downstream signaling between LAYN and MMP repression not mapped","Direct HA binding not biochemically demonstrated here"]},{"year":2014,"claim":"Showed LAYN extracellular engagement actively drives inflammatory mediator secretion, framing it as a signaling receptor and not merely an adhesion molecule.","evidence":"Anti-LAYN antibody cross-linking of chondrosarcoma/chondrocyte extracellular domain with ELISA for IL-8 and C5/C5a","pmids":["25150153"],"confidence":"Medium","gaps":["Intracellular signaling pathway not defined","Cross-linking antibody may not reflect physiological ligand engagement"]},{"year":2015,"claim":"Linked LAYN to cytokine-specific epithelial plasticity, showing it is selectively required for TNF-α- but not TGF-β-induced EMT.","evidence":"siRNA knockdown in KMRC-1 renal tubular cells with EMT marker readouts and in vivo TNF-α administration","pmids":["26410531"],"confidence":"Medium","gaps":["How TNF-α selectively engages LAYN signaling unknown","Downstream EMT effectors of LAYN not identified"]},{"year":2015,"claim":"Implicated LAYN in the suppressive function of human Tregs through gain- and loss-of-function in suppression assays.","evidence":"siRNA knockdown in Tregs and overexpression in Tconvs with in vitro suppression assay","pmids":["26686412"],"confidence":"Low","gaps":["Single functional assay without mechanistic dissection","Effect on suppression not reconciled with later in vivo Treg findings"]},{"year":2020,"claim":"Defined the core molecular mechanism: LAYN colocalizes with and activates LFA-1 to drive T cell adhesion and antitumor cytotoxicity.","evidence":"Colocalization microscopy, cross-linking, integrin activation assay, CRISPR editing in human CD8+ T cells, and conditional knockout mice with tumor growth and ex vivo killing readouts","pmids":["32539073"],"confidence":"High","gaps":["Direct biochemical coupling between LAYN cytoplasmic tail and integrin machinery not resolved","Ligand driving LFA-1 activation in vivo unspecified"]},{"year":2021,"claim":"Resolved LAYN's role in Tregs as a tissue-anchoring/motility-limiting factor distinct from suppressive capacity, revealing a counterintuitive antitumor consequence of its deletion.","evidence":"Treg-specific conditional knockout mice with live in vivo motility imaging and in vitro suppression assays","pmids":["34470859"],"confidence":"High","gaps":["Molecular basis of motility restriction not defined","Tissue ligand anchoring Tregs unidentified"]},{"year":2021,"claim":"Extended LAYN's HA-receptor adhesion role to tumor-stroma interactions in breast cancer.","evidence":"Co-culture adhesion assay between MDA-MB-231 cells and bmMSCs with HA matrix manipulation","pmids":["34707175"],"confidence":"Low","gaps":["Single adhesion assay without mechanistic dissection","No demonstration of downstream signaling"]},{"year":2022,"claim":"Placed LAYN under NR4A1 transcriptional control and linked its expression to suppression of CD8+ T cell killing, with therapeutic modulation by anti-VEGFR2.","evidence":"LAYN overexpression in CD8+ T cells, co-culture killing assay, in vivo anti-VEGFR2 treatment, NR4A1 analysis","pmids":["36260222"],"confidence":"Low","gaps":["NR4A1-LAYN regulatory link not mechanistically dissected","Overexpression phenotype apparently opposite to knockout data, unreconciled"]},{"year":2023,"claim":"Mapped a discrete HA-oligosaccharide binding region on LAYN and connected its activation to NF-κB-driven chemokine secretion and pro-metastatic macrophage recruitment.","evidence":"Domain mapping/binding assays, NF-κB reporter, CCL20 ELISA, blocking antibody, and in vitro/in vivo metastasis assays in colorectal cancer","pmids":["36805871"],"confidence":"Medium","gaps":["Structural basis of oHA binding not resolved","Receptor proximal signaling to NF-κB not detailed"]},{"year":2023,"claim":"Revealed a cytoskeletal/morphogenetic function: LAYN organizes the apical actin cap required for multiciliated cell formation.","evidence":"Single-cell RNA-seq, super-resolution microscopy localizing LAYN to motile cilia, and siRNA knockdown impairing multiciliogenesis across human, mouse, and pig models","pmids":["37102425"],"confidence":"Medium","gaps":["Molecular link between LAYN and apical actin assembly not defined","Whether HA binding is involved in this role unknown"]},{"year":2024,"claim":"Provided the intracellular adaptor mechanism: LAYN binds talin-1 to drive β1 integrin/MAPK signaling and metastasis, under CREB1 transcriptional control.","evidence":"ChIP for CREB1 promoter binding, Co-IP for LAYN-TLN1, western blots of MAPK phosphorylation, knockdown/overexpression lines, and a nude mouse tail-vein metastasis model in cholangiocarcinoma","pmids":["39286102"],"confidence":"Medium","gaps":["LAYN-TLN1 interaction shown by single Co-IP without reciprocal/structural validation","Direct versus indirect nature of the interaction unresolved"]},{"year":null,"claim":"How LAYN cytoplasmic engagement of talin/integrin machinery is regulated and reconciled across opposing pro- and anti-tumor functions in different cell types remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the LAYN cytoplasmic tail-talin-integrin interface","Context-dependent switch between adhesion-promoting and motility-limiting outputs not explained","Physiological in vivo HA ligands for each role not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,11]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[4,5]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[6,10]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[10]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,5]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[4]}],"complexes":[],"partners":["ITGAL","ITGB2","TLN1","CREB1","NR4A1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6UX15","full_name":"Layilin","aliases":[],"length_aa":382,"mass_kda":43.1,"function":"Receptor for hyaluronate","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q6UX15/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LAYN","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LAYN","total_profiled":1310},"omim":[{"mim_id":"618843","title":"LAYILIN; LAYN","url":"https://www.omim.org/entry/618843"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LAYN"},"hgnc":{"alias_symbol":["FLJ30977","FLJ31092"],"prev_symbol":[]},"alphafold":{"accession":"Q6UX15","domains":[{"cath_id":"3.10.100.10","chopping":"41-187","consensus_level":"high","plddt":91.3923,"start":41,"end":187},{"cath_id":"1.20.5","chopping":"227-264","consensus_level":"medium","plddt":88.4868,"start":227,"end":264}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UX15","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UX15-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UX15-F1-predicted_aligned_error_v6.png","plddt_mean":68.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LAYN","jax_strain_url":"https://www.jax.org/strain/search?query=LAYN"},"sequence":{"accession":"Q6UX15","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6UX15.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6UX15/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UX15"}},"corpus_meta":[{"pmid":"27851914","id":"PMC_27851914","title":"Transcriptional 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LAYN deletion results in attenuated LFA-1-dependent cellular adhesion, and lineage-specific deletion of layilin on murine CD8+ T cells reduced their accumulation in tumors and increased tumor growth in vivo. Gene editing of LAYN in human CD8+ T cells reduced direct tumor cell killing ex vivo.\",\n      \"method\": \"Colocalization microscopy, cross-linking experiments, integrin activation assay, CRISPR gene editing in human T cells, conditional knockout in mice with tumor growth readout\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional experiments in both human and mouse systems, multiple orthogonal methods (colocalization, integrin activation assay, KO with defined cellular phenotype, ex vivo killing assay)\",\n      \"pmids\": [\"32539073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Layilin expression on Tregs is induced by TCR-mediated activation in the presence of IL-2 or TGF-β. In vivo, layilin expression on Tregs exerts a cumulative anchoring/motility-limiting effect, reducing Treg dynamic motility in tissue. Conditional deletion of layilin in Tregs reduced their accumulation in tumors but paradoxically enhanced immune regulation (increased tumor growth), without affecting Treg activation or suppressive capacity in vitro.\",\n      \"method\": \"Conditional knockout mice (Treg-specific LAYN deletion), live in vivo motility imaging, in vitro Treg suppression assay, flow cytometry, TCR activation experiments with cytokine stimulation\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined in vivo phenotype, live imaging of motility, in vitro functional assay with multiple orthogonal methods in single lab\",\n      \"pmids\": [\"34470859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Layilin (LAYN) is involved in TNF-α-induced epithelial-mesenchymal transformation (EMT) of renal tubular epithelial cells. TNF-α (but not TGF-β) upregulates LAYN expression, and knockdown of LAYN in KMRC-1 cells prevents TNF-α-induced vimentin upregulation, E-cadherin downregulation, and fibroblast-like morphological change. TGF-β-induced EMT was not affected by LAYN knockdown, indicating specificity to the TNF-α pathway.\",\n      \"method\": \"siRNA knockdown, qPCR, western blotting, immunocytochemistry, in vivo TNF-α administration in mice\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined cellular phenotype and specificity control (TGF-β negative result), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26410531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Antibody-mediated cross-linking of the extracellular domain of layilin (LAYN) on chondrosarcoma cells enhances secretion of inflammatory factors IL-8 and complement C5/C5a. TNF-α upregulates LAYN expression in human articular chondrocytes. These findings establish LAYN as a receptor whose signaling promotes inflammatory mediator secretion in chondrocytes.\",\n      \"method\": \"Anti-LAYN antibody stimulation of extracellular domain, ELISA for cytokine secretion, qPCR, western blotting\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — antibody cross-linking functional assay and cytokine measurement, single lab, multiple readouts\",\n      \"pmids\": [\"25150153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LAYN functions as a hyaluronan (HA) receptor in human articular chondrocytes. HA represses IL-1β-induced MMP-1 and MMP-13 production in chondrocytes, and this effect is significantly abrogated when LAYN is knocked down by siRNA, placing LAYN as a mediator of HA's anti-inflammatory/chondroprotective signaling. IL-1β suppresses LAYN expression in chondrocytes and synoviocytes.\",\n      \"method\": \"siRNA knockdown, ELISA for MMP-1 and MMP-13, IL-1β and TNFα stimulation experiments, in vitro cell culture\",\n      \"journal\": \"Modern rheumatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined molecular phenotype (MMP production), pathway placement (HA-LAYN-MMP axis), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22722918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In colorectal cancer cells, hyaluronan oligosaccharides (oHA) activate LAYN by binding to the 60–68th amino acid region of its extracellular segment. oHA-induced LAYN activation promotes cancer cell metastasis and CCL20 secretion through the NF-κB pathway. A blocking antibody targeting LAYN prevents oHA-mediated tumor metastasis, tumor-associated macrophage (TAM) infiltration, and M2 macrophage polarization in vivo.\",\n      \"method\": \"Domain mapping (extracellular segment mutagenesis/binding assay), NF-κB pathway reporter, CCL20 ELISA, blocking antibody experiments, in vitro and in vivo metastasis assays\",\n      \"journal\": \"Matrix biology : journal of the International Society for Matrix Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding domain mapped, downstream pathway identified, blocking antibody with in vivo functional readout, single lab\",\n      \"pmids\": [\"36805871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CREB1 binds to the LAYN promoter (validated by chromatin immunoprecipitation) and transcriptionally regulates LAYN expression. LAYN interacts with TLN1 (talin-1) as demonstrated by co-immunoprecipitation. The LAYN-TLN1 axis promotes β1 integrin signaling, including phosphorylation of c-Jun, p38 MAPK, and ERK, driving cholangiocarcinoma metastasis. Knockdown of LAYN suppressed EMT and metastasis in vivo in a nude mouse model.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP), western blot, KD/OE cell lines, CCK-8 and Transwell assays, nude mouse tail vein metastasis model, immunofluorescence\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for transcriptional regulation, Co-IP for protein interaction, KO with in vivo phenotype, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39286102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"LAYN was identified as a downstream effector of the p53-p21 and p16-pRB tumour suppressor pathways in mediating cellular senescence. Direct silencing of LAYN using lentiviral shRNAmirs bypassed senescence in conditionally immortalised human fibroblasts in which these pathways were activated.\",\n      \"method\": \"RNA interference screen, lentiviral shRNAmir knockdown, microarray expression profiling, conditional senescence induction system\",\n      \"journal\": \"BMC genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic epistasis via RNAi screen validated by direct knockdown with clear phenotypic readout (senescence bypass), single lab\",\n      \"pmids\": [\"21740549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Knockdown of LAYN in human Tregs or overexpression in conventional T cells (Tconvs) affects Treg suppression activity in an in vitro human Treg suppression assay, implicating LAYN in the suppressive function of Tregs.\",\n      \"method\": \"siRNA knockdown in human Tregs, overexpression in Tconvs, in vitro suppression assay\",\n      \"journal\": \"Human immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single functional assay, limited mechanistic detail in abstract\",\n      \"pmids\": [\"26686412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LAYN expression on CD8+ T cells is transcriptionally regulated by the upstream transcription factor NR4A1. Overexpression of LAYN in CD8+ T cells inhibited their killing function against tumor cells in co-culture. Low-dose anti-VEGFR2 antibody treatment downregulated LAYN expression on tumor-infiltrating CD8+ T cells, correlating with enhanced anti-tumor immunity.\",\n      \"method\": \"CD8+ T cell overexpression of LAYN, co-culture tumor killing assay, flow cytometry, in vivo anti-VEGFR2 treatment, NR4A1 transcription factor analysis\",\n      \"journal\": \"Cellular oncology (Dordrecht, Netherlands)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, overexpression + killing assay, NR4A1 regulatory link not fully mechanistically dissected in abstract\",\n      \"pmids\": [\"36260222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Layilin/LAYN protein is expressed in the apical membrane regions or throughout motile cilia of multiciliated cells (MCCs), but is absent from primary cilia. LAYN silencing altered apical actin cap formation and multiciliogenesis in human, mouse, and pig MCC models, indicating a functional role in MCC formation.\",\n      \"method\": \"Single-cell RNA-seq, super-resolution microscopy, siRNA knockdown with multiciliogenesis phenotype readout\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by super-resolution microscopy tied to functional consequence (KD impairs multiciliogenesis and actin cap), multiple species, single lab\",\n      \"pmids\": [\"37102425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Adhesion of invasive breast cancer cells (MDA-MB-231) to bone marrow-derived mesenchymal stem cells (bmMSCs) is facilitated by a tumor-cell-induced HA-rich matrix and is mediated by the HA receptor LAYN, as demonstrated in co-culture adhesion experiments.\",\n      \"method\": \"Co-culture adhesion assay, HA matrix manipulation, identification of LAYN as mediator of adhesion\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single adhesion assay, single lab, limited mechanistic dissection described in abstract\",\n      \"pmids\": [\"34707175\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Layilin (LAYN) is a C-type lectin transmembrane receptor that functions as a hyaluronan receptor and cytoskeletal adaptor, promoting integrin activation (particularly LFA-1/αLβ2) to enhance cellular adhesion; in T cells it limits motility to anchor regulatory T cells in tissue and maintains cytotoxic CD8+ T cell killing potential; its expression is transcriptionally regulated by NR4A1 and CREB1, it interacts with talin-1 (TLN1) to activate β1 integrin/MAPK signaling driving cancer metastasis, and it acts downstream of the p53-p21 and p16-pRB pathways to mediate cellular senescence, with additional roles in TNF-α-induced EMT in renal epithelial cells, inflammatory cytokine secretion in chondrocytes, and multiciliated cell formation through apical actin cap organization.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Layilin (LAYN) is a transmembrane hyaluronan (HA) receptor that couples extracellular matrix sensing to integrin activation and cytoskeletal organization, governing cell adhesion, motility, and immune effector function [#0, #4, #6]. In CD8+ T cells, LAYN colocalizes with integrin \\u03b1L\\u03b22 (LFA-1) and cross-linking drives LFA-1 into its activated extended state, so that LAYN loss attenuates LFA-1-dependent adhesion, reduces intratumoral T cell accumulation, and impairs direct tumor cell killing [#0]; in regulatory T cells, activation-induced LAYN limits dynamic motility to anchor Tregs within tissue [#1]. Intracellularly, LAYN interacts with talin-1 (TLN1) to drive \\u03b21 integrin signaling through c-Jun, p38 MAPK, and ERK phosphorylation, promoting EMT and cancer metastasis, with its expression controlled transcriptionally by CREB1 [#6] and NR4A1 [#9]. As an HA receptor, LAYN transduces matrix cues bidirectionally: HA signaling through LAYN represses IL-1\\u03b2-induced MMP production in chondrocytes [#4], whereas HA oligosaccharides binding the 60\\u201368 amino acid region of its extracellular domain activate NF-\\u03baB-dependent CCL20 secretion and pro-metastatic macrophage recruitment [#5]. LAYN additionally organizes the apical actin cap required for multiciliogenesis [#10] and acts as a downstream effector of the p53-p21 and p16-pRB pathways in cellular senescence [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established LAYN as a functional output of tumor-suppressor pathways rather than a passive marker, by showing it is required to execute senescence.\",\n      \"evidence\": \"RNAi screen and lentiviral shRNAmir knockdown in conditionally immortalized human fibroblasts with senescence-bypass readout\",\n      \"pmids\": [\"21740549\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking LAYN to p53-p21/p16-pRB outputs not defined\", \"No molecular partners identified in the senescence context\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified LAYN as a hyaluronan receptor mediating HA's chondroprotective signaling, connecting matrix sensing to suppression of matrix-degrading enzymes.\",\n      \"evidence\": \"siRNA knockdown in human articular chondrocytes with ELISA readout of IL-1\\u03b2-induced MMP-1/MMP-13\",\n      \"pmids\": [\"22722918\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling between LAYN and MMP repression not mapped\", \"Direct HA binding not biochemically demonstrated here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed LAYN extracellular engagement actively drives inflammatory mediator secretion, framing it as a signaling receptor and not merely an adhesion molecule.\",\n      \"evidence\": \"Anti-LAYN antibody cross-linking of chondrosarcoma/chondrocyte extracellular domain with ELISA for IL-8 and C5/C5a\",\n      \"pmids\": [\"25150153\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Intracellular signaling pathway not defined\", \"Cross-linking antibody may not reflect physiological ligand engagement\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked LAYN to cytokine-specific epithelial plasticity, showing it is selectively required for TNF-\\u03b1- but not TGF-\\u03b2-induced EMT.\",\n      \"evidence\": \"siRNA knockdown in KMRC-1 renal tubular cells with EMT marker readouts and in vivo TNF-\\u03b1 administration\",\n      \"pmids\": [\"26410531\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How TNF-\\u03b1 selectively engages LAYN signaling unknown\", \"Downstream EMT effectors of LAYN not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Implicated LAYN in the suppressive function of human Tregs through gain- and loss-of-function in suppression assays.\",\n      \"evidence\": \"siRNA knockdown in Tregs and overexpression in Tconvs with in vitro suppression assay\",\n      \"pmids\": [\"26686412\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single functional assay without mechanistic dissection\", \"Effect on suppression not reconciled with later in vivo Treg findings\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the core molecular mechanism: LAYN colocalizes with and activates LFA-1 to drive T cell adhesion and antitumor cytotoxicity.\",\n      \"evidence\": \"Colocalization microscopy, cross-linking, integrin activation assay, CRISPR editing in human CD8+ T cells, and conditional knockout mice with tumor growth and ex vivo killing readouts\",\n      \"pmids\": [\"32539073\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical coupling between LAYN cytoplasmic tail and integrin machinery not resolved\", \"Ligand driving LFA-1 activation in vivo unspecified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved LAYN's role in Tregs as a tissue-anchoring/motility-limiting factor distinct from suppressive capacity, revealing a counterintuitive antitumor consequence of its deletion.\",\n      \"evidence\": \"Treg-specific conditional knockout mice with live in vivo motility imaging and in vitro suppression assays\",\n      \"pmids\": [\"34470859\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of motility restriction not defined\", \"Tissue ligand anchoring Tregs unidentified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended LAYN's HA-receptor adhesion role to tumor-stroma interactions in breast cancer.\",\n      \"evidence\": \"Co-culture adhesion assay between MDA-MB-231 cells and bmMSCs with HA matrix manipulation\",\n      \"pmids\": [\"34707175\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single adhesion assay without mechanistic dissection\", \"No demonstration of downstream signaling\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed LAYN under NR4A1 transcriptional control and linked its expression to suppression of CD8+ T cell killing, with therapeutic modulation by anti-VEGFR2.\",\n      \"evidence\": \"LAYN overexpression in CD8+ T cells, co-culture killing assay, in vivo anti-VEGFR2 treatment, NR4A1 analysis\",\n      \"pmids\": [\"36260222\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"NR4A1-LAYN regulatory link not mechanistically dissected\", \"Overexpression phenotype apparently opposite to knockout data, unreconciled\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mapped a discrete HA-oligosaccharide binding region on LAYN and connected its activation to NF-\\u03baB-driven chemokine secretion and pro-metastatic macrophage recruitment.\",\n      \"evidence\": \"Domain mapping/binding assays, NF-\\u03baB reporter, CCL20 ELISA, blocking antibody, and in vitro/in vivo metastasis assays in colorectal cancer\",\n      \"pmids\": [\"36805871\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of oHA binding not resolved\", \"Receptor proximal signaling to NF-\\u03baB not detailed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a cytoskeletal/morphogenetic function: LAYN organizes the apical actin cap required for multiciliated cell formation.\",\n      \"evidence\": \"Single-cell RNA-seq, super-resolution microscopy localizing LAYN to motile cilia, and siRNA knockdown impairing multiciliogenesis across human, mouse, and pig models\",\n      \"pmids\": [\"37102425\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between LAYN and apical actin assembly not defined\", \"Whether HA binding is involved in this role unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided the intracellular adaptor mechanism: LAYN binds talin-1 to drive \\u03b21 integrin/MAPK signaling and metastasis, under CREB1 transcriptional control.\",\n      \"evidence\": \"ChIP for CREB1 promoter binding, Co-IP for LAYN-TLN1, western blots of MAPK phosphorylation, knockdown/overexpression lines, and a nude mouse tail-vein metastasis model in cholangiocarcinoma\",\n      \"pmids\": [\"39286102\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"LAYN-TLN1 interaction shown by single Co-IP without reciprocal/structural validation\", \"Direct versus indirect nature of the interaction unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LAYN cytoplasmic engagement of talin/integrin machinery is regulated and reconciled across opposing pro- and anti-tumor functions in different cell types remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the LAYN cytoplasmic tail-talin-integrin interface\", \"Context-dependent switch between adhesion-promoting and motility-limiting outputs not explained\", \"Physiological in vivo HA ligands for each role not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 11]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [6, 10]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 5]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ITGAL\", \"ITGB2\", \"TLN1\", \"CREB1\", \"NR4A1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":5,"faith_pct":100.0}}