{"gene":"LAMA5","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2016,"finding":"LAMA5 (laminin α5) acts as a substrate for BCAM (basal cell adhesion molecule) on endothelial cells, and the BCAM/LAMA5 interaction mediates adhesion of KRAS-mutant colorectal cancer cells specifically to endothelial cells (but not pericytes or hepatocytes); genetic suppression or biochemical inhibition of either BCAM or LAMA5 impaired this adhesion.","method":"Adhesion assays with genetic suppression (siRNA/shRNA) and biochemical inhibition of BCAM and LAMA5; immunohistochemistry validation in preclinical models and human specimens; phage display screen","journal":"Clinical Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal functional assays (adhesion + genetic suppression + biochemical inhibition), single lab, two orthogonal methods","pmids":["27143691"],"is_preprint":false},{"year":2016,"finding":"MMP1 cleaves LAMA5 to generate internal and C-terminal proteolytic fragments that are secreted by oncogenically transformed (H-Ras) epithelial cells; these fragments promote endothelial cell angiogenesis (vessel length and branching) in a VEGF-independent manner via integrin αvβ3 on endothelial cells.","method":"In vitro MMP1 knockdown/secretome analysis; endothelial angiogenesis assays; antibody-based integrin αvβ3 inhibition; in vivo xenograft tumor growth assay","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays (knockdown, secretome, angiogenesis, antibody inhibition), single lab, orthogonal methods","pmids":["27324842"],"is_preprint":false},{"year":2012,"finding":"Laminin α5 (encoded by Lama5) inhibits Wnt signaling and activates PI3K signaling in intestinal epithelial and mesenchymal cells; loss of Lama5 in mice causes conflicting Wnt/PI3K signals, altering cell adhesion, migration, and differentiation, establishing laminin-511 as a regulator of interconnected PI3K/Akt and Wnt pathways.","method":"RNA profiling of lama5 knockout mouse embryonic intestinal tissue; cell culture knockdown experiments; epistasis via signaling pathway modulation","journal":"PLoS One","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with RNA profiling plus in vitro knockdown, single lab, two orthogonal approaches","pmids":["22666383"],"is_preprint":false},{"year":2017,"finding":"The LAMA5 missense mutation p.V3140M alters the amount of LAMA5 peptides derived from protein cleavage, perturbs epithelial-mesenchymal signaling, causes upregulation of Sonic Hedgehog and GLI1, and strongly inhibits ECM proteins COL1A1, MMP1, and MMP3 in cells from affected individuals; skin biopsies showed alteration of dermal papilla with reduction of germinative layer.","method":"WES and RNAseq of affected human family; expression studies in patient-derived cells; skin biopsy histology; knock-in mouse model generation","journal":"Journal of Medical Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetics plus functional cell/tissue studies plus mouse model, single lab, multiple orthogonal methods","pmids":["28735299"],"is_preprint":false},{"year":2017,"finding":"The LAMA5 variant p.Arg2659Trp causes decreased binding of laminin α5 to SV2A (synaptic vesicle glycoprotein 2A) and impairs laminin-521 cell adhesion and cell projection support in primary neuronal cultures, resulting in presynaptic failure with reduced endplate potential quantal content and denuded nerve terminals.","method":"Expression studies in primary neuronal cultures; cell adhesion assays; electrophysiological endplate studies; electron microscopy; repetitive nerve stimulation","journal":"American Journal of Medical Genetics Part A","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay, neuronal culture assays, electrophysiology, single lab, multiple orthogonal methods","pmids":["28544784"],"is_preprint":false},{"year":2018,"finding":"The LAMA5 variant p.Arg2659Trp causes decreased binding of laminin α5 to SV2A and impairs laminin-521 cell adhesion and cell projection support in primary neuronal cultures, contributing to presynaptic neuromuscular transmission failure; endplates showed normal postsynaptic folding but denuded or partially occupied nerve terminals.","method":"Expression studies; cell adhesion and projection assays in primary neuronal cultures; endplate electrophysiology; electron microscopy","journal":"Annals of the New York Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — replication of prior study with same methods, same lab, confirms binding to SV2A finding","pmids":["29377152"],"is_preprint":false},{"year":2019,"finding":"LAMA5 expression in colorectal cancer cells is induced by TNFα/NFκB pathway signaling activated by tumour-derived CD11b+ myeloid cell-conditioned medium; shRNA-mediated downregulation of LAMA5 in cancer cells impaired hepatic metastatic growth, reduced intratumoural vessel branching, and increased Notch pathway gene expression in metastasis-derived endothelia.","method":"shRNA knockdown in cancer cells; orthotopic hepatic metastasis mouse model; qPCR with human-specific primers; Notch pathway gene expression analysis; conditioned medium experiments with TNFα/NFκB pathway","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KD model plus in vitro mechanistic dissection, single lab, multiple orthogonal methods","pmids":["31064120"],"is_preprint":false},{"year":2020,"finding":"Biallelic loss-of-function mutations in LAMA5 disrupt a focal adhesion signaling complex: loss of LAMA5 alters β1 integrin signaling through non-canonical kinase PYK2 and skeletal-enriched SRC kinase FYN, negatively impacts the actin cytoskeleton, disrupts vinculin localization, and impairs WNT signaling in cartilage, producing a bent bone skeletal dysplasia.","method":"Exome sequencing; Sanger sequencing; qPCR; western blot; immunohistochemistry; luciferase assay for WNT signaling; migration and wound healing assays","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays on patient-derived material and cell models, single lab","pmids":["33242826"],"is_preprint":false},{"year":2021,"finding":"A missense mutation (E884G) in the L4a domain of LAMA5 reduces LAMA5 protein levels in vivo and significantly reduces assembly of the laminin 521 heterotrimer in vitro; homozygous mice develop nephrotic syndrome with proteinuria and glomerular changes; genetic background modifies disease progression.","method":"In vitro heterotrimer assembly assay; mouse knockin model; proteomic analysis of glomerular extracellular fraction; histology; ultrastructure analysis","journal":"Kidney International","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro heterotrimer reconstitution assay plus mouse model with multiple orthogonal analyses, single lab","pmids":["34774562"],"is_preprint":false},{"year":2021,"finding":"Canonical Wnt/β-catenin signaling negatively regulates submandibular gland branching morphogenesis through regulation of Lama5 levels; FGF signaling acts upstream as a negative regulator of Wnt, whose effect is partially reversed by Wnt3a; inhibition of Wnt promotes branching while overactivation suppresses it via Lama5.","method":"Embryonic mouse SMG organ culture; branching morphogenesis assay; gene expression analysis; pharmacological manipulation of Wnt and FGF pathways","journal":"The International Journal of Developmental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic/pharmacologic epistasis in organ culture model, single lab, multiple pathway perturbations","pmids":["33629734"],"is_preprint":false},{"year":2021,"finding":"LAMA5 biallelic truncating variants produce smaller laminin α5 proteins that nevertheless form trimers with laminin β1 and γ1 chains, demonstrating that truncated LAMA5 retains heterotrimer formation capacity but causes infantile nephrotic syndrome in patients.","method":"In vitro heterotrimer formation assays; targeted next-generation sequencing; clinical characterization","journal":"Kidney360","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution (heterotrimer formation assay) with genetic evidence, single lab","pmids":["35419533"],"is_preprint":false},{"year":2022,"finding":"A heterozygous LAMA5 variant (p.Val3687Met) causes cell-type-dependent changes in secretion of variant laminin α5 LG4-5 domain; heterozygous and homozygous knockin mice develop FSGS-like pathology with reduced laminin α5 and increased glomerular vinculin levels, suggesting impaired cell adhesion underlies the glomerulopathy.","method":"In vitro secretion assay of LG4-5 domain; heterozygous and homozygous knockin mouse model; immunohistochemistry; whole-exome sequencing","journal":"JCI Insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro secretion assay plus knockin mouse model, single lab, orthogonal methods","pmids":["36173685"],"is_preprint":false},{"year":2023,"finding":"CAF-secreted LAMA5 activates integrin α4/STAT3 signaling axis in acinar cells to drive acinar-to-ductal metaplasia (ADM); depletion of LAMA5 or ITGA4 in acinar cells abolishes CAF-mediated transdifferentiation.","method":"Proteomic (LC-MS/MS) and transcriptomic (RNA-seq) data integration; confocal microscopy; immunoblotting; qRT-PCR; acinar cell organoids, explants, and CAF cocultures; mCAF coculture models","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-platform proteomic/transcriptomic integration plus functional validation in multiple model systems, single lab","pmids":["38154529"],"is_preprint":false},{"year":2023,"finding":"LAMA5 knockdown in ovarian cancer cell lines inhibits cell proliferation, migration, and invasion in vitro and in vivo, and reduces expression of EMT markers and Notch signaling pathway-related markers, placing LAMA5 upstream of Notch-mediated EMT.","method":"Lentiviral shRNA knockdown; in vitro proliferation, migration, invasion assays; in vivo tumor xenograft; IHC; western blot for EMT and Notch markers","journal":"FASEB Journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, KD with phenotype but pathway placement based on marker expression only, no direct mechanistic dissection of Notch pathway","pmids":["37527216"],"is_preprint":false},{"year":2018,"finding":"LAMA5 knockdown in HUVECs or hypoxia/reoxygenation reduces HUVEC proliferation, migration, and vascular formation, and downregulates PI3K downstream targets p-AKT and p-mTOR, placing LAMA5 upstream of PI3K-AKT-mTOR signaling in endothelial cells.","method":"siRNA knockdown; CCK-8 proliferation assay; transwell migration assay; tube formation assay; western blot for p-AKT and p-mTOR","journal":"The Journal of Maternal-Fetal & Neonatal Medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single KD approach, pathway assignment by protein level only without epistasis confirmation","pmids":["30200802"],"is_preprint":false},{"year":2011,"finding":"Human laminin α5 expressed transgenically in mice deposits into basement membranes of heart, liver, spleen, and kidney; high-level transgenic human LAMA5 expression suppresses endogenous mouse Lama5 mRNA and laminin α5 protein in kidney, suggesting a laminin expression monitoring/feedback mechanism in kidney.","method":"Transgenic mouse (BAC-based human LAMA5 locus); immunoelectron microscopy; quantitative mRNA analysis; immunofluorescence","journal":"PLoS One","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vivo transgenic experiment with protein and mRNA level analysis, single lab, orthogonal methods","pmids":["21915268"],"is_preprint":false},{"year":2023,"finding":"LAMA5 silencing in the palatal process inhibits proliferation (reduced ki67, cyclin D1) and promotes apoptosis (increased caspase 3) in mouse palatal cells via the SHH/GLI1 axis (reduced gli1), causing failure of palate fusion; E-cadherin, vimentin, Shh, and ptch1 were not significantly changed, indicating the mechanism is proliferation/apoptosis rather than EMT.","method":"LAMA5-shRNA adenovirus transfection into embryonic mouse palatal process in vitro organ culture; PCR; western blot; fluorescence microscopy for fusion assessment","journal":"Biomedical Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional KD in organ culture with multiple protein/mRNA readouts and negative controls for EMT, single lab","pmids":["37390938"],"is_preprint":false},{"year":2025,"finding":"MAZ transcription factor binds the LAMA5 promoter to activate its transcription; LAMA5 promotes gastric cancer cell proliferation and migration through STAT3 signaling; Colivelin (STAT3 activator) reverses the anti-tumor effects of LAMA5 knockdown.","method":"ChIP assay; luciferase reporter assay; siRNA knockdown of LAMA5 and MAZ; CCK-8, colony formation, EdU, wound healing, Transwell assays; in vivo tumor model","journal":"Functional & Integrative Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase for transcriptional regulation, epistasis via STAT3 activator rescue, multiple functional assays, single lab","pmids":["40072648"],"is_preprint":false},{"year":2025,"finding":"Corticosterone activates glucocorticoid receptor (GR), which directly targets and activates the Lama5 gene; the corticosterone-GR-LAMA5 axis mediates chronic psychological stress-induced cardiomyocyte hypertrophy in vivo and in vitro.","method":"Animal stress models; in vitro corticosterone treatment; GR manipulation; in vivo and in vitro confirmation of GR-Lama5 regulatory axis; multiple independent animal experiment batches","journal":"Advanced Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct regulatory axis confirmed in vivo and in vitro with multiple experimental batches, single lab","pmids":["40642838"],"is_preprint":false},{"year":2025,"finding":"CRISPR/Cas9 knockout of LAMA5 in urine-derived stem cells impairs chondrogenesis and disrupts cell–cell junction programs; loss of LAMA5 attenuates canonical WNT signaling (reduced WNT7A expression); pharmacological WNT activation with LiCl partially restores WNT7A, FLI1, TFAP2A, GRHL2, and PITX1 expression toward wild-type levels.","method":"CRISPR/Cas9 KO; 2D and 3D chondrogenic differentiation; bulk RNA sequencing; WGCNA; pharmacological WNT activation (LiCl); qPCR","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with transcriptomic analysis and pharmacological rescue, single lab, preprint","pmids":[],"is_preprint":true},{"year":2025,"finding":"In zebrafish, laminin α5 (lama5) is a key basement membrane component underlying the migrating posterior lateral line primordium; loss of lama5 alone compromises basement membrane integrity without blocking migration, but simultaneous depletion of lama5 and integrin α6b (itga6b) markedly decreases migration velocity and ultimately blocks collective migration, indicating functional redundancy between these adhesion components.","method":"Zebrafish loss-of-function genetics; live imaging of pLLP migration; combinatorial lama5/itga6b double mutant analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with live in vivo imaging in zebrafish, single lab, preprint","pmids":[],"is_preprint":true},{"year":2025,"finding":"In zebrafish epidermis, loss of laminin α5 reduces E-cadherin localization and increases cell spreading with dynamic cell boundaries and increased cell proliferation (mesenchymal traits); this phenotype is recapitulated by integrin α6b mutation and is not exacerbated in the double mutant, indicating that laminin α5 and integrin α6b function in the same pathway to maintain epithelial apicobasal polarity.","method":"Zebrafish lama5 and itga6b loss-of-function mutants; immunofluorescence for E-cadherin, aPKC, Lgl; double mutant epistasis analysis","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genetic epistasis in zebrafish, single lab, preprint without peer review","pmids":[],"is_preprint":true},{"year":2025,"finding":"Endothelial-specific loss of laminin α5 (Tek-cre:Lama5-/-) in mice alters cerebrovascular transcriptional identity; compensatory upregulation of laminin α5 in Lama4-/- vessels enhances expression of junctional proteins (Ocln, Cldn5) and promotes vessel contractility, demonstrating that the laminin α4/α5 ratio in vascular basement membranes regulates functional zonation between arterioles, capillaries, and postcapillary venules.","method":"Single-cell RNA sequencing of cerebral blood vessels from Lama4-/-, Tek-cre:Lama5-/-, and wild-type mice; in vitro and in vivo functional studies; immunohistochemistry","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endothelial-specific KO and global KO with scRNAseq plus in vitro/in vivo functional validation, single lab, preprint","pmids":[],"is_preprint":true}],"current_model":"LAMA5 encodes laminin α5, a secreted extracellular matrix glycoprotein that assembles into heterotrimeric laminin-511/521 complexes in basement membranes; it signals bidirectionally through β1 integrin-PYK2-FYN focal adhesion complexes and integrin α4/α6 to regulate WNT and PI3K/AKT pathways, controls cell adhesion, proliferation, migration, and epithelial polarity across multiple tissues, binds SV2A at the neuromuscular junction to support presynaptic terminal maintenance, is transcriptionally activated by GR and MAZ, and is proteolytically processed by MMP1 to generate pro-angiogenic fragments that act via integrin αvβ3."},"narrative":{"mechanistic_narrative":"LAMA5 encodes laminin α5, a secreted basement-membrane glycoprotein that assembles with laminin β1 and γ1 chains into laminin-511/521 heterotrimers and acts as a master regulator of cell adhesion, proliferation, polarity, and morphogenesis across epithelial, vascular, neuromuscular, and skeletal tissues [PMID:34774562, PMID:35419533, PMID:21915268]. A recurrent theme is that laminin α5 transduces basement-membrane attachment into intracellular signaling that balances WNT and PI3K/AKT outputs: it restrains canonical Wnt while activating PI3K/Akt in intestinal cells [PMID:22666383], and its loss disrupts β1 integrin signaling through the kinases PYK2 and FYN, destabilizes vinculin localization and the actin cytoskeleton, and impairs WNT signaling to produce a bent-bone skeletal dysplasia [PMID:33242826]; WNT-dependent control of laminin α5 levels in turn governs branching morphogenesis and chondrogenesis [PMID:33629734]. Laminin α5 supports tissue integrity through receptor partners including SV2A at the neuromuscular junction, where a binding-disrupting variant causes presynaptic transmission failure [PMID:28544784, PMID:29377152], and integrin α6b, with which it acts redundantly or in a shared pathway to maintain collective migration and apicobasal polarity. In disease, pathogenic LAMA5 variants impair heterotrimer assembly or secretion and cause nephrotic syndrome and FSGS-like glomerulopathy with reduced laminin α5 and increased glomerular vinculin [PMID:34774562, PMID:35419533, PMID:36173685]. In cancer, laminin α5 mediates KRAS-mutant tumor-cell adhesion to endothelium via BCAM [PMID:27143691], drives hepatic metastasis and tumor angiogenesis downstream of TNFα/NFκB [PMID:31064120], and promotes proliferation and migration through integrin α4/STAT3 signaling, with MAZ acting as a transcriptional activator of LAMA5 [PMID:38154529, PMID:40072648]. Beyond intact trimers, MMP1 cleaves laminin α5 into fragments that drive VEGF-independent angiogenesis via integrin αvβ3 [PMID:27324842], and its transcription is also activated by glucocorticoid receptor in stress-induced cardiomyocyte hypertrophy [PMID:40642838].","teleology":[{"year":2011,"claim":"Established that human laminin α5 incorporates into basement membranes of multiple organs in vivo and that kidney enforces a feedback control on laminin α5 abundance.","evidence":"BAC transgenic mice with human LAMA5; immunoelectron microscopy and quantitative mRNA analysis","pmids":["21915268"],"confidence":"Medium","gaps":["Molecular basis of the proposed kidney expression-monitoring/feedback mechanism unidentified","Did not resolve which receptors mediate deposition into specific basement membranes"]},{"year":2012,"claim":"Connected laminin α5 to interconnected intracellular signaling by showing it suppresses Wnt while activating PI3K, framing it as a signaling hub rather than a passive structural protein.","evidence":"Lama5 knockout mouse intestinal RNA profiling plus in vitro knockdown and pathway modulation","pmids":["22666383"],"confidence":"Medium","gaps":["Receptor linking laminin α5 to Wnt/PI3K crosstalk not defined","Direct versus indirect contribution to each pathway not separated"]},{"year":2016,"claim":"Defined two distinct extracellular activities of laminin α5 in cancer: a BCAM-dependent adhesion substrate for tumor-endothelial attachment, and an MMP1-generated fragment that drives angiogenesis through integrin αvβ3.","evidence":"Adhesion assays with genetic/biochemical inhibition of BCAM and LAMA5; MMP1 knockdown/secretome with endothelial angiogenesis and integrin αvβ3 antibody blockade","pmids":["27143691","27324842"],"confidence":"Medium","gaps":["Cleavage site mapping of MMP1 fragments incomplete","In vivo relevance of BCAM/LAMA5 adhesion in metastasis not directly tested"]},{"year":2017,"claim":"Linked LAMA5 variants to human disease through two mechanisms: an SV2A-binding-disrupting variant causing presynaptic neuromuscular failure, and a cleavage-altering variant perturbing epithelial-mesenchymal SHH/GLI signaling.","evidence":"WES/RNAseq of affected families; patient-derived cell expression; neuronal adhesion and endplate electrophysiology; knock-in mouse generation","pmids":["28735299","28544784"],"confidence":"Medium","gaps":["Structural basis of laminin α5–SV2A interaction unresolved","Mechanism connecting LAMA5 cleavage to SHH/GLI1 upregulation not dissected"]},{"year":2018,"claim":"Replicated and extended the SV2A-binding deficit at the neuromuscular junction and placed laminin α5 upstream of endothelial PI3K-AKT-mTOR signaling.","evidence":"Repeat neuronal culture binding/adhesion and endplate EM/electrophysiology; HUVEC siRNA knockdown with p-AKT/p-mTOR immunoblotting and tube formation","pmids":["29377152","30200802"],"confidence":"Medium","gaps":["Endothelial pathway assignment rests on protein-level changes without epistasis","How laminin α5 engages the PI3K axis (which receptor) untested"]},{"year":2019,"claim":"Showed LAMA5 is an inducible, microenvironment-regulated gene in metastasis, induced by myeloid-derived TNFα/NFκB signaling and required for hepatic metastatic growth and tumor vascularization.","evidence":"shRNA knockdown in cancer cells; orthotopic hepatic metastasis model; conditioned-medium and Notch gene expression analysis","pmids":["31064120"],"confidence":"Medium","gaps":["Direct NFκB binding to LAMA5 regulatory regions not shown","Mechanism of Notch modulation in metastatic endothelia unresolved"]},{"year":2020,"claim":"Resolved the intracellular signaling complex through which laminin α5 loss acts, defining a β1 integrin–PYK2–FYN–vinculin–actin–WNT axis underlying a skeletal dysplasia.","evidence":"Exome sequencing of patients; western blot, IHC, WNT luciferase, and migration/wound-healing assays on patient-derived material","pmids":["33242826"],"confidence":"Medium","gaps":["Direct biochemical chain from integrin engagement to PYK2/FYN activation not reconstituted","Tissue specificity of the bent-bone phenotype unexplained"]},{"year":2021,"claim":"Established the structural disease mechanism in kidney by showing that LAMA5 variants reduce protein levels and heterotrimer assembly (or retain trimer formation despite truncation), causing nephrotic syndrome, and connected WNT to control of Lama5 in branching morphogenesis.","evidence":"In vitro heterotrimer assembly assays; knock-in mouse nephrotic models with proteomics/ultrastructure; embryonic SMG organ culture with Wnt/FGF manipulation","pmids":["34774562","35419533","33629734"],"confidence":"Medium","gaps":["Why truncated trimer-competent laminin α5 still causes disease unresolved","Genetic background modifiers of nephrotic progression unmapped"]},{"year":2022,"claim":"Linked a glomerulopathy variant to defective LG4-5 domain secretion and impaired cell adhesion (increased glomerular vinculin), reinforcing adhesion failure as a unifying disease mechanism.","evidence":"In vitro LG4-5 secretion assay; heterozygous/homozygous knockin mice with IHC; WES","pmids":["36173685"],"confidence":"Medium","gaps":["Cell-type dependence of secretion defect mechanistically unexplained","Causal link between vinculin elevation and FSGS not directly demonstrated"]},{"year":2023,"claim":"Defined laminin α5 as a stromal driver of tumor cell-state transitions, acting through integrin α4/STAT3 to drive acinar-to-ductal metaplasia and upstream of Notch-mediated EMT in ovarian cancer.","evidence":"CAF coculture organoid/explant models with LAMA5/ITGA4 depletion; proteomic-transcriptomic integration; ovarian cancer shRNA knockdown with EMT/Notch marker analysis and xenografts","pmids":["38154529","37527216"],"confidence":"Medium","gaps":["Ovarian Notch placement is marker-based without mechanistic dissection","Whether integrin α4/STAT3 axis operates in non-pancreatic contexts untested"]},{"year":2023,"claim":"Extended SHH/GLI1 control of palatogenesis, showing laminin α5 silencing reduces proliferation and increases apoptosis via the SHH/GLI1 axis to cause cleft palate, distinct from an EMT mechanism.","evidence":"LAMA5-shRNA adenovirus in embryonic mouse palatal organ culture; PCR, western blot, fusion imaging with EMT-marker negative controls","pmids":["37390938"],"confidence":"Medium","gaps":["How laminin α5 signals to SHH/GLI1 not defined","Receptor mediating the proliferation/apoptosis response unidentified"]},{"year":2025,"claim":"Identified transcriptional activators of LAMA5 (MAZ in gastric cancer via STAT3; glucocorticoid receptor in stress cardiomyocyte hypertrophy), tying laminin α5 induction to defined upstream transcription factors and downstream effectors.","evidence":"ChIP and luciferase for MAZ promoter binding plus STAT3-activator rescue and tumor models; animal stress models with GR manipulation in vivo and in vitro","pmids":["40072648","40642838"],"confidence":"Medium","gaps":["Whether MAZ/GR regulation of LAMA5 generalizes across tissues unknown","Direct GR-LAMA5 promoter occupancy versus indirect activation not fully separated"]},{"year":2025,"claim":"Genetic dissection in zebrafish and mice clarified laminin α5–integrin α6b relationships and vascular zonation: redundancy with itga6b in collective migration, a shared pathway maintaining epithelial polarity, and a laminin α4/α5 ratio controlling cerebrovascular functional identity.","evidence":"Zebrafish single and lama5/itga6b double mutants with live imaging and polarity markers; endothelial-specific and global mouse KO with scRNA-seq and functional validation (preprints)","pmids":[],"confidence":"Medium","gaps":["Preprints not yet peer-reviewed","Molecular signal distinguishing redundant versus same-pathway integrin α6b interactions unresolved","How laminin α4/α5 ratio is sensed by endothelium unknown"]},{"year":null,"claim":"It remains unresolved how a single basement-membrane laminin reconciles its opposing regulatory outputs (WNT suppression versus PI3K/STAT3 activation) across tissues, and what receptor logic selects between adhesion, proliferation, and polarity programs in each context.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified receptor-to-pathway map across tissues","Structural basis of SV2A and BCAM binding unsolved","Direct in vivo reconstitution of the integrin-PYK2-FYN-vinculin module lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[8,10,15]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,4,7]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,7,12]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,12,15]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[8,15]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[8,10,15]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,7,12,17]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,7,8,10,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[9,16,20]}],"complexes":["laminin-511/521 heterotrimer (laminin α5/β1/γ1)"],"partners":["BCAM","SV2A","ITGB1","PYK2","FYN","ITGA4","ITGA6","ITGAV"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O15230","full_name":"Laminin subunit alpha-5","aliases":["Laminin-10 subunit alpha","Laminin-11 subunit alpha","Laminin-15 subunit alpha"],"length_aa":3695,"mass_kda":399.7,"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. Plays a role in the regulation of skeletogenesis, through a mechanism that involves integrin-mediated signaling and PTK2B/PYK2 (PubMed:33242826)","subcellular_location":"Secreted, extracellular space, extracellular matrix, basement membrane","url":"https://www.uniprot.org/uniprotkb/O15230/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LAMA5","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/LAMA5","total_profiled":1310},"omim":[{"mim_id":"620076","title":"BENT BONE DYSPLASIA SYNDROME 2; BBDS2","url":"https://www.omim.org/entry/620076"},{"mim_id":"620049","title":"NEPHROTIC SYNDROME, TYPE 26; NPHS26","url":"https://www.omim.org/entry/620049"},{"mim_id":"618689","title":"NETRIN G2; NTNG2","url":"https://www.omim.org/entry/618689"},{"mim_id":"618138","title":"MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 23; LGMDR23","url":"https://www.omim.org/entry/618138"},{"mim_id":"614592","title":"BENT BONE DYSPLASIA SYNDROME 1; BBDS1","url":"https://www.omim.org/entry/614592"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Vesicles","reliability":"Uncertain"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LAMA5"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"O15230","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15230","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15230-2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15230-2-F1-predicted_aligned_error_v6.png","plddt_mean":79.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LAMA5","jax_strain_url":"https://www.jax.org/strain/search?query=LAMA5"},"sequence":{"accession":"O15230","fasta_url":"https://rest.uniprot.org/uniprotkb/O15230.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15230/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15230"}},"corpus_meta":[{"pmid":"31064120","id":"PMC_31064120","title":"Tumour-Derived Laminin α5 (LAMA5) Promotes Colorectal Liver Metastasis Growth, Branching Angiogenesis and Notch Pathway Inhibition.","date":"2019","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/31064120","citation_count":70,"is_preprint":false},{"pmid":"27143691","id":"PMC_27143691","title":"BCAM and LAMA5 Mediate the Recognition between Tumor Cells and the Endothelium in the Metastatic Spreading of KRAS-Mutant Colorectal Cancer.","date":"2016","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/27143691","citation_count":59,"is_preprint":false},{"pmid":"28735299","id":"PMC_28735299","title":"Identification of the first dominant mutation of LAMA5 gene causing a complex multisystem syndrome due to dysfunction of the extracellular matrix.","date":"2017","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28735299","citation_count":39,"is_preprint":false},{"pmid":"29764427","id":"PMC_29764427","title":"COL4A5 and LAMA5 variants co-inherited in familial hematuria: digenic inheritance or genetic modifier effect?","date":"2018","source":"BMC nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/29764427","citation_count":37,"is_preprint":false},{"pmid":"38154529","id":"PMC_38154529","title":"Cancer-Associated Fibroblast Induces Acinar-to-Ductal Cell Transdifferentiation and Pancreatic Cancer Initiation Via LAMA5/ITGA4 Axis.","date":"2023","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/38154529","citation_count":33,"is_preprint":false},{"pmid":"28544784","id":"PMC_28544784","title":"Presynaptic congenital myasthenic syndrome with a homozygous sequence variant in LAMA5 combines myopia, facial tics, and failure of neuromuscular transmission.","date":"2017","source":"American journal of medical genetics. 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impaired this adhesion.\",\n      \"method\": \"Adhesion assays with genetic suppression (siRNA/shRNA) and biochemical inhibition of BCAM and LAMA5; immunohistochemistry validation in preclinical models and human specimens; phage display screen\",\n      \"journal\": \"Clinical Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional assays (adhesion + genetic suppression + biochemical inhibition), single lab, two orthogonal methods\",\n      \"pmids\": [\"27143691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MMP1 cleaves LAMA5 to generate internal and C-terminal proteolytic fragments that are secreted by oncogenically transformed (H-Ras) epithelial cells; these fragments promote endothelial cell angiogenesis (vessel length and branching) in a VEGF-independent manner via integrin αvβ3 on endothelial cells.\",\n      \"method\": \"In vitro MMP1 knockdown/secretome analysis; endothelial angiogenesis assays; antibody-based integrin αvβ3 inhibition; in vivo xenograft tumor growth assay\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays (knockdown, secretome, angiogenesis, antibody inhibition), single lab, orthogonal methods\",\n      \"pmids\": [\"27324842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Laminin α5 (encoded by Lama5) inhibits Wnt signaling and activates PI3K signaling in intestinal epithelial and mesenchymal cells; loss of Lama5 in mice causes conflicting Wnt/PI3K signals, altering cell adhesion, migration, and differentiation, establishing laminin-511 as a regulator of interconnected PI3K/Akt and Wnt pathways.\",\n      \"method\": \"RNA profiling of lama5 knockout mouse embryonic intestinal tissue; cell culture knockdown experiments; epistasis via signaling pathway modulation\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with RNA profiling plus in vitro knockdown, single lab, two orthogonal approaches\",\n      \"pmids\": [\"22666383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The LAMA5 missense mutation p.V3140M alters the amount of LAMA5 peptides derived from protein cleavage, perturbs epithelial-mesenchymal signaling, causes upregulation of Sonic Hedgehog and GLI1, and strongly inhibits ECM proteins COL1A1, MMP1, and MMP3 in cells from affected individuals; skin biopsies showed alteration of dermal papilla with reduction of germinative layer.\",\n      \"method\": \"WES and RNAseq of affected human family; expression studies in patient-derived cells; skin biopsy histology; knock-in mouse model generation\",\n      \"journal\": \"Journal of Medical Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetics plus functional cell/tissue studies plus mouse model, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"28735299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The LAMA5 variant p.Arg2659Trp causes decreased binding of laminin α5 to SV2A (synaptic vesicle glycoprotein 2A) and impairs laminin-521 cell adhesion and cell projection support in primary neuronal cultures, resulting in presynaptic failure with reduced endplate potential quantal content and denuded nerve terminals.\",\n      \"method\": \"Expression studies in primary neuronal cultures; cell adhesion assays; electrophysiological endplate studies; electron microscopy; repetitive nerve stimulation\",\n      \"journal\": \"American Journal of Medical Genetics Part A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay, neuronal culture assays, electrophysiology, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"28544784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The LAMA5 variant p.Arg2659Trp causes decreased binding of laminin α5 to SV2A and impairs laminin-521 cell adhesion and cell projection support in primary neuronal cultures, contributing to presynaptic neuromuscular transmission failure; endplates showed normal postsynaptic folding but denuded or partially occupied nerve terminals.\",\n      \"method\": \"Expression studies; cell adhesion and projection assays in primary neuronal cultures; endplate electrophysiology; electron microscopy\",\n      \"journal\": \"Annals of the New York Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — replication of prior study with same methods, same lab, confirms binding to SV2A finding\",\n      \"pmids\": [\"29377152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LAMA5 expression in colorectal cancer cells is induced by TNFα/NFκB pathway signaling activated by tumour-derived CD11b+ myeloid cell-conditioned medium; shRNA-mediated downregulation of LAMA5 in cancer cells impaired hepatic metastatic growth, reduced intratumoural vessel branching, and increased Notch pathway gene expression in metastasis-derived endothelia.\",\n      \"method\": \"shRNA knockdown in cancer cells; orthotopic hepatic metastasis mouse model; qPCR with human-specific primers; Notch pathway gene expression analysis; conditioned medium experiments with TNFα/NFκB pathway\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KD model plus in vitro mechanistic dissection, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"31064120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Biallelic loss-of-function mutations in LAMA5 disrupt a focal adhesion signaling complex: loss of LAMA5 alters β1 integrin signaling through non-canonical kinase PYK2 and skeletal-enriched SRC kinase FYN, negatively impacts the actin cytoskeleton, disrupts vinculin localization, and impairs WNT signaling in cartilage, producing a bent bone skeletal dysplasia.\",\n      \"method\": \"Exome sequencing; Sanger sequencing; qPCR; western blot; immunohistochemistry; luciferase assay for WNT signaling; migration and wound healing assays\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays on patient-derived material and cell models, single lab\",\n      \"pmids\": [\"33242826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A missense mutation (E884G) in the L4a domain of LAMA5 reduces LAMA5 protein levels in vivo and significantly reduces assembly of the laminin 521 heterotrimer in vitro; homozygous mice develop nephrotic syndrome with proteinuria and glomerular changes; genetic background modifies disease progression.\",\n      \"method\": \"In vitro heterotrimer assembly assay; mouse knockin model; proteomic analysis of glomerular extracellular fraction; histology; ultrastructure analysis\",\n      \"journal\": \"Kidney International\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro heterotrimer reconstitution assay plus mouse model with multiple orthogonal analyses, single lab\",\n      \"pmids\": [\"34774562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Canonical Wnt/β-catenin signaling negatively regulates submandibular gland branching morphogenesis through regulation of Lama5 levels; FGF signaling acts upstream as a negative regulator of Wnt, whose effect is partially reversed by Wnt3a; inhibition of Wnt promotes branching while overactivation suppresses it via Lama5.\",\n      \"method\": \"Embryonic mouse SMG organ culture; branching morphogenesis assay; gene expression analysis; pharmacological manipulation of Wnt and FGF pathways\",\n      \"journal\": \"The International Journal of Developmental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic/pharmacologic epistasis in organ culture model, single lab, multiple pathway perturbations\",\n      \"pmids\": [\"33629734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LAMA5 biallelic truncating variants produce smaller laminin α5 proteins that nevertheless form trimers with laminin β1 and γ1 chains, demonstrating that truncated LAMA5 retains heterotrimer formation capacity but causes infantile nephrotic syndrome in patients.\",\n      \"method\": \"In vitro heterotrimer formation assays; targeted next-generation sequencing; clinical characterization\",\n      \"journal\": \"Kidney360\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution (heterotrimer formation assay) with genetic evidence, single lab\",\n      \"pmids\": [\"35419533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A heterozygous LAMA5 variant (p.Val3687Met) causes cell-type-dependent changes in secretion of variant laminin α5 LG4-5 domain; heterozygous and homozygous knockin mice develop FSGS-like pathology with reduced laminin α5 and increased glomerular vinculin levels, suggesting impaired cell adhesion underlies the glomerulopathy.\",\n      \"method\": \"In vitro secretion assay of LG4-5 domain; heterozygous and homozygous knockin mouse model; immunohistochemistry; whole-exome sequencing\",\n      \"journal\": \"JCI Insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro secretion assay plus knockin mouse model, single lab, orthogonal methods\",\n      \"pmids\": [\"36173685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CAF-secreted LAMA5 activates integrin α4/STAT3 signaling axis in acinar cells to drive acinar-to-ductal metaplasia (ADM); depletion of LAMA5 or ITGA4 in acinar cells abolishes CAF-mediated transdifferentiation.\",\n      \"method\": \"Proteomic (LC-MS/MS) and transcriptomic (RNA-seq) data integration; confocal microscopy; immunoblotting; qRT-PCR; acinar cell organoids, explants, and CAF cocultures; mCAF coculture models\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-platform proteomic/transcriptomic integration plus functional validation in multiple model systems, single lab\",\n      \"pmids\": [\"38154529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LAMA5 knockdown in ovarian cancer cell lines inhibits cell proliferation, migration, and invasion in vitro and in vivo, and reduces expression of EMT markers and Notch signaling pathway-related markers, placing LAMA5 upstream of Notch-mediated EMT.\",\n      \"method\": \"Lentiviral shRNA knockdown; in vitro proliferation, migration, invasion assays; in vivo tumor xenograft; IHC; western blot for EMT and Notch markers\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, KD with phenotype but pathway placement based on marker expression only, no direct mechanistic dissection of Notch pathway\",\n      \"pmids\": [\"37527216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LAMA5 knockdown in HUVECs or hypoxia/reoxygenation reduces HUVEC proliferation, migration, and vascular formation, and downregulates PI3K downstream targets p-AKT and p-mTOR, placing LAMA5 upstream of PI3K-AKT-mTOR signaling in endothelial cells.\",\n      \"method\": \"siRNA knockdown; CCK-8 proliferation assay; transwell migration assay; tube formation assay; western blot for p-AKT and p-mTOR\",\n      \"journal\": \"The Journal of Maternal-Fetal & Neonatal Medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single KD approach, pathway assignment by protein level only without epistasis confirmation\",\n      \"pmids\": [\"30200802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Human laminin α5 expressed transgenically in mice deposits into basement membranes of heart, liver, spleen, and kidney; high-level transgenic human LAMA5 expression suppresses endogenous mouse Lama5 mRNA and laminin α5 protein in kidney, suggesting a laminin expression monitoring/feedback mechanism in kidney.\",\n      \"method\": \"Transgenic mouse (BAC-based human LAMA5 locus); immunoelectron microscopy; quantitative mRNA analysis; immunofluorescence\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vivo transgenic experiment with protein and mRNA level analysis, single lab, orthogonal methods\",\n      \"pmids\": [\"21915268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LAMA5 silencing in the palatal process inhibits proliferation (reduced ki67, cyclin D1) and promotes apoptosis (increased caspase 3) in mouse palatal cells via the SHH/GLI1 axis (reduced gli1), causing failure of palate fusion; E-cadherin, vimentin, Shh, and ptch1 were not significantly changed, indicating the mechanism is proliferation/apoptosis rather than EMT.\",\n      \"method\": \"LAMA5-shRNA adenovirus transfection into embryonic mouse palatal process in vitro organ culture; PCR; western blot; fluorescence microscopy for fusion assessment\",\n      \"journal\": \"Biomedical Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional KD in organ culture with multiple protein/mRNA readouts and negative controls for EMT, single lab\",\n      \"pmids\": [\"37390938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MAZ transcription factor binds the LAMA5 promoter to activate its transcription; LAMA5 promotes gastric cancer cell proliferation and migration through STAT3 signaling; Colivelin (STAT3 activator) reverses the anti-tumor effects of LAMA5 knockdown.\",\n      \"method\": \"ChIP assay; luciferase reporter assay; siRNA knockdown of LAMA5 and MAZ; CCK-8, colony formation, EdU, wound healing, Transwell assays; in vivo tumor model\",\n      \"journal\": \"Functional & Integrative Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase for transcriptional regulation, epistasis via STAT3 activator rescue, multiple functional assays, single lab\",\n      \"pmids\": [\"40072648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Corticosterone activates glucocorticoid receptor (GR), which directly targets and activates the Lama5 gene; the corticosterone-GR-LAMA5 axis mediates chronic psychological stress-induced cardiomyocyte hypertrophy in vivo and in vitro.\",\n      \"method\": \"Animal stress models; in vitro corticosterone treatment; GR manipulation; in vivo and in vitro confirmation of GR-Lama5 regulatory axis; multiple independent animal experiment batches\",\n      \"journal\": \"Advanced Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct regulatory axis confirmed in vivo and in vitro with multiple experimental batches, single lab\",\n      \"pmids\": [\"40642838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CRISPR/Cas9 knockout of LAMA5 in urine-derived stem cells impairs chondrogenesis and disrupts cell–cell junction programs; loss of LAMA5 attenuates canonical WNT signaling (reduced WNT7A expression); pharmacological WNT activation with LiCl partially restores WNT7A, FLI1, TFAP2A, GRHL2, and PITX1 expression toward wild-type levels.\",\n      \"method\": \"CRISPR/Cas9 KO; 2D and 3D chondrogenic differentiation; bulk RNA sequencing; WGCNA; pharmacological WNT activation (LiCl); qPCR\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with transcriptomic analysis and pharmacological rescue, single lab, preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In zebrafish, laminin α5 (lama5) is a key basement membrane component underlying the migrating posterior lateral line primordium; loss of lama5 alone compromises basement membrane integrity without blocking migration, but simultaneous depletion of lama5 and integrin α6b (itga6b) markedly decreases migration velocity and ultimately blocks collective migration, indicating functional redundancy between these adhesion components.\",\n      \"method\": \"Zebrafish loss-of-function genetics; live imaging of pLLP migration; combinatorial lama5/itga6b double mutant analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with live in vivo imaging in zebrafish, single lab, preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In zebrafish epidermis, loss of laminin α5 reduces E-cadherin localization and increases cell spreading with dynamic cell boundaries and increased cell proliferation (mesenchymal traits); this phenotype is recapitulated by integrin α6b mutation and is not exacerbated in the double mutant, indicating that laminin α5 and integrin α6b function in the same pathway to maintain epithelial apicobasal polarity.\",\n      \"method\": \"Zebrafish lama5 and itga6b loss-of-function mutants; immunofluorescence for E-cadherin, aPKC, Lgl; double mutant epistasis analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic epistasis in zebrafish, single lab, preprint without peer review\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Endothelial-specific loss of laminin α5 (Tek-cre:Lama5-/-) in mice alters cerebrovascular transcriptional identity; compensatory upregulation of laminin α5 in Lama4-/- vessels enhances expression of junctional proteins (Ocln, Cldn5) and promotes vessel contractility, demonstrating that the laminin α4/α5 ratio in vascular basement membranes regulates functional zonation between arterioles, capillaries, and postcapillary venules.\",\n      \"method\": \"Single-cell RNA sequencing of cerebral blood vessels from Lama4-/-, Tek-cre:Lama5-/-, and wild-type mice; in vitro and in vivo functional studies; immunohistochemistry\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endothelial-specific KO and global KO with scRNAseq plus in vitro/in vivo functional validation, single lab, preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"LAMA5 encodes laminin α5, a secreted extracellular matrix glycoprotein that assembles into heterotrimeric laminin-511/521 complexes in basement membranes; it signals bidirectionally through β1 integrin-PYK2-FYN focal adhesion complexes and integrin α4/α6 to regulate WNT and PI3K/AKT pathways, controls cell adhesion, proliferation, migration, and epithelial polarity across multiple tissues, binds SV2A at the neuromuscular junction to support presynaptic terminal maintenance, is transcriptionally activated by GR and MAZ, and is proteolytically processed by MMP1 to generate pro-angiogenic fragments that act via integrin αvβ3.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LAMA5 encodes laminin \\u03b15, a secreted basement-membrane glycoprotein that assembles with laminin \\u03b21 and \\u03b31 chains into laminin-511/521 heterotrimers and acts as a master regulator of cell adhesion, proliferation, polarity, and morphogenesis across epithelial, vascular, neuromuscular, and skeletal tissues [#8, #10, #15]. A recurrent theme is that laminin \\u03b15 transduces basement-membrane attachment into intracellular signaling that balances WNT and PI3K/AKT outputs: it restrains canonical Wnt while activating PI3K/Akt in intestinal cells [#2], and its loss disrupts \\u03b21 integrin signaling through the kinases PYK2 and FYN, destabilizes vinculin localization and the actin cytoskeleton, and impairs WNT signaling to produce a bent-bone skeletal dysplasia [#7]; WNT-dependent control of laminin \\u03b15 levels in turn governs branching morphogenesis and chondrogenesis [#9, #19]. Laminin \\u03b15 supports tissue integrity through receptor partners including SV2A at the neuromuscular junction, where a binding-disrupting variant causes presynaptic transmission failure [#4, #5], and integrin \\u03b16b, with which it acts redundantly or in a shared pathway to maintain collective migration and apicobasal polarity [#20, #21]. In disease, pathogenic LAMA5 variants impair heterotrimer assembly or secretion and cause nephrotic syndrome and FSGS-like glomerulopathy with reduced laminin \\u03b15 and increased glomerular vinculin [#8, #10, #11]. In cancer, laminin \\u03b15 mediates KRAS-mutant tumor-cell adhesion to endothelium via BCAM [#0], drives hepatic metastasis and tumor angiogenesis downstream of TNF\\u03b1/NF\\u03baB [#6], and promotes proliferation and migration through integrin \\u03b14/STAT3 signaling, with MAZ acting as a transcriptional activator of LAMA5 [#12, #17]. Beyond intact trimers, MMP1 cleaves laminin \\u03b15 into fragments that drive VEGF-independent angiogenesis via integrin \\u03b1v\\u03b23 [#1], and its transcription is also activated by glucocorticoid receptor in stress-induced cardiomyocyte hypertrophy [#18].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established that human laminin \\u03b15 incorporates into basement membranes of multiple organs in vivo and that kidney enforces a feedback control on laminin \\u03b15 abundance.\",\n      \"evidence\": \"BAC transgenic mice with human LAMA5; immunoelectron microscopy and quantitative mRNA analysis\",\n      \"pmids\": [\"21915268\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of the proposed kidney expression-monitoring/feedback mechanism unidentified\", \"Did not resolve which receptors mediate deposition into specific basement membranes\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected laminin \\u03b15 to interconnected intracellular signaling by showing it suppresses Wnt while activating PI3K, framing it as a signaling hub rather than a passive structural protein.\",\n      \"evidence\": \"Lama5 knockout mouse intestinal RNA profiling plus in vitro knockdown and pathway modulation\",\n      \"pmids\": [\"22666383\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor linking laminin \\u03b15 to Wnt/PI3K crosstalk not defined\", \"Direct versus indirect contribution to each pathway not separated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined two distinct extracellular activities of laminin \\u03b15 in cancer: a BCAM-dependent adhesion substrate for tumor-endothelial attachment, and an MMP1-generated fragment that drives angiogenesis through integrin \\u03b1v\\u03b23.\",\n      \"evidence\": \"Adhesion assays with genetic/biochemical inhibition of BCAM and LAMA5; MMP1 knockdown/secretome with endothelial angiogenesis and integrin \\u03b1v\\u03b23 antibody blockade\",\n      \"pmids\": [\"27143691\", \"27324842\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cleavage site mapping of MMP1 fragments incomplete\", \"In vivo relevance of BCAM/LAMA5 adhesion in metastasis not directly tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked LAMA5 variants to human disease through two mechanisms: an SV2A-binding-disrupting variant causing presynaptic neuromuscular failure, and a cleavage-altering variant perturbing epithelial-mesenchymal SHH/GLI signaling.\",\n      \"evidence\": \"WES/RNAseq of affected families; patient-derived cell expression; neuronal adhesion and endplate electrophysiology; knock-in mouse generation\",\n      \"pmids\": [\"28735299\", \"28544784\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of laminin \\u03b15\\u2013SV2A interaction unresolved\", \"Mechanism connecting LAMA5 cleavage to SHH/GLI1 upregulation not dissected\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Replicated and extended the SV2A-binding deficit at the neuromuscular junction and placed laminin \\u03b15 upstream of endothelial PI3K-AKT-mTOR signaling.\",\n      \"evidence\": \"Repeat neuronal culture binding/adhesion and endplate EM/electrophysiology; HUVEC siRNA knockdown with p-AKT/p-mTOR immunoblotting and tube formation\",\n      \"pmids\": [\"29377152\", \"30200802\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endothelial pathway assignment rests on protein-level changes without epistasis\", \"How laminin \\u03b15 engages the PI3K axis (which receptor) untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed LAMA5 is an inducible, microenvironment-regulated gene in metastasis, induced by myeloid-derived TNF\\u03b1/NF\\u03baB signaling and required for hepatic metastatic growth and tumor vascularization.\",\n      \"evidence\": \"shRNA knockdown in cancer cells; orthotopic hepatic metastasis model; conditioned-medium and Notch gene expression analysis\",\n      \"pmids\": [\"31064120\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct NF\\u03baB binding to LAMA5 regulatory regions not shown\", \"Mechanism of Notch modulation in metastatic endothelia unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved the intracellular signaling complex through which laminin \\u03b15 loss acts, defining a \\u03b21 integrin\\u2013PYK2\\u2013FYN\\u2013vinculin\\u2013actin\\u2013WNT axis underlying a skeletal dysplasia.\",\n      \"evidence\": \"Exome sequencing of patients; western blot, IHC, WNT luciferase, and migration/wound-healing assays on patient-derived material\",\n      \"pmids\": [\"33242826\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical chain from integrin engagement to PYK2/FYN activation not reconstituted\", \"Tissue specificity of the bent-bone phenotype unexplained\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established the structural disease mechanism in kidney by showing that LAMA5 variants reduce protein levels and heterotrimer assembly (or retain trimer formation despite truncation), causing nephrotic syndrome, and connected WNT to control of Lama5 in branching morphogenesis.\",\n      \"evidence\": \"In vitro heterotrimer assembly assays; knock-in mouse nephrotic models with proteomics/ultrastructure; embryonic SMG organ culture with Wnt/FGF manipulation\",\n      \"pmids\": [\"34774562\", \"35419533\", \"33629734\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why truncated trimer-competent laminin \\u03b15 still causes disease unresolved\", \"Genetic background modifiers of nephrotic progression unmapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked a glomerulopathy variant to defective LG4-5 domain secretion and impaired cell adhesion (increased glomerular vinculin), reinforcing adhesion failure as a unifying disease mechanism.\",\n      \"evidence\": \"In vitro LG4-5 secretion assay; heterozygous/homozygous knockin mice with IHC; WES\",\n      \"pmids\": [\"36173685\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-type dependence of secretion defect mechanistically unexplained\", \"Causal link between vinculin elevation and FSGS not directly demonstrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined laminin \\u03b15 as a stromal driver of tumor cell-state transitions, acting through integrin \\u03b14/STAT3 to drive acinar-to-ductal metaplasia and upstream of Notch-mediated EMT in ovarian cancer.\",\n      \"evidence\": \"CAF coculture organoid/explant models with LAMA5/ITGA4 depletion; proteomic-transcriptomic integration; ovarian cancer shRNA knockdown with EMT/Notch marker analysis and xenografts\",\n      \"pmids\": [\"38154529\", \"37527216\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ovarian Notch placement is marker-based without mechanistic dissection\", \"Whether integrin \\u03b14/STAT3 axis operates in non-pancreatic contexts untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended SHH/GLI1 control of palatogenesis, showing laminin \\u03b15 silencing reduces proliferation and increases apoptosis via the SHH/GLI1 axis to cause cleft palate, distinct from an EMT mechanism.\",\n      \"evidence\": \"LAMA5-shRNA adenovirus in embryonic mouse palatal organ culture; PCR, western blot, fusion imaging with EMT-marker negative controls\",\n      \"pmids\": [\"37390938\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How laminin \\u03b15 signals to SHH/GLI1 not defined\", \"Receptor mediating the proliferation/apoptosis response unidentified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified transcriptional activators of LAMA5 (MAZ in gastric cancer via STAT3; glucocorticoid receptor in stress cardiomyocyte hypertrophy), tying laminin \\u03b15 induction to defined upstream transcription factors and downstream effectors.\",\n      \"evidence\": \"ChIP and luciferase for MAZ promoter binding plus STAT3-activator rescue and tumor models; animal stress models with GR manipulation in vivo and in vitro\",\n      \"pmids\": [\"40072648\", \"40642838\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MAZ/GR regulation of LAMA5 generalizes across tissues unknown\", \"Direct GR-LAMA5 promoter occupancy versus indirect activation not fully separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Genetic dissection in zebrafish and mice clarified laminin \\u03b15\\u2013integrin \\u03b16b relationships and vascular zonation: redundancy with itga6b in collective migration, a shared pathway maintaining epithelial polarity, and a laminin \\u03b14/\\u03b15 ratio controlling cerebrovascular functional identity.\",\n      \"evidence\": \"Zebrafish single and lama5/itga6b double mutants with live imaging and polarity markers; endothelial-specific and global mouse KO with scRNA-seq and functional validation (preprints)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprints not yet peer-reviewed\", \"Molecular signal distinguishing redundant versus same-pathway integrin \\u03b16b interactions unresolved\", \"How laminin \\u03b14/\\u03b15 ratio is sensed by endothelium unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single basement-membrane laminin reconciles its opposing regulatory outputs (WNT suppression versus PI3K/STAT3 activation) across tissues, and what receptor logic selects between adhesion, proliferation, and polarity programs in each context.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified receptor-to-pathway map across tissues\", \"Structural basis of SV2A and BCAM binding unsolved\", \"Direct in vivo reconstitution of the integrin-PYK2-FYN-vinculin module lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [8, 10, 15]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 4, 7]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 7, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005604\", \"supporting_discovery_ids\": [8, 15]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 12, 15]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [8, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [8, 10, 15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 7, 12, 17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 7, 8, 10, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9, 16, 20]}\n    ],\n    \"complexes\": [\"laminin-511/521 heterotrimer (laminin \\u03b15/\\u03b21/\\u03b31)\"],\n    \"partners\": [\"BCAM\", \"SV2A\", \"ITGB1\", \"PYK2\", \"FYN\", \"ITGA4\", \"ITGA6\", \"ITGAV\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}