{"gene":"LAMA3","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1991,"finding":"Epiligrin (LAMA3-containing complex) is a direct adhesion ligand for integrin α3β1 in epithelial basement membranes; immunopurified epiligrin induced cell adhesion and localization of integrin α3β1 in focal adhesions, and adhesion was blocked by anti-α3β1 antibody. Epiligrin also colocalized with integrin α6β4 in hemidesmosome-like stable anchoring contacts (SACs), forming a complex adhesion superstructure.","method":"Immunopurification, cell adhesion assay, monoclonal antibody blocking, immunolocalization/co-localization","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal inhibition with blocking antibodies, immunopurified ligand used in functional adhesion assay, replicated across multiple cell types and tissues","pmids":["2032285"],"is_preprint":false},{"year":1992,"finding":"Blocking integrin α3β1 (the epiligrin receptor) uniquely enhanced keratinocyte migration on fibronectin and collagen matrices, indicating that α3β1–epiligrin interaction is associated with immobility rather than motility, defining an anti-migratory function for this receptor–ligand pair.","method":"Keratinocyte migration assay with monospecific blocking antibodies against integrin subunits","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean functional assay with specific antibody blocking, single lab, two integrin subunits tested in parallel as controls","pmids":["1569325"],"is_preprint":false},{"year":1993,"finding":"Epiligrin (LAMA3-containing ECM) is an adhesion ligand for α3β1-positive T lymphocytes; adhesion was inhibitable by anti-α3 and anti-β1 antibodies and by an anti-epiligrin monoclonal antibody (P3H9-2), and could be upregulated by activating anti-β1 antibodies, demonstrating affinity-regulated binding.","method":"Cell adhesion assay with blocking monoclonal antibodies, flow cytometry, immunohistochemistry of patient skin biopsies","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional adhesion assay with reciprocal antibody inhibition, single lab, multiple antibody controls","pmids":["8501119"],"is_preprint":false},{"year":1994,"finding":"The LamA3 gene encodes two distinct transcripts (α3EpA and α3EpB) with structural homology to laminin α1 and α2 chains from domain IIIa through the C-terminal G domain; the G domain contains five subdomains individually related to G subdomains of other laminin α chains, with sequence divergence suggesting functional distinctiveness from other laminins. The LAMA3 gene maps to chromosome 18q11.2.","method":"cDNA cloning and sequencing, fluorescence in situ hybridization (FISH), Northern hybridization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct sequencing of multiple independent cDNA clones, chromosomal mapping by FISH, structural analysis with domain assignment","pmids":["8077230"],"is_preprint":false},{"year":1995,"finding":"Anchorage of integrin α6β4 to laminin 5 (epiligrin) specifically regulates tyrosine phosphorylation of a membrane-associated 80-kD protein (p80); dissociation of α6β4 from laminin 5 induced p80 phosphorylation, while blocking α3β1 function did not affect p80 phosphorylation, identifying a distinct α6β4-specific signaling event downstream of laminin 5 binding. A kinase activity for p80 phosphorylation was identified in suspended HFKs but not attached cells.","method":"Low-temperature adhesion system, immunoprecipitation/phosphorylation assays, blocking antibodies against integrin subunits, cytochalasin D treatment, in vitro kinase assay, subcellular fractionation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay, multiple orthogonal approaches (pharmacological, antibody blocking, fractionation), subcellular localization with functional consequence","pmids":["8647901"],"is_preprint":false},{"year":1995,"finding":"Keratinocyte adhesion to purified epiligrin (but not other matrix components) specifically reduces involucrin expression induced by anti-α3β1 antibody (P1B5), demonstrating that epiligrin–α3β1 interaction inhibits α3β1-mediated epidermal differentiation.","method":"Culture on purified epiligrin, antibody-triggered differentiation assay, involucrin expression measurement","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assay on purified ligand vs. other ECM components, single lab, defined molecular readout","pmids":["7769020"],"is_preprint":false},{"year":1999,"finding":"Targeted disruption of the LAMA3 gene in mice (removing all α3-laminin isoforms from epithelial BMs) caused: (1) failure of integrin α6β4 to form stable adhesion to mutant BM, consistent with hemidesmosome loss; (2) epithelial cell survival defect rescuable by exogenous laminin 5, collagen, or anti-integrin α6β4 antibody, indicating signaling through β1 or β4 integrins is sufficient for survival; (3) ameloblast differentiation defects; and (4) emergence of an alternative α3β1 ligand in the epidermal BM in the absence of laminin 5.","method":"Gene targeting/knockout, novel tissue adhesion assay, survival rescue experiments with exogenous matrix proteins and antibodies, histology, electron microscopy","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — constitutive knockout with multiple defined phenotypic readouts and rescue experiments using orthogonal reagents (exogenous protein, antibody), well-controlled study","pmids":["10366601"],"is_preprint":false},{"year":2002,"finding":"The lama3 gene promoter contains a non-canonical E-box bound by USF-1 following UV stress; USF-1 binding relieves repression of lama3 in fibroblasts (where a repressor complex normally silences the gene), while expression remains constitutively high in keratinocytes. An epithelial enhancer with AP-1 binding sites controls cell-type-specific lama3 expression. Chromatin immunoprecipitation confirmed UV-induced USF binding to the lama3 promoter in vivo.","method":"Chromatin immunoprecipitation (ChIP), reporter assays, UV stress induction, promoter deletion/mutagenesis analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP demonstrating in vivo promoter binding, reporter assays, multiple orthogonal methods in one study","pmids":["11937633"],"is_preprint":false},{"year":2006,"finding":"Targeted disruption of lama3 in mice arrested glomerular maturation at the early capillary loop stage: endothelial cells failed to attenuate, develop fenestrae, or form lumens, and mesangial cells were absent. LAMA3 protein was localized to the basement membrane adjacent to glomerular endothelial cells (GEnCs), and lama3 mRNA/protein were identified in isolated glomeruli and cultured GEnCs but not in mesangial cells, establishing a required role for LAMA3 in GEnC differentiation and mesangial cell migration.","method":"Gene knockout mouse model, immunohistochemistry/protein localization, in situ hybridization, cell fractionation of isolated glomeruli, cultured GEnCs","journal":"Kidney international","confidence":"High","confidence_rationale":"Tier 2 / Moderate — constitutive knockout with defined developmental arrest phenotype, protein localization by multiple methods, cell-type-specific expression validated in isolated primary cells","pmids":["16850021"],"is_preprint":false},{"year":2016,"finding":"Conditional disruption of the Lama3 gene in basal keratinocytes of adult mice caused gradual loss of α3 chain-containing laminins at the dermal-epidermal junction, subepidermal blistering, nail loss, skin inflammation, and fibrosis with extensive accumulation of interstitial and microfibrillar collagens and scattered collagen VII deposition, demonstrating that α3-laminin isoforms are required for adult skin homeostasis.","method":"Conditional/inducible gene knockout in adult mice, histology, immunofluorescence, collagen staining","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — inducible conditional knockout with defined molecular and phenotypic consequences, multiple histological readouts","pmids":["27729280"],"is_preprint":false},{"year":2016,"finding":"Heterozygous functional null mutations in LAMA3 cause localized enamel pitting (haploinsufficiency) in the absence of skin blistering, demonstrating that a half-dose of laminin α3 chain is insufficient for normal enamel formation, establishing a dosage-sensitive role for LAMA3 in amelogenesis.","method":"Clinical phenotyping of heterozygous carriers, molecular analysis (identification of nonsense c.2377C>T and splice-site c.4684+1G>A mutations), family segregation analysis","journal":"European journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetic loss-of-function with defined phenotype, two independent mutations showing same phenotype, family segregation confirmed","pmids":["27827380"],"is_preprint":false},{"year":2019,"finding":"LINC00628 recruits DNMT1, DNMT3A, and DNMT3B to the LAMA3 promoter, promoting CpG methylation and silencing LAMA3 expression; LINC00628 silencing reduced LAMA3 promoter methylation and restored its expression, with functional consequences including decreased lung adenocarcinoma cell proliferation, migration, invasion, and vincristine resistance.","method":"ChIP assay (DNMT recruitment), pyrosequencing (methylation), siRNA knockdown, 5-azacytidine treatment, cell functional assays, in vivo xenograft","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating DNMT recruitment, methylation quantified by pyrosequencing, functional rescue with methylation inhibitor, single lab","pmids":["31557618"],"is_preprint":false},{"year":2024,"finding":"METTL3 upregulates LAMA3 expression via N6-methyladenosine (m6A) modification-dependent stabilization of LAMA3 transcripts in oral squamous cell carcinoma; methylated RNA immunoprecipitation and mRNA stability assays confirmed this regulatory mechanism, and low METTL3 partially reversed the enhanced malignant phenotype induced by LAMA3 overexpression.","method":"Methylated RNA immunoprecipitation (MeRIP), mRNA stability assay, siRNA knockdown, cell functional assays, RT-qPCR","journal":"Critical reviews in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP plus mRNA stability assay establishes m6A-dependent mechanism, single lab, rescue experiment performed","pmids":["38305336"],"is_preprint":false},{"year":2025,"finding":"LAMA3 knockdown sensitizes colon cancer cells to oxaliplatin by modulating the Hippo-YAP pathway; overexpression of YAP counteracted the enhanced oxaliplatin sensitivity caused by LAMA3 knockdown, placing LAMA3 upstream of YAP in regulating drug resistance. This was confirmed in vitro and in CC xenograft models.","method":"siRNA knockdown, YAP overexpression rescue, western blot (pathway analysis), KEGG enrichment, in vivo xenograft","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via rescue experiment (YAP OE reverting LAMA3-KD phenotype), pathway placement, in vivo confirmation, single lab","pmids":["39798821"],"is_preprint":false},{"year":2025,"finding":"SPI1 (PU.1) transcription factor binds to the LAMA3 promoter and directly activates its transcription in esophageal squamous cell carcinoma, as demonstrated by ChIP and dual luciferase reporter assays; LAMA3 silencing suppressed tumor growth, angiogenesis (tube formation), and induced ferroptosis and oxidative stress in ESCC cells.","method":"ChIP assay, dual luciferase reporter assay, siRNA knockdown, CCK-8/EdU/colony formation, tube formation assay, in vivo xenograft, ferroptosis/oxidative stress markers","journal":"General physiology and biophysics","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — ChIP and dual-luciferase confirm direct promoter binding and transcriptional activation, multiple functional readouts, single lab","pmids":["41217226"],"is_preprint":false},{"year":2025,"finding":"HEYL binds to the LAMA3 promoter and activates its transcription; in vitro and in vivo rescue experiments demonstrated that HEYL-mediated transcriptional activation of LAMA3 reduces esophageal cancer radiosensitivity by inducing the epithelial-to-mesenchymal transition (EMT) pathway.","method":"Chromatin binding assay (HEYL-LAMA3 promoter interaction), RT-qPCR, western blot, transwell/wound healing/CCK-8/EdU assays, in vivo radioresistant model, immunofluorescence","journal":"Esophagus","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcription factor-promoter interaction with functional rescue demonstrating pathway placement, in vivo confirmation, single lab","pmids":["40833662"],"is_preprint":false},{"year":2025,"finding":"miR-212-5p directly targets LAMA3 (and LAMC2), as demonstrated by dual-luciferase reporter assay; LAMA3 positively regulates the PI3K-AKT pathway and negatively regulates the NF-κB pathway, thereby controlling PM2.5-induced apoptosis rates.","method":"Dual-luciferase reporter assay (direct miRNA target validation), pathway western blot, apoptosis flow cytometry","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual-luciferase establishes direct miRNA–LAMA3 3'UTR interaction, pathway modulation shown by western blot, single lab","pmids":["40004224"],"is_preprint":false},{"year":2025,"finding":"Mosaic epidermal-specific loss of laminin-α3β3γ2 (Lama3) in embryonic mice, generated by in utero lentiviral delivery, increases keratinocyte delamination (basal-to-suprabasal transition) without causing epidermal-dermal separation embryonically, demonstrating a causal role for hemidesmosomal laminin in regulating epidermal differentiation through the delamination mechanism.","method":"In utero lentiviral-mediated mosaic knockout, live imaging/cell tracking, immunofluorescence, cell division orientation analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean mosaic loss-of-function with defined differentiation readout in embryonic skin, preprint not yet peer-reviewed, single lab","pmids":[],"is_preprint":true}],"current_model":"LAMA3 encodes the α3 chain of laminin-332 (laminin 5/epiligrin), a basement membrane glycoprotein that serves as a direct extracellular ligand for integrin α3β1 (promoting focal adhesion and inhibiting keratinocyte migration) and integrin α6β4 (anchoring hemidesmosomes and triggering specific tyrosine phosphorylation signaling via a membrane-associated 80-kDa kinase substrate); it is required for epithelial survival, differentiation, enamel formation, and glomerular maturation as established by knockout and rescue experiments, and its expression is regulated at the transcriptional level by AP-1/USF-1 on a non-canonical E-box, by DNMT-mediated CpG methylation recruited by LINC00628, by m6A modification via METTL3, and by transcription factors SPI1 and HEYL, while functionally it modulates the Hippo-YAP pathway to influence drug resistance and the EMT pathway to influence radiosensitivity."},"narrative":{"mechanistic_narrative":"LAMA3 encodes the α3 chain of laminin-332 (epiligrin/laminin 5), a basement membrane glycoprotein that functions as a direct extracellular adhesion ligand coordinating epithelial attachment, differentiation, and survival [PMID:2032285, PMID:10366601]. As immunopurified epiligrin it engages integrin α3β1 to drive focal adhesion and suppress keratinocyte migration—marking this receptor–ligand pair as anti-migratory—while colocalizing with integrin α6β4 in hemidesmosome-like stable anchoring contacts [PMID:2032285, PMID:1569325]. Anchorage of α6β4 to laminin 5 governs a distinct signaling event: dissociation of α6β4 from the ligand triggers tyrosine phosphorylation of a membrane-associated 80-kDa substrate by a kinase active in suspended keratinocytes, a pathway not affected by α3β1 blockade [PMID:8647901]. Adhesion through α3β1 also restrains epidermal differentiation by reducing involucrin induction [PMID:7769020]. The gene produces α3EpA and α3EpB transcripts whose C-terminal G domain is structurally related to other laminin α chains, and it maps to chromosome 18q11.2 [PMID:8077230]. Genetic ablation in mice establishes its physiological requirements: loss eliminates stable α6β4 adhesion and hemidesmosomes, impairs epithelial survival (rescuable by exogenous laminin 5, collagen, or anti-α6β4 antibody), and disrupts ameloblast differentiation [PMID:10366601]; conditional adult deletion causes subepidermal blistering, skin inflammation, and fibrosis [PMID:27729280]; and disruption arrests glomerular maturation, with LAMA3 required for glomerular endothelial cell differentiation and mesangial cell migration [PMID:16850021]. Human haploinsufficiency causes localized enamel pitting, defining a dosage-sensitive role in amelogenesis [PMID:27827380]. LAMA3 transcription is regulated cell-type-specifically through an AP-1 epithelial enhancer and UV-induced USF-1 binding at a non-canonical promoter E-box [PMID:11937633], and in cancer contexts by LINC00628-recruited DNMT-mediated CpG methylation [PMID:31557618], METTL3-dependent m6A stabilization [PMID:38305336], miR-212-5p targeting [PMID:40004224], and the transcription factors SPI1 and HEYL [PMID:41217226, PMID:40833662]; through these routes LAMA3 modulates Hippo-YAP signaling to influence oxaliplatin resistance [PMID:39798821] and EMT to influence radiosensitivity [PMID:40833662].","teleology":[{"year":1991,"claim":"Established that the LAMA3-containing complex epiligrin is a bona fide extracellular adhesion ligand, identifying integrin α3β1 as its focal-adhesion receptor and α6β4 as a co-localizing partner in stable anchoring contacts.","evidence":"Immunopurified epiligrin in cell adhesion assays with reciprocal antibody blocking and immunolocalization across cell types","pmids":["2032285"],"confidence":"High","gaps":["Did not resolve which laminin domain mediates α3β1 versus α6β4 engagement","Functional consequence of dual-receptor superstructure not yet defined"]},{"year":1992,"claim":"Defined the cellular consequence of α3β1–epiligrin binding by showing it immobilizes keratinocytes, framing this pair as anti-migratory rather than promotile.","evidence":"Keratinocyte migration assays with monospecific integrin-blocking antibodies on multiple matrices","pmids":["1569325"],"confidence":"Medium","gaps":["Single-lab finding","Downstream signaling controlling immobility not identified"]},{"year":1993,"claim":"Extended epiligrin–α3β1 adhesion beyond epithelium to T lymphocytes and demonstrated it is affinity-regulated, indicating activation-state control of the interaction.","evidence":"Adhesion assays with reciprocal and activating anti-β1 antibodies, flow cytometry, patient biopsy immunohistochemistry","pmids":["8501119"],"confidence":"Medium","gaps":["Physiological role of lymphocyte adhesion to epiligrin unclear","Mechanism of affinity regulation not resolved"]},{"year":1994,"claim":"Resolved the molecular identity of LAMA3, defining its two transcripts, conserved G-domain architecture, and chromosomal location.","evidence":"cDNA cloning and sequencing of independent clones, FISH mapping, Northern hybridization","pmids":["8077230"],"confidence":"High","gaps":["Functional distinctness of α3EpA vs α3EpB not tested","G-domain ligand specificities not assigned"]},{"year":1995,"claim":"Separated α6β4 signaling from α3β1 by showing that α6β4 anchorage to laminin 5 specifically controls phosphorylation of an 80-kDa membrane substrate, revealing distinct receptor-specific signaling outputs from a single ligand.","evidence":"Low-temperature adhesion, immunoprecipitation/phosphorylation and in vitro kinase assays, antibody blocking, subcellular fractionation","pmids":["8647901"],"confidence":"High","gaps":["Molecular identity of the 80-kDa substrate and its kinase not determined","Downstream functional consequence of p80 phosphorylation unknown"]},{"year":1995,"claim":"Linked α3β1–epiligrin adhesion to control of epidermal differentiation by showing it suppresses antibody-induced involucrin expression.","evidence":"Culture on purified epiligrin versus other ECM with antibody-triggered differentiation readout","pmids":["7769020"],"confidence":"Medium","gaps":["Signaling pathway connecting adhesion to involucrin repression not mapped","Single defined differentiation marker tested"]},{"year":1999,"claim":"Established the in vivo requirements for LAMA3 in epithelial biology, showing it is needed for hemidesmosome-mediated α6β4 adhesion, epithelial survival, and ameloblast differentiation, and that survival signaling can be supplied via β1/β4 integrins.","evidence":"Constitutive knockout mouse with tissue adhesion assays and rescue using exogenous matrix proteins and anti-α6β4 antibody, histology, EM","pmids":["10366601"],"confidence":"High","gaps":["Identity of the alternative α3β1 ligand emerging in knockout BM unknown","Mechanism linking adhesion to survival not fully defined"]},{"year":2002,"claim":"Defined cell-type-specific transcriptional control of LAMA3 through an AP-1 epithelial enhancer and UV-stress-induced USF-1 binding at a non-canonical promoter E-box that relieves fibroblast repression.","evidence":"ChIP demonstrating in vivo USF binding, reporter assays, UV induction, promoter mutagenesis","pmids":["11937633"],"confidence":"High","gaps":["Composition of the fibroblast repressor complex not identified","Physiological role of UV-induced upregulation not established"]},{"year":2006,"claim":"Revealed a developmental role beyond skin, showing LAMA3 is required for glomerular endothelial cell differentiation and mesangial cell migration during kidney maturation.","evidence":"Knockout mouse with developmental arrest phenotype, protein localization, in situ hybridization, primary GEnC culture","pmids":["16850021"],"confidence":"High","gaps":["Receptor mediating LAMA3 effects on GEnCs not identified","Mechanism of mesangial cell recruitment unresolved"]},{"year":2016,"claim":"Demonstrated that α3-laminins are required for adult skin homeostasis, not only development, with their loss driving blistering, inflammation, and collagen-rich fibrosis.","evidence":"Inducible conditional knockout in adult mouse keratinocytes with histology, immunofluorescence, collagen staining","pmids":["27729280"],"confidence":"High","gaps":["Mechanism linking laminin loss to fibrotic collagen accumulation not defined","Contribution of inflammation versus direct adhesion loss unresolved"]},{"year":2016,"claim":"Established LAMA3 dosage sensitivity in humans, showing heterozygous null mutations cause enamel pitting in the absence of blistering.","evidence":"Clinical phenotyping, identification of nonsense and splice-site mutations, family segregation","pmids":["27827380"],"confidence":"Medium","gaps":["Tissue-specific threshold explaining enamel-only phenotype not defined","Molecular mechanism of amelogenesis dependence unresolved"]},{"year":2024,"claim":"Identified post-transcriptional control of LAMA3 by METTL3-mediated m6A modification that stabilizes its transcripts and promotes malignant phenotype in oral squamous cell carcinoma.","evidence":"MeRIP, mRNA stability assay, siRNA knockdown with rescue, functional assays","pmids":["38305336"],"confidence":"Medium","gaps":["m6A reader mediating stabilization not identified","Single cancer context"]},{"year":2025,"claim":"Placed LAMA3 upstream of Hippo-YAP signaling in controlling chemoresistance, showing its knockdown sensitizes colon cancer to oxaliplatin in a YAP-dependent manner.","evidence":"siRNA knockdown with YAP overexpression epistasis rescue, western blot, xenograft","pmids":["39798821"],"confidence":"Medium","gaps":["Molecular link between extracellular LAMA3 and intracellular YAP not defined","Single-lab finding"]},{"year":2025,"claim":"Identified additional transcriptional and microRNA regulators (SPI1, HEYL, miR-212-5p) controlling LAMA3 expression and linked LAMA3 to EMT-driven radioresistance, PI3K-AKT/NF-κB signaling, and tumor angiogenesis/ferroptosis.","evidence":"ChIP, dual-luciferase reporter assays, knockdown with rescue, pathway western blots, functional and xenograft assays","pmids":["41217226","40833662","40004224"],"confidence":"Medium","gaps":["Mechanism connecting secreted laminin to intracellular signaling pathways not established","Findings each from single labs in distinct cancer types"]},{"year":2025,"claim":"Refined the role of hemidesmosomal laminin in differentiation, showing embryonic mosaic Lama3 loss increases keratinocyte delamination without embryonic epidermal-dermal separation.","evidence":"In utero lentiviral mosaic knockout with live imaging and division-orientation analysis (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Signaling controlling delamination downstream of laminin not defined"]},{"year":null,"claim":"How the membrane-proximal signaling outputs of laminin-332 (the 80-kDa substrate and its kinase) connect mechanistically to the intracellular pathways modulating cancer phenotypes (Hippo-YAP, PI3K-AKT, NF-κB, EMT) remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["Identity of the 80-kDa substrate/kinase still unknown","No mechanistic bridge between extracellular adhesion and intracellular oncogenic signaling established","Receptor usage in non-epithelial and tumor contexts not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,3,6]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0030312","term_label":"external encapsulating structure","supporting_discovery_ids":[0,6,8]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,8,9]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,6,9]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6,8]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,4]}],"complexes":["laminin-332 (laminin 5/epiligrin)","hemidesmosome"],"partners":["ITGA3","ITGB1","ITGA6","ITGB4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q16787","full_name":"Laminin subunit alpha-3","aliases":["Epiligrin 170 kDa subunit","E170","Epiligrin subunit alpha","Kalinin subunit alpha","Laminin-5 subunit alpha","Laminin-6 subunit alpha","Laminin-7 subunit alpha","Nicein subunit alpha"],"length_aa":3333,"mass_kda":366.6,"function":"Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components Laminin-5 is thought to be involved in (1) cell adhesion via integrin alpha-3/beta-1 in focal adhesion and integrin alpha-6/beta-4 in hemidesmosomes, (2) signal transduction via tyrosine phosphorylation of pp125-FAK and p80, (3) differentiation of keratinocytes","subcellular_location":"Secreted, extracellular space, extracellular matrix, basement membrane","url":"https://www.uniprot.org/uniprotkb/Q16787/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LAMA3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LAMA3","total_profiled":1310},"omim":[{"mim_id":"621324","title":"SECRETORY CALCIUM-BINDING PHOSPHOPROTEIN, PROLINE- AND GLUTAMINE-RICH, 1; SCPPPQ1","url":"https://www.omim.org/entry/621324"},{"mim_id":"619784","title":"EPIDERMOLYSIS BULLOSA, JUNCTIONAL 2B, SEVERE; JEB2B","url":"https://www.omim.org/entry/619784"},{"mim_id":"619783","title":"EPIDERMOLYSIS BULLOSA, JUNCTIONAL 2A, INTERMEDIATE; JEB2A","url":"https://www.omim.org/entry/619783"},{"mim_id":"600805","title":"LAMININ, ALPHA-3; LAMA3","url":"https://www.omim.org/entry/600805"},{"mim_id":"600133","title":"LAMININ, ALPHA-4; LAMA4","url":"https://www.omim.org/entry/600133"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LAMA3"},"hgnc":{"alias_symbol":["nicein-150kDa","kalinin-165kDa","BM600-150kDa","epiligrin"],"prev_symbol":["LAMNA"]},"alphafold":{"accession":"Q16787","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16787","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q16787-4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q16787-4-F1-predicted_aligned_error_v6.png","plddt_mean":73.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LAMA3","jax_strain_url":"https://www.jax.org/strain/search?query=LAMA3"},"sequence":{"accession":"Q16787","fasta_url":"https://rest.uniprot.org/uniprotkb/Q16787.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q16787/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16787"}},"corpus_meta":[{"pmid":"2032285","id":"PMC_2032285","title":"Epiligrin, a new cell adhesion ligand for integrin alpha 3 beta 1 in epithelial basement membranes.","date":"1991","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/2032285","citation_count":715,"is_preprint":false},{"pmid":"10366601","id":"PMC_10366601","title":"Targeted disruption of the LAMA3 gene in mice reveals abnormalities in survival and late stage differentiation of epithelial cells.","date":"1999","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/10366601","citation_count":262,"is_preprint":false},{"pmid":"8077230","id":"PMC_8077230","title":"Cloning of the LamA3 gene encoding the alpha 3 chain of the adhesive ligand epiligrin. 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Epiligrin also colocalized with integrin α6β4 in hemidesmosome-like stable anchoring contacts (SACs), forming a complex adhesion superstructure.\",\n      \"method\": \"Immunopurification, cell adhesion assay, monoclonal antibody blocking, immunolocalization/co-localization\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal inhibition with blocking antibodies, immunopurified ligand used in functional adhesion assay, replicated across multiple cell types and tissues\",\n      \"pmids\": [\"2032285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Blocking integrin α3β1 (the epiligrin receptor) uniquely enhanced keratinocyte migration on fibronectin and collagen matrices, indicating that α3β1–epiligrin interaction is associated with immobility rather than motility, defining an anti-migratory function for this receptor–ligand pair.\",\n      \"method\": \"Keratinocyte migration assay with monospecific blocking antibodies against integrin subunits\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean functional assay with specific antibody blocking, single lab, two integrin subunits tested in parallel as controls\",\n      \"pmids\": [\"1569325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Epiligrin (LAMA3-containing ECM) is an adhesion ligand for α3β1-positive T lymphocytes; adhesion was inhibitable by anti-α3 and anti-β1 antibodies and by an anti-epiligrin monoclonal antibody (P3H9-2), and could be upregulated by activating anti-β1 antibodies, demonstrating affinity-regulated binding.\",\n      \"method\": \"Cell adhesion assay with blocking monoclonal antibodies, flow cytometry, immunohistochemistry of patient skin biopsies\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional adhesion assay with reciprocal antibody inhibition, single lab, multiple antibody controls\",\n      \"pmids\": [\"8501119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The LamA3 gene encodes two distinct transcripts (α3EpA and α3EpB) with structural homology to laminin α1 and α2 chains from domain IIIa through the C-terminal G domain; the G domain contains five subdomains individually related to G subdomains of other laminin α chains, with sequence divergence suggesting functional distinctiveness from other laminins. The LAMA3 gene maps to chromosome 18q11.2.\",\n      \"method\": \"cDNA cloning and sequencing, fluorescence in situ hybridization (FISH), Northern hybridization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct sequencing of multiple independent cDNA clones, chromosomal mapping by FISH, structural analysis with domain assignment\",\n      \"pmids\": [\"8077230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Anchorage of integrin α6β4 to laminin 5 (epiligrin) specifically regulates tyrosine phosphorylation of a membrane-associated 80-kD protein (p80); dissociation of α6β4 from laminin 5 induced p80 phosphorylation, while blocking α3β1 function did not affect p80 phosphorylation, identifying a distinct α6β4-specific signaling event downstream of laminin 5 binding. A kinase activity for p80 phosphorylation was identified in suspended HFKs but not attached cells.\",\n      \"method\": \"Low-temperature adhesion system, immunoprecipitation/phosphorylation assays, blocking antibodies against integrin subunits, cytochalasin D treatment, in vitro kinase assay, subcellular fractionation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay, multiple orthogonal approaches (pharmacological, antibody blocking, fractionation), subcellular localization with functional consequence\",\n      \"pmids\": [\"8647901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Keratinocyte adhesion to purified epiligrin (but not other matrix components) specifically reduces involucrin expression induced by anti-α3β1 antibody (P1B5), demonstrating that epiligrin–α3β1 interaction inhibits α3β1-mediated epidermal differentiation.\",\n      \"method\": \"Culture on purified epiligrin, antibody-triggered differentiation assay, involucrin expression measurement\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assay on purified ligand vs. other ECM components, single lab, defined molecular readout\",\n      \"pmids\": [\"7769020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Targeted disruption of the LAMA3 gene in mice (removing all α3-laminin isoforms from epithelial BMs) caused: (1) failure of integrin α6β4 to form stable adhesion to mutant BM, consistent with hemidesmosome loss; (2) epithelial cell survival defect rescuable by exogenous laminin 5, collagen, or anti-integrin α6β4 antibody, indicating signaling through β1 or β4 integrins is sufficient for survival; (3) ameloblast differentiation defects; and (4) emergence of an alternative α3β1 ligand in the epidermal BM in the absence of laminin 5.\",\n      \"method\": \"Gene targeting/knockout, novel tissue adhesion assay, survival rescue experiments with exogenous matrix proteins and antibodies, histology, electron microscopy\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — constitutive knockout with multiple defined phenotypic readouts and rescue experiments using orthogonal reagents (exogenous protein, antibody), well-controlled study\",\n      \"pmids\": [\"10366601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The lama3 gene promoter contains a non-canonical E-box bound by USF-1 following UV stress; USF-1 binding relieves repression of lama3 in fibroblasts (where a repressor complex normally silences the gene), while expression remains constitutively high in keratinocytes. An epithelial enhancer with AP-1 binding sites controls cell-type-specific lama3 expression. Chromatin immunoprecipitation confirmed UV-induced USF binding to the lama3 promoter in vivo.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), reporter assays, UV stress induction, promoter deletion/mutagenesis analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP demonstrating in vivo promoter binding, reporter assays, multiple orthogonal methods in one study\",\n      \"pmids\": [\"11937633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Targeted disruption of lama3 in mice arrested glomerular maturation at the early capillary loop stage: endothelial cells failed to attenuate, develop fenestrae, or form lumens, and mesangial cells were absent. LAMA3 protein was localized to the basement membrane adjacent to glomerular endothelial cells (GEnCs), and lama3 mRNA/protein were identified in isolated glomeruli and cultured GEnCs but not in mesangial cells, establishing a required role for LAMA3 in GEnC differentiation and mesangial cell migration.\",\n      \"method\": \"Gene knockout mouse model, immunohistochemistry/protein localization, in situ hybridization, cell fractionation of isolated glomeruli, cultured GEnCs\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — constitutive knockout with defined developmental arrest phenotype, protein localization by multiple methods, cell-type-specific expression validated in isolated primary cells\",\n      \"pmids\": [\"16850021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Conditional disruption of the Lama3 gene in basal keratinocytes of adult mice caused gradual loss of α3 chain-containing laminins at the dermal-epidermal junction, subepidermal blistering, nail loss, skin inflammation, and fibrosis with extensive accumulation of interstitial and microfibrillar collagens and scattered collagen VII deposition, demonstrating that α3-laminin isoforms are required for adult skin homeostasis.\",\n      \"method\": \"Conditional/inducible gene knockout in adult mice, histology, immunofluorescence, collagen staining\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible conditional knockout with defined molecular and phenotypic consequences, multiple histological readouts\",\n      \"pmids\": [\"27729280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Heterozygous functional null mutations in LAMA3 cause localized enamel pitting (haploinsufficiency) in the absence of skin blistering, demonstrating that a half-dose of laminin α3 chain is insufficient for normal enamel formation, establishing a dosage-sensitive role for LAMA3 in amelogenesis.\",\n      \"method\": \"Clinical phenotyping of heterozygous carriers, molecular analysis (identification of nonsense c.2377C>T and splice-site c.4684+1G>A mutations), family segregation analysis\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetic loss-of-function with defined phenotype, two independent mutations showing same phenotype, family segregation confirmed\",\n      \"pmids\": [\"27827380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LINC00628 recruits DNMT1, DNMT3A, and DNMT3B to the LAMA3 promoter, promoting CpG methylation and silencing LAMA3 expression; LINC00628 silencing reduced LAMA3 promoter methylation and restored its expression, with functional consequences including decreased lung adenocarcinoma cell proliferation, migration, invasion, and vincristine resistance.\",\n      \"method\": \"ChIP assay (DNMT recruitment), pyrosequencing (methylation), siRNA knockdown, 5-azacytidine treatment, cell functional assays, in vivo xenograft\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating DNMT recruitment, methylation quantified by pyrosequencing, functional rescue with methylation inhibitor, single lab\",\n      \"pmids\": [\"31557618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL3 upregulates LAMA3 expression via N6-methyladenosine (m6A) modification-dependent stabilization of LAMA3 transcripts in oral squamous cell carcinoma; methylated RNA immunoprecipitation and mRNA stability assays confirmed this regulatory mechanism, and low METTL3 partially reversed the enhanced malignant phenotype induced by LAMA3 overexpression.\",\n      \"method\": \"Methylated RNA immunoprecipitation (MeRIP), mRNA stability assay, siRNA knockdown, cell functional assays, RT-qPCR\",\n      \"journal\": \"Critical reviews in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP plus mRNA stability assay establishes m6A-dependent mechanism, single lab, rescue experiment performed\",\n      \"pmids\": [\"38305336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LAMA3 knockdown sensitizes colon cancer cells to oxaliplatin by modulating the Hippo-YAP pathway; overexpression of YAP counteracted the enhanced oxaliplatin sensitivity caused by LAMA3 knockdown, placing LAMA3 upstream of YAP in regulating drug resistance. This was confirmed in vitro and in CC xenograft models.\",\n      \"method\": \"siRNA knockdown, YAP overexpression rescue, western blot (pathway analysis), KEGG enrichment, in vivo xenograft\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via rescue experiment (YAP OE reverting LAMA3-KD phenotype), pathway placement, in vivo confirmation, single lab\",\n      \"pmids\": [\"39798821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SPI1 (PU.1) transcription factor binds to the LAMA3 promoter and directly activates its transcription in esophageal squamous cell carcinoma, as demonstrated by ChIP and dual luciferase reporter assays; LAMA3 silencing suppressed tumor growth, angiogenesis (tube formation), and induced ferroptosis and oxidative stress in ESCC cells.\",\n      \"method\": \"ChIP assay, dual luciferase reporter assay, siRNA knockdown, CCK-8/EdU/colony formation, tube formation assay, in vivo xenograft, ferroptosis/oxidative stress markers\",\n      \"journal\": \"General physiology and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP and dual-luciferase confirm direct promoter binding and transcriptional activation, multiple functional readouts, single lab\",\n      \"pmids\": [\"41217226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HEYL binds to the LAMA3 promoter and activates its transcription; in vitro and in vivo rescue experiments demonstrated that HEYL-mediated transcriptional activation of LAMA3 reduces esophageal cancer radiosensitivity by inducing the epithelial-to-mesenchymal transition (EMT) pathway.\",\n      \"method\": \"Chromatin binding assay (HEYL-LAMA3 promoter interaction), RT-qPCR, western blot, transwell/wound healing/CCK-8/EdU assays, in vivo radioresistant model, immunofluorescence\",\n      \"journal\": \"Esophagus\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcription factor-promoter interaction with functional rescue demonstrating pathway placement, in vivo confirmation, single lab\",\n      \"pmids\": [\"40833662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"miR-212-5p directly targets LAMA3 (and LAMC2), as demonstrated by dual-luciferase reporter assay; LAMA3 positively regulates the PI3K-AKT pathway and negatively regulates the NF-κB pathway, thereby controlling PM2.5-induced apoptosis rates.\",\n      \"method\": \"Dual-luciferase reporter assay (direct miRNA target validation), pathway western blot, apoptosis flow cytometry\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual-luciferase establishes direct miRNA–LAMA3 3'UTR interaction, pathway modulation shown by western blot, single lab\",\n      \"pmids\": [\"40004224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Mosaic epidermal-specific loss of laminin-α3β3γ2 (Lama3) in embryonic mice, generated by in utero lentiviral delivery, increases keratinocyte delamination (basal-to-suprabasal transition) without causing epidermal-dermal separation embryonically, demonstrating a causal role for hemidesmosomal laminin in regulating epidermal differentiation through the delamination mechanism.\",\n      \"method\": \"In utero lentiviral-mediated mosaic knockout, live imaging/cell tracking, immunofluorescence, cell division orientation analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean mosaic loss-of-function with defined differentiation readout in embryonic skin, preprint not yet peer-reviewed, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"LAMA3 encodes the α3 chain of laminin-332 (laminin 5/epiligrin), a basement membrane glycoprotein that serves as a direct extracellular ligand for integrin α3β1 (promoting focal adhesion and inhibiting keratinocyte migration) and integrin α6β4 (anchoring hemidesmosomes and triggering specific tyrosine phosphorylation signaling via a membrane-associated 80-kDa kinase substrate); it is required for epithelial survival, differentiation, enamel formation, and glomerular maturation as established by knockout and rescue experiments, and its expression is regulated at the transcriptional level by AP-1/USF-1 on a non-canonical E-box, by DNMT-mediated CpG methylation recruited by LINC00628, by m6A modification via METTL3, and by transcription factors SPI1 and HEYL, while functionally it modulates the Hippo-YAP pathway to influence drug resistance and the EMT pathway to influence radiosensitivity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LAMA3 encodes the \\u03b13 chain of laminin-332 (epiligrin/laminin 5), a basement membrane glycoprotein that functions as a direct extracellular adhesion ligand coordinating epithelial attachment, differentiation, and survival [#0, #6]. As immunopurified epiligrin it engages integrin \\u03b13\\u03b21 to drive focal adhesion and suppress keratinocyte migration\\u2014marking this receptor\\u2013ligand pair as anti-migratory\\u2014while colocalizing with integrin \\u03b16\\u03b24 in hemidesmosome-like stable anchoring contacts [#0, #1]. Anchorage of \\u03b16\\u03b24 to laminin 5 governs a distinct signaling event: dissociation of \\u03b16\\u03b24 from the ligand triggers tyrosine phosphorylation of a membrane-associated 80-kDa substrate by a kinase active in suspended keratinocytes, a pathway not affected by \\u03b13\\u03b21 blockade [#4]. Adhesion through \\u03b13\\u03b21 also restrains epidermal differentiation by reducing involucrin induction [#5]. The gene produces \\u03b13EpA and \\u03b13EpB transcripts whose C-terminal G domain is structurally related to other laminin \\u03b1 chains, and it maps to chromosome 18q11.2 [#3]. Genetic ablation in mice establishes its physiological requirements: loss eliminates stable \\u03b16\\u03b24 adhesion and hemidesmosomes, impairs epithelial survival (rescuable by exogenous laminin 5, collagen, or anti-\\u03b16\\u03b24 antibody), and disrupts ameloblast differentiation [#6]; conditional adult deletion causes subepidermal blistering, skin inflammation, and fibrosis [#9]; and disruption arrests glomerular maturation, with LAMA3 required for glomerular endothelial cell differentiation and mesangial cell migration [#8]. Human haploinsufficiency causes localized enamel pitting, defining a dosage-sensitive role in amelogenesis [#10]. LAMA3 transcription is regulated cell-type-specifically through an AP-1 epithelial enhancer and UV-induced USF-1 binding at a non-canonical promoter E-box [#7], and in cancer contexts by LINC00628-recruited DNMT-mediated CpG methylation [#11], METTL3-dependent m6A stabilization [#12], miR-212-5p targeting [#16], and the transcription factors SPI1 and HEYL [#14, #15]; through these routes LAMA3 modulates Hippo-YAP signaling to influence oxaliplatin resistance [#13] and EMT to influence radiosensitivity [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Established that the LAMA3-containing complex epiligrin is a bona fide extracellular adhesion ligand, identifying integrin \\u03b13\\u03b21 as its focal-adhesion receptor and \\u03b16\\u03b24 as a co-localizing partner in stable anchoring contacts.\",\n      \"evidence\": \"Immunopurified epiligrin in cell adhesion assays with reciprocal antibody blocking and immunolocalization across cell types\",\n      \"pmids\": [\"2032285\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which laminin domain mediates \\u03b13\\u03b21 versus \\u03b16\\u03b24 engagement\", \"Functional consequence of dual-receptor superstructure not yet defined\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Defined the cellular consequence of \\u03b13\\u03b21\\u2013epiligrin binding by showing it immobilizes keratinocytes, framing this pair as anti-migratory rather than promotile.\",\n      \"evidence\": \"Keratinocyte migration assays with monospecific integrin-blocking antibodies on multiple matrices\",\n      \"pmids\": [\"1569325\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding\", \"Downstream signaling controlling immobility not identified\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Extended epiligrin\\u2013\\u03b13\\u03b21 adhesion beyond epithelium to T lymphocytes and demonstrated it is affinity-regulated, indicating activation-state control of the interaction.\",\n      \"evidence\": \"Adhesion assays with reciprocal and activating anti-\\u03b21 antibodies, flow cytometry, patient biopsy immunohistochemistry\",\n      \"pmids\": [\"8501119\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological role of lymphocyte adhesion to epiligrin unclear\", \"Mechanism of affinity regulation not resolved\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Resolved the molecular identity of LAMA3, defining its two transcripts, conserved G-domain architecture, and chromosomal location.\",\n      \"evidence\": \"cDNA cloning and sequencing of independent clones, FISH mapping, Northern hybridization\",\n      \"pmids\": [\"8077230\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional distinctness of \\u03b13EpA vs \\u03b13EpB not tested\", \"G-domain ligand specificities not assigned\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Separated \\u03b16\\u03b24 signaling from \\u03b13\\u03b21 by showing that \\u03b16\\u03b24 anchorage to laminin 5 specifically controls phosphorylation of an 80-kDa membrane substrate, revealing distinct receptor-specific signaling outputs from a single ligand.\",\n      \"evidence\": \"Low-temperature adhesion, immunoprecipitation/phosphorylation and in vitro kinase assays, antibody blocking, subcellular fractionation\",\n      \"pmids\": [\"8647901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular identity of the 80-kDa substrate and its kinase not determined\", \"Downstream functional consequence of p80 phosphorylation unknown\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Linked \\u03b13\\u03b21\\u2013epiligrin adhesion to control of epidermal differentiation by showing it suppresses antibody-induced involucrin expression.\",\n      \"evidence\": \"Culture on purified epiligrin versus other ECM with antibody-triggered differentiation readout\",\n      \"pmids\": [\"7769020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling pathway connecting adhesion to involucrin repression not mapped\", \"Single defined differentiation marker tested\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Established the in vivo requirements for LAMA3 in epithelial biology, showing it is needed for hemidesmosome-mediated \\u03b16\\u03b24 adhesion, epithelial survival, and ameloblast differentiation, and that survival signaling can be supplied via \\u03b21/\\u03b24 integrins.\",\n      \"evidence\": \"Constitutive knockout mouse with tissue adhesion assays and rescue using exogenous matrix proteins and anti-\\u03b16\\u03b24 antibody, histology, EM\",\n      \"pmids\": [\"10366601\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the alternative \\u03b13\\u03b21 ligand emerging in knockout BM unknown\", \"Mechanism linking adhesion to survival not fully defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined cell-type-specific transcriptional control of LAMA3 through an AP-1 epithelial enhancer and UV-stress-induced USF-1 binding at a non-canonical promoter E-box that relieves fibroblast repression.\",\n      \"evidence\": \"ChIP demonstrating in vivo USF binding, reporter assays, UV induction, promoter mutagenesis\",\n      \"pmids\": [\"11937633\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Composition of the fibroblast repressor complex not identified\", \"Physiological role of UV-induced upregulation not established\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Revealed a developmental role beyond skin, showing LAMA3 is required for glomerular endothelial cell differentiation and mesangial cell migration during kidney maturation.\",\n      \"evidence\": \"Knockout mouse with developmental arrest phenotype, protein localization, in situ hybridization, primary GEnC culture\",\n      \"pmids\": [\"16850021\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating LAMA3 effects on GEnCs not identified\", \"Mechanism of mesangial cell recruitment unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated that \\u03b13-laminins are required for adult skin homeostasis, not only development, with their loss driving blistering, inflammation, and collagen-rich fibrosis.\",\n      \"evidence\": \"Inducible conditional knockout in adult mouse keratinocytes with histology, immunofluorescence, collagen staining\",\n      \"pmids\": [\"27729280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking laminin loss to fibrotic collagen accumulation not defined\", \"Contribution of inflammation versus direct adhesion loss unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established LAMA3 dosage sensitivity in humans, showing heterozygous null mutations cause enamel pitting in the absence of blistering.\",\n      \"evidence\": \"Clinical phenotyping, identification of nonsense and splice-site mutations, family segregation\",\n      \"pmids\": [\"27827380\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue-specific threshold explaining enamel-only phenotype not defined\", \"Molecular mechanism of amelogenesis dependence unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified post-transcriptional control of LAMA3 by METTL3-mediated m6A modification that stabilizes its transcripts and promotes malignant phenotype in oral squamous cell carcinoma.\",\n      \"evidence\": \"MeRIP, mRNA stability assay, siRNA knockdown with rescue, functional assays\",\n      \"pmids\": [\"38305336\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"m6A reader mediating stabilization not identified\", \"Single cancer context\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed LAMA3 upstream of Hippo-YAP signaling in controlling chemoresistance, showing its knockdown sensitizes colon cancer to oxaliplatin in a YAP-dependent manner.\",\n      \"evidence\": \"siRNA knockdown with YAP overexpression epistasis rescue, western blot, xenograft\",\n      \"pmids\": [\"39798821\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between extracellular LAMA3 and intracellular YAP not defined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified additional transcriptional and microRNA regulators (SPI1, HEYL, miR-212-5p) controlling LAMA3 expression and linked LAMA3 to EMT-driven radioresistance, PI3K-AKT/NF-\\u03baB signaling, and tumor angiogenesis/ferroptosis.\",\n      \"evidence\": \"ChIP, dual-luciferase reporter assays, knockdown with rescue, pathway western blots, functional and xenograft assays\",\n      \"pmids\": [\"41217226\", \"40833662\", \"40004224\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting secreted laminin to intracellular signaling pathways not established\", \"Findings each from single labs in distinct cancer types\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Refined the role of hemidesmosomal laminin in differentiation, showing embryonic mosaic Lama3 loss increases keratinocyte delamination without embryonic epidermal-dermal separation.\",\n      \"evidence\": \"In utero lentiviral mosaic knockout with live imaging and division-orientation analysis (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Signaling controlling delamination downstream of laminin not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the membrane-proximal signaling outputs of laminin-332 (the 80-kDa substrate and its kinase) connect mechanistically to the intracellular pathways modulating cancer phenotypes (Hippo-YAP, PI3K-AKT, NF-\\u03baB, EMT) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Identity of the 80-kDa substrate/kinase still unknown\", \"No mechanistic bridge between extracellular adhesion and intracellular oncogenic signaling established\", \"Receptor usage in non-epithelial and tumor contexts not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 3, 6]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0030312\", \"supporting_discovery_ids\": [0, 6, 8]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 8, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 6, 9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"complexes\": [\n      \"laminin-332 (laminin 5/epiligrin)\",\n      \"hemidesmosome\"\n    ],\n    \"partners\": [\n      \"ITGA3\",\n      \"ITGB1\",\n      \"ITGA6\",\n      \"ITGB4\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}