{"gene":"ADAM19","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2000,"finding":"ADAM19 (meltrin beta) participates in the proteolytic processing of membrane-anchored neuregulin-1 beta (NRG-beta1), with preference for beta-type NRGs over alpha-type; overexpression potentiates NRG-beta1 processing while protease-deficient mutants exert dominant negative effects; processing occurs intracellularly rather than at the cell surface.","method":"Overexpression of wild-type and protease-deficient dominant-negative mutants in L929 cells; secretory pathway inhibitor treatment; western blot for extracellular domain release","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal gain/dominant-negative loss-of-function with defined substrate specificity, replicated across NRG isoforms","pmids":["11116142"],"is_preprint":false},{"year":2003,"finding":"Recombinant soluble ADAM19 exhibits metalloprotease activity (autocatalytic tag removal, cleavage of myelin basic protein and insulin B chain), is inhibited by hydroxamic acid metalloprotease inhibitor BB94 but not by TIMPs 1-3, cleaves peptides corresponding to TNF-alpha, TRANCE, and KL-1 cleavage sites in vitro, and negatively regulates KL-1 shedding in cells rather than acting directly as its sheddase.","method":"In vitro protease assay with recombinant soluble ADAM19; peptide cleavage assays; BB94 and TIMP inhibition assays; COS-7 and MEF overexpression/knockout studies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with recombinant enzyme plus multiple substrate assays and inhibitor characterization","pmids":["12682046"],"is_preprint":false},{"year":2001,"finding":"Human ADAM19 forms a complex with and cleaves alpha-2 macroglobulin; its proteolytic activity is blocked by 1,10-phenanthroline, EDTA, EGTA, and a synthetic MMP inhibitor but not by TIMP-1 or TIMP-2.","method":"Recombinant protein expression in human cells; co-immunoprecipitation/complex detection; metalloprotease inhibitor assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1-2 — in vitro assay with recombinant enzyme and substrate, single study","pmids":["11162584"],"is_preprint":false},{"year":2004,"finding":"ADAM19-mediated ectodomain shedding of NRG-beta1 occurs specifically in lipid rafts of neurons; the membrane-anchoring region of ADAM19 is required for its lipid raft localization, and NRG-beta1 shedding is not enhanced if ADAM19 cannot reach the lipid rafts.","method":"Lipid raft fractionation; deletion mutant analysis of membrane-anchoring region; NRG-beta1 shedding assay in neuronal cells","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 2 — subcellular fractionation with functional consequence (shedding defect) linked to specific domain; moderate evidence from single lab with multiple methods","pmids":["15030395"],"is_preprint":false},{"year":2007,"finding":"ADAM19 (meltrin beta) mediates ectodomain shedding of NRG-beta1 in the Golgi apparatus (not at the cell surface); subcellular fractionation showed soluble NRG-beta1 generated by ADAM19 is recovered in Golgi-enriched fractions, whereas TACE/ADAM17-cleaved NRG-beta1 is in lighter fractions; fluorescence correlation spectroscopy in living cells confirmed conversion of GFP-tagged NRG-beta1 from membrane-anchored to soluble form within the Golgi.","method":"Subcellular fractionation; fluorescence correlation spectroscopy (FCS) in living cells; localization by immunofluorescence in developing sensory neurons","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (fractionation + live-cell FCS) establishing Golgi as shedding compartment, single lab","pmids":["17352738"],"is_preprint":false},{"year":2007,"finding":"ADAM19 overexpression reduces the amount of Endo-H-resistant mature KitL1 available for phorbol ester-stimulated ectodomain shedding, thereby indirectly decreasing ADAM17-mediated KitL1 shedding; ADAM17, not ADAM19, is the major phorbol-ester-stimulated sheddase of KitL1 and KitL2.","method":"Overexpression of ADAM family members in COS-7 cells; Endo-H glycosylation assay; phorbol ester stimulation; KitL shedding assay in MEFs from ADAM-knockout mice","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout MEFs plus biochemical glycosylation assay; mechanistic distinction from ADAM17; replicated across KitL isoforms","pmids":["17344430"],"is_preprint":false},{"year":2006,"finding":"ADAM19 has constitutive alpha-secretase activity for amyloid precursor protein (APP): overexpression in HEK293 cells increases sAPP-alpha release; RNAi knockdown in A172 cells reduces constitutive sAPP-alpha by ~21%; no regulated (PMA-stimulated) activity was detected.","method":"Overexpression in HEK293 cells with sAPP-alpha ELISA/western blot; RNAi knockdown in A172 cells; phorbol ester (PMA) stimulation assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — loss- and gain-of-function with defined molecular readout; single lab, two orthogonal approaches","pmids":["17112471"],"is_preprint":false},{"year":2004,"finding":"Human ADAM19 autolytic processing within its cysteine-rich domain (at Glu586-Ser587) is regulated by disulfide bonds; DTT treatment and acidic pH (6.5) block autolytic processing, while pH 8.5 promotes it; specific cysteine residues (Cys605, Cys633, Cys639, Cys643) in the C-fragment are partially responsible for covalent association between N- and C-fragments; ADAM19 is activated by furin-mediated prodomain cleavage followed by intramolecular autolysis.","method":"Stable MDCK transfectants expressing soluble ADAM19; DTT and pH manipulation; site-directed mutagenesis of cysteine residues; Ilomastat/GM6001 inhibition; identification of new autolytic cleavage site","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis of active-site cysteines combined with chemical manipulation; single lab but multiple orthogonal approaches","pmids":["15242783"],"is_preprint":false},{"year":2011,"finding":"ADAM19 is the protease responsible for cleaving the (pro)renin receptor ((P)RR) in the Golgi, generating an amino-terminal fragment (NTF-(P)RR) that is secreted into the extracellular space; transfected ADAM19 evokes (P)RR shedding and dominant-negative ADAM19 suppresses it; furin is not responsible for this cleavage; secreted NTF-(P)RR induces prorenin activity.","method":"Overexpression and dominant-negative ADAM19 in CHO cells; western blot for (P)RR fragments; immunofluorescence localization; furin-deficient LoVo cells and furin inhibitor controls","journal":"Hypertension research : official journal of the Japanese Society of Hypertension","confidence":"High","confidence_rationale":"Tier 2 — gain-of-function plus dominant-negative plus genetic (furin-deficient cells) controls; single lab with multiple orthogonal methods","pmids":["21270819"],"is_preprint":false},{"year":2008,"finding":"In Xenopus, ADAM19 knockdown decreases phospho-AKT (a downstream target of EGF signaling), reduces neural markers (N-tubulin, NRP1), neural crest markers, and disrupts cranial neural crest migration in a cell-autonomous manner; somite organization and fibronectin localization at intersomitic boundaries are also perturbed.","method":"Morpholino knockdown in Xenopus embryos; targeted (cell-autonomous) knockdown; phospho-AKT western blot; in situ hybridization for marker genes; EGF receptor inhibitor treatment","journal":"Mechanisms of development","confidence":"Medium","confidence_rationale":"Tier 2 — morpholino loss-of-function with multiple molecular readouts; ortholog in Xenopus consistent with mammalian gene function","pmids":["19027850"],"is_preprint":false},{"year":2008,"finding":"ADAM19 (meltrin beta) interacts with EphA4 in developing motor neurons; coexpression of ADAM19 and EphA4 blocks vesicular internalization of ephrin-A5-EphA4 complexes independently of ADAM19's protease activity, stabilizing ephrin-A5-EphA4 interaction and contributing to neuromuscular junction (NMJ) formation; meltrin-beta-deficient mice show broader AChR alpha mRNA distribution and excess motor nerve terminal sprouting.","method":"Co-immunoprecipitation of ADAM19 and EphA4; knockout mouse analysis (AChR distribution, nerve sprouting); microarray; protease-dead mutant analysis of ephrin endocytosis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus KO mouse phenotype plus protease-dead mutant establishing non-proteolytic mechanism; multiple orthogonal approaches","pmids":["18830404"],"is_preprint":false},{"year":2008,"finding":"ADAM19 (meltrin beta) promotes Schwann cell differentiation and remyelination after sciatic nerve crush injury; ADAM19-deficient mice show delayed Krox-20 activation and myelin protein expression; ADAM19 modulates juxtacrine axon-Schwann cell signaling that activates Akt (but not Erk) phosphorylation, which is required for Krox-20 expression and myelination.","method":"Sciatic nerve crush in ADAM19 knockout mice; morphometric analysis of remyelination; western blot for pAkt, pErk, Krox-20, myelin proteins; membrane-loaded Schwann cell Akt activation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with defined cellular and molecular phenotype, pathway placement via pAkt vs. pErk discrimination, single lab with multiple methods","pmids":["19049978"],"is_preprint":false},{"year":2002,"finding":"The cytoplasmic tail of ADAM19 interacts with ArgBP1 through ADAM19's SH3 ligand-binding sites and the P4 region of ArgBP1; this interaction is specific (ArgBP1 does not bind ADAM22, ADAM29, or ADAM9); beta-COP, ubiquitin, and a novel protein also interact with the ADAM19 cytoplasmic tail.","method":"Yeast two-hybrid screen of human fetal brain cDNA library; GST-pulldown confirmation; deletion mutant mapping of interaction domains","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — yeast two-hybrid confirmed by GST-pulldown; single study, two methods","pmids":["12463424"],"is_preprint":false},{"year":2010,"finding":"ADAM19 undergoes autolytic processing activated by LPS stimulation, and through its disintegrin and cysteine-rich domains interacts with and promotes non-classical secretion of cysteine-rich protein 2 (CRIP2); CRIP2 secretion increases with ADAM19 autolytic processing and decreases upon ADAM19 knockdown.","method":"Yeast two-hybrid screen using ADAM19 extracellular domain; LPS stimulation of cells; western blot for ADAM19 processing and CRIP2 secretion; ADAM19 siRNA knockdown","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 — yeast two-hybrid plus functional secretion assay; single lab, single study","pmids":["20460109"],"is_preprint":false},{"year":2018,"finding":"In Xenopus, ADAM19 functions non-proteolytically in neural crest specification by physically interacting with its close paralog ADAM13 and inhibiting its proteasomal degradation, thereby sustaining Wnt signaling at the neural plate border; canonical Wnt signaling activity is severely downregulated upon ADAM19 knockdown, and ectopic expression of proteasome-resistant ADAM13 mutants rescues neural crest induction via Wnt signaling.","method":"Morpholino knockdown in Xenopus; Co-immunoprecipitation of ADAM19 with ADAM13; proteasome inhibitor rescue; epistasis with stabilized ADAM13 mutants; Wnt reporter assay","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — Co-IP plus genetic epistasis with rescue by stabilized mutant; multiple orthogonal methods in Xenopus ortholog system","pmids":["29540504"],"is_preprint":false},{"year":2002,"finding":"A novel ADAM19 splice isoform (meltrin beta mini) lacking the prodomain, metalloprotease, and disintegrin domains induces neurite outgrowth in neuronal cells, a function not shared by full-length ADAM19, suggesting a distinct non-proteolytic role mediated by the remaining domains.","method":"RT-PCR identification of isoform; cDNA/genomic sequence comparison; overexpression of meltrin beta mini vs. full-length ADAM19 in neuronal cell lines","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2-3 — gain-of-function overexpression with defined morphological readout; single lab, comparative analysis between isoforms","pmids":["12482604"],"is_preprint":false},{"year":2009,"finding":"ADAM19 overexpression in JEG-3 trophoblast cells reduces cell invasion and increases cell adhesiveness and E-cadherin expression without changing beta-catenin expression.","method":"ADAM19 overexpression in JEG-3 choriocarcinoma cells; invasion assay; adhesion assay; western blot for E-cadherin and beta-catenin","journal":"Science in China. Series C, Life sciences","confidence":"Low","confidence_rationale":"Tier 3 — gain-of-function in a cancer cell line with phenotypic readout but limited mechanistic follow-up; single lab","pmids":["19727588"],"is_preprint":false},{"year":2013,"finding":"ADAM19 and phospho-ErbB3 co-localize in co-cultured neural NG108-15 cells; electrical stimulation increases ADAM19 precursor and activated form, phospho-ErbB3, and ERK1 levels in a stimulation duration-dependent manner, implicating ADAM19/neuregulin/ErbB signaling in NMJ formation.","method":"Immunofluorescence localization; immunoblotting for ADAM19, pErbB3, ERK1, synapsin 1 in electrically stimulated co-cultures","journal":"Neuroscience letters","confidence":"Low","confidence_rationale":"Tier 3 — correlative western blot and immunofluorescence without direct loss-of-function; single lab, single study","pmids":["23603262"],"is_preprint":false},{"year":2024,"finding":"ADAM19 cleaves the parathyroid hormone receptor (PTHR1) at a site mapped between amino acids 64-65 (verified by mass spectrometry); WT ADAM19 cleaves PTHR1 while a truncated/mutated ADAM19 allele found in brachydactyly type E patients does not; ADAM19-mediated PTHR1 cleavage increases Gq and decreases Gs activation, and increases beta-arrestin2 recruitment without altering cAMP accumulation.","method":"Linkage and whole genome sequencing in BDE pedigree; ADAM19 cleavage assay with WT vs. mutant ADAM19; mass spectrometry cleavage site mapping; Gq/Gs activation assays; beta-arrestin2 recruitment assay; cAMP accumulation assay","journal":"Life science alliance","confidence":"High","confidence_rationale":"Tier 1 — in vitro cleavage assay with mass spectrometry site mapping plus signaling readouts and disease-associated mutant comparison; multiple orthogonal methods","pmids":["38331475"],"is_preprint":false},{"year":2025,"finding":"ADAM19 inhibition (siRNA knockdown or pharmacological inhibition with batimastat-94) in human primary fibroblasts decreases specific SASP factor expression and SA-beta-gal levels in senescent cells; proteomics of senescent cell secretome reveals decreased SASP factors associated with ADAM19 cleavage sites; in mice, batimastat-94 treatment reduces gut permeability and gut inflammation.","method":"siRNA knockdown in human primary fibroblasts; pharmacological inhibition (batimastat-94) in mice; secretome proteomics; SA-beta-gal assay; Drosophila meltrin GWAS/knockdown for initial identification","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (KD, pharmacological, proteomics) in human cells and in vivo; single recent study","pmids":["40117561"],"is_preprint":false},{"year":2008,"finding":"TGF-beta1 signaling induces SMAD4 nuclear translocation and upregulates ADAM19 transcription in normal ovarian surface epithelial cells; in TGF-beta1-refractory ovarian cancer cells, impaired SMAD4 nuclear translocation correlates with repressive histone modifications (trimethyl-H3K27, dimethyl-H3K9) and HDAC association at the ADAM19 promoter, leading to ADAM19 silencing.","method":"TGF-beta1 stimulation; nuclear fractionation for SMAD4; ChIP for histone modifications (H3K27me3, H3K9me2) and HDAC at ADAM19 promoter; RT-PCR; promoter CpG methylation analysis","journal":"Neoplasia (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP assays with pathway-linked stimulus; multiple epigenetic marks; single lab","pmids":["18714391"],"is_preprint":false},{"year":2005,"finding":"ADAM19 (MADDAM) expression in dendritic cells (but not macrophages) is regulated by histone acetylation: TSA (HDAC inhibitor) induces ADAM19 mRNA in THP-1 monocytic cells; ChIP assays show high acetylated histone H3 at the ADAM19 proximal promoter in TSA-treated THP-1 and dendritic cells compared to macrophages.","method":"TSA treatment; RT-PCR; ChIP with anti-acetylated H3 antibody; reporter assay with minimal promoter construct","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP demonstrating active chromatin mark correlating with cell-type-specific expression plus TSA functional induction; single lab","pmids":["15896713"],"is_preprint":false},{"year":2017,"finding":"Neutralizing ADAM19 in a diet-induced obesity mouse model results in weight loss, improved insulin sensitivity, and reduced liver TNF-alpha levels, implicating ADAM19 as a pro-obesogenic factor that enhances insulin resistance.","method":"In vivo neutralizing antibody treatment in diet-induced obesity mouse model; body weight measurement; insulin sensitivity testing (HOMA-IR); liver TNF-alpha quantification","journal":"Mediators of inflammation","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo loss-of-function with defined metabolic readouts; single lab, single study","pmids":["28265178"],"is_preprint":false},{"year":2024,"finding":"Adam19 knockout mice show altered pulmonary function (decreased respiratory system elastance, tissue damping, tissue elastance, FEF50 but higher FEV0.1 and FVC at baseline), attenuated inflammatory responses to LPS (reduced neutrophil extravasation), and negative enrichment for TNF signaling pathways by RNA-seq, establishing a causal role for ADAM19 in lung function regulation.","method":"Adam19 knockout mouse generation; flexiVent lung function measurement; LPS challenge; BAL neutrophil counting; RNA-seq with gene set enrichment analysis","journal":"Lung","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined functional phenotype (pulmonary mechanics) plus molecular pathway analysis; single lab with multiple orthogonal methods","pmids":["39153120"],"is_preprint":false}],"current_model":"ADAM19 is a membrane-anchored zinc-dependent metalloprotease (ADAM family) that cleaves multiple substrates including NRG-beta1 (preferentially in the Golgi, within lipid rafts), APP (constitutive alpha-secretase), PTHR1 (at the ectodomain), the (pro)renin receptor, TRANCE, and membrane-bound TNF-alpha; its autolytic processing is regulated by disulfide bonds within its cysteine-rich domain; it also functions non-proteolytically by interacting with EphA4 to regulate ephrin endocytosis at the NMJ and by stabilizing ADAM13 to sustain Wnt signaling during neural crest specification; its cytoplasmic tail engages ArgBP1 through SH3 ligand-binding sites; and loss-of-function studies in mice establish causal roles in pulmonary function, remyelination via axon-Schwann cell Akt/Krox-20 signaling, and metabolic regulation."},"narrative":{"teleology":[{"year":2000,"claim":"Identifying ADAM19 as a NRG-β1 sheddase established its first defined substrate and showed it acts intracellularly rather than at the cell surface, distinguishing it from other ADAMs.","evidence":"Overexpression/dominant-negative mutants in L929 cells with secretory pathway inhibitors and NRG isoform comparisons","pmids":["11116142"],"confidence":"High","gaps":["Intracellular compartment of cleavage not yet identified","Endogenous validation in neuronal tissue lacking"]},{"year":2001,"claim":"Demonstration that ADAM19 cleaves α2-macroglobulin and is blocked by chelating agents but not TIMPs began to define its inhibitor profile and broad substrate range.","evidence":"Recombinant ADAM19 with co-immunoprecipitation and metalloprotease inhibitor panel","pmids":["11162584"],"confidence":"Medium","gaps":["α2-macroglobulin cleavage not confirmed in vivo","Physiological relevance of this substrate unclear"]},{"year":2002,"claim":"Identification of ArgBP1 as a cytoplasmic tail interactor via SH3-ligand sites, plus discovery of a truncated isoform (meltrin β mini) that induces neurite outgrowth, revealed that ADAM19 signals through its intracellular domain and possesses isoform-specific non-proteolytic functions.","evidence":"Yeast two-hybrid/GST-pulldown for ArgBP1; RT-PCR cloning and overexpression of meltrin β mini in neuronal cells","pmids":["12463424","12482604"],"confidence":"Medium","gaps":["Functional significance of ArgBP1 interaction uncharacterized","Neurite outgrowth mechanism of meltrin β mini undefined","No in vivo validation of isoform-specific roles"]},{"year":2003,"claim":"Reconstitution of soluble ADAM19 with defined peptide substrates (TNF-α, TRANCE, KL-1 sites) and inhibitor profiling (sensitive to BB94, resistant to TIMPs 1–3) established its enzymatic specificity and showed it indirectly regulates KitL1 shedding rather than acting as its direct sheddase.","evidence":"In vitro protease assays with recombinant soluble ADAM19; peptide cleavage; COS-7 and ADAM-knockout MEF studies","pmids":["12682046"],"confidence":"High","gaps":["Direct in vivo substrates versus indirect regulatory targets not fully delineated","Structural basis for TIMP resistance unknown"]},{"year":2004,"claim":"Mapping autolytic processing to a specific site in the cysteine-rich domain regulated by disulfide bonds and pH resolved how ADAM19 matures after furin-mediated prodomain removal.","evidence":"Site-directed mutagenesis of cysteines, DTT/pH manipulation, and Ilomastat inhibition in stable MDCK transfectants","pmids":["15242783"],"confidence":"High","gaps":["Structural model of cysteine-rich domain lacking","Whether autolysis is required for all substrates untested"]},{"year":2004,"claim":"Localizing NRG-β1 shedding to lipid rafts and showing that ADAM19's membrane-anchoring region is required for raft targeting linked its subcellular positioning to substrate access.","evidence":"Lipid raft fractionation and deletion mutant analysis in neuronal cells","pmids":["15030395"],"confidence":"High","gaps":["Raft-targeting determinants in the membrane anchor not mapped at residue level"]},{"year":2007,"claim":"Fluorescence correlation spectroscopy in living cells pinpointed the Golgi as the compartment where ADAM19 converts membrane-anchored NRG-β1 to soluble form, distinguishing its spatial activity from ADAM17 at the cell surface.","evidence":"Subcellular fractionation plus live-cell FCS with GFP-NRG-β1 in neurons","pmids":["17352738"],"confidence":"High","gaps":["Mechanism of ADAM19 retention/recycling within the Golgi unresolved"]},{"year":2008,"claim":"Three concurrent studies expanded ADAM19's roles beyond proteolysis: it interacts with EphA4 to block ephrin endocytosis at the NMJ independently of its metalloprotease activity, it promotes Schwann cell remyelination via axon–Schwann cell Akt/Krox-20 signaling, and its knockdown in Xenopus disrupts neural crest migration and pAkt levels.","evidence":"KO mouse NMJ analysis with protease-dead mutants; sciatic nerve crush in KO mice with pAkt/Krox-20 readouts; Xenopus morpholino knockdown with marker analysis","pmids":["18830404","19049978","19027850"],"confidence":"High","gaps":["Identity of the NRG/ErbB ligand processed by ADAM19 in Schwann cell signaling not confirmed","Whether EphA4 interaction and NRG shedding are coordinated at the NMJ unknown"]},{"year":2011,"claim":"Identifying the (pro)renin receptor as a Golgi-resident ADAM19 substrate, with secreted NTF activating prorenin, connected ADAM19 to renin-angiotensin signaling.","evidence":"Overexpression/dominant-negative in CHO cells; furin-deficient LoVo cell controls","pmids":["21270819"],"confidence":"High","gaps":["In vivo confirmation of ADAM19 as the physiological (P)RR sheddase not yet shown"]},{"year":2017,"claim":"Neutralizing ADAM19 in diet-induced obese mice improved insulin sensitivity and reduced liver TNF-α, establishing a metabolic function and linking its TNF-α shedding capability to obesity phenotypes.","evidence":"In vivo neutralizing antibody in mouse obesity model; HOMA-IR and liver TNF-α measurement","pmids":["28265178"],"confidence":"Medium","gaps":["Direct substrate(s) responsible for metabolic effects not identified","Antibody specificity for ADAM19 over other ADAMs not fully validated"]},{"year":2018,"claim":"Discovery that ADAM19 stabilizes ADAM13 by preventing its proteasomal degradation to sustain Wnt signaling during neural crest specification established a non-catalytic chaperone-like function for an ADAM protease.","evidence":"Xenopus morpholino knockdown; Co-IP of ADAM19–ADAM13; rescue with proteasome-resistant ADAM13 mutants; Wnt reporter","pmids":["29540504"],"confidence":"High","gaps":["Whether this stabilization mechanism operates in mammals unknown","Structural basis of ADAM19–ADAM13 interaction undefined"]},{"year":2024,"claim":"Mass spectrometry mapping of the PTHR1 cleavage site and demonstration that a brachydactyly type E (BDE)-associated ADAM19 mutant cannot cleave PTHR1 linked ADAM19 loss-of-function to a Mendelian skeletal phenotype and showed cleavage biases PTHR1 signaling from Gs toward Gq/β-arrestin2.","evidence":"Linkage/WGS in BDE pedigree; in vitro cleavage with WT vs. mutant ADAM19; MS site mapping; Gq/Gs and β-arrestin2 assays","pmids":["38331475"],"confidence":"High","gaps":["Whether ADAM19-PTHR1 axis explains the full BDE phenotype in vivo not demonstrated","Crystal structure of ADAM19–PTHR1 complex unavailable"]},{"year":2024,"claim":"Adam19 knockout mice showed altered pulmonary mechanics and attenuated LPS-induced neutrophil influx with negative enrichment for TNF signaling, causally establishing ADAM19 in lung function and inflammation.","evidence":"Knockout mouse flexiVent measurements; BAL analysis after LPS challenge; RNA-seq/GSEA","pmids":["39153120"],"confidence":"High","gaps":["Specific pulmonary substrates of ADAM19 driving altered elastance not identified"]},{"year":2025,"claim":"ADAM19 knockdown or pharmacological inhibition reduced senescence-associated secretory phenotype (SASP) factors and senescence markers in human fibroblasts, suggesting a role in cellular senescence and age-related inflammation.","evidence":"siRNA in human primary fibroblasts; batimastat-94 in mice; secretome proteomics; SA-β-gal assay","pmids":["40117561"],"confidence":"Medium","gaps":["Batimastat-94 is not ADAM19-specific; contribution of other metalloproteases not excluded","Mechanism linking ADAM19 cleavage to SASP factor regulation unclear"]},{"year":null,"claim":"Key open questions include the structural basis for ADAM19's TIMP resistance, the full in vivo substrate repertoire in specific tissues, whether its non-proteolytic functions (ADAM13 stabilization, EphA4 interaction) are conserved in mammals, and the identity of the specific substrates mediating its pulmonary and metabolic phenotypes.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal structure of ADAM19 catalytic or cysteine-rich domains","Comprehensive in vivo substrate identification by unbiased proteomics lacking","Mammalian validation of ADAM13-stabilization mechanism absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,6,7,8,18]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1,2,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,10,14]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[4,8]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,8,11,18]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[9,10,14]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[10,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[23]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[7]}],"complexes":[],"partners":["NRG1","EPHA4","ADAM13","ATP6AP2","PTH1R","APP","SORBS2","CRIP2"],"other_free_text":[]},"mechanistic_narrative":"ADAM19 is a membrane-anchored zinc-dependent metalloprotease of the ADAM family that cleaves diverse substrates—including neuregulin-1 beta (NRG-β1), amyloid precursor protein (APP), parathyroid hormone receptor (PTHR1), and the (pro)renin receptor—primarily within the Golgi apparatus and lipid rafts, and also performs non-proteolytic functions through protein–protein interactions [PMID:11116142, PMID:15030395, PMID:17352738, PMID:38331475, PMID:21270819, PMID:17112471]. Its catalytic maturation involves furin-mediated prodomain removal followed by disulfide-bond-regulated autolytic processing within the cysteine-rich domain, and its activity is sensitive to hydroxamic acid metalloprotease inhibitors but resistant to TIMPs 1–3 [PMID:15242783, PMID:12682046]. Independent of its protease activity, ADAM19 interacts with EphA4 to block ephrin-A5 endocytosis at neuromuscular junctions and stabilizes ADAM13 to sustain canonical Wnt signaling during neural crest specification [PMID:18830404, PMID:29540504]. Loss-of-function studies in mice establish causal roles in Schwann cell remyelination via Akt/Krox-20 signaling, pulmonary mechanics and inflammatory responses, and metabolic regulation including insulin sensitivity [PMID:19049978, PMID:39153120, PMID:28265178]."},"prefetch_data":{"uniprot":{"accession":"Q9H013","full_name":"Disintegrin and metalloproteinase domain-containing protein 19","aliases":["Meltrin-beta","Metalloprotease and disintegrin dendritic antigen marker","MADDAM"],"length_aa":955,"mass_kda":105.0,"function":"Participates in the proteolytic processing of beta-type neuregulin isoforms which are involved in neurogenesis and synaptogenesis, suggesting a regulatory role in glial cell. Also cleaves alpha-2 macroglobulin. May be involved in osteoblast differentiation and/or osteoblast activity in bone (By similarity)","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q9H013/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADAM19","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ADAM19","total_profiled":1310},"omim":[{"mim_id":"619455","title":"SH3 AND PX DOMAINS-CONTAINING PROTEIN 2A; SH3PXD2A","url":"https://www.omim.org/entry/619455"},{"mim_id":"607114","title":"A DISINTEGRIN AND METALLOPROTEINASE DOMAIN 33; ADAM33","url":"https://www.omim.org/entry/607114"},{"mim_id":"604094","title":"MITOTIC ARREST-DEFICIENT 2 LIKE 2; MAD2L2","url":"https://www.omim.org/entry/604094"},{"mim_id":"603640","title":"A DISINTEGRIN AND METALLOPROTEINASE DOMAIN 19; ADAM19","url":"https://www.omim.org/entry/603640"},{"mim_id":"603639","title":"A DISINTEGRIN AND METALLOPROTEINASE DOMAIN 17; ADAM17","url":"https://www.omim.org/entry/603639"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ADAM19"},"hgnc":{"alias_symbol":["MLTNB"],"prev_symbol":[]},"alphafold":{"accession":"Q9H013","domains":[{"cath_id":"-","chopping":"44-83_114-167","consensus_level":"high","plddt":85.3009,"start":44,"end":167},{"cath_id":"3.40.390.10","chopping":"204-399","consensus_level":"high","plddt":88.7455,"start":204,"end":399},{"cath_id":"-","chopping":"411-459","consensus_level":"medium","plddt":80.4924,"start":411,"end":459},{"cath_id":"-","chopping":"505-643","consensus_level":"high","plddt":84.9999,"start":505,"end":643}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H013","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H013-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H013-F1-predicted_aligned_error_v6.png","plddt_mean":69.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADAM19","jax_strain_url":"https://www.jax.org/strain/search?query=ADAM19"},"sequence":{"accession":"Q9H013","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H013.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H013/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H013"}},"corpus_meta":[{"pmid":"11116142","id":"PMC_11116142","title":"Roles of Meltrin beta /ADAM19 in the processing of neuregulin.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11116142","citation_count":161,"is_preprint":false},{"pmid":"21270819","id":"PMC_21270819","title":"The (pro)renin receptor is cleaved by ADAM19 in the Golgi leading to its secretion into extracellular space.","date":"2011","source":"Hypertension research : official journal of the Japanese Society of Hypertension","url":"https://pubmed.ncbi.nlm.nih.gov/21270819","citation_count":110,"is_preprint":false},{"pmid":"12682046","id":"PMC_12682046","title":"Catalytic properties of ADAM19.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12682046","citation_count":103,"is_preprint":false},{"pmid":"9622634","id":"PMC_9622634","title":"Spatially- and temporally-restricted expression of meltrin alpha (ADAM12) and beta (ADAM19) in mouse embryo.","date":"1998","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/9622634","citation_count":90,"is_preprint":false},{"pmid":"25475731","id":"PMC_25475731","title":"MiR-153 inhibits migration and invasion of human non-small-cell lung cancer by targeting ADAM19.","date":"2014","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/25475731","citation_count":75,"is_preprint":false},{"pmid":"18714391","id":"PMC_18714391","title":"Aberrant transforming growth factor beta1 signaling and SMAD4 nuclear translocation confer epigenetic repression of ADAM19 in ovarian cancer.","date":"2008","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/18714391","citation_count":60,"is_preprint":false},{"pmid":"17344430","id":"PMC_17344430","title":"Different ADAMs have distinct influences on Kit ligand processing: phorbol-ester-stimulated ectodomain shedding of Kitl1 by ADAM17 is reduced by ADAM19.","date":"2007","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/17344430","citation_count":54,"is_preprint":false},{"pmid":"17352738","id":"PMC_17352738","title":"Meltrin beta (ADAM19) mediates ectodomain shedding of Neuregulin beta1 in the Golgi apparatus: fluorescence correlation spectroscopic observation of the dynamics of ectodomain shedding in living cells.","date":"2007","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/17352738","citation_count":53,"is_preprint":false},{"pmid":"19601835","id":"PMC_19601835","title":"ADAM19/adamalysin 19 structure, function, and role as a putative target in tumors and inflammatory diseases.","date":"2009","source":"Current pharmaceutical design","url":"https://pubmed.ncbi.nlm.nih.gov/19601835","citation_count":52,"is_preprint":false},{"pmid":"25799050","id":"PMC_25799050","title":"Role of microRNA-30c targeting ADAM19 in colorectal cancer.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25799050","citation_count":49,"is_preprint":false},{"pmid":"11162584","id":"PMC_11162584","title":"Expression and enzymatic activity of human disintegrin and metalloproteinase ADAM19/meltrin beta.","date":"2001","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11162584","citation_count":48,"is_preprint":false},{"pmid":"17112471","id":"PMC_17112471","title":"ADAM19 is tightly associated with constitutive Alzheimer's disease APP alpha-secretase in A172 cells.","date":"2006","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/17112471","citation_count":48,"is_preprint":false},{"pmid":"15030395","id":"PMC_15030395","title":"Lipid rafts identified as locations of ectodomain shedding mediated by Meltrin beta/ADAM19.","date":"2004","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15030395","citation_count":38,"is_preprint":false},{"pmid":"19027850","id":"PMC_19027850","title":"Xenopus ADAM19 is involved in neural, neural crest and muscle development.","date":"2008","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/19027850","citation_count":37,"is_preprint":false},{"pmid":"18830404","id":"PMC_18830404","title":"Meltrin beta/ADAM19 interacting with EphA4 in developing neural cells participates in formation of the neuromuscular junction.","date":"2008","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/18830404","citation_count":36,"is_preprint":false},{"pmid":"35902972","id":"PMC_35902972","title":"Human umbilical cord mesenchymal stem cell-derived exosomal miR-335-5p attenuates the inflammation and tubular epithelial-myofibroblast transdifferentiation of renal tubular epithelial cells by reducing ADAM19 protein levels.","date":"2022","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/35902972","citation_count":33,"is_preprint":false},{"pmid":"35871166","id":"PMC_35871166","title":"Exosomal circPABPC1 promotes colorectal cancer liver metastases by regulating HMGA2 in the nucleus and BMP4/ADAM19 in the cytoplasm.","date":"2022","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/35871166","citation_count":32,"is_preprint":false},{"pmid":"16900093","id":"PMC_16900093","title":"ADAM19 expression in human nephrogenesis and renal disease: associations with clinical and structural deterioration.","date":"2006","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/16900093","citation_count":32,"is_preprint":false},{"pmid":"19049978","id":"PMC_19049978","title":"Roles of meltrin-beta/ADAM19 in progression of Schwann cell differentiation and myelination during sciatic nerve regeneration.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19049978","citation_count":30,"is_preprint":false},{"pmid":"14632642","id":"PMC_14632642","title":"Inverse regulation of the ADAM-family members, decysin and MADDAM/ADAM19 during monocyte differentiation.","date":"2003","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/14632642","citation_count":29,"is_preprint":false},{"pmid":"26823772","id":"PMC_26823772","title":"MiR-145 suppressed human retinoblastoma cell proliferation and invasion by targeting ADAM19.","date":"2015","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26823772","citation_count":27,"is_preprint":false},{"pmid":"36862227","id":"PMC_36862227","title":"Synovial mesenchymal stem cell-derived exosomal microRNA-320c facilitates cartilage damage repair by targeting ADAM19-dependent Wnt signalling in osteoarthritis rats.","date":"2023","source":"Inflammopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36862227","citation_count":27,"is_preprint":false},{"pmid":"32055266","id":"PMC_32055266","title":"Long noncoding RNA NORAD regulates lung cancer cell proliferation, apoptosis, migration, and invasion by the miR-30a-5p/ADAM19 axis.","date":"2020","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/32055266","citation_count":27,"is_preprint":false},{"pmid":"15901844","id":"PMC_15901844","title":"Expression of adamalysin 19/ADAM19 in the endometrium and placenta of rhesus monkey (Macaca mulatta) during early pregnancy.","date":"2005","source":"Molecular human reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/15901844","citation_count":26,"is_preprint":false},{"pmid":"27078193","id":"PMC_27078193","title":"Genetic Variants in IL6R and ADAM19 are Associated with COPD Severity in a Mexican Mestizo Population.","date":"2016","source":"COPD","url":"https://pubmed.ncbi.nlm.nih.gov/27078193","citation_count":26,"is_preprint":false},{"pmid":"33548228","id":"PMC_33548228","title":"The elevated transcription of ADAM19 by the oncohistone H2BE76K contributes to oncogenic properties in breast cancer.","date":"2021","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33548228","citation_count":23,"is_preprint":false},{"pmid":"23429442","id":"PMC_23429442","title":"High expression of the \"A Disintegrin And Metalloprotease\" 19 (ADAM19), a sheddase for TNF-α in the mucosa of patients with inflammatory bowel diseases.","date":"2013","source":"Inflammatory bowel diseases","url":"https://pubmed.ncbi.nlm.nih.gov/23429442","citation_count":22,"is_preprint":false},{"pmid":"32844346","id":"PMC_32844346","title":"Circular RNA has_circ_0000034 accelerates retinoblastoma advancement through the miR-361-3p/ADAM19 axis.","date":"2020","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32844346","citation_count":21,"is_preprint":false},{"pmid":"31298334","id":"PMC_31298334","title":"MiR-145 changes sensitivity of non-small cell lung cancer to gefitinib through targeting ADAM19.","date":"2019","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31298334","citation_count":20,"is_preprint":false},{"pmid":"34927445","id":"PMC_34927445","title":"Synovial mesenchymal stem cell-derived exosomal miR-320c enhances chondrogenesis by targeting ADAM19.","date":"2021","source":"Future medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34927445","citation_count":19,"is_preprint":false},{"pmid":"29540504","id":"PMC_29540504","title":"Xenopus ADAM19 regulates Wnt signaling and neural crest specification by stabilizing ADAM13.","date":"2018","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/29540504","citation_count":18,"is_preprint":false},{"pmid":"23603262","id":"PMC_23603262","title":"Electrical stimulation accelerates neuromuscular junction formation through ADAM19/neuregulin/ErbB signaling in vitro.","date":"2013","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/23603262","citation_count":17,"is_preprint":false},{"pmid":"36890812","id":"PMC_36890812","title":"Promotion of colorectal cancer by transcription factor BHLHE40 involves upregulation of ADAM19 and KLF7.","date":"2023","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36890812","citation_count":16,"is_preprint":false},{"pmid":"16827870","id":"PMC_16827870","title":"Upregulation of ADAM19 in chronic allograft nephropathy.","date":"2006","source":"American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons","url":"https://pubmed.ncbi.nlm.nih.gov/16827870","citation_count":16,"is_preprint":false},{"pmid":"12482604","id":"PMC_12482604","title":"Meltrin beta mini, a new ADAM19 isoform lacking metalloprotease and disintegrin domains, induces morphological changes in neuronal cells.","date":"2002","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/12482604","citation_count":15,"is_preprint":false},{"pmid":"28265178","id":"PMC_28265178","title":"ADAM19: A Novel Target for Metabolic Syndrome in Humans and Mice.","date":"2017","source":"Mediators of inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/28265178","citation_count":14,"is_preprint":false},{"pmid":"12463424","id":"PMC_12463424","title":"Screen and identification of proteins interacting with ADAM19 cytoplasmic tail.","date":"2002","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/12463424","citation_count":13,"is_preprint":false},{"pmid":"10753657","id":"PMC_10753657","title":"Meltrin beta (ADAM19) gene: cloning, mapping, and analysis of the regulatory region.","date":"2000","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/10753657","citation_count":13,"is_preprint":false},{"pmid":"15896713","id":"PMC_15896713","title":"Epigenetic regulation of the dendritic cell-marker gene ADAM19.","date":"2005","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/15896713","citation_count":11,"is_preprint":false},{"pmid":"29190936","id":"PMC_29190936","title":"MiR-145 inhibits the epithelial-to-mesenchymal transition via targeting ADAM19 in human glioblastoma.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29190936","citation_count":11,"is_preprint":false},{"pmid":"21492148","id":"PMC_21492148","title":"Regional expression of ADAM19 during chicken embryonic development.","date":"2011","source":"Development, growth & differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/21492148","citation_count":11,"is_preprint":false},{"pmid":"24951661","id":"PMC_24951661","title":"ADAM19 and HTR4 variants and pulmonary function: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.","date":"2014","source":"Circulation. Cardiovascular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24951661","citation_count":11,"is_preprint":false},{"pmid":"19727588","id":"PMC_19727588","title":"Dynamic change of Adamalysin 19 (ADAM19) in human placentas and its effects on cell invasion and adhesion in human trophoblastic cells.","date":"2009","source":"Science in China. Series C, Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/19727588","citation_count":11,"is_preprint":false},{"pmid":"25573302","id":"PMC_25573302","title":"Variants in SELL, MRPS36P2, TP63, DDB2, CACNA1H, ADAM19, GNAI1, CDH13 and GABRG2 interact to confer risk of acne in Chinese population.","date":"2015","source":"The Journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/25573302","citation_count":10,"is_preprint":false},{"pmid":"39927476","id":"PMC_39927476","title":"Rejuvenating Hyaline Cartilage with Senescence-Targeting Si-ADAM19 Delivery for Osteoarthritis Therapy.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39927476","citation_count":7,"is_preprint":false},{"pmid":"37676254","id":"PMC_37676254","title":"miR-146b-5p downregulates IRAK1 and ADAM19 to suppress trophoblast proliferation, invasion, and migration in miscarriage†.","date":"2023","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/37676254","citation_count":6,"is_preprint":false},{"pmid":"20460109","id":"PMC_20460109","title":"ADAM19 autolysis is activated by LPS and promotes non-classical secretion of cysteine-rich protein 2.","date":"2010","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/20460109","citation_count":6,"is_preprint":false},{"pmid":"16884740","id":"PMC_16884740","title":"Developmental and hormonal regulation of meltrin beta (ADAM19) expression in mouse testes during embryonic and postnatal life.","date":"2006","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/16884740","citation_count":6,"is_preprint":false},{"pmid":"38455406","id":"PMC_38455406","title":"YY1-induced lncRNA00511 promotes melanoma progression via the miR-150-5p/ADAM19 axis.","date":"2024","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/38455406","citation_count":5,"is_preprint":false},{"pmid":"15242783","id":"PMC_15242783","title":"Evidence for disulfide involvement in the regulation of intramolecular autolytic processing by human adamalysin19/ADAM19.","date":"2004","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/15242783","citation_count":5,"is_preprint":false},{"pmid":"40117561","id":"PMC_40117561","title":"Inhibition of the metalloprotease ADAM19 as a novel senomorphic strategy to ameliorate gut permeability and senescence markers by modulating senescence-associated secretory phenotype (SASP).","date":"2025","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/40117561","citation_count":2,"is_preprint":false},{"pmid":"18458692","id":"PMC_18458692","title":"[Expression and clinical significance of ADAM19 in endometrial carcinoma].","date":"2008","source":"Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/18458692","citation_count":2,"is_preprint":false},{"pmid":"38331475","id":"PMC_38331475","title":"ADAM19 cleaves the PTH receptor and associates with brachydactyly type E.","date":"2024","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/38331475","citation_count":1,"is_preprint":false},{"pmid":"40658522","id":"PMC_40658522","title":"Cell-free miRNA-150-5p serves as a biomarker and regulator of PROM-related preterm labor by targeting chorionic ADAM19.","date":"2025","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/40658522","citation_count":1,"is_preprint":false},{"pmid":"39153120","id":"PMC_39153120","title":"Adam19 Deficiency Impacts Pulmonary Function: Human GWAS Follow-up in a Mouse Knockout Model.","date":"2024","source":"Lung","url":"https://pubmed.ncbi.nlm.nih.gov/39153120","citation_count":1,"is_preprint":false},{"pmid":"32960074","id":"PMC_32960074","title":"Comparison of ADAM19 and CUEDC2 expression in EHCC and their clinicopathological significance.","date":"2020","source":"Biomarkers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32960074","citation_count":0,"is_preprint":false},{"pmid":"38659817","id":"PMC_38659817","title":"Adam19 Deficiency Impacts Pulmonary Function: Human GWAS Follow-up in Mouse.","date":"2024","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/38659817","citation_count":0,"is_preprint":false},{"pmid":"38149560","id":"PMC_38149560","title":"Long non-coding RNA LINC00565 regulates ADAM19 expression through sponging microRNA-532-3p, thereby facilitating clear cell renal cell carcinoma progression.","date":"2023","source":"The Chinese journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/38149560","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.05.30.596458","title":"Human skeletal muscle possesses an epigenetic memory of high intensity interval training","date":"2024-06-03","source":"bioRxiv","url":"https://doi.org/10.1101/2024.05.30.596458","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":30605,"output_tokens":6387,"usd":0.09381},"stage2":{"model":"claude-opus-4-6","input_tokens":9945,"output_tokens":3541,"usd":0.207375},"total_usd":0.301185,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"ADAM19 (meltrin beta) participates in the proteolytic processing of membrane-anchored neuregulin-1 beta (NRG-beta1), with preference for beta-type NRGs over alpha-type; overexpression potentiates NRG-beta1 processing while protease-deficient mutants exert dominant negative effects; processing occurs intracellularly rather than at the cell surface.\",\n      \"method\": \"Overexpression of wild-type and protease-deficient dominant-negative mutants in L929 cells; secretory pathway inhibitor treatment; western blot for extracellular domain release\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal gain/dominant-negative loss-of-function with defined substrate specificity, replicated across NRG isoforms\",\n      \"pmids\": [\"11116142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Recombinant soluble ADAM19 exhibits metalloprotease activity (autocatalytic tag removal, cleavage of myelin basic protein and insulin B chain), is inhibited by hydroxamic acid metalloprotease inhibitor BB94 but not by TIMPs 1-3, cleaves peptides corresponding to TNF-alpha, TRANCE, and KL-1 cleavage sites in vitro, and negatively regulates KL-1 shedding in cells rather than acting directly as its sheddase.\",\n      \"method\": \"In vitro protease assay with recombinant soluble ADAM19; peptide cleavage assays; BB94 and TIMP inhibition assays; COS-7 and MEF overexpression/knockout studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with recombinant enzyme plus multiple substrate assays and inhibitor characterization\",\n      \"pmids\": [\"12682046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Human ADAM19 forms a complex with and cleaves alpha-2 macroglobulin; its proteolytic activity is blocked by 1,10-phenanthroline, EDTA, EGTA, and a synthetic MMP inhibitor but not by TIMP-1 or TIMP-2.\",\n      \"method\": \"Recombinant protein expression in human cells; co-immunoprecipitation/complex detection; metalloprotease inhibitor assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro assay with recombinant enzyme and substrate, single study\",\n      \"pmids\": [\"11162584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ADAM19-mediated ectodomain shedding of NRG-beta1 occurs specifically in lipid rafts of neurons; the membrane-anchoring region of ADAM19 is required for its lipid raft localization, and NRG-beta1 shedding is not enhanced if ADAM19 cannot reach the lipid rafts.\",\n      \"method\": \"Lipid raft fractionation; deletion mutant analysis of membrane-anchoring region; NRG-beta1 shedding assay in neuronal cells\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — subcellular fractionation with functional consequence (shedding defect) linked to specific domain; moderate evidence from single lab with multiple methods\",\n      \"pmids\": [\"15030395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ADAM19 (meltrin beta) mediates ectodomain shedding of NRG-beta1 in the Golgi apparatus (not at the cell surface); subcellular fractionation showed soluble NRG-beta1 generated by ADAM19 is recovered in Golgi-enriched fractions, whereas TACE/ADAM17-cleaved NRG-beta1 is in lighter fractions; fluorescence correlation spectroscopy in living cells confirmed conversion of GFP-tagged NRG-beta1 from membrane-anchored to soluble form within the Golgi.\",\n      \"method\": \"Subcellular fractionation; fluorescence correlation spectroscopy (FCS) in living cells; localization by immunofluorescence in developing sensory neurons\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (fractionation + live-cell FCS) establishing Golgi as shedding compartment, single lab\",\n      \"pmids\": [\"17352738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ADAM19 overexpression reduces the amount of Endo-H-resistant mature KitL1 available for phorbol ester-stimulated ectodomain shedding, thereby indirectly decreasing ADAM17-mediated KitL1 shedding; ADAM17, not ADAM19, is the major phorbol-ester-stimulated sheddase of KitL1 and KitL2.\",\n      \"method\": \"Overexpression of ADAM family members in COS-7 cells; Endo-H glycosylation assay; phorbol ester stimulation; KitL shedding assay in MEFs from ADAM-knockout mice\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout MEFs plus biochemical glycosylation assay; mechanistic distinction from ADAM17; replicated across KitL isoforms\",\n      \"pmids\": [\"17344430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ADAM19 has constitutive alpha-secretase activity for amyloid precursor protein (APP): overexpression in HEK293 cells increases sAPP-alpha release; RNAi knockdown in A172 cells reduces constitutive sAPP-alpha by ~21%; no regulated (PMA-stimulated) activity was detected.\",\n      \"method\": \"Overexpression in HEK293 cells with sAPP-alpha ELISA/western blot; RNAi knockdown in A172 cells; phorbol ester (PMA) stimulation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss- and gain-of-function with defined molecular readout; single lab, two orthogonal approaches\",\n      \"pmids\": [\"17112471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Human ADAM19 autolytic processing within its cysteine-rich domain (at Glu586-Ser587) is regulated by disulfide bonds; DTT treatment and acidic pH (6.5) block autolytic processing, while pH 8.5 promotes it; specific cysteine residues (Cys605, Cys633, Cys639, Cys643) in the C-fragment are partially responsible for covalent association between N- and C-fragments; ADAM19 is activated by furin-mediated prodomain cleavage followed by intramolecular autolysis.\",\n      \"method\": \"Stable MDCK transfectants expressing soluble ADAM19; DTT and pH manipulation; site-directed mutagenesis of cysteine residues; Ilomastat/GM6001 inhibition; identification of new autolytic cleavage site\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis of active-site cysteines combined with chemical manipulation; single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"15242783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ADAM19 is the protease responsible for cleaving the (pro)renin receptor ((P)RR) in the Golgi, generating an amino-terminal fragment (NTF-(P)RR) that is secreted into the extracellular space; transfected ADAM19 evokes (P)RR shedding and dominant-negative ADAM19 suppresses it; furin is not responsible for this cleavage; secreted NTF-(P)RR induces prorenin activity.\",\n      \"method\": \"Overexpression and dominant-negative ADAM19 in CHO cells; western blot for (P)RR fragments; immunofluorescence localization; furin-deficient LoVo cells and furin inhibitor controls\",\n      \"journal\": \"Hypertension research : official journal of the Japanese Society of Hypertension\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function plus dominant-negative plus genetic (furin-deficient cells) controls; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"21270819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In Xenopus, ADAM19 knockdown decreases phospho-AKT (a downstream target of EGF signaling), reduces neural markers (N-tubulin, NRP1), neural crest markers, and disrupts cranial neural crest migration in a cell-autonomous manner; somite organization and fibronectin localization at intersomitic boundaries are also perturbed.\",\n      \"method\": \"Morpholino knockdown in Xenopus embryos; targeted (cell-autonomous) knockdown; phospho-AKT western blot; in situ hybridization for marker genes; EGF receptor inhibitor treatment\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — morpholino loss-of-function with multiple molecular readouts; ortholog in Xenopus consistent with mammalian gene function\",\n      \"pmids\": [\"19027850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ADAM19 (meltrin beta) interacts with EphA4 in developing motor neurons; coexpression of ADAM19 and EphA4 blocks vesicular internalization of ephrin-A5-EphA4 complexes independently of ADAM19's protease activity, stabilizing ephrin-A5-EphA4 interaction and contributing to neuromuscular junction (NMJ) formation; meltrin-beta-deficient mice show broader AChR alpha mRNA distribution and excess motor nerve terminal sprouting.\",\n      \"method\": \"Co-immunoprecipitation of ADAM19 and EphA4; knockout mouse analysis (AChR distribution, nerve sprouting); microarray; protease-dead mutant analysis of ephrin endocytosis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus KO mouse phenotype plus protease-dead mutant establishing non-proteolytic mechanism; multiple orthogonal approaches\",\n      \"pmids\": [\"18830404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ADAM19 (meltrin beta) promotes Schwann cell differentiation and remyelination after sciatic nerve crush injury; ADAM19-deficient mice show delayed Krox-20 activation and myelin protein expression; ADAM19 modulates juxtacrine axon-Schwann cell signaling that activates Akt (but not Erk) phosphorylation, which is required for Krox-20 expression and myelination.\",\n      \"method\": \"Sciatic nerve crush in ADAM19 knockout mice; morphometric analysis of remyelination; western blot for pAkt, pErk, Krox-20, myelin proteins; membrane-loaded Schwann cell Akt activation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined cellular and molecular phenotype, pathway placement via pAkt vs. pErk discrimination, single lab with multiple methods\",\n      \"pmids\": [\"19049978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The cytoplasmic tail of ADAM19 interacts with ArgBP1 through ADAM19's SH3 ligand-binding sites and the P4 region of ArgBP1; this interaction is specific (ArgBP1 does not bind ADAM22, ADAM29, or ADAM9); beta-COP, ubiquitin, and a novel protein also interact with the ADAM19 cytoplasmic tail.\",\n      \"method\": \"Yeast two-hybrid screen of human fetal brain cDNA library; GST-pulldown confirmation; deletion mutant mapping of interaction domains\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — yeast two-hybrid confirmed by GST-pulldown; single study, two methods\",\n      \"pmids\": [\"12463424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ADAM19 undergoes autolytic processing activated by LPS stimulation, and through its disintegrin and cysteine-rich domains interacts with and promotes non-classical secretion of cysteine-rich protein 2 (CRIP2); CRIP2 secretion increases with ADAM19 autolytic processing and decreases upon ADAM19 knockdown.\",\n      \"method\": \"Yeast two-hybrid screen using ADAM19 extracellular domain; LPS stimulation of cells; western blot for ADAM19 processing and CRIP2 secretion; ADAM19 siRNA knockdown\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — yeast two-hybrid plus functional secretion assay; single lab, single study\",\n      \"pmids\": [\"20460109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In Xenopus, ADAM19 functions non-proteolytically in neural crest specification by physically interacting with its close paralog ADAM13 and inhibiting its proteasomal degradation, thereby sustaining Wnt signaling at the neural plate border; canonical Wnt signaling activity is severely downregulated upon ADAM19 knockdown, and ectopic expression of proteasome-resistant ADAM13 mutants rescues neural crest induction via Wnt signaling.\",\n      \"method\": \"Morpholino knockdown in Xenopus; Co-immunoprecipitation of ADAM19 with ADAM13; proteasome inhibitor rescue; epistasis with stabilized ADAM13 mutants; Wnt reporter assay\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus genetic epistasis with rescue by stabilized mutant; multiple orthogonal methods in Xenopus ortholog system\",\n      \"pmids\": [\"29540504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"A novel ADAM19 splice isoform (meltrin beta mini) lacking the prodomain, metalloprotease, and disintegrin domains induces neurite outgrowth in neuronal cells, a function not shared by full-length ADAM19, suggesting a distinct non-proteolytic role mediated by the remaining domains.\",\n      \"method\": \"RT-PCR identification of isoform; cDNA/genomic sequence comparison; overexpression of meltrin beta mini vs. full-length ADAM19 in neuronal cell lines\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — gain-of-function overexpression with defined morphological readout; single lab, comparative analysis between isoforms\",\n      \"pmids\": [\"12482604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ADAM19 overexpression in JEG-3 trophoblast cells reduces cell invasion and increases cell adhesiveness and E-cadherin expression without changing beta-catenin expression.\",\n      \"method\": \"ADAM19 overexpression in JEG-3 choriocarcinoma cells; invasion assay; adhesion assay; western blot for E-cadherin and beta-catenin\",\n      \"journal\": \"Science in China. Series C, Life sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — gain-of-function in a cancer cell line with phenotypic readout but limited mechanistic follow-up; single lab\",\n      \"pmids\": [\"19727588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ADAM19 and phospho-ErbB3 co-localize in co-cultured neural NG108-15 cells; electrical stimulation increases ADAM19 precursor and activated form, phospho-ErbB3, and ERK1 levels in a stimulation duration-dependent manner, implicating ADAM19/neuregulin/ErbB signaling in NMJ formation.\",\n      \"method\": \"Immunofluorescence localization; immunoblotting for ADAM19, pErbB3, ERK1, synapsin 1 in electrically stimulated co-cultures\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — correlative western blot and immunofluorescence without direct loss-of-function; single lab, single study\",\n      \"pmids\": [\"23603262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ADAM19 cleaves the parathyroid hormone receptor (PTHR1) at a site mapped between amino acids 64-65 (verified by mass spectrometry); WT ADAM19 cleaves PTHR1 while a truncated/mutated ADAM19 allele found in brachydactyly type E patients does not; ADAM19-mediated PTHR1 cleavage increases Gq and decreases Gs activation, and increases beta-arrestin2 recruitment without altering cAMP accumulation.\",\n      \"method\": \"Linkage and whole genome sequencing in BDE pedigree; ADAM19 cleavage assay with WT vs. mutant ADAM19; mass spectrometry cleavage site mapping; Gq/Gs activation assays; beta-arrestin2 recruitment assay; cAMP accumulation assay\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro cleavage assay with mass spectrometry site mapping plus signaling readouts and disease-associated mutant comparison; multiple orthogonal methods\",\n      \"pmids\": [\"38331475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ADAM19 inhibition (siRNA knockdown or pharmacological inhibition with batimastat-94) in human primary fibroblasts decreases specific SASP factor expression and SA-beta-gal levels in senescent cells; proteomics of senescent cell secretome reveals decreased SASP factors associated with ADAM19 cleavage sites; in mice, batimastat-94 treatment reduces gut permeability and gut inflammation.\",\n      \"method\": \"siRNA knockdown in human primary fibroblasts; pharmacological inhibition (batimastat-94) in mice; secretome proteomics; SA-beta-gal assay; Drosophila meltrin GWAS/knockdown for initial identification\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KD, pharmacological, proteomics) in human cells and in vivo; single recent study\",\n      \"pmids\": [\"40117561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TGF-beta1 signaling induces SMAD4 nuclear translocation and upregulates ADAM19 transcription in normal ovarian surface epithelial cells; in TGF-beta1-refractory ovarian cancer cells, impaired SMAD4 nuclear translocation correlates with repressive histone modifications (trimethyl-H3K27, dimethyl-H3K9) and HDAC association at the ADAM19 promoter, leading to ADAM19 silencing.\",\n      \"method\": \"TGF-beta1 stimulation; nuclear fractionation for SMAD4; ChIP for histone modifications (H3K27me3, H3K9me2) and HDAC at ADAM19 promoter; RT-PCR; promoter CpG methylation analysis\",\n      \"journal\": \"Neoplasia (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP assays with pathway-linked stimulus; multiple epigenetic marks; single lab\",\n      \"pmids\": [\"18714391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ADAM19 (MADDAM) expression in dendritic cells (but not macrophages) is regulated by histone acetylation: TSA (HDAC inhibitor) induces ADAM19 mRNA in THP-1 monocytic cells; ChIP assays show high acetylated histone H3 at the ADAM19 proximal promoter in TSA-treated THP-1 and dendritic cells compared to macrophages.\",\n      \"method\": \"TSA treatment; RT-PCR; ChIP with anti-acetylated H3 antibody; reporter assay with minimal promoter construct\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrating active chromatin mark correlating with cell-type-specific expression plus TSA functional induction; single lab\",\n      \"pmids\": [\"15896713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Neutralizing ADAM19 in a diet-induced obesity mouse model results in weight loss, improved insulin sensitivity, and reduced liver TNF-alpha levels, implicating ADAM19 as a pro-obesogenic factor that enhances insulin resistance.\",\n      \"method\": \"In vivo neutralizing antibody treatment in diet-induced obesity mouse model; body weight measurement; insulin sensitivity testing (HOMA-IR); liver TNF-alpha quantification\",\n      \"journal\": \"Mediators of inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo loss-of-function with defined metabolic readouts; single lab, single study\",\n      \"pmids\": [\"28265178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Adam19 knockout mice show altered pulmonary function (decreased respiratory system elastance, tissue damping, tissue elastance, FEF50 but higher FEV0.1 and FVC at baseline), attenuated inflammatory responses to LPS (reduced neutrophil extravasation), and negative enrichment for TNF signaling pathways by RNA-seq, establishing a causal role for ADAM19 in lung function regulation.\",\n      \"method\": \"Adam19 knockout mouse generation; flexiVent lung function measurement; LPS challenge; BAL neutrophil counting; RNA-seq with gene set enrichment analysis\",\n      \"journal\": \"Lung\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined functional phenotype (pulmonary mechanics) plus molecular pathway analysis; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39153120\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADAM19 is a membrane-anchored zinc-dependent metalloprotease (ADAM family) that cleaves multiple substrates including NRG-beta1 (preferentially in the Golgi, within lipid rafts), APP (constitutive alpha-secretase), PTHR1 (at the ectodomain), the (pro)renin receptor, TRANCE, and membrane-bound TNF-alpha; its autolytic processing is regulated by disulfide bonds within its cysteine-rich domain; it also functions non-proteolytically by interacting with EphA4 to regulate ephrin endocytosis at the NMJ and by stabilizing ADAM13 to sustain Wnt signaling during neural crest specification; its cytoplasmic tail engages ArgBP1 through SH3 ligand-binding sites; and loss-of-function studies in mice establish causal roles in pulmonary function, remyelination via axon-Schwann cell Akt/Krox-20 signaling, and metabolic regulation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ADAM19 is a membrane-anchored zinc-dependent metalloprotease of the ADAM family that cleaves diverse substrates—including neuregulin-1 beta (NRG-β1), amyloid precursor protein (APP), parathyroid hormone receptor (PTHR1), and the (pro)renin receptor—primarily within the Golgi apparatus and lipid rafts, and also performs non-proteolytic functions through protein–protein interactions [PMID:11116142, PMID:15030395, PMID:17352738, PMID:38331475, PMID:21270819, PMID:17112471]. Its catalytic maturation involves furin-mediated prodomain removal followed by disulfide-bond-regulated autolytic processing within the cysteine-rich domain, and its activity is sensitive to hydroxamic acid metalloprotease inhibitors but resistant to TIMPs 1–3 [PMID:15242783, PMID:12682046]. Independent of its protease activity, ADAM19 interacts with EphA4 to block ephrin-A5 endocytosis at neuromuscular junctions and stabilizes ADAM13 to sustain canonical Wnt signaling during neural crest specification [PMID:18830404, PMID:29540504]. Loss-of-function studies in mice establish causal roles in Schwann cell remyelination via Akt/Krox-20 signaling, pulmonary mechanics and inflammatory responses, and metabolic regulation including insulin sensitivity [PMID:19049978, PMID:39153120, PMID:28265178].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Identifying ADAM19 as a NRG-β1 sheddase established its first defined substrate and showed it acts intracellularly rather than at the cell surface, distinguishing it from other ADAMs.\",\n      \"evidence\": \"Overexpression/dominant-negative mutants in L929 cells with secretory pathway inhibitors and NRG isoform comparisons\",\n      \"pmids\": [\"11116142\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular compartment of cleavage not yet identified\", \"Endogenous validation in neuronal tissue lacking\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstration that ADAM19 cleaves α2-macroglobulin and is blocked by chelating agents but not TIMPs began to define its inhibitor profile and broad substrate range.\",\n      \"evidence\": \"Recombinant ADAM19 with co-immunoprecipitation and metalloprotease inhibitor panel\",\n      \"pmids\": [\"11162584\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"α2-macroglobulin cleavage not confirmed in vivo\", \"Physiological relevance of this substrate unclear\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identification of ArgBP1 as a cytoplasmic tail interactor via SH3-ligand sites, plus discovery of a truncated isoform (meltrin β mini) that induces neurite outgrowth, revealed that ADAM19 signals through its intracellular domain and possesses isoform-specific non-proteolytic functions.\",\n      \"evidence\": \"Yeast two-hybrid/GST-pulldown for ArgBP1; RT-PCR cloning and overexpression of meltrin β mini in neuronal cells\",\n      \"pmids\": [\"12463424\", \"12482604\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of ArgBP1 interaction uncharacterized\", \"Neurite outgrowth mechanism of meltrin β mini undefined\", \"No in vivo validation of isoform-specific roles\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Reconstitution of soluble ADAM19 with defined peptide substrates (TNF-α, TRANCE, KL-1 sites) and inhibitor profiling (sensitive to BB94, resistant to TIMPs 1–3) established its enzymatic specificity and showed it indirectly regulates KitL1 shedding rather than acting as its direct sheddase.\",\n      \"evidence\": \"In vitro protease assays with recombinant soluble ADAM19; peptide cleavage; COS-7 and ADAM-knockout MEF studies\",\n      \"pmids\": [\"12682046\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct in vivo substrates versus indirect regulatory targets not fully delineated\", \"Structural basis for TIMP resistance unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Mapping autolytic processing to a specific site in the cysteine-rich domain regulated by disulfide bonds and pH resolved how ADAM19 matures after furin-mediated prodomain removal.\",\n      \"evidence\": \"Site-directed mutagenesis of cysteines, DTT/pH manipulation, and Ilomastat inhibition in stable MDCK transfectants\",\n      \"pmids\": [\"15242783\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural model of cysteine-rich domain lacking\", \"Whether autolysis is required for all substrates untested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Localizing NRG-β1 shedding to lipid rafts and showing that ADAM19's membrane-anchoring region is required for raft targeting linked its subcellular positioning to substrate access.\",\n      \"evidence\": \"Lipid raft fractionation and deletion mutant analysis in neuronal cells\",\n      \"pmids\": [\"15030395\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Raft-targeting determinants in the membrane anchor not mapped at residue level\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Fluorescence correlation spectroscopy in living cells pinpointed the Golgi as the compartment where ADAM19 converts membrane-anchored NRG-β1 to soluble form, distinguishing its spatial activity from ADAM17 at the cell surface.\",\n      \"evidence\": \"Subcellular fractionation plus live-cell FCS with GFP-NRG-β1 in neurons\",\n      \"pmids\": [\"17352738\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of ADAM19 retention/recycling within the Golgi unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Three concurrent studies expanded ADAM19's roles beyond proteolysis: it interacts with EphA4 to block ephrin endocytosis at the NMJ independently of its metalloprotease activity, it promotes Schwann cell remyelination via axon–Schwann cell Akt/Krox-20 signaling, and its knockdown in Xenopus disrupts neural crest migration and pAkt levels.\",\n      \"evidence\": \"KO mouse NMJ analysis with protease-dead mutants; sciatic nerve crush in KO mice with pAkt/Krox-20 readouts; Xenopus morpholino knockdown with marker analysis\",\n      \"pmids\": [\"18830404\", \"19049978\", \"19027850\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the NRG/ErbB ligand processed by ADAM19 in Schwann cell signaling not confirmed\", \"Whether EphA4 interaction and NRG shedding are coordinated at the NMJ unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identifying the (pro)renin receptor as a Golgi-resident ADAM19 substrate, with secreted NTF activating prorenin, connected ADAM19 to renin-angiotensin signaling.\",\n      \"evidence\": \"Overexpression/dominant-negative in CHO cells; furin-deficient LoVo cell controls\",\n      \"pmids\": [\"21270819\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo confirmation of ADAM19 as the physiological (P)RR sheddase not yet shown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Neutralizing ADAM19 in diet-induced obese mice improved insulin sensitivity and reduced liver TNF-α, establishing a metabolic function and linking its TNF-α shedding capability to obesity phenotypes.\",\n      \"evidence\": \"In vivo neutralizing antibody in mouse obesity model; HOMA-IR and liver TNF-α measurement\",\n      \"pmids\": [\"28265178\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate(s) responsible for metabolic effects not identified\", \"Antibody specificity for ADAM19 over other ADAMs not fully validated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery that ADAM19 stabilizes ADAM13 by preventing its proteasomal degradation to sustain Wnt signaling during neural crest specification established a non-catalytic chaperone-like function for an ADAM protease.\",\n      \"evidence\": \"Xenopus morpholino knockdown; Co-IP of ADAM19–ADAM13; rescue with proteasome-resistant ADAM13 mutants; Wnt reporter\",\n      \"pmids\": [\"29540504\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this stabilization mechanism operates in mammals unknown\", \"Structural basis of ADAM19–ADAM13 interaction undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mass spectrometry mapping of the PTHR1 cleavage site and demonstration that a brachydactyly type E (BDE)-associated ADAM19 mutant cannot cleave PTHR1 linked ADAM19 loss-of-function to a Mendelian skeletal phenotype and showed cleavage biases PTHR1 signaling from Gs toward Gq/β-arrestin2.\",\n      \"evidence\": \"Linkage/WGS in BDE pedigree; in vitro cleavage with WT vs. mutant ADAM19; MS site mapping; Gq/Gs and β-arrestin2 assays\",\n      \"pmids\": [\"38331475\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ADAM19-PTHR1 axis explains the full BDE phenotype in vivo not demonstrated\", \"Crystal structure of ADAM19–PTHR1 complex unavailable\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Adam19 knockout mice showed altered pulmonary mechanics and attenuated LPS-induced neutrophil influx with negative enrichment for TNF signaling, causally establishing ADAM19 in lung function and inflammation.\",\n      \"evidence\": \"Knockout mouse flexiVent measurements; BAL analysis after LPS challenge; RNA-seq/GSEA\",\n      \"pmids\": [\"39153120\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific pulmonary substrates of ADAM19 driving altered elastance not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"ADAM19 knockdown or pharmacological inhibition reduced senescence-associated secretory phenotype (SASP) factors and senescence markers in human fibroblasts, suggesting a role in cellular senescence and age-related inflammation.\",\n      \"evidence\": \"siRNA in human primary fibroblasts; batimastat-94 in mice; secretome proteomics; SA-β-gal assay\",\n      \"pmids\": [\"40117561\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Batimastat-94 is not ADAM19-specific; contribution of other metalloproteases not excluded\", \"Mechanism linking ADAM19 cleavage to SASP factor regulation unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the structural basis for ADAM19's TIMP resistance, the full in vivo substrate repertoire in specific tissues, whether its non-proteolytic functions (ADAM13 stabilization, EphA4 interaction) are conserved in mammals, and the identity of the specific substrates mediating its pulmonary and metabolic phenotypes.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure of ADAM19 catalytic or cysteine-rich domains\", \"Comprehensive in vivo substrate identification by unbiased proteomics lacking\", \"Mammalian validation of ADAM13-stabilization mechanism absent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 6, 7, 8, 18]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1, 2, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 10, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [4, 8]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [0, 8, 11, 18]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 8, 11, 18]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9, 10, 14]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [10, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [23]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"NRG1\",\n      \"EphA4\",\n      \"ADAM13\",\n      \"ATP6AP2\",\n      \"PTH1R\",\n      \"APP\",\n      \"SORBS2\",\n      \"CRIP2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}