{"gene":"NID1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1981,"finding":"Entactin (NID1) is a sulfated glycoprotein of approximately 158 kDa isolated from extracellular basement membrane-like matrix; it is immunologically and biochemically distinct from laminin (GP-2) and fibronectin, and localizes predominantly at epithelial cell surfaces adjacent to basement membranes in mouse and rat kidney.","method":"Protein isolation, antibody preparation, immunoelectron microscopy, SDS-PAGE, cyanogen bromide peptide fragmentation, H235SO4 incorporation, chondroitinase ABC treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — original biochemical isolation with multiple orthogonal characterization methods (fractionation, immunoelectron microscopy, peptide mapping), foundational discovery replicated widely","pmids":["6262321"],"is_preprint":false},{"year":1988,"finding":"The complete amino acid sequence of mouse entactin predicts a 1,245-residue polypeptide organized into three structural domains: an N-terminal globular domain (~70 kDa), a cysteine-rich stalk (~28 kDa) containing six EGF-type repeats and one thyroglobulin-type repeat, and a C-terminal globular domain (~36 kDa) with homology to EGF precursor and LDL receptor. Two potential Ca2+-binding sites are present. An RGD cell-recognition sequence is located in one EGF-type repeat and a synthetic RGD-containing peptide promotes mammary tumor cell attachment.","method":"cDNA cloning and sequencing, sequence analysis, synthetic peptide cell attachment assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — full cDNA sequencing with functional peptide validation, foundational domain architecture paper replicated across labs","pmids":["3264556"],"is_preprint":false},{"year":1990,"finding":"Entactin promotes cell attachment of mouse mammary tumor, human melanoma, and other cells; the RGD sequence in entactin mediates approximately 60% of this attachment (inhibited by RGDS peptide), indicating additional non-RGD cell recognition sequences exist. Entactin directly binds calcium ions, with binding sites residing in the NH2-terminal region (demonstrated by recombinant N-terminal 330 aa fragment and synthetic calcium-binding peptides).","method":"Cell attachment assay, peptide inhibition assay, baculovirus-expressed recombinant entactin, 45Ca2+ binding assay, synthetic peptides","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with recombinant protein, peptide mutagenesis-equivalent blocking, and direct calcium binding assay; replicated across multiple cell types","pmids":["2191952"],"is_preprint":false},{"year":1990,"finding":"Entactin's C-terminal globular domain binds tightly to the inner rod-like segment of laminin's short arms, and the same region mediates attachment to type IV collagen approximately 80 nm from its carboxyl non-collagenous end. Transfection of entactin cDNA into JAR choriocarcinoma cells (which lack entactin) stimulated incorporation of laminin and type IV collagen into extracellular matrix, demonstrating entactin's bridging role in basement membrane assembly.","method":"Transfection assay, immunofluorescence, binding studies, domain analysis","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell transfection with defined phenotypic readout plus domain-level binding data, single review-style paper but based on described experiments","pmids":["2119632"],"is_preprint":false},{"year":1990,"finding":"Recombinant entactin expressed in a baculovirus system is correctly processed (signal peptide cleaved), promotes cell attachment, and exhibits calcium- and temperature-dependent self-aggregation. Immunoelectron microscopy showed the majority of recombinant entactin localizes intracellularly forming insoluble aggregates in insect cells.","method":"Baculovirus expression system, amino terminus sequence analysis, cell attachment assay, calcium/temperature-dependent aggregation assay, immunoelectron microscopy","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — recombinant protein reconstitution with functional assays, single lab study","pmids":["2180961"],"is_preprint":false},{"year":1991,"finding":"Entactin specifically binds to the Aα and Bβ chains of fibrinogen in a divalent cation-independent, saturable, and concentration-dependent manner. Entactin can be cross-linked to itself and to fibrin(ogen) by transglutaminase.","method":"Solid phase binding assay with 35S-labeled entactin, competitive inhibition with antibodies and unlabeled ligands, transglutaminase cross-linking assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro binding assay with purified proteins, multiple inhibition controls, and cross-linking experiment in one study","pmids":["1680863"],"is_preprint":false},{"year":1992,"finding":"The cell surface receptor for entactin on PC-3 prostate carcinoma cells is integrin α3β1. The receptor was isolated by affinity chromatography on entactin-Sepharose, bound in a divalent cation-dependent manner (Ca2+, Mg2+, Mn2+), was eluted with EDTA but not RGD-containing peptides, and anti-α3 antibody (P1B5) inhibited cell attachment to entactin but not to laminin.","method":"Affinity chromatography on entactin-Sepharose, 125I surface labeling, anti-integrin antibody identification, purified α3β1 binding assay, liposome reconstitution, antibody inhibition of cell attachment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — receptor isolation by affinity chromatography, identification by antibody panel, purified integrin binding reconstitution, functional inhibition assay — multiple orthogonal methods","pmids":["1527019"],"is_preprint":false},{"year":1992,"finding":"Entactin mediates neutrophil (PMN) adhesion and chemotaxis through its RGD domain via the leukocyte response integrin (LRI). An RGD-containing synthetic peptide (S-RGD) reproduced the effect; a mutant entactin with RGE substitution at Asp674 had no adhesive or chemotactic activity. Anti-LRI monoclonal antibodies blocked both adhesion and chemotaxis, while anti-β1 and anti-β2 integrin antibodies had no effect.","method":"Cell adhesion assay, chemotaxis assay, synthetic peptide competition, site-directed mutant recombinant entactin (RGD→RGE), monoclonal antibody blocking, HL-60 differentiation model","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of active site (RGD→RGE) combined with receptor blocking antibodies and synthetic peptide competition, multiple orthogonal methods","pmids":["1469085"],"is_preprint":false},{"year":1993,"finding":"Entactin is a substrate for matrix metalloproteinases, with matrilysin being ~100-fold more effective than interstitial collagenase and ~600-fold more effective than 92-kDa gelatinase. The Km of matrilysin for entactin is 8.9×10−7 M and Vmax is 21 molecules/enzyme/min at 37°C. Cleavage sites consistently occur amino-terminal to leucine or isoleucine residues.","method":"In vitro MMP cleavage assay, kinetic analysis (Km, Vmax, Arrhenius plot), Edman degradation of cleavage fragments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — rigorous in vitro enzymatic kinetics with three MMPs, precise cleavage site determination by Edman degradation","pmids":["8380588"],"is_preprint":false},{"year":1993,"finding":"Entactin binds to laminin, collagen IV, fibrinogen, fibronectin, and is assembled into complex with laminin intracellularly in parietal endoderm M1536-B3 cells, then transported in membrane-enclosed vesicles to the extracellular compartment. Transfection of entactin into JAR cells (lacking entactin) results in entactin incorporation into extracellular matrix associated with laminin and collagen IV. Entactin also co-localizes with fibronectin in 4CQ cell extracellular matrix.","method":"Cell fractionation, immunofluorescence, cDNA transfection, indirect immunostaining","journal":"Kidney international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transfection with defined matrix assembly phenotype, multiple binding partner localizations demonstrated, single lab","pmids":["8433553"],"is_preprint":false},{"year":1993,"finding":"Recombinant entactin promotes mouse primary trophoblast cell adhesion and migration (blastocyst outgrowth) in a dose-dependent manner via its RGD recognition site. A mutant recombinant entactin with Glu substituted for Asp at the RGD site provided no trophoblast adhesive activity, and RGD-containing peptide reversibly inhibited entactin-mediated outgrowth.","method":"Blastocyst outgrowth assay, site-directed mutagenesis (RGD→RGE), antibody inhibition, peptide competition assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — active site mutagenesis (RGD→RGE) abolishing function, combined with peptide competition and antibody blocking","pmids":["8491783"],"is_preprint":false},{"year":1994,"finding":"The 29 kDa amino-terminal fragment of fibronectin binds specifically to the G2 domain of entactin (half-saturation ~5 nM), but not to G1, E, or G3 domains, identifying G2 as the fibronectin-binding domain of entactin.","method":"GST-fusion protein domain analysis, solid phase binding assay with 125I-labeled fibronectin fragment","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-specific binding assay with purified proteins, saturation binding kinetics, single lab","pmids":["8147897"],"is_preprint":false},{"year":1994,"finding":"Entactin binds specifically to Candida albicans cell wall components in both yeast and hyphal forms; binding is partially inhibited by RGDS peptide and completely abolished by anti-entactin antiserum. Cell wall proteins of ~25, 44, and 65 kDa from both morphologies bind entactin in ligand affinity blotting.","method":"Indirect immunofluorescence, ELISA binding assay, ligand affinity blotting, RGDS peptide competition","journal":"Infection and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay with identified molecular weight components, peptide competition, single lab","pmids":["7927722"],"is_preprint":false},{"year":1995,"finding":"Entactin has two distinct cell attachment sites: (1) the RGD sequence in the EGF-like stalk (E domain), recognized by αvβ3 integrin; and (2) a 39-amino acid cysteine-rich EGF repeat in the G2 domain, which serves as a second attachment site recognized by a β1 family integrin (possibly α3β1), independent of RGD.","method":"GST-fusion protein domain constructs, RGD deletion and Glu-for-Asp substitution mutagenesis, full-length mutant entactin in baculovirus system, cell attachment assay, anti-integrin antibody inhibition","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — domain-level mutagenesis combined with full-length protein validation and integrin receptor identification by antibody blocking","pmids":["7797588"],"is_preprint":false},{"year":1996,"finding":"Entactin E domain (containing RGD) ligates the leukocyte response integrin (beta3-like) and signals for neutrophil chemotaxis, while the G2 domain signals for enhancement of Fc receptor-mediated phagocytosis via ligation of α3β1. These are distinct receptor-domain interactions mediating different neutrophil functions. Matrilysin cleavage of entactin liberates peptides retaining both E domain-mediated chemotaxis and G2 domain-mediated phagocytosis enhancement.","method":"GST-domain fusion proteins (G1, G2, E, G3), neutrophil chemotaxis assay, phagocytosis assay, anti-integrin antibody blocking, matrilysin cleavage","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — domain-specific GST fusion proteins, two orthogonal functional assays (chemotaxis, phagocytosis), receptor identification by antibody blocking, protease cleavage functional retention","pmids":["8940031"],"is_preprint":false},{"year":1996,"finding":"Stromelysin-1 (MMP-3) specifically cleaves entactin in the mammary gland extracellular matrix in vivo; enhanced entactin cleavage to above-normal levels was directly correlated with apoptosis of overlying mammary epithelial cells. TIMP-1 overexpression suppressed MMP activity, prevented entactin degradation, and extinguished the apoptosis.","method":"Transgenic mouse crosses (stromelysin-1 autoactivating transgene × TIMP-1 transgene), in vivo genetic epistasis, quantification of entactin cleavage products, apoptosis assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic epistasis with range of protease:inhibitor genotypes, direct causal link between entactin cleavage and epithelial apoptosis established","pmids":["8978831"],"is_preprint":false},{"year":1991,"finding":"Entactin forms a complex with fibronectin and co-localizes in extracellular matrix of the 4CQ embryonal carcinoma cell line, which lacks laminin. The entactin-fibronectin interaction was confirmed by affinity column chromatography and solid phase assay, demonstrating direct binding.","method":"Immunofluorescence co-localization, affinity column chromatography, solid phase binding assay, Northern blot","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding confirmed by two orthogonal methods (affinity chromatography and solid phase assay), single lab","pmids":["1872841"],"is_preprint":false},{"year":1988,"finding":"Tyrosine sulfation of entactin occurs in medial Golgi cisternae (not trans-Golgi), and is not the last modification before secretion. Four intracellular precursor forms of entactin (EN1–4) at different modification stages were identified; the mature secreted form is tyrosine-sulfated.","method":"Metabolic labeling with [35S]methionine and H235SO4, tunicamycin and monensin inhibitor experiments, pulse-chase analysis in 3T3-L1 adipocytes","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological block of distinct Golgi steps combined with metabolic labeling, single lab","pmids":["3042455"],"is_preprint":false},{"year":2002,"finding":"Targeted disruption of the entactin-1 (nidogen-1) gene in mice causes neurological deficits (seizure-like symptoms, loss of hindleg muscle control) and selective structural alterations in basement membranes at brain capillaries and lens capsule, while basement membranes in most other tissues appeared morphologically normal.","method":"Gene targeting/knockout mouse, behavioral observation, immunohistochemistry, electron microscopy of basement membranes","journal":"Laboratory investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean gene knockout with defined neurological phenotype and tissue-specific basement membrane structural analysis","pmids":["12480912"],"is_preprint":false},{"year":2003,"finding":"In entactin-1-null mice, glomerular basement membranes show thickening, altered anionic charge distribution, and increased αv-integrin density at glomerular cell membranes compared to wild type. Filtration permselectivity is altered (endogenous albumin distribution across basement membrane is changed). Laminin and type IV collagen distributions remain unchanged.","method":"Immunocytochemistry, protein A-gold quantitative electron microscopy, albumin distribution assay in knockout vs. wild-type mice","journal":"The journal of histochemistry and cytochemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — quantitative immunoelectron microscopy in knockout vs. wild-type, multiple structural and functional parameters assessed","pmids":["14566019"],"is_preprint":false},{"year":1992,"finding":"Entactin is required for long-term adhesion and maintenance of contractile skeletal myotubes on diluted Matrigel. Anti-entactin antibodies did not inhibit myoblast attachment or fusion, but myotubes exposed to anti-entactin detached after spontaneous contractions began, identifying a specific role for entactin in post-fusion myotube stabilization.","method":"Antibody blocking with anti-entactin, anti-laminin, anti-collagen IV, anti-HSPG; myotube culture on Matrigel; contractility observation","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — function-blocking antibody with specific stage-dependent phenotype (myotube but not myoblast), single lab","pmids":["1734030"],"is_preprint":false},{"year":1994,"finding":"A novel entactin epitope (recognized by monoclonal antibody 9H6) is selectively present at the synaptic cleft of the neuromuscular junction but not at extrasynaptic sites. This synaptic epitope is dependent on N-glycosylation (N-glycanase treatment reduces molecular mass and eliminates 9H6 binding), identifying a glycosylation-dependent, synapse-specific form of entactin.","method":"Monoclonal antibody generation, immunofluorescence, Western blot, N-glycanase treatment, N-terminal sequence analysis","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — N-glycanase functional ablation of epitope combined with precise localization, single lab","pmids":["7514212"],"is_preprint":false},{"year":1995,"finding":"The mouse entactin gene spans >65 kb, contains 20 exons, and its exon organization directly corresponds to the polypeptide's structural domains (each EGF-like repeat, the thyroglobulin repeat, and each globular domain encoded by separate exons), with regional homology to the LDL receptor gene including conservation of four intron positions, indicating evolution via exon shuffling.","method":"Genomic cloning, restriction mapping, DNA sequencing, exon-intron boundary determination","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — complete exon-intron structure determination with domain correspondence analysis, single lab","pmids":["7601446"],"is_preprint":false},{"year":1998,"finding":"Human mesangial cells use both αvβ3 (via the RGD sequence in entactin's E/rod domain) and a β1-containing integrin to adhere to native entactin. Adhesion requires divalent cations. Recombinant entactin lacking the E domain RGD still supported some mesangial cell adhesion via β1 integrin, and tertiary structure of native entactin may contribute to binding properties.","method":"Cell adhesion assay, anti-integrin monoclonal antibody blocking, wild-type and RGD-mutant recombinant entactin fragments, metabolic labeling and immunoprecipitation","journal":"Cell adhesion and communication","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple integrin antibodies and domain mutants used, single lab","pmids":["9686320"],"is_preprint":false},{"year":2000,"finding":"Entactin-1 (nidogen-1) is exclusively produced and secreted by mesenchymal peritubular cells (not Sertoli cells) in rat testis. Anti-entactin-1 monoclonal antibodies caused loss of adhesion specifically in peritubular cells but not Sertoli cells, demonstrating an autocrine adhesion function of entactin-1 for peritubular cells.","method":"DD-RT-PCR, Western blot of co-cultures and monocultures, antibody perturbation assay, immunofluorescence","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — function-blocking antibody with cell-type-specific phenotype, source cell identified by Western blot, single lab","pmids":["10727019"],"is_preprint":false},{"year":2001,"finding":"Entactin significantly inhibits amyloid beta-protein (Aβ1-40) fibril formation in vitro at a 50:1 molar ratio (Aβ:entactin). The inhibitory mechanism involves entactin inducing a random coil structure in Aβ40, as shown by circular dichroism spectroscopy.","method":"Thioflavin T fluorometric assay, electron microscopy, circular dichroism spectroscopy","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with multiple readouts (fluorometry, EM, CD), single lab","pmids":["11376898"],"is_preprint":false},{"year":2013,"finding":"Heterozygous mutations in NID1 cause autosomal dominant Dandy-Walker malformation with occipital cephaloceles. Structural modeling of the NID1-LAMC1 complex showed that a NID1 mutation disrupts the NID1-LAMC1 (laminin γ1) protein interaction, identifying NID1 binding to laminin as functionally critical for posterior fossa development.","method":"Whole-exome sequencing, protein interaction network analysis, structural modeling of NID1-LAMC1 complex","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetics combined with structural modeling of binding interface disruption, two independent families with mutations in interacting partners","pmids":["23674478"],"is_preprint":false},{"year":2014,"finding":"An 855 bp deletion in bovine NID1 spanning exon 19/intron 19 border causes skipping of exon 19, frameshifting, and premature stop (p.1164fs27X), truncating the C-terminal domain essential for binding with matrix assembly complexes. This causes autosomal recessive inherited cataract and neurological abnormalities in cattle.","method":"Genome-wide association study, homozygosity mapping, whole genome sequencing, RT-PCR (demonstrating exon skipping), pedigree analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — naturally occurring loss-of-function mutation with confirmed splicing consequence and defined domain truncation, animal model","pmids":["25347398"],"is_preprint":false},{"year":2018,"finding":"In C. elegans, NID-1/Nidogen localizes to all basement membranes; its localization depends on Laminin (loss of Laminin strongly reduces NID-1 BM localization). Ndg/nid-1 null mutants have ultrastructural BM defects compromising barrier function and stability. Genetic epistasis places nid-1 in the same pathway as unc-52/Perlecan and the netrin axon guidance signaling cassette for establishing correct somatosensory dendrite number; UNC-52/Perlecan is required to correctly localize NID-1.","method":"Genetic knockout (Ndg-null and unc-52 mutants), ultrastructural analysis (EM), barrier function assay, genetic epistasis, fluorescence localization","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — combined structural (EM), functional (barrier assay), and genetic epistasis with multiple mutant combinations in two papers (Drosophila and C. elegans)","pmids":["30567930","29678816"],"is_preprint":false},{"year":2006,"finding":"Entactin-1 overexpression in myoblasts (retroviral system) leads to higher proliferation rate and reduced expression of myogenic differentiation markers after induction, demonstrating that entactin-1 opposes myogenic differentiation. Conversely, entactin-2 is a primary response gene transiently induced during myogenesis.","method":"Retroviral overexpression, siRNA knockdown, RT-PCR for differentiation markers, cycloheximide and actinomycin D treatment, p38 MAPK inhibitors","journal":"Differentiation; research in biological diversity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — retroviral overexpression with defined differentiation markers, single lab","pmids":["17177854"],"is_preprint":false},{"year":2019,"finding":"NID1 is a downstream target of p53/miR-192/miR-215 axis in colorectal cancer cells. p53 activates miR-192 and miR-215, which directly target NID1 mRNA to repress its expression. Secreted NID1 is required and sufficient for inducing EMT, invasion, and migration in epithelial-like CRC cells via paracrine signaling.","method":"miRNA target prediction and validation, conditioned medium transfer, NID1 knockdown and overexpression, CRC cell migration/invasion assays, cytokine array","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct miRNA targeting of NID1 mRNA with knockdown and rescue experiments, paracrine mechanism demonstrated, single lab","pmids":["30831320"],"is_preprint":false},{"year":2021,"finding":"Nid1 is secreted by enteric neurons and elevated in the Ndrg4-/- enteric nervous system secretome. ENS-derived Nid1 (and Fibulin-2) enhances migration capacities of colorectal cancer cells and promotes organoid growth.","method":"Ndrg4 knockout mouse, in vitro co-culture of ENS cells and intestinal organoids, quantitative proteomics of secretome, CRC cell migration assay","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse combined with proteomics and functional cell migration assay, single lab","pmids":["33890711"],"is_preprint":false},{"year":2022,"finding":"NID-1 is highly secreted by skeletal muscle fibro-adipogenic/mesenchymal progenitors (FAPs) during obesity. Increased muscle NID-1 impairs muscle stem cell proliferation and primes FAPs for fibrogenic differentiation leading to excessive ECM deposition.","method":"High fat diet mouse model, cell secretome analysis, in vitro myoblast treatment with NID-1, immunofluorescence, muscle stem cell functional assay","journal":"Matrix biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo obesity model combined with in vitro functional assay of purified NID-1, single lab","pmids":["35963565"],"is_preprint":false},{"year":2023,"finding":"NID1 is a direct transcriptional target of the EMT-inducing transcription factor SNAIL: ectopic SNAIL expression induces NID1, and SNAIL occupancy was detected at an E-box upstream of the NID1 transcription start site by ChIP. NID1 signals through its receptors ITGA3, ITGB1, and ITGAV; ectopic NID1 or NID1-conditioned medium conferred lung metastatic capacity to non-metastatic CRC cells in xenotransplantation.","method":"ChIP assay for SNAIL at NID1 E-box, ectopic expression of SNAIL and NID1, xenotransplantation lung metastasis model, bioinformatics of patient datasets, ITGAV knockdown viability assay","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional gain-of-function in vivo metastasis model, single lab","pmids":["38001576"],"is_preprint":false},{"year":2023,"finding":"COL4A1 physically binds to NID1, as confirmed by co-immunoprecipitation in OSCC cells. NID1 overexpression rescues the inhibitory effects of COL4A1 knockdown on cell proliferation, migration, invasion, and EMT, placing NID1 downstream of COL4A1.","method":"Co-immunoprecipitation, COL4A1 knockdown, NID1 overexpression rescue experiment, proliferation/migration/invasion assays","journal":"Experimental and therapeutic medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP binding confirmation plus epistatic rescue experiment, single lab","pmids":["37006878"],"is_preprint":false},{"year":2026,"finding":"In C. elegans, NID-1 expressed by body wall muscles or hypodermis promotes local guidance of regenerating motor axons alongside neighboring neuronal processes (PVD dendrites). Loss of nid-1 disrupts axon-PVD colocalization, increases displacement from the pre-injury dorsal nerve cord contact point, and impairs synapse reformation and functional recovery. Muscle-derived NID-1 specifically is required for synapse reformation. Genetic data indicate NID-1 guides regenerating axons in coordination with laminin and integrin; ectopic integrin expression in GABAergic neurons reroutes their regenerating axons alongside PVD dendrites in a NID-1-dependent manner.","method":"nid-1 null mutant C. elegans, laser axotomy/axon regeneration assay, tissue-specific rescue (muscle, hypodermis, neuron), fluorescence imaging of axon guidance, synapse reformation assay, functional recovery assay, genetic epistasis with laminin and integrin","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with tissue-specific rescue and multiple functional readouts, preprint not yet peer-reviewed","pmids":["41890084"],"is_preprint":true}],"current_model":"NID1/entactin is a multidomain sulfated glycoprotein that serves as a molecular bridge in basement membrane assembly by binding laminin (via its C-terminal G3 domain) and type IV collagen, as well as fibronectin (via G2) and fibrinogen (Aα/Bβ chains); it promotes cell adhesion, migration, and neutrophil chemotaxis through an RGD sequence in its EGF-like stalk domain (recognized by αvβ3 and the leukocyte response integrin) and a second RGD-independent site in the G2 domain (recognized by α3β1 integrin); it is degraded by matrix metalloproteinases (especially matrilysin) at Leu/Ile-preceding sites, and this cleavage can trigger epithelial apoptosis in vivo; NID1 loss in mice and C. elegans causes tissue-specific basement membrane defects, neurological phenotypes, and impaired axon regeneration guidance; and transcriptionally NID1 is a direct target of SNAIL and is repressed by the p53/miR-192/215 axis."},"narrative":{"mechanistic_narrative":"NID1 (entactin/nidogen-1) is a sulfated, multidomain basement membrane glycoprotein that acts as a molecular bridge organizing the assembly of basement-membrane networks and as a ligand directing integrin-dependent cell adhesion and migration [PMID:6262321, PMID:2119632]. Its C-terminal globular (G3) domain binds tightly to the inner short-arm segment of laminin and to type IV collagen, and ectopic expression of NID1 in cells lacking it drives incorporation of laminin and collagen IV into extracellular matrix, establishing its bridging role in matrix assembly [PMID:2119632, PMID:8433553]. The protein presents two genetically separable cell-attachment activities: an RGD motif within an EGF-like repeat of the central stalk (E domain), recognized by alphaV-beta3 and the leukocyte response integrin, and an RGD-independent site in the G2 domain recognized by a beta1 integrin (alpha3-beta1); mutation of the RGD aspartate to glutamate abolishes RGD-dependent adhesion, chemotaxis, and trophoblast outgrowth [PMID:1469085, PMID:7797588, PMID:1527019, PMID:8491783]. Through these domains NID1 also binds fibrinogen Aalpha/Bbeta chains and a G2-localized fibronectin site, integrating it into broader matrix and clotting networks [PMID:1680863, PMID:8147897]. NID1 is a preferred substrate of matrix metalloproteinases, cleaved most efficiently by matrilysin at sites amino-terminal to Leu/Ile, and excessive stromelysin-1-mediated entactin cleavage in mammary basement membrane directly triggers epithelial apoptosis in vivo [PMID:8380588, PMID:8978831]. Loss-of-function studies define its physiological roles: nidogen-1-null mice display neurological deficits and selective basement-membrane defects at brain capillaries and lens capsule, and in C. elegans laminin- and perlecan-dependent NID-1 deposition maintains basement-membrane integrity and patterns axon/dendrite guidance [PMID:12480912, PMID:30567930, PMID:29678816]. Heterozygous NID1 mutations disrupting the NID1-laminin gamma1 interface cause autosomal dominant Dandy-Walker malformation, and a C-terminal-truncating NID1 deletion causes recessive cataract with neurological abnormalities in cattle [PMID:23674478, PMID:25347398]. In cancer, NID1 is a direct transcriptional target of SNAIL and is repressed by the p53/miR-192/miR-215 axis; secreted NID1 acts in a paracrine fashion through ITGA3/ITGB1/ITGAV to drive EMT, invasion, and metastatic capacity [PMID:30831320, PMID:38001576].","teleology":[{"year":1981,"claim":"Established that NID1/entactin is a distinct basement-membrane component, separating it biochemically and immunologically from the co-purifying laminin and fibronectin that had obscured it.","evidence":"Protein isolation, immunoelectron microscopy, peptide mapping and sulfate labeling from kidney matrix","pmids":["6262321"],"confidence":"High","gaps":["Domain architecture and binding partners not yet defined","Function inferred only from localization at this stage"]},{"year":1988,"claim":"Defined the three-domain architecture (N-globular, EGF/thyroglobulin stalk, C-globular) and located an RGD cell-recognition motif, providing the structural framework for all subsequent functional dissection.","evidence":"Full-length mouse cDNA cloning and sequencing plus synthetic RGD peptide attachment assay; Golgi tyrosine sulfation mapped by metabolic labeling","pmids":["3264556","3042455"],"confidence":"High","gaps":["Receptors for the RGD motif not identified","Functional contribution of non-RGD regions unknown"]},{"year":1990,"claim":"Showed NID1 functions as a matrix bridge by binding laminin short arms and type IV collagen through its C-terminal domain and driving their incorporation into matrix when expressed in deficient cells.","evidence":"Domain binding studies plus entactin cDNA transfection into entactin-lacking JAR cells with matrix incorporation readout; recombinant baculovirus protein with calcium-dependent self-aggregation","pmids":["2119632","2180961","2191952"],"confidence":"Medium","gaps":["Stoichiometry and structural basis of the laminin/collagen bridge not resolved","RGD-independent attachment activity noted but not localized"]},{"year":1991,"claim":"Extended NID1's ligand repertoire beyond the canonical laminin/collagen network to fibrinogen and fibronectin, implying roles in provisional matrix and clotting contexts.","evidence":"Solid-phase binding with labeled entactin, transglutaminase cross-linking, and affinity chromatography/co-localization in laminin-deficient cells","pmids":["1680863","1872841"],"confidence":"High","gaps":["Domain mediating fibrinogen binding not mapped here","Physiological relevance of fibrinogen/fibronectin binding in vivo untested"]},{"year":1992,"claim":"Identified specific integrin receptors and proved the RGD motif is functionally required, distinguishing RGD-dependent (alphaV-beta3/leukocyte response integrin) from cation-dependent, RGD-independent (alpha3-beta1) adhesion.","evidence":"Affinity isolation of alpha3-beta1 on entactin-Sepharose; RGD-to-RGE mutant entactin and anti-LRI blocking in neutrophil adhesion/chemotaxis; myotube maintenance antibody-blocking assay","pmids":["1527019","1469085","1734030"],"confidence":"High","gaps":["Precise domain location of the alpha3-beta1 site not yet defined","Downstream signaling from integrin ligation uncharacterized"]},{"year":1993,"claim":"Defined NID1 as a metalloproteinase substrate, establishing matrilysin as a far more efficient protease than collagenase or gelatinase and mapping Leu/Ile-preceding cleavage sites.","evidence":"In vitro MMP kinetics (Km, Vmax) and Edman degradation of cleavage fragments; intracellular laminin complex assembly and vesicular transport shown by fractionation/transfection","pmids":["8380588","8433553","8491783"],"confidence":"High","gaps":["In vivo consequences of cleavage not yet established at this stage","Whether cleavage products retain activity untested here"]},{"year":1995,"claim":"Resolved the two-site adhesion model at domain resolution, assigning the RGD/alphaV-beta3 activity to the E domain and a separate cysteine-rich EGF repeat in G2 to a beta1-integrin attachment site.","evidence":"GST-fusion domain constructs, RGD deletion/Glu-substitution mutagenesis in full-length protein, anti-integrin blocking; genomic exon-intron mapping correlating exons to domains","pmids":["7797588","7601446"],"confidence":"High","gaps":["Exact beta1 integrin partner at G2 not definitively assigned","Crystal/structural basis of dual integrin engagement absent"]},{"year":1996,"claim":"Linked the two adhesion domains to distinct cellular outputs and showed matrilysin cleavage liberates functionally active fragments, connecting proteolysis to biological consequence.","evidence":"Domain GST fusions in neutrophil chemotaxis vs Fc-phagocytosis assays; transgenic stromelysin-1 x TIMP-1 epistasis tying entactin cleavage to mammary epithelial apoptosis in vivo","pmids":["8940031","8978831"],"confidence":"High","gaps":["Molecular pathway from entactin loss to apoptosis not delineated","Generality of cleavage-driven apoptosis across tissues unknown"]},{"year":2003,"claim":"Defined physiological requirement in vivo: nidogen-1 loss causes neurological deficits and selective basement-membrane defects despite normal laminin/collagen distribution, indicating context-dependent rather than universal necessity.","evidence":"Targeted knockout mouse with behavioral, immunohistochemical, and quantitative immuno-EM analysis of brain capillary, lens, and glomerular basement membranes","pmids":["12480912","14566019"],"confidence":"High","gaps":["Compensation by nidogen-2 not addressed","Mechanism linking NID1 loss to altered charge/permselectivity unresolved"]},{"year":2013,"claim":"Established a human Mendelian disease link, showing heterozygous NID1 mutations that disrupt the NID1-laminin gamma1 interface cause Dandy-Walker malformation, validating the laminin-binding bridge as developmentally critical.","evidence":"Whole-exome sequencing of families plus structural modeling of the NID1-LAMC1 complex; bovine recessive cataract from a C-terminal-truncating NID1 deletion confirmed by RT-PCR exon skipping","pmids":["23674478","25347398"],"confidence":"Medium","gaps":["Functional binding disruption inferred from modeling, not biochemically measured for the mutant","Cellular pathology of posterior fossa development not directly tested"]},{"year":2019,"claim":"Recast NID1 as a paracrine cancer effector, showing it is a direct target of p53/miR-192/215 repression and of SNAIL activation, and that secreted NID1 drives EMT, invasion, and metastasis via integrins.","evidence":"miRNA target validation, conditioned-medium transfer, knockdown/rescue, ChIP for SNAIL at the NID1 E-box, and xenotransplant metastasis assays; COL4A1 co-IP and epistatic rescue in OSCC","pmids":["30831320","38001576","37006878"],"confidence":"Medium","gaps":["Which integrin-engaged domain drives the metastatic signal not dissected","Single-lab cancer models; in-vivo human relevance limited to bioinformatic correlation"]},{"year":2021,"claim":"Identified non-tumor stromal sources of secreted NID1 (enteric neurons, muscle FAPs) that modulate cancer cell migration and tissue remodeling, broadening NID1's signaling role beyond classical matrix scaffolding.","evidence":"Ndrg4-knockout ENS secretome proteomics with organoid/migration assays; high-fat-diet muscle FAP secretome with myoblast and muscle stem cell functional assays","pmids":["33890711","35963565"],"confidence":"Medium","gaps":["Receptor and signaling cascade for stromal NID1 not defined","Causal contribution in vivo vs correlative secretome change uncertain"]},{"year":2026,"claim":"Demonstrated a guidance function for NID-1 in axon regeneration, showing tissue-specific muscle/hypodermal NID-1 directs regenerating motor axons and synapse reformation in coordination with laminin and integrin.","evidence":"C. elegans nid-1 null with laser axotomy, tissue-specific rescue, synapse and functional recovery readouts, and genetic epistasis (preprint)","pmids":["41890084"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Molecular mechanism of axon-NID-1-integrin guidance not biochemically resolved","Conservation in mammals untested"]},{"year":null,"claim":"How NID1's molecular bridging and integrin-signaling activities are differentially deployed across tissue-specific basement-membrane assembly, proteolytic remodeling, and paracrine cancer signaling remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of NID1 bound to laminin and collagen simultaneously","Mechanism connecting secreted NID1 to integrin signaling in cancer undefined","Redundancy with nidogen-2 not systematically resolved in vivo"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[7,13,6,10]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,3,9]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[14,33]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[25]}],"localization":[{"term_id":"GO:0030312","term_label":"external encapsulating structure","supporting_discovery_ids":[0,9,28]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[9,30,31]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[3,9,32]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[3,9,28]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[18,26,28]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[26,27,30,33]}],"complexes":["nidogen-laminin-type IV collagen basement membrane network"],"partners":["LAMC1","COL4A1","FN1","FGA","FGB","ITGA3","ITGB1","ITGAV"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P14543","full_name":"Nidogen-1","aliases":["Entactin"],"length_aa":1247,"mass_kda":136.4,"function":"Sulfated glycoprotein widely distributed in basement membranes and tightly associated with laminin. 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     \"method\": \"Protein isolation, antibody preparation, immunoelectron microscopy, SDS-PAGE, cyanogen bromide peptide fragmentation, H235SO4 incorporation, chondroitinase ABC treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — original biochemical isolation with multiple orthogonal characterization methods (fractionation, immunoelectron microscopy, peptide mapping), foundational discovery replicated widely\",\n      \"pmids\": [\"6262321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"The complete amino acid sequence of mouse entactin predicts a 1,245-residue polypeptide organized into three structural domains: an N-terminal globular domain (~70 kDa), a cysteine-rich stalk (~28 kDa) containing six EGF-type repeats and one thyroglobulin-type repeat, and a C-terminal globular domain (~36 kDa) with homology to EGF precursor and LDL receptor. Two potential Ca2+-binding sites are present. An RGD cell-recognition sequence is located in one EGF-type repeat and a synthetic RGD-containing peptide promotes mammary tumor cell attachment.\",\n      \"method\": \"cDNA cloning and sequencing, sequence analysis, synthetic peptide cell attachment assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — full cDNA sequencing with functional peptide validation, foundational domain architecture paper replicated across labs\",\n      \"pmids\": [\"3264556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Entactin promotes cell attachment of mouse mammary tumor, human melanoma, and other cells; the RGD sequence in entactin mediates approximately 60% of this attachment (inhibited by RGDS peptide), indicating additional non-RGD cell recognition sequences exist. Entactin directly binds calcium ions, with binding sites residing in the NH2-terminal region (demonstrated by recombinant N-terminal 330 aa fragment and synthetic calcium-binding peptides).\",\n      \"method\": \"Cell attachment assay, peptide inhibition assay, baculovirus-expressed recombinant entactin, 45Ca2+ binding assay, synthetic peptides\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with recombinant protein, peptide mutagenesis-equivalent blocking, and direct calcium binding assay; replicated across multiple cell types\",\n      \"pmids\": [\"2191952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Entactin's C-terminal globular domain binds tightly to the inner rod-like segment of laminin's short arms, and the same region mediates attachment to type IV collagen approximately 80 nm from its carboxyl non-collagenous end. Transfection of entactin cDNA into JAR choriocarcinoma cells (which lack entactin) stimulated incorporation of laminin and type IV collagen into extracellular matrix, demonstrating entactin's bridging role in basement membrane assembly.\",\n      \"method\": \"Transfection assay, immunofluorescence, binding studies, domain analysis\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell transfection with defined phenotypic readout plus domain-level binding data, single review-style paper but based on described experiments\",\n      \"pmids\": [\"2119632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Recombinant entactin expressed in a baculovirus system is correctly processed (signal peptide cleaved), promotes cell attachment, and exhibits calcium- and temperature-dependent self-aggregation. Immunoelectron microscopy showed the majority of recombinant entactin localizes intracellularly forming insoluble aggregates in insect cells.\",\n      \"method\": \"Baculovirus expression system, amino terminus sequence analysis, cell attachment assay, calcium/temperature-dependent aggregation assay, immunoelectron microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — recombinant protein reconstitution with functional assays, single lab study\",\n      \"pmids\": [\"2180961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Entactin specifically binds to the Aα and Bβ chains of fibrinogen in a divalent cation-independent, saturable, and concentration-dependent manner. Entactin can be cross-linked to itself and to fibrin(ogen) by transglutaminase.\",\n      \"method\": \"Solid phase binding assay with 35S-labeled entactin, competitive inhibition with antibodies and unlabeled ligands, transglutaminase cross-linking assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding assay with purified proteins, multiple inhibition controls, and cross-linking experiment in one study\",\n      \"pmids\": [\"1680863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The cell surface receptor for entactin on PC-3 prostate carcinoma cells is integrin α3β1. The receptor was isolated by affinity chromatography on entactin-Sepharose, bound in a divalent cation-dependent manner (Ca2+, Mg2+, Mn2+), was eluted with EDTA but not RGD-containing peptides, and anti-α3 antibody (P1B5) inhibited cell attachment to entactin but not to laminin.\",\n      \"method\": \"Affinity chromatography on entactin-Sepharose, 125I surface labeling, anti-integrin antibody identification, purified α3β1 binding assay, liposome reconstitution, antibody inhibition of cell attachment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — receptor isolation by affinity chromatography, identification by antibody panel, purified integrin binding reconstitution, functional inhibition assay — multiple orthogonal methods\",\n      \"pmids\": [\"1527019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Entactin mediates neutrophil (PMN) adhesion and chemotaxis through its RGD domain via the leukocyte response integrin (LRI). An RGD-containing synthetic peptide (S-RGD) reproduced the effect; a mutant entactin with RGE substitution at Asp674 had no adhesive or chemotactic activity. Anti-LRI monoclonal antibodies blocked both adhesion and chemotaxis, while anti-β1 and anti-β2 integrin antibodies had no effect.\",\n      \"method\": \"Cell adhesion assay, chemotaxis assay, synthetic peptide competition, site-directed mutant recombinant entactin (RGD→RGE), monoclonal antibody blocking, HL-60 differentiation model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of active site (RGD→RGE) combined with receptor blocking antibodies and synthetic peptide competition, multiple orthogonal methods\",\n      \"pmids\": [\"1469085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Entactin is a substrate for matrix metalloproteinases, with matrilysin being ~100-fold more effective than interstitial collagenase and ~600-fold more effective than 92-kDa gelatinase. The Km of matrilysin for entactin is 8.9×10−7 M and Vmax is 21 molecules/enzyme/min at 37°C. Cleavage sites consistently occur amino-terminal to leucine or isoleucine residues.\",\n      \"method\": \"In vitro MMP cleavage assay, kinetic analysis (Km, Vmax, Arrhenius plot), Edman degradation of cleavage fragments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — rigorous in vitro enzymatic kinetics with three MMPs, precise cleavage site determination by Edman degradation\",\n      \"pmids\": [\"8380588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Entactin binds to laminin, collagen IV, fibrinogen, fibronectin, and is assembled into complex with laminin intracellularly in parietal endoderm M1536-B3 cells, then transported in membrane-enclosed vesicles to the extracellular compartment. Transfection of entactin into JAR cells (lacking entactin) results in entactin incorporation into extracellular matrix associated with laminin and collagen IV. Entactin also co-localizes with fibronectin in 4CQ cell extracellular matrix.\",\n      \"method\": \"Cell fractionation, immunofluorescence, cDNA transfection, indirect immunostaining\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transfection with defined matrix assembly phenotype, multiple binding partner localizations demonstrated, single lab\",\n      \"pmids\": [\"8433553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Recombinant entactin promotes mouse primary trophoblast cell adhesion and migration (blastocyst outgrowth) in a dose-dependent manner via its RGD recognition site. A mutant recombinant entactin with Glu substituted for Asp at the RGD site provided no trophoblast adhesive activity, and RGD-containing peptide reversibly inhibited entactin-mediated outgrowth.\",\n      \"method\": \"Blastocyst outgrowth assay, site-directed mutagenesis (RGD→RGE), antibody inhibition, peptide competition assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — active site mutagenesis (RGD→RGE) abolishing function, combined with peptide competition and antibody blocking\",\n      \"pmids\": [\"8491783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The 29 kDa amino-terminal fragment of fibronectin binds specifically to the G2 domain of entactin (half-saturation ~5 nM), but not to G1, E, or G3 domains, identifying G2 as the fibronectin-binding domain of entactin.\",\n      \"method\": \"GST-fusion protein domain analysis, solid phase binding assay with 125I-labeled fibronectin fragment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-specific binding assay with purified proteins, saturation binding kinetics, single lab\",\n      \"pmids\": [\"8147897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Entactin binds specifically to Candida albicans cell wall components in both yeast and hyphal forms; binding is partially inhibited by RGDS peptide and completely abolished by anti-entactin antiserum. Cell wall proteins of ~25, 44, and 65 kDa from both morphologies bind entactin in ligand affinity blotting.\",\n      \"method\": \"Indirect immunofluorescence, ELISA binding assay, ligand affinity blotting, RGDS peptide competition\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay with identified molecular weight components, peptide competition, single lab\",\n      \"pmids\": [\"7927722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Entactin has two distinct cell attachment sites: (1) the RGD sequence in the EGF-like stalk (E domain), recognized by αvβ3 integrin; and (2) a 39-amino acid cysteine-rich EGF repeat in the G2 domain, which serves as a second attachment site recognized by a β1 family integrin (possibly α3β1), independent of RGD.\",\n      \"method\": \"GST-fusion protein domain constructs, RGD deletion and Glu-for-Asp substitution mutagenesis, full-length mutant entactin in baculovirus system, cell attachment assay, anti-integrin antibody inhibition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — domain-level mutagenesis combined with full-length protein validation and integrin receptor identification by antibody blocking\",\n      \"pmids\": [\"7797588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Entactin E domain (containing RGD) ligates the leukocyte response integrin (beta3-like) and signals for neutrophil chemotaxis, while the G2 domain signals for enhancement of Fc receptor-mediated phagocytosis via ligation of α3β1. These are distinct receptor-domain interactions mediating different neutrophil functions. Matrilysin cleavage of entactin liberates peptides retaining both E domain-mediated chemotaxis and G2 domain-mediated phagocytosis enhancement.\",\n      \"method\": \"GST-domain fusion proteins (G1, G2, E, G3), neutrophil chemotaxis assay, phagocytosis assay, anti-integrin antibody blocking, matrilysin cleavage\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — domain-specific GST fusion proteins, two orthogonal functional assays (chemotaxis, phagocytosis), receptor identification by antibody blocking, protease cleavage functional retention\",\n      \"pmids\": [\"8940031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Stromelysin-1 (MMP-3) specifically cleaves entactin in the mammary gland extracellular matrix in vivo; enhanced entactin cleavage to above-normal levels was directly correlated with apoptosis of overlying mammary epithelial cells. TIMP-1 overexpression suppressed MMP activity, prevented entactin degradation, and extinguished the apoptosis.\",\n      \"method\": \"Transgenic mouse crosses (stromelysin-1 autoactivating transgene × TIMP-1 transgene), in vivo genetic epistasis, quantification of entactin cleavage products, apoptosis assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic epistasis with range of protease:inhibitor genotypes, direct causal link between entactin cleavage and epithelial apoptosis established\",\n      \"pmids\": [\"8978831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Entactin forms a complex with fibronectin and co-localizes in extracellular matrix of the 4CQ embryonal carcinoma cell line, which lacks laminin. The entactin-fibronectin interaction was confirmed by affinity column chromatography and solid phase assay, demonstrating direct binding.\",\n      \"method\": \"Immunofluorescence co-localization, affinity column chromatography, solid phase binding assay, Northern blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding confirmed by two orthogonal methods (affinity chromatography and solid phase assay), single lab\",\n      \"pmids\": [\"1872841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"Tyrosine sulfation of entactin occurs in medial Golgi cisternae (not trans-Golgi), and is not the last modification before secretion. Four intracellular precursor forms of entactin (EN1–4) at different modification stages were identified; the mature secreted form is tyrosine-sulfated.\",\n      \"method\": \"Metabolic labeling with [35S]methionine and H235SO4, tunicamycin and monensin inhibitor experiments, pulse-chase analysis in 3T3-L1 adipocytes\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological block of distinct Golgi steps combined with metabolic labeling, single lab\",\n      \"pmids\": [\"3042455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Targeted disruption of the entactin-1 (nidogen-1) gene in mice causes neurological deficits (seizure-like symptoms, loss of hindleg muscle control) and selective structural alterations in basement membranes at brain capillaries and lens capsule, while basement membranes in most other tissues appeared morphologically normal.\",\n      \"method\": \"Gene targeting/knockout mouse, behavioral observation, immunohistochemistry, electron microscopy of basement membranes\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean gene knockout with defined neurological phenotype and tissue-specific basement membrane structural analysis\",\n      \"pmids\": [\"12480912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In entactin-1-null mice, glomerular basement membranes show thickening, altered anionic charge distribution, and increased αv-integrin density at glomerular cell membranes compared to wild type. Filtration permselectivity is altered (endogenous albumin distribution across basement membrane is changed). Laminin and type IV collagen distributions remain unchanged.\",\n      \"method\": \"Immunocytochemistry, protein A-gold quantitative electron microscopy, albumin distribution assay in knockout vs. wild-type mice\",\n      \"journal\": \"The journal of histochemistry and cytochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — quantitative immunoelectron microscopy in knockout vs. wild-type, multiple structural and functional parameters assessed\",\n      \"pmids\": [\"14566019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Entactin is required for long-term adhesion and maintenance of contractile skeletal myotubes on diluted Matrigel. Anti-entactin antibodies did not inhibit myoblast attachment or fusion, but myotubes exposed to anti-entactin detached after spontaneous contractions began, identifying a specific role for entactin in post-fusion myotube stabilization.\",\n      \"method\": \"Antibody blocking with anti-entactin, anti-laminin, anti-collagen IV, anti-HSPG; myotube culture on Matrigel; contractility observation\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — function-blocking antibody with specific stage-dependent phenotype (myotube but not myoblast), single lab\",\n      \"pmids\": [\"1734030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"A novel entactin epitope (recognized by monoclonal antibody 9H6) is selectively present at the synaptic cleft of the neuromuscular junction but not at extrasynaptic sites. This synaptic epitope is dependent on N-glycosylation (N-glycanase treatment reduces molecular mass and eliminates 9H6 binding), identifying a glycosylation-dependent, synapse-specific form of entactin.\",\n      \"method\": \"Monoclonal antibody generation, immunofluorescence, Western blot, N-glycanase treatment, N-terminal sequence analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — N-glycanase functional ablation of epitope combined with precise localization, single lab\",\n      \"pmids\": [\"7514212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The mouse entactin gene spans >65 kb, contains 20 exons, and its exon organization directly corresponds to the polypeptide's structural domains (each EGF-like repeat, the thyroglobulin repeat, and each globular domain encoded by separate exons), with regional homology to the LDL receptor gene including conservation of four intron positions, indicating evolution via exon shuffling.\",\n      \"method\": \"Genomic cloning, restriction mapping, DNA sequencing, exon-intron boundary determination\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — complete exon-intron structure determination with domain correspondence analysis, single lab\",\n      \"pmids\": [\"7601446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Human mesangial cells use both αvβ3 (via the RGD sequence in entactin's E/rod domain) and a β1-containing integrin to adhere to native entactin. Adhesion requires divalent cations. Recombinant entactin lacking the E domain RGD still supported some mesangial cell adhesion via β1 integrin, and tertiary structure of native entactin may contribute to binding properties.\",\n      \"method\": \"Cell adhesion assay, anti-integrin monoclonal antibody blocking, wild-type and RGD-mutant recombinant entactin fragments, metabolic labeling and immunoprecipitation\",\n      \"journal\": \"Cell adhesion and communication\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple integrin antibodies and domain mutants used, single lab\",\n      \"pmids\": [\"9686320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Entactin-1 (nidogen-1) is exclusively produced and secreted by mesenchymal peritubular cells (not Sertoli cells) in rat testis. Anti-entactin-1 monoclonal antibodies caused loss of adhesion specifically in peritubular cells but not Sertoli cells, demonstrating an autocrine adhesion function of entactin-1 for peritubular cells.\",\n      \"method\": \"DD-RT-PCR, Western blot of co-cultures and monocultures, antibody perturbation assay, immunofluorescence\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — function-blocking antibody with cell-type-specific phenotype, source cell identified by Western blot, single lab\",\n      \"pmids\": [\"10727019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Entactin significantly inhibits amyloid beta-protein (Aβ1-40) fibril formation in vitro at a 50:1 molar ratio (Aβ:entactin). The inhibitory mechanism involves entactin inducing a random coil structure in Aβ40, as shown by circular dichroism spectroscopy.\",\n      \"method\": \"Thioflavin T fluorometric assay, electron microscopy, circular dichroism spectroscopy\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with multiple readouts (fluorometry, EM, CD), single lab\",\n      \"pmids\": [\"11376898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Heterozygous mutations in NID1 cause autosomal dominant Dandy-Walker malformation with occipital cephaloceles. Structural modeling of the NID1-LAMC1 complex showed that a NID1 mutation disrupts the NID1-LAMC1 (laminin γ1) protein interaction, identifying NID1 binding to laminin as functionally critical for posterior fossa development.\",\n      \"method\": \"Whole-exome sequencing, protein interaction network analysis, structural modeling of NID1-LAMC1 complex\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetics combined with structural modeling of binding interface disruption, two independent families with mutations in interacting partners\",\n      \"pmids\": [\"23674478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"An 855 bp deletion in bovine NID1 spanning exon 19/intron 19 border causes skipping of exon 19, frameshifting, and premature stop (p.1164fs27X), truncating the C-terminal domain essential for binding with matrix assembly complexes. This causes autosomal recessive inherited cataract and neurological abnormalities in cattle.\",\n      \"method\": \"Genome-wide association study, homozygosity mapping, whole genome sequencing, RT-PCR (demonstrating exon skipping), pedigree analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — naturally occurring loss-of-function mutation with confirmed splicing consequence and defined domain truncation, animal model\",\n      \"pmids\": [\"25347398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In C. elegans, NID-1/Nidogen localizes to all basement membranes; its localization depends on Laminin (loss of Laminin strongly reduces NID-1 BM localization). Ndg/nid-1 null mutants have ultrastructural BM defects compromising barrier function and stability. Genetic epistasis places nid-1 in the same pathway as unc-52/Perlecan and the netrin axon guidance signaling cassette for establishing correct somatosensory dendrite number; UNC-52/Perlecan is required to correctly localize NID-1.\",\n      \"method\": \"Genetic knockout (Ndg-null and unc-52 mutants), ultrastructural analysis (EM), barrier function assay, genetic epistasis, fluorescence localization\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — combined structural (EM), functional (barrier assay), and genetic epistasis with multiple mutant combinations in two papers (Drosophila and C. elegans)\",\n      \"pmids\": [\"30567930\", \"29678816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Entactin-1 overexpression in myoblasts (retroviral system) leads to higher proliferation rate and reduced expression of myogenic differentiation markers after induction, demonstrating that entactin-1 opposes myogenic differentiation. Conversely, entactin-2 is a primary response gene transiently induced during myogenesis.\",\n      \"method\": \"Retroviral overexpression, siRNA knockdown, RT-PCR for differentiation markers, cycloheximide and actinomycin D treatment, p38 MAPK inhibitors\",\n      \"journal\": \"Differentiation; research in biological diversity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — retroviral overexpression with defined differentiation markers, single lab\",\n      \"pmids\": [\"17177854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NID1 is a downstream target of p53/miR-192/miR-215 axis in colorectal cancer cells. p53 activates miR-192 and miR-215, which directly target NID1 mRNA to repress its expression. Secreted NID1 is required and sufficient for inducing EMT, invasion, and migration in epithelial-like CRC cells via paracrine signaling.\",\n      \"method\": \"miRNA target prediction and validation, conditioned medium transfer, NID1 knockdown and overexpression, CRC cell migration/invasion assays, cytokine array\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct miRNA targeting of NID1 mRNA with knockdown and rescue experiments, paracrine mechanism demonstrated, single lab\",\n      \"pmids\": [\"30831320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Nid1 is secreted by enteric neurons and elevated in the Ndrg4-/- enteric nervous system secretome. ENS-derived Nid1 (and Fibulin-2) enhances migration capacities of colorectal cancer cells and promotes organoid growth.\",\n      \"method\": \"Ndrg4 knockout mouse, in vitro co-culture of ENS cells and intestinal organoids, quantitative proteomics of secretome, CRC cell migration assay\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse combined with proteomics and functional cell migration assay, single lab\",\n      \"pmids\": [\"33890711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NID-1 is highly secreted by skeletal muscle fibro-adipogenic/mesenchymal progenitors (FAPs) during obesity. Increased muscle NID-1 impairs muscle stem cell proliferation and primes FAPs for fibrogenic differentiation leading to excessive ECM deposition.\",\n      \"method\": \"High fat diet mouse model, cell secretome analysis, in vitro myoblast treatment with NID-1, immunofluorescence, muscle stem cell functional assay\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo obesity model combined with in vitro functional assay of purified NID-1, single lab\",\n      \"pmids\": [\"35963565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NID1 is a direct transcriptional target of the EMT-inducing transcription factor SNAIL: ectopic SNAIL expression induces NID1, and SNAIL occupancy was detected at an E-box upstream of the NID1 transcription start site by ChIP. NID1 signals through its receptors ITGA3, ITGB1, and ITGAV; ectopic NID1 or NID1-conditioned medium conferred lung metastatic capacity to non-metastatic CRC cells in xenotransplantation.\",\n      \"method\": \"ChIP assay for SNAIL at NID1 E-box, ectopic expression of SNAIL and NID1, xenotransplantation lung metastasis model, bioinformatics of patient datasets, ITGAV knockdown viability assay\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional gain-of-function in vivo metastasis model, single lab\",\n      \"pmids\": [\"38001576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"COL4A1 physically binds to NID1, as confirmed by co-immunoprecipitation in OSCC cells. NID1 overexpression rescues the inhibitory effects of COL4A1 knockdown on cell proliferation, migration, invasion, and EMT, placing NID1 downstream of COL4A1.\",\n      \"method\": \"Co-immunoprecipitation, COL4A1 knockdown, NID1 overexpression rescue experiment, proliferation/migration/invasion assays\",\n      \"journal\": \"Experimental and therapeutic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP binding confirmation plus epistatic rescue experiment, single lab\",\n      \"pmids\": [\"37006878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In C. elegans, NID-1 expressed by body wall muscles or hypodermis promotes local guidance of regenerating motor axons alongside neighboring neuronal processes (PVD dendrites). Loss of nid-1 disrupts axon-PVD colocalization, increases displacement from the pre-injury dorsal nerve cord contact point, and impairs synapse reformation and functional recovery. Muscle-derived NID-1 specifically is required for synapse reformation. Genetic data indicate NID-1 guides regenerating axons in coordination with laminin and integrin; ectopic integrin expression in GABAergic neurons reroutes their regenerating axons alongside PVD dendrites in a NID-1-dependent manner.\",\n      \"method\": \"nid-1 null mutant C. elegans, laser axotomy/axon regeneration assay, tissue-specific rescue (muscle, hypodermis, neuron), fluorescence imaging of axon guidance, synapse reformation assay, functional recovery assay, genetic epistasis with laminin and integrin\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with tissue-specific rescue and multiple functional readouts, preprint not yet peer-reviewed\",\n      \"pmids\": [\"41890084\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"NID1/entactin is a multidomain sulfated glycoprotein that serves as a molecular bridge in basement membrane assembly by binding laminin (via its C-terminal G3 domain) and type IV collagen, as well as fibronectin (via G2) and fibrinogen (Aα/Bβ chains); it promotes cell adhesion, migration, and neutrophil chemotaxis through an RGD sequence in its EGF-like stalk domain (recognized by αvβ3 and the leukocyte response integrin) and a second RGD-independent site in the G2 domain (recognized by α3β1 integrin); it is degraded by matrix metalloproteinases (especially matrilysin) at Leu/Ile-preceding sites, and this cleavage can trigger epithelial apoptosis in vivo; NID1 loss in mice and C. elegans causes tissue-specific basement membrane defects, neurological phenotypes, and impaired axon regeneration guidance; and transcriptionally NID1 is a direct target of SNAIL and is repressed by the p53/miR-192/215 axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NID1 (entactin/nidogen-1) is a sulfated, multidomain basement membrane glycoprotein that acts as a molecular bridge organizing the assembly of basement-membrane networks and as a ligand directing integrin-dependent cell adhesion and migration [#0, #3]. Its C-terminal globular (G3) domain binds tightly to the inner short-arm segment of laminin and to type IV collagen, and ectopic expression of NID1 in cells lacking it drives incorporation of laminin and collagen IV into extracellular matrix, establishing its bridging role in matrix assembly [#3, #9]. The protein presents two genetically separable cell-attachment activities: an RGD motif within an EGF-like repeat of the central stalk (E domain), recognized by alphaV-beta3 and the leukocyte response integrin, and an RGD-independent site in the G2 domain recognized by a beta1 integrin (alpha3-beta1); mutation of the RGD aspartate to glutamate abolishes RGD-dependent adhesion, chemotaxis, and trophoblast outgrowth [#7, #13, #6, #10]. Through these domains NID1 also binds fibrinogen Aalpha/Bbeta chains and a G2-localized fibronectin site, integrating it into broader matrix and clotting networks [#5, #11]. NID1 is a preferred substrate of matrix metalloproteinases, cleaved most efficiently by matrilysin at sites amino-terminal to Leu/Ile, and excessive stromelysin-1-mediated entactin cleavage in mammary basement membrane directly triggers epithelial apoptosis in vivo [#8, #15]. Loss-of-function studies define its physiological roles: nidogen-1-null mice display neurological deficits and selective basement-membrane defects at brain capillaries and lens capsule, and in C. elegans laminin- and perlecan-dependent NID-1 deposition maintains basement-membrane integrity and patterns axon/dendrite guidance [#18, #28]. Heterozygous NID1 mutations disrupting the NID1-laminin gamma1 interface cause autosomal dominant Dandy-Walker malformation, and a C-terminal-truncating NID1 deletion causes recessive cataract with neurological abnormalities in cattle [#26, #27]. In cancer, NID1 is a direct transcriptional target of SNAIL and is repressed by the p53/miR-192/miR-215 axis; secreted NID1 acts in a paracrine fashion through ITGA3/ITGB1/ITGAV to drive EMT, invasion, and metastatic capacity [#30, #33].\",\n  \"teleology\": [\n    {\n      \"year\": 1981,\n      \"claim\": \"Established that NID1/entactin is a distinct basement-membrane component, separating it biochemically and immunologically from the co-purifying laminin and fibronectin that had obscured it.\",\n      \"evidence\": \"Protein isolation, immunoelectron microscopy, peptide mapping and sulfate labeling from kidney matrix\",\n      \"pmids\": [\"6262321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain architecture and binding partners not yet defined\", \"Function inferred only from localization at this stage\"]\n    },\n    {\n      \"year\": 1988,\n      \"claim\": \"Defined the three-domain architecture (N-globular, EGF/thyroglobulin stalk, C-globular) and located an RGD cell-recognition motif, providing the structural framework for all subsequent functional dissection.\",\n      \"evidence\": \"Full-length mouse cDNA cloning and sequencing plus synthetic RGD peptide attachment assay; Golgi tyrosine sulfation mapped by metabolic labeling\",\n      \"pmids\": [\"3264556\", \"3042455\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptors for the RGD motif not identified\", \"Functional contribution of non-RGD regions unknown\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Showed NID1 functions as a matrix bridge by binding laminin short arms and type IV collagen through its C-terminal domain and driving their incorporation into matrix when expressed in deficient cells.\",\n      \"evidence\": \"Domain binding studies plus entactin cDNA transfection into entactin-lacking JAR cells with matrix incorporation readout; recombinant baculovirus protein with calcium-dependent self-aggregation\",\n      \"pmids\": [\"2119632\", \"2180961\", \"2191952\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and structural basis of the laminin/collagen bridge not resolved\", \"RGD-independent attachment activity noted but not localized\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Extended NID1's ligand repertoire beyond the canonical laminin/collagen network to fibrinogen and fibronectin, implying roles in provisional matrix and clotting contexts.\",\n      \"evidence\": \"Solid-phase binding with labeled entactin, transglutaminase cross-linking, and affinity chromatography/co-localization in laminin-deficient cells\",\n      \"pmids\": [\"1680863\", \"1872841\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain mediating fibrinogen binding not mapped here\", \"Physiological relevance of fibrinogen/fibronectin binding in vivo untested\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Identified specific integrin receptors and proved the RGD motif is functionally required, distinguishing RGD-dependent (alphaV-beta3/leukocyte response integrin) from cation-dependent, RGD-independent (alpha3-beta1) adhesion.\",\n      \"evidence\": \"Affinity isolation of alpha3-beta1 on entactin-Sepharose; RGD-to-RGE mutant entactin and anti-LRI blocking in neutrophil adhesion/chemotaxis; myotube maintenance antibody-blocking assay\",\n      \"pmids\": [\"1527019\", \"1469085\", \"1734030\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise domain location of the alpha3-beta1 site not yet defined\", \"Downstream signaling from integrin ligation uncharacterized\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Defined NID1 as a metalloproteinase substrate, establishing matrilysin as a far more efficient protease than collagenase or gelatinase and mapping Leu/Ile-preceding cleavage sites.\",\n      \"evidence\": \"In vitro MMP kinetics (Km, Vmax) and Edman degradation of cleavage fragments; intracellular laminin complex assembly and vesicular transport shown by fractionation/transfection\",\n      \"pmids\": [\"8380588\", \"8433553\", \"8491783\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo consequences of cleavage not yet established at this stage\", \"Whether cleavage products retain activity untested here\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Resolved the two-site adhesion model at domain resolution, assigning the RGD/alphaV-beta3 activity to the E domain and a separate cysteine-rich EGF repeat in G2 to a beta1-integrin attachment site.\",\n      \"evidence\": \"GST-fusion domain constructs, RGD deletion/Glu-substitution mutagenesis in full-length protein, anti-integrin blocking; genomic exon-intron mapping correlating exons to domains\",\n      \"pmids\": [\"7797588\", \"7601446\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Exact beta1 integrin partner at G2 not definitively assigned\", \"Crystal/structural basis of dual integrin engagement absent\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Linked the two adhesion domains to distinct cellular outputs and showed matrilysin cleavage liberates functionally active fragments, connecting proteolysis to biological consequence.\",\n      \"evidence\": \"Domain GST fusions in neutrophil chemotaxis vs Fc-phagocytosis assays; transgenic stromelysin-1 x TIMP-1 epistasis tying entactin cleavage to mammary epithelial apoptosis in vivo\",\n      \"pmids\": [\"8940031\", \"8978831\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular pathway from entactin loss to apoptosis not delineated\", \"Generality of cleavage-driven apoptosis across tissues unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined physiological requirement in vivo: nidogen-1 loss causes neurological deficits and selective basement-membrane defects despite normal laminin/collagen distribution, indicating context-dependent rather than universal necessity.\",\n      \"evidence\": \"Targeted knockout mouse with behavioral, immunohistochemical, and quantitative immuno-EM analysis of brain capillary, lens, and glomerular basement membranes\",\n      \"pmids\": [\"12480912\", \"14566019\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Compensation by nidogen-2 not addressed\", \"Mechanism linking NID1 loss to altered charge/permselectivity unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established a human Mendelian disease link, showing heterozygous NID1 mutations that disrupt the NID1-laminin gamma1 interface cause Dandy-Walker malformation, validating the laminin-binding bridge as developmentally critical.\",\n      \"evidence\": \"Whole-exome sequencing of families plus structural modeling of the NID1-LAMC1 complex; bovine recessive cataract from a C-terminal-truncating NID1 deletion confirmed by RT-PCR exon skipping\",\n      \"pmids\": [\"23674478\", \"25347398\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional binding disruption inferred from modeling, not biochemically measured for the mutant\", \"Cellular pathology of posterior fossa development not directly tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Recast NID1 as a paracrine cancer effector, showing it is a direct target of p53/miR-192/215 repression and of SNAIL activation, and that secreted NID1 drives EMT, invasion, and metastasis via integrins.\",\n      \"evidence\": \"miRNA target validation, conditioned-medium transfer, knockdown/rescue, ChIP for SNAIL at the NID1 E-box, and xenotransplant metastasis assays; COL4A1 co-IP and epistatic rescue in OSCC\",\n      \"pmids\": [\"30831320\", \"38001576\", \"37006878\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which integrin-engaged domain drives the metastatic signal not dissected\", \"Single-lab cancer models; in-vivo human relevance limited to bioinformatic correlation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified non-tumor stromal sources of secreted NID1 (enteric neurons, muscle FAPs) that modulate cancer cell migration and tissue remodeling, broadening NID1's signaling role beyond classical matrix scaffolding.\",\n      \"evidence\": \"Ndrg4-knockout ENS secretome proteomics with organoid/migration assays; high-fat-diet muscle FAP secretome with myoblast and muscle stem cell functional assays\",\n      \"pmids\": [\"33890711\", \"35963565\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor and signaling cascade for stromal NID1 not defined\", \"Causal contribution in vivo vs correlative secretome change uncertain\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated a guidance function for NID-1 in axon regeneration, showing tissue-specific muscle/hypodermal NID-1 directs regenerating motor axons and synapse reformation in coordination with laminin and integrin.\",\n      \"evidence\": \"C. elegans nid-1 null with laser axotomy, tissue-specific rescue, synapse and functional recovery readouts, and genetic epistasis (preprint)\",\n      \"pmids\": [\"41890084\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Molecular mechanism of axon-NID-1-integrin guidance not biochemically resolved\", \"Conservation in mammals untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NID1's molecular bridging and integrin-signaling activities are differentially deployed across tissue-specific basement-membrane assembly, proteolytic remodeling, and paracrine cancer signaling remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of NID1 bound to laminin and collagen simultaneously\", \"Mechanism connecting secreted NID1 to integrin signaling in cancer undefined\", \"Redundancy with nidogen-2 not systematically resolved in vivo\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [7, 13, 6, 10]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 3, 9]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [14, 33]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0030312\", \"supporting_discovery_ids\": [0, 9, 28]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [9, 30, 31]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [3, 9, 32]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [3, 9, 28]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [18, 26, 28]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [26, 27, 30, 33]}\n    ],\n    \"complexes\": [\"nidogen-laminin-type IV collagen basement membrane network\"],\n    \"partners\": [\"LAMC1\", \"COL4A1\", \"FN1\", \"FGA\", \"FGB\", \"ITGA3\", \"ITGB1\", \"ITGAV\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}