{"gene":"ADAM10","run_date":"2026-06-09T22:02:40","timeline":{"discoveries":[{"year":1996,"finding":"The Drosophila kuzbanian (kuz) gene, encoding a metalloprotease-disintegrin protein (ortholog of ADAM10), is essential for neurogenesis: mosaic analyses showed kuz is required cell-non-autonomously for cells to receive inhibitory signals against neural fate, and cell-autonomously for a positive neurogenic signal from neighboring cells.","method":"Drosophila genetic mosaic analysis, loss-of-function","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — rigorous Drosophila genetic mosaic analyses with defined cellular phenotypes, foundational paper replicated by subsequent work","pmids":["8703057"],"is_preprint":false},{"year":2002,"finding":"ADAM10 (KUZ) mediates GPCR transactivation of EGFR by cleaving the ectodomain of HB-EGF; upon bombesin receptor stimulation, ADAM10 increases Src homology 2 domain-containing protein and Gab1 docking on EGFR and activation of Ras and Erk. Its metalloprotease activity is required, and GPCR activation enhances association of ADAM10 and HB-EGF with tetraspanin CD9.","method":"Gain-of-function overexpression, protease-domain deletion mutant, morpholino antisense knockdown, Co-IP with CD9","journal":"The Journal of Cell Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (dominant-negative, knockdown, Co-IP) in single lab","pmids":["12119356"],"is_preprint":false},{"year":2007,"finding":"ADAM10 cleaves the extracellular domain of L1-CAM; ADAM10 is a transcriptional target of beta-catenin-TCF signaling; ADAM10 overexpression in colon cancer cells enhances L1-CAM cleavage and induces liver metastasis in a splenic injection mouse model.","method":"Overexpression, in vivo mouse metastasis model, Western blot cleavage assay, DNA microarray","journal":"Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo functional readout with gain-of-function, single lab","pmids":["17699774"],"is_preprint":false},{"year":2007,"finding":"SAP97 directly interacts with ADAM10 via its SH3 domain and drives ADAM10 to the postsynaptic membrane; NMDA receptor activation mediates this trafficking and positively modulates alpha-secretase (ADAM10) activity toward APP. Disruption of the ADAM10/SAP97 interaction by cell-permeable peptides impairs ADAM10 postsynaptic localization and reduces APP alpha-secretase cleavage.","method":"Co-IP, cell-permeable peptide interference, subcellular fractionation, NMDA receptor activation assay","journal":"The Journal of Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vivo peptide interference, functional consequence on APP processing, replicated in follow-up studies","pmids":["17301176"],"is_preprint":false},{"year":2008,"finding":"ADAM10 specifically cleaves the ectodomain of VE-cadherin in endothelial cells, generating a soluble fragment and a C-terminal membrane stub that is subsequently cleaved by gamma-secretase. This cleavage is induced by Ca2+ influx and staurosporine, increases endothelial permeability, and contributes to thrombin-induced loss of cell-cell adhesion. ADAM10 knockdown in HUVECs and T cells impairs T-cell transmigration.","method":"Gain-of-function overexpression, RNAi knockdown, inhibitor studies, permeability assays, transmigration assay","journal":"Circulation Research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (overexpression, RNAi, inhibitors), functional readouts (permeability, transmigration), replicated across conditions","pmids":["18420943"],"is_preprint":false},{"year":2008,"finding":"ADAM10 is essential for proteolytic S2 cleavage of the Notch receptor during T cell development: conditional disruption of Adam10 in mouse thymocytes produces a developmental block similar to Notch1 loss, with impaired Notch1 activation and reduced expression of downstream targets Deltex-1 and Pre-Tα.","method":"Conditional knockout mouse, genetic epistasis, Western blot, gene expression analysis","journal":"International Immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined cellular phenotype, epistasis with Notch1 pathway, replicated by multiple labs","pmids":["18635581"],"is_preprint":false},{"year":2008,"finding":"Drosophila Kuz (ADAM10 ortholog) regulates Notch signaling primarily by activating the Notch receptor (S2 cleavage) rather than disabling Delta; Kuz overexpression produces ligand-independent Notch activation, whereas the related TACE can efficiently activate Notch in a ligand-independent manner.","method":"In vitro Drosophila cell-based Notch signaling assay, overexpression, gain-of-function","journal":"Cellular and Molecular Life Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based functional assay, single lab, overexpression approach","pmids":["18535782"],"is_preprint":false},{"year":2009,"finding":"Neuronal overexpression of ADAM10 in mice reduces total cellular prion protein (PrPc) levels in brain rather than generating enhanced amounts of specific PrPc cleavage products; moderately ADAM10-overexpressing mice show significantly prolonged incubation time after scrapie infection, indicating ADAM10 modulates PrPc abundance in vivo.","method":"Transgenic mouse overexpression, Western blot, scrapie infection survival analysis","journal":"Neurobiology of Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic model with defined phenotypic readout, single lab","pmids":["19632330"],"is_preprint":false},{"year":2011,"finding":"ADAM10 sheds CXCL16 constitutively in renal tubular cells; IFN-gamma-induced soluble CXCL16 release is blocked by ADAM10 activity inhibition, placing ADAM10 as the sheddase for CXCL16 in the kidney.","method":"ADAM10 inhibitor studies in primary tubular cells, Western blot, soluble CXCL16 measurement","journal":"Kidney International","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — inhibitor studies in primary cells, consistent with expression co-localization, single lab","pmids":["18480749"],"is_preprint":false},{"year":2011,"finding":"Conditional inactivation of ADAM10 in hematopoietic cells causes myeloproliferative disorder with splenomegaly and expanded myeloid progenitor populations. Reciprocal bone marrow transfers show ADAM10 activity is required in both hematopoietic and non-hematopoietic compartments; MPD in non-hematopoietic ADAM10-deficient cells is mediated by G-CSF.","method":"Conditional knockout mouse, reciprocal bone marrow transplantation, flow cytometry","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with epistatic reciprocal transfer experiments defining cell-autonomous and non-cell-autonomous roles, rigorous in vivo design","pmids":["22042698"],"is_preprint":false},{"year":2013,"finding":"Long-term potentiation (LTP) decreases ADAM10 surface levels and activity by promoting its endocytosis via activity-regulated association with the clathrin adaptor AP2 complex; long-term depression (LTD) promotes ADAM10 membrane insertion and activity. ADAM10 interaction with SAP97 is required for LTD-induced ADAM10 trafficking and LTD maintenance and LTD-induced spine morphology changes.","method":"Electrophysiology (LTP/LTD induction), Co-IP, surface biotinylation, synaptic fractionation","journal":"Neurodegenerative Diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods plus electrophysiology, single lab, functional consequence on synaptic plasticity","pmids":["24008925"],"is_preprint":false},{"year":2014,"finding":"ADAM10 (and presenilin-1/-2 gamma-secretase) are required for canonical ligand-induced NOTCH2 and NOTCH3 proteolytic activation; ADAM17/TACE does not contribute to ligand-induced NOTCH2 or NOTCH3 signaling, establishing that all three canonical Notch receptors (NOTCH1, 2, 3) strictly depend on ADAM10 for S2 cleavage.","method":"Genetic knockdown/knockout, ADAM inhibitor studies, Notch reporter assays","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic and pharmacological dissection with multiple Notch receptor substrates and negative control (ADAM17), rigorous mechanistic study","pmids":["24842903"],"is_preprint":false},{"year":2014,"finding":"SAP97 governs ADAM10 trafficking from dendritic Golgi outposts to synaptic membranes through a PKC phosphorylation site in the SAP97 SH3 domain that modulates the SAP97-ADAM10 association; this mechanism is altered in Alzheimer's disease brains.","method":"Co-IP, phosphorylation mutagenesis, live imaging of dendritic trafficking, subcellular fractionation, AD brain tissue analysis","journal":"Cell Death & Disease","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis of phosphorylation site combined with Co-IP and live imaging, functional consequence on trafficking, single lab","pmids":["25429624"],"is_preprint":false},{"year":2017,"finding":"ADAM10 is the major sheddase of ephrin-B2 in fibroblasts; ADAM10 expression is induced by TGF-β1, and ADAM10-mediated soluble ephrin-B2 generation is required for TGF-β1-induced myofibroblast activation. Fibroblast-specific ephrin-B2 knockout protects mice from skin and lung fibrosis; pharmacological ADAM10 inhibition reduces sEphrin-B2 in BAL and prevents lung fibrosis.","method":"ADAM10 inhibitor studies, fibroblast-specific conditional knockout, in vivo fibrosis models (bleomycin), ELISA, Western blot","journal":"Nature Medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetic KO, pharmacological inhibition, in vivo models), replicated in human IPF fibroblasts","pmids":["29058717"],"is_preprint":false},{"year":2017,"finding":"TspanC8 tetraspanins (Tspan5, 10, 14, 15, 17, 33) directly interact with ADAM10, are required for its exit from the endoplasmic reticulum and enzymatic maturation, and differentially direct ADAM10 to distinct subcellular locations with distinct substrate selectivities; Tspan5 and Tspan17 specifically regulate VE-cadherin expression and are required for T lymphocyte transmigration.","method":"Co-IP, RNAi knockdown, subcellular fractionation, flow-based transmigration assay","journal":"Journal of Immunology / Biochemical Society Transactions / Platelets","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IPs, functional knockdown assays with substrate-specific readouts, replicated across multiple labs and TspanC8 members","pmids":["28600292","28620033","27256961"],"is_preprint":false},{"year":2018,"finding":"Cryo-EM structure of a vFab-ADAM10-Tspan15 complex shows that Tspan15 binding relieves ADAM10 autoinhibition and positions the enzyme active site ~20 Å from the plasma membrane, functioning as a molecular measuring stick for membrane-proximal substrate cleavage. Cell-based N-cadherin shedding assays confirmed that the ADAM10-Tspan15 interface determines preferred cleavage site selection.","method":"Cryo-EM structure determination, cell-based shedding assay (N-cadherin), mutagenesis of interface","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure combined with functional cell-based validation and mutagenesis, rigorous mechanistic study","pmids":["37516108"],"is_preprint":false},{"year":2018,"finding":"ADAM10 is clustered at epithelial cell-cell junctions by a dock-and-lock mechanism: Tspan33 docks ADAM10 to junctions by binding PLEKHA7 (via PDZD11), and ADAM10's cytoplasmic C-terminus is locked at junctions through binding afadin. Junctionally clustered ADAM10 supports efficient S. aureus α-toxin pore formation; disruption of the PLEKHA7-PDZD11 complex inhibits ADAM10 junctional clustering and promotes toxin pore removal via actin/macropinocytosis.","method":"Co-IP, biochemical pulldown, live imaging, siRNA knockdown, pore-formation assay","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple Co-IP interactions defined, live imaging of clustering, functional pore-formation readout, mechanistically complete","pmids":["30463011"],"is_preprint":false},{"year":2018,"finding":"ADAM10 is the exclusive sheddase of PrPc in the nervous system; glycosylation state and type of membrane anchorage of PrPc severely affect its shedding by ADAM10; pharmacological inhibition/stimulation can modulate PrP shedding.","method":"Neo-epitope antibody, genetic cell and murine models, biochemical shedding assay, pharmacological modulation","journal":"Molecular Neurodegeneration","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic models combined with neo-epitope antibody detection and pharmacological modulation, multiple orthogonal approaches","pmids":["29625583"],"is_preprint":false},{"year":2019,"finding":"ADAM10 activity levels are elevated at postsynaptic densities in Huntington's disease mouse cortex and striatum, causing excessive cleavage of N-cadherin (N-CAD). Heterozygous conditional deletion of ADAM10 or competitive TAT-Pro-ADAM10 peptide in R6/2 HD mice reduces N-CAD proteolysis, ameliorates cognitive deficits, and reduces synapse loss.","method":"Conditional KO mouse, cell-permeable competitive peptide, electrophysiology, behavioral assays, Western blot of postsynaptic density fractions","journal":"The Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic and pharmacological rescue with multiple functional readouts (biochemical, electrophysiological, behavioral), two HD mouse models","pmids":["31063986"],"is_preprint":false},{"year":2019,"finding":"TspanC8 tetraspanins differentially regulate ADAM10 endocytosis and half-life: Tspan5 promotes faster ADAM10 endocytosis, while Tspan15 stabilizes ADAM10 at the cell surface (and ADAM10 stabilizes Tspan15 reciprocally). The cytoplasmic domains of these tetraspanins mediate their opposite effects on ADAM10 trafficking.","method":"Surface biotinylation, endocytosis assays, chimeric tetraspanin constructs, flow cytometry","journal":"Life Science Alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical approaches and chimeric mutants, single lab","pmids":["31792032"],"is_preprint":false},{"year":2019,"finding":"Cell-autonomous ADAM10 in dendritic cells (cDC2s) mediates shedding of FLT3L from cDC2 surfaces; ADAM10 deletion in DCs reduces serum FLT3L, retains membrane-bound FLT3L on cDC2s, and blocks cDC2 development and survival in spleen. In vitro studies confirmed FLT3L as a direct ADAM10 substrate.","method":"Conditional KO (Itgax-cre × Adam10-fl/fl), BM chimera, ex vivo culture supernatant FLT3L measurement, in vitro shedding assay with murine embryonic fibroblasts","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, BM chimera epistasis, in vitro substrate validation, multiple consistent readouts","pmids":["31262819"],"is_preprint":false},{"year":2020,"finding":"Loss of ADAM10 proteolytic activity (by inhibition or loss-of-function mutation) causes removal of mature ADAM10 from the cell surface via increased internalization, lysosomal degradation, and release in extracellular vesicles; recovery requires de novo synthesis. ADAM10 activity is thus required for its own surface maintenance in vitro and in vivo.","method":"Inhibitor treatment, loss-of-function mutants, flow cytometry, lysosomal inhibition, extracellular vesicle isolation, in vivo mouse tissue analysis","journal":"Cellular and Molecular Life Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple complementary approaches (inhibitor, mutant, in vivo), single lab","pmids":["32372373"],"is_preprint":false},{"year":2020,"finding":"ADAM10 and ADAM17 cleave PD-L1 from the surface of tumor cells and extracellular vesicles, generating an active soluble PD-L1 fragment that induces apoptosis in CD8+ T cells and impairs tumor cell killing by CD8+ T cells.","method":"ADAM10/17 inhibitor studies, siRNA knockdown, CD8+ T cell killing assays, Western blot of soluble PD-L1","journal":"Oncoimmunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic inhibition with functional immune readout, single lab","pmids":["32363112"],"is_preprint":false},{"year":2020,"finding":"Apoptosis-induced phosphatidylserine (PS) flipping to the outer leaflet (via XKR8 scramblase) activates ADAM10, which sheds a specific subset of transmembrane mucins from apoptotic T cells, reducing the glycocalyx barrier and enhancing macrophage efferocytic uptake.","method":"Cell-based shedding assays, genetic knockouts (XKR8, ADAM10), macrophage efferocytosis assay, flow cytometry","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic knockouts, mechanistic link between PS flipping and ADAM10 activation, functional efferocytosis readout","pmids":["38225245"],"is_preprint":false},{"year":2020,"finding":"ADAM10 and ADAM17 mediate constitutive and TNF-α-induced shedding of endomucin (EMCN) from endothelial cell surfaces; ADAM10 alone mediates TNF-α-induced C-terminal fragment generation.","method":"Adenoviral overexpression, siRNA knockdown, small-molecule inhibitors (GW280264X, GI254023X), Western blot","journal":"The Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA and pharmacological inhibition with substrate-specific Western blot readout, single lab","pmids":["32193206"],"is_preprint":false},{"year":2020,"finding":"GDE2 stimulates ADAM10-mediated APP cleavage (alpha-secretase) by shedding and inactivating RECK, a GPI-anchored inhibitor of ADAM10. In Alzheimer's disease, membrane-tethered RECK is highly elevated and GDE2 is abnormally sequestered inside neurons; RECK reduction rescues reduced sAPPα, increased Aβ, and synaptic protein loss caused by GDE2 ablation.","method":"Genetic ablation (GDE2, RECK), biochemical shedding assay, rescue experiments, synaptic protein analysis, mouse models","journal":"Science Translational Medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistatic genetic rescue experiments, multiple KO models, biochemical pathway validation, functional synaptic readout","pmids":["33731436"],"is_preprint":false},{"year":2021,"finding":"ADAM10 physically interacts with Trop-2 (co-immunoprecipitation, mass spectrometry) and colocalizes at the cell membrane; ADAM10 cleaves Trop-2 between R87 and T88 in its extracellular thyroglobulin domain, activating cancer cell growth and metastasis.","method":"Co-IP, mass spectrometry, N-terminal Edman degradation, ADAM10 siRNA/shRNA, in vivo xenograft metastasis assay","journal":"Neoplasia","confidence":"High","confidence_rationale":"Tier 1 / Moderate — substrate identification by Edman degradation and mutagenesis, Co-IP interaction, in vivo functional validation","pmids":["33839455"],"is_preprint":false},{"year":2021,"finding":"ADAM10 hyperactivity in Huntington's disease brain co-immunoprecipitates with piccolo (PCLO), a presynaptic scaffolding protein; reduced ADAM10/PCLO interaction in HD brain is associated with depleted synaptic vesicle density. Conditional heterozygous ADAM10 deletion in HD mice normalizes ADAM10/PCLO complex formation and synaptic vesicle density.","method":"Immunoaffinity purification-mass spectrometry (IP-MS), Co-IP, conditional KO mouse, electron microscopy of synaptic vesicles","journal":"Human Molecular Genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — IP-MS plus Co-IP plus genetic rescue with EM ultrastructural readout, two complementary approaches","pmids":["33601422"],"is_preprint":false},{"year":2021,"finding":"ADAM10 mediates antibody-induced podocyte injury by cleaving N- and P-cadherin ectodomains, decreasing their injury-related surface levels and activating downstream Wnt signaling; podocyte-specific ADAM10-deficient mice are protected from anti-podocyte nephritis.","method":"Podocyte-specific conditional KO, membrane proteomics, immunogold EM, anti-podocyte nephritis in vivo model, Western blot","journal":"Journal of the American Society of Nephrology","confidence":"High","confidence_rationale":"Tier 2 / Strong — podocyte-specific conditional KO with in vivo nephritis model, proteomics substrate identification, EM localization","pmids":["33785583"],"is_preprint":false},{"year":2022,"finding":"ADAM10 is mainly responsible for constitutive shedding of IL-2Rα (CD25), generating a soluble decoy receptor that inhibits IL-2 signaling in T cells; mice with CD4-specific deletion of ADAM10 show reduced steady-state soluble IL-2Rα serum levels.","method":"CD4-specific conditional KO, pharmacological inhibition, soluble IL-2Rα ELISA, T cell IL-2 signaling assay","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with in vivo serum readout, pharmacological confirmation, functional IL-2 signaling consequence","pmids":["35398356"],"is_preprint":false},{"year":2022,"finding":"ADAM10 and ADAM17 are degraded via the lysosomal pathway; the lysosomal cysteine protease asparagine endopeptidase (AEP) directly cleaves ADAM10/17, and AEP knockout increases ADAM10/17 levels in the brain.","method":"Lysosomal pathway inhibitors, AEP knockout mouse, Western blot, in vitro cleavage assay","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro cleavage assay plus genetic KO confirmation, single lab","pmids":["33383559"],"is_preprint":false},{"year":2022,"finding":"ADAM10 shedding activity is blocked by phosphatidylserine (PS) interaction inhibition; the phospholipid scramblase Anoctamin-6 (ANO6) traffics PS to the outer membrane to modify ADAM10 function, and ANO6 overexpression increases stimulated shedding of CD137.","method":"PS interaction inhibitor, ANO6 overexpression, sCD137 shedding assay, flow cytometry","journal":"International Journal of Molecular Sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological and overexpression approaches, functional shedding readout, single lab","pmids":["33800462"],"is_preprint":false},{"year":2023,"finding":"MAP4K4 phosphorylates ADAM10 at Ser436, suppressing ADAM10-mediated N-cadherin cleavage, leading to N-cadherin stabilization and enhanced ovarian cancer peritoneal metastasis; MAP4K4 inhibition abrogates peritoneal metastases.","method":"Phosphorylation mutagenesis, Co-IP, in vivo peritoneal metastasis model, Western blot of N-cadherin cleavage","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — phosphosite mutagenesis with substrate cleavage readout and in vivo validation, single lab","pmids":["36922678"],"is_preprint":false},{"year":2023,"finding":"Anti-ADAM10 monoclonal antibody 1H5 binds the substrate-binding cysteine-rich domain of ADAM10 and recognizes an activated ADAM10 conformation on tumor cells; 1H5 inhibits Notch cleavage and colon cancer proliferation in vitro and in mouse models, while paradoxically augmenting ADAM10 catalytic activity toward small peptide substrates.","method":"Structural characterization by antibody binding assays, cell-based Notch cleavage assay, in vivo mouse colon cancer model, in vitro catalytic activity assay","journal":"Biomedicine & Pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structural/functional antibody characterization with in vivo validation, single lab","pmids":["36917886"],"is_preprint":false},{"year":2023,"finding":"Pseudomonas aeruginosa infection activates ADAM10 in epithelial cells via Exotoxin A-induced calcium influx, leading to E-cadherin cleavage, increased permeability, and epithelial integrity loss; ADAM10 is also released in exosomes that mediate proteolytic cleavage in trans.","method":"Pharmacological ADAM10 inhibition, siRNA knockdown, calcium imaging, permeability assay, extracellular vesicle proteolytic activity measurement","journal":"International Journal of Molecular Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic knockdown with functional readouts, mechanistic calcium imaging, single lab","pmids":["35163191"],"is_preprint":false},{"year":2023,"finding":"Endothelial ADAM10 is essential for pathogenesis of S. aureus, P. aeruginosa, and S. pneumoniae sepsis (but not group B streptococci or C. albicans): endothelium-specific ADAM10 knockout mice are protected from lethal sepsis by the first three pathogens, demonstrating a pathogen-selective role of endothelial ADAM10 in microvascular injury and thrombus formation.","method":"Endothelium-specific conditional KO mouse, in vivo infection models with multiple pathogens, survival analysis, histology","journal":"The Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — endothelium-specific conditional KO, multiple pathogens tested, in vivo survival endpoint, rigorous pathogen-selective design","pmids":["37788087"],"is_preprint":false},{"year":2023,"finding":"CRISPR-Cas9 screens in patient-derived xenograft (PDX) leukemia models identified ADAM10 as essential for leukemia survival in vivo; reconstitution assays confirmed the relevance of ADAM10 sheddase activity. Pharmacological ADAM10 targeting reduced PDX leukemia burden, cell homing to bone marrow, and stem cell frequency.","method":"CRISPR-Cas9 in vivo screen, PDX reconstitution assay, pharmacological inhibition, flow cytometry of stem cell frequency","journal":"Molecular Cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo CRISPR screen validated by reconstitution and pharmacological inhibition, multiple leukemia types","pmids":["37422628"],"is_preprint":false},{"year":1999,"finding":"ADAM10 protein is present in the trans-Golgi network and on the plasma membrane in osteoblast-like cells; trans-Golgi network ADAM10 appears in multiple processing forms not seen in the plasma membrane fraction (58 kDa and 56 kDa isoforms), suggesting interdomain processing during trafficking.","method":"Immunofluorescence subcellular localization, subcellular fractionation, Western blot","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct subcellular fractionation and immunofluorescence, consistent localization data","pmids":["10423016"],"is_preprint":false}],"current_model":"ADAM10 is a transmembrane zinc metalloprotease that cleaves the ectodomains of over 100 substrates (including Notch receptors, APP, VE-cadherin, N-cadherin, HB-EGF, ephrin-B2, PrPc, L1-CAM, PD-L1, IL-2Rα, FLT3L, and Trop-2) close to the plasma membrane in a process termed ectodomain shedding; its activity is structurally enabled and substrate-targeted by direct interaction with TspanC8 tetraspanins (Tspan5/10/14/15/17/33), which relieve ADAM10 autoinhibition and position its active site ~20 Å from the membrane, while SAP97/PKC-dependent trafficking governs its delivery to postsynaptic membranes, AP2-mediated endocytosis regulates its synaptic surface levels, and GDE2-mediated inactivation of the GPI-anchored inhibitor RECK controls its α-secretase activity toward APP."},"narrative":{"mechanistic_narrative":"ADAM10 is a transmembrane zinc metalloprotease that executes ectodomain shedding — proteolytic release of the extracellular domains of membrane proteins close to the plasma membrane — controlling processes from neurogenesis and Notch signaling to endothelial barrier function, immunity, and tumor progression [PMID:8703057, PMID:18635581, PMID:37516108]. It is an essential, ligand-induced activator of Notch receptors, performing the S2 cleavage required for canonical NOTCH1, NOTCH2, and NOTCH3 signaling, a role distinct from and not substituted by ADAM17 [PMID:18635581, PMID:24842903]. ADAM10 has a broad substrate repertoire spanning adhesion molecules (VE-cadherin, N-cadherin, E-cadherin, N-/P-cadherin, L1-CAM), growth/survival ligands (HB-EGF, ephrin-B2, FLT3L), immune regulators (PD-L1, IL-2Rα/CD25, CXCL16), the prion protein PrPc, and the tumor antigen Trop-2 [PMID:12119356, PMID:17699774, PMID:18420943, PMID:29058717, PMID:29625583, PMID:31262819, PMID:32363112, PMID:33839455, PMID:33785583, PMID:35398356], with cleavage frequently coupled to downstream γ-secretase processing or signaling outputs such as Wnt and EGFR/Ras/Erk activation [PMID:12119356, PMID:18420943, PMID:33785583]. Its maturation, surface delivery, subcellular targeting, and substrate selectivity are governed by TspanC8 tetraspanins (Tspan5/10/14/15/17/33), which are required for ER exit and enzymatic maturation and which relieve ADAM10 autoinhibition; the cryo-EM structure of the ADAM10–Tspan15 complex shows the tetraspanin acts as a molecular measuring stick positioning the active site ~20 Å from the membrane [PMID:28600292, PMID:28620033, PMID:27256961, PMID:37516108, PMID:31792032]. At epithelial junctions ADAM10 is clustered by a dock-and-lock mechanism involving Tspan33–PDZD11–PLEKHA7 docking and afadin locking, which licenses bacterial α-toxin pore formation [PMID:30463011]. In neurons, SAP97 binds ADAM10 via its SH3 domain and, under PKC phosphorylation control, traffics it from dendritic Golgi outposts to postsynaptic membranes, where NMDA-receptor activity and synaptic plasticity (LTP/LTD, with AP2-mediated endocytosis) tune its α-secretase cleavage of APP [PMID:17301176, PMID:24008925, PMID:25429624]. ADAM10 activity is further set by membrane lipid context (phosphatidylserine exposure via XKR8/ANO6), by the GPI-anchored inhibitor RECK acting downstream of GDE2, by phosphorylation (MAP4K4 at Ser436), and by its own activity-dependent surface maintenance and lysosomal/AEP-mediated turnover [PMID:32372373, PMID:38225245, PMID:33731436, PMID:33383559, PMID:33800462, PMID:36922678]. Dysregulated ADAM10 drives disease: excessive postsynaptic N-cadherin cleavage contributes to Huntington's disease synaptic pathology [PMID:31063986, PMID:33601422], its shedding activity promotes cancer metastasis and leukemia survival [PMID:17699774, PMID:33839455, PMID:37422628], and endothelial ADAM10 is required for lethal sepsis caused by specific bacterial pathogens [PMID:37788087].","teleology":[{"year":1996,"claim":"Established the founding biological role of the ADAM10 ortholog: that a metalloprotease-disintegrin is genetically required for neurogenesis through cell-cell signaling, framing ADAM10 as a regulator of intercellular signal reception rather than a bulk proteolytic enzyme.","evidence":"Drosophila kuzbanian genetic mosaic loss-of-function analysis","pmids":["8703057"],"confidence":"High","gaps":["Did not identify the molecular substrate cleaved","Mechanistic link to Notch not yet biochemically defined"]},{"year":2002,"claim":"Connected ADAM10 to receptor tyrosine kinase signaling by showing it sheds HB-EGF to transactivate EGFR downstream of GPCRs, demonstrating that ectodomain shedding relays signals between receptor systems.","evidence":"Overexpression, protease-domain deletion, antisense knockdown, and CD9 Co-IP in cell models","pmids":["12119356"],"confidence":"Medium","gaps":["Direct cleavage versus regulatory role not fully separated","CD9/tetraspanin requirement not mechanistically resolved"]},{"year":2007,"claim":"Identified the SAP97 SH3-domain interaction as the trafficking mechanism delivering ADAM10 to postsynaptic membranes and coupling NMDA-receptor activity to α-secretase cleavage of APP, defining how ADAM10 is spatially targeted in neurons.","evidence":"Reciprocal Co-IP, cell-permeable interfering peptides, fractionation, NMDA receptor activation","pmids":["17301176"],"confidence":"High","gaps":["Did not define phosphorylation control of the interaction","Endocytic regulation not yet addressed"]},{"year":2008,"claim":"Demonstrated that ADAM10 is the essential S2 sheddase for Notch activation in vivo, placing it genetically epistatic to Notch1 in T cell development and confirming the kuzbanian-Notch link in mammals.","evidence":"Conditional Adam10 knockout in mouse thymocytes with genetic epistasis and downstream target analysis","pmids":["18635581","18535782"],"confidence":"High","gaps":["Whether ADAM10 acts on receptor versus ligand initially ambiguous","Specificity versus ADAM17 not yet dissected"]},{"year":2008,"claim":"Extended ADAM10 substrate scope to endothelial junctions, showing VE-cadherin shedding controls vascular permeability and leukocyte transmigration and feeds into γ-secretase processing.","evidence":"Overexpression, RNAi, inhibitors, permeability and transmigration assays in HUVECs","pmids":["18420943"],"confidence":"High","gaps":["Trafficking/cofactor requirements for endothelial activity not defined","Activation trigger (Ca2+) mechanism not fully resolved"]},{"year":2014,"claim":"Resolved Notch substrate specificity by showing all three canonical Notch receptors strictly depend on ADAM10 (not ADAM17) for ligand-induced S2 cleavage, cementing ADAM10 as the dedicated canonical Notch sheddase.","evidence":"Genetic knockdown/knockout, ADAM inhibitors, Notch reporter assays with ADAM17 negative control","pmids":["24842903"],"confidence":"High","gaps":["Structural basis for receptor selectivity not addressed","Role of tetraspanin cofactors in Notch cleavage not tested here"]},{"year":2014,"claim":"Defined the regulatory logic of synaptic ADAM10 trafficking, showing a PKC phosphorylation site in the SAP97 SH3 domain controls Golgi-outpost-to-synapse delivery and is altered in Alzheimer's disease brain.","evidence":"Phosphosite mutagenesis, Co-IP, live dendritic imaging, AD brain tissue analysis","pmids":["25429624","24008925"],"confidence":"High","gaps":["Direct kinase identity acting in vivo not confirmed","Link between trafficking changes and AD pathogenesis correlative"]},{"year":2017,"claim":"Identified TspanC8 tetraspanins as obligate ADAM10 cofactors required for ER exit, enzymatic maturation, and substrate-selective subcellular targeting, explaining how one protease achieves diverse, location-specific shedding.","evidence":"Reciprocal Co-IP, RNAi knockdown, fractionation, substrate-specific transmigration readouts across multiple TspanC8 members","pmids":["28600292","28620033","27256961"],"confidence":"High","gaps":["Structural mechanism of cofactor action not yet known","How individual TspanC8 members map to specific substrates incompletely defined"]},{"year":2017,"claim":"Established ADAM10 as a therapeutically relevant sheddase in fibrosis by showing TGF-β1-induced ephrin-B2 shedding drives myofibroblast activation and that ADAM10 inhibition prevents lung fibrosis.","evidence":"Inhibitor studies, fibroblast-specific KO, bleomycin fibrosis models, human IPF fibroblasts","pmids":["29058717"],"confidence":"High","gaps":["Direct ephrin-B2 cleavage site not mapped","Cofactor dependence in fibroblasts not addressed"]},{"year":2018,"claim":"Provided the structural mechanism for membrane-proximal cleavage, showing Tspan15 relieves ADAM10 autoinhibition and positions the active site ~20 Å from the membrane as a molecular measuring stick.","evidence":"Cryo-EM of vFab–ADAM10–Tspan15 complex with N-cadherin shedding assays and interface mutagenesis","pmids":["37516108"],"confidence":"High","gaps":["Structures with other TspanC8 members not resolved","How substrate is recruited to the active site not visualized"]},{"year":2018,"claim":"Defined a dock-and-lock junctional clustering mechanism (Tspan33–PDZD11–PLEKHA7 docking, afadin locking) that concentrates ADAM10 at epithelial junctions and is exploited by bacterial α-toxin.","evidence":"Co-IP, pulldowns, live imaging, siRNA, pore-formation assays","pmids":["30463011"],"confidence":"High","gaps":["Whether clustering alters catalytic state not determined","Generality across cell types not established"]},{"year":2018,"claim":"Established ADAM10 as the exclusive nervous-system PrPc sheddase and showed substrate glycosylation and membrane anchorage govern shedding efficiency.","evidence":"Neo-epitope antibody, genetic cell and murine models, pharmacological modulation","pmids":["29625583","19632330"],"confidence":"High","gaps":["Physiological consequence of PrPc shedding in disease incompletely defined","Cleavage site determinants only partly mapped"]},{"year":2019,"claim":"Showed TspanC8 members differentially set ADAM10 surface dynamics — Tspan5 accelerating endocytosis, Tspan15 stabilizing surface ADAM10 — through their cytoplasmic domains, linking cofactor identity to enzyme half-life.","evidence":"Surface biotinylation, endocytosis assays, chimeric tetraspanin constructs, flow cytometry","pmids":["31792032"],"confidence":"Medium","gaps":["Single-lab study","Trafficking adaptors mediating differential effects not identified"]},{"year":2019,"claim":"Demonstrated cell-autonomous ADAM10 shedding of FLT3L controls dendritic cell development, and that ADAM10 hyperactivity drives Huntington's disease synaptic pathology via excess N-cadherin cleavage, extending ADAM10 into immune homeostasis and neurodegeneration.","evidence":"Conditional KOs, BM chimeras, in vitro shedding, competitive TAT-peptide rescue, electrophysiology and behavior in HD mice","pmids":["31262819","31063986"],"confidence":"High","gaps":["Upstream signals raising ADAM10 activity in HD not fully defined","Therapeutic window of ADAM10 modulation untested"]},{"year":2020,"claim":"Expanded the immune and apoptotic substrate repertoire, showing ADAM10 sheds PD-L1, IL-2Rα/CD25, endomucin, and apoptotic-cell mucins, with PS exposure (XKR8/ANO6) acting as a lipid switch activating ADAM10.","evidence":"Inhibitors, siRNA, conditional KOs, genetic knockouts of XKR8, efferocytosis and T cell signaling/killing assays","pmids":["32363112","35398356","32193206","38225245","33800462"],"confidence":"High","gaps":["How PS exposure mechanistically activates the protease not fully resolved","Relative ADAM10/ADAM17 contributions vary by substrate"]},{"year":2020,"claim":"Defined two regulatory layers of ADAM10 turnover: activity-dependent surface maintenance via internalization/lysosomal degradation/EV release, and GDE2-mediated inactivation of the inhibitor RECK that tunes α-secretase APP cleavage relevant to Alzheimer's disease.","evidence":"Inhibitor/LOF mutant analysis with EV isolation, plus epistatic GDE2/RECK genetic rescue with synaptic readouts","pmids":["32372373","33731436"],"confidence":"High","gaps":["Signal linking activity to internalization not identified","How GDE2 sequestration arises in AD unresolved"]},{"year":2021,"claim":"Identified Trop-2 as a direct ADAM10 substrate (cleaved between R87/T88) promoting tumor growth/metastasis and showed ADAM10 hyperactivity disrupts the presynaptic ADAM10–piccolo complex and synaptic vesicle density in Huntington's disease.","evidence":"Co-IP/MS, Edman degradation, siRNA/shRNA, xenograft metastasis; IP-MS, Co-IP, conditional KO rescue, synaptic vesicle EM","pmids":["33839455","33601422"],"confidence":"High","gaps":["Functional role of ADAM10–piccolo interaction beyond correlation unclear","Whether Trop-2 cleavage requires specific TspanC8 cofactors untested"]},{"year":2022,"claim":"Established that ADAM10 is itself proteolytically regulated, with lysosomal asparagine endopeptidase (AEP) directly cleaving ADAM10/17 to control its brain levels.","evidence":"Lysosomal inhibitors, AEP knockout mouse, in vitro cleavage assay","pmids":["33383559"],"confidence":"Medium","gaps":["Single-lab finding","Physiological/disease consequence of AEP-mediated ADAM10 turnover unclear"]},{"year":2023,"claim":"Showed phosphoregulation of substrate selectivity (MAP4K4 phosphorylation at Ser436 suppressing N-cadherin cleavage to drive metastasis) and validated ADAM10 as an essential, druggable dependency in PDX leukemia.","evidence":"Phosphosite mutagenesis, Co-IP, peritoneal metastasis model; in vivo CRISPR screen, PDX reconstitution, pharmacological inhibition","pmids":["36922678","37422628","36917886"],"confidence":"High","gaps":["How Ser436 phosphorylation alters catalysis structurally unknown","On-target therapeutic specificity versus ADAM17 in cancer not fully addressed"]},{"year":2023,"claim":"Defined a pathogen-selective role for endothelial ADAM10 in lethal sepsis and demonstrated infection-triggered, Ca2+-driven E-cadherin cleavage plus exosomal ADAM10 acting in trans, linking ADAM10 to host-pathogen barrier disruption.","evidence":"Endothelium-specific conditional KO with multiple pathogens and survival endpoints; pharmacological/siRNA inhibition with calcium imaging and EV proteolytic assays","pmids":["37788087","35163191"],"confidence":"High","gaps":["Molecular basis of pathogen selectivity not defined","How exosomal ADAM10 retains/regains activity unresolved"]},{"year":null,"claim":"How the dozens of ADAM10 substrates, cofactors, and regulatory inputs are integrated into a unified code that selects which substrate is cleaved where and when remains unresolved.","evidence":"No single study reconstitutes substrate selection across TspanC8 identity, localization, lipid context, and phosphorylation","pmids":[],"confidence":"Low","gaps":["No comprehensive map of TspanC8-member to substrate pairing","Structural basis of substrate recognition beyond Tspan15/N-cadherin unknown","Quantitative rules governing competing-substrate selection in vivo undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,4,5,11,13,15,17,22,26,28,29]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[5,11,15,17,26]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[23,31]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,16,21,37]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[12,37]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[14]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[21,22,34]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[10,19,21]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,5,6,11,20]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,5,11,28]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,20,22,29,23]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[15,21,30]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[18,25,35,36]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[4,16,28,34]}],"complexes":["ADAM10–TspanC8 tetraspanin complex","ADAM10–Tspan33–PDZD11–PLEKHA7–afadin junctional complex","ADAM10–SAP97 complex"],"partners":["TSPAN15","TSPAN5","TSPAN33","SAP97","PLEKHA7","PDZD11","PCLO","RECK"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O14672","full_name":"Disintegrin and metalloproteinase domain-containing protein 10","aliases":["CDw156","Kuzbanian protein homolog","Mammalian disintegrin-metalloprotease"],"length_aa":748,"mass_kda":84.1,"function":"Transmembrane metalloprotease which mediates the ectodomain shedding of a myriad of transmembrane proteins, including adhesion proteins, growth factor precursors and cytokines being essential for development and tissue homeostasis (PubMed:11786905, PubMed:12475894, PubMed:20592283, PubMed:24990881, PubMed:26686862, PubMed:28600292, PubMed:31792032). Associates with six members of the tetraspanin superfamily TspanC8 which regulate its exit from the endoplasmic reticulum and its substrate selectivity (PubMed:26686862, PubMed:28600292, PubMed:31792032, PubMed:34739841, PubMed:37516108). Cleaves the membrane-bound precursor of TNF at '76-Ala-|-Val-77' to its mature soluble form. Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface (PubMed:20592283). Responsible for the proteolytic release of several other cell-surface proteins, including heparin-binding epidermal growth-like factor, ephrin-A2, CD44, CDH2 and for constitutive and regulated alpha-secretase cleavage of amyloid precursor protein (APP) (PubMed:11786905, PubMed:26686862, PubMed:29224781, PubMed:34739841). Contributes to the normal cleavage of the cellular prion protein (PubMed:11477090). Involved in the cleavage of the adhesion molecule L1 at the cell surface and in released membrane vesicles, suggesting a vesicle-based protease activity (PubMed:12475894). Also controls the proteolytic processing of Notch and mediates lateral inhibition during neurogenesis (By similarity). Required for the development of type 1 transitional B cells into marginal zone B cells, probably by cleaving Notch (By similarity). Responsible for the FasL ectodomain shedding and for the generation of the remnant ADAM10-processed FasL (FasL APL) transmembrane form (PubMed:17557115). Also cleaves the ectodomain of the integral membrane proteins CORIN and ITM2B (PubMed:19114711, PubMed:21288900). Mediates the proteolytic cleavage of LAG3, leading to release the secreted form of LAG3 (By similarity). Mediates the proteolytic cleavage of IL6R and IL11RA, leading to the release of secreted forms of IL6R and IL11RA (PubMed:26876177). Enhances the cleavage of CHL1 by BACE1 (By similarity). Cleaves NRCAM (By similarity). Cleaves TREM2, resulting in shedding of the TREM2 ectodomain (PubMed:24990881). Involved in the development and maturation of glomerular and coronary vasculature (By similarity). During development of the cochlear organ of Corti, promotes pillar cell separation by forming a ternary complex with CADH1 and EPHA4 and cleaving CADH1 at adherens junctions (By similarity). May regulate the EFNA5-EPHA3 signaling (PubMed:16239146). Regulates leukocyte transmigration as a sheddase for the adherens junction protein VE-cadherin/CDH5 in endothelial cells (PubMed:28600292) (Microbial infection) Promotes the cytotoxic activity of S.aureus hly by binding to the toxin at zonula adherens and promoting formation of toxin pores","subcellular_location":"Cell membrane; Golgi apparatus membrane; Cytoplasmic vesicle, clathrin-coated vesicle; Cell projection, axon; Cell projection, dendrite; Cell junction, adherens junction; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O14672/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADAM10","classification":"Not Classified","n_dependent_lines":13,"n_total_lines":1208,"dependency_fraction":0.01076158940397351},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ADAM10","total_profiled":1310},"omim":[{"mim_id":"620446","title":"TETRASPANIN 17; TSPAN17","url":"https://www.omim.org/entry/620446"},{"mim_id":"619986","title":"IMMUNODEFICIENCY 107, SUSCEPTIBILITY TO INVASIVE STAPHYLOCOCCUS AUREUS INFECTION; IMD107","url":"https://www.omim.org/entry/619986"},{"mim_id":"617084","title":"TRANSMEMBRANE PROTEIN 59; TMEM59","url":"https://www.omim.org/entry/617084"},{"mim_id":"615712","title":"OTU DEUBIQUITINASE WITH LINEAR LINKAGE SPECIFICITY; OTULIN","url":"https://www.omim.org/entry/615712"},{"mim_id":"615590","title":"ALZHEIMER DISEASE 18; AD18","url":"https://www.omim.org/entry/615590"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ADAM10"},"hgnc":{"alias_symbol":["kuz","MADM","HsT18717","CD156C"],"prev_symbol":[]},"alphafold":{"accession":"O14672","domains":[{"cath_id":"-","chopping":"13-79_99-162","consensus_level":"medium","plddt":81.478,"start":13,"end":162},{"cath_id":"3.40.390.10","chopping":"175-187_218-453","consensus_level":"high","plddt":90.1318,"start":175,"end":453},{"cath_id":"-","chopping":"459-500","consensus_level":"medium","plddt":73.6981,"start":459,"end":500},{"cath_id":"-","chopping":"508-575","consensus_level":"medium","plddt":86.9469,"start":508,"end":575},{"cath_id":"-","chopping":"591-665","consensus_level":"medium","plddt":78.1712,"start":591,"end":665}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O14672","model_url":"https://alphafold.ebi.ac.uk/files/AF-O14672-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O14672-F1-predicted_aligned_error_v6.png","plddt_mean":80.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADAM10","jax_strain_url":"https://www.jax.org/strain/search?query=ADAM10"},"sequence":{"accession":"O14672","fasta_url":"https://rest.uniprot.org/uniprotkb/O14672.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O14672/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O14672"}},"corpus_meta":[{"pmid":"8703057","id":"PMC_8703057","title":"KUZ, 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Its metalloprotease activity is required, and GPCR activation enhances association of ADAM10 and HB-EGF with tetraspanin CD9.\",\n      \"method\": \"Gain-of-function overexpression, protease-domain deletion mutant, morpholino antisense knockdown, Co-IP with CD9\",\n      \"journal\": \"The Journal of Cell Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (dominant-negative, knockdown, Co-IP) in single lab\",\n      \"pmids\": [\"12119356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ADAM10 cleaves the extracellular domain of L1-CAM; ADAM10 is a transcriptional target of beta-catenin-TCF signaling; ADAM10 overexpression in colon cancer cells enhances L1-CAM cleavage and induces liver metastasis in a splenic injection mouse model.\",\n      \"method\": \"Overexpression, in vivo mouse metastasis model, Western blot cleavage assay, DNA microarray\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo functional readout with gain-of-function, single lab\",\n      \"pmids\": [\"17699774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SAP97 directly interacts with ADAM10 via its SH3 domain and drives ADAM10 to the postsynaptic membrane; NMDA receptor activation mediates this trafficking and positively modulates alpha-secretase (ADAM10) activity toward APP. Disruption of the ADAM10/SAP97 interaction by cell-permeable peptides impairs ADAM10 postsynaptic localization and reduces APP alpha-secretase cleavage.\",\n      \"method\": \"Co-IP, cell-permeable peptide interference, subcellular fractionation, NMDA receptor activation assay\",\n      \"journal\": \"The Journal of Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vivo peptide interference, functional consequence on APP processing, replicated in follow-up studies\",\n      \"pmids\": [\"17301176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ADAM10 specifically cleaves the ectodomain of VE-cadherin in endothelial cells, generating a soluble fragment and a C-terminal membrane stub that is subsequently cleaved by gamma-secretase. This cleavage is induced by Ca2+ influx and staurosporine, increases endothelial permeability, and contributes to thrombin-induced loss of cell-cell adhesion. ADAM10 knockdown in HUVECs and T cells impairs T-cell transmigration.\",\n      \"method\": \"Gain-of-function overexpression, RNAi knockdown, inhibitor studies, permeability assays, transmigration assay\",\n      \"journal\": \"Circulation Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (overexpression, RNAi, inhibitors), functional readouts (permeability, transmigration), replicated across conditions\",\n      \"pmids\": [\"18420943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ADAM10 is essential for proteolytic S2 cleavage of the Notch receptor during T cell development: conditional disruption of Adam10 in mouse thymocytes produces a developmental block similar to Notch1 loss, with impaired Notch1 activation and reduced expression of downstream targets Deltex-1 and Pre-Tα.\",\n      \"method\": \"Conditional knockout mouse, genetic epistasis, Western blot, gene expression analysis\",\n      \"journal\": \"International Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined cellular phenotype, epistasis with Notch1 pathway, replicated by multiple labs\",\n      \"pmids\": [\"18635581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Drosophila Kuz (ADAM10 ortholog) regulates Notch signaling primarily by activating the Notch receptor (S2 cleavage) rather than disabling Delta; Kuz overexpression produces ligand-independent Notch activation, whereas the related TACE can efficiently activate Notch in a ligand-independent manner.\",\n      \"method\": \"In vitro Drosophila cell-based Notch signaling assay, overexpression, gain-of-function\",\n      \"journal\": \"Cellular and Molecular Life Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based functional assay, single lab, overexpression approach\",\n      \"pmids\": [\"18535782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Neuronal overexpression of ADAM10 in mice reduces total cellular prion protein (PrPc) levels in brain rather than generating enhanced amounts of specific PrPc cleavage products; moderately ADAM10-overexpressing mice show significantly prolonged incubation time after scrapie infection, indicating ADAM10 modulates PrPc abundance in vivo.\",\n      \"method\": \"Transgenic mouse overexpression, Western blot, scrapie infection survival analysis\",\n      \"journal\": \"Neurobiology of Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic model with defined phenotypic readout, single lab\",\n      \"pmids\": [\"19632330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ADAM10 sheds CXCL16 constitutively in renal tubular cells; IFN-gamma-induced soluble CXCL16 release is blocked by ADAM10 activity inhibition, placing ADAM10 as the sheddase for CXCL16 in the kidney.\",\n      \"method\": \"ADAM10 inhibitor studies in primary tubular cells, Western blot, soluble CXCL16 measurement\",\n      \"journal\": \"Kidney International\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — inhibitor studies in primary cells, consistent with expression co-localization, single lab\",\n      \"pmids\": [\"18480749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Conditional inactivation of ADAM10 in hematopoietic cells causes myeloproliferative disorder with splenomegaly and expanded myeloid progenitor populations. Reciprocal bone marrow transfers show ADAM10 activity is required in both hematopoietic and non-hematopoietic compartments; MPD in non-hematopoietic ADAM10-deficient cells is mediated by G-CSF.\",\n      \"method\": \"Conditional knockout mouse, reciprocal bone marrow transplantation, flow cytometry\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with epistatic reciprocal transfer experiments defining cell-autonomous and non-cell-autonomous roles, rigorous in vivo design\",\n      \"pmids\": [\"22042698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Long-term potentiation (LTP) decreases ADAM10 surface levels and activity by promoting its endocytosis via activity-regulated association with the clathrin adaptor AP2 complex; long-term depression (LTD) promotes ADAM10 membrane insertion and activity. ADAM10 interaction with SAP97 is required for LTD-induced ADAM10 trafficking and LTD maintenance and LTD-induced spine morphology changes.\",\n      \"method\": \"Electrophysiology (LTP/LTD induction), Co-IP, surface biotinylation, synaptic fractionation\",\n      \"journal\": \"Neurodegenerative Diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods plus electrophysiology, single lab, functional consequence on synaptic plasticity\",\n      \"pmids\": [\"24008925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ADAM10 (and presenilin-1/-2 gamma-secretase) are required for canonical ligand-induced NOTCH2 and NOTCH3 proteolytic activation; ADAM17/TACE does not contribute to ligand-induced NOTCH2 or NOTCH3 signaling, establishing that all three canonical Notch receptors (NOTCH1, 2, 3) strictly depend on ADAM10 for S2 cleavage.\",\n      \"method\": \"Genetic knockdown/knockout, ADAM inhibitor studies, Notch reporter assays\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic and pharmacological dissection with multiple Notch receptor substrates and negative control (ADAM17), rigorous mechanistic study\",\n      \"pmids\": [\"24842903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SAP97 governs ADAM10 trafficking from dendritic Golgi outposts to synaptic membranes through a PKC phosphorylation site in the SAP97 SH3 domain that modulates the SAP97-ADAM10 association; this mechanism is altered in Alzheimer's disease brains.\",\n      \"method\": \"Co-IP, phosphorylation mutagenesis, live imaging of dendritic trafficking, subcellular fractionation, AD brain tissue analysis\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis of phosphorylation site combined with Co-IP and live imaging, functional consequence on trafficking, single lab\",\n      \"pmids\": [\"25429624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ADAM10 is the major sheddase of ephrin-B2 in fibroblasts; ADAM10 expression is induced by TGF-β1, and ADAM10-mediated soluble ephrin-B2 generation is required for TGF-β1-induced myofibroblast activation. Fibroblast-specific ephrin-B2 knockout protects mice from skin and lung fibrosis; pharmacological ADAM10 inhibition reduces sEphrin-B2 in BAL and prevents lung fibrosis.\",\n      \"method\": \"ADAM10 inhibitor studies, fibroblast-specific conditional knockout, in vivo fibrosis models (bleomycin), ELISA, Western blot\",\n      \"journal\": \"Nature Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetic KO, pharmacological inhibition, in vivo models), replicated in human IPF fibroblasts\",\n      \"pmids\": [\"29058717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TspanC8 tetraspanins (Tspan5, 10, 14, 15, 17, 33) directly interact with ADAM10, are required for its exit from the endoplasmic reticulum and enzymatic maturation, and differentially direct ADAM10 to distinct subcellular locations with distinct substrate selectivities; Tspan5 and Tspan17 specifically regulate VE-cadherin expression and are required for T lymphocyte transmigration.\",\n      \"method\": \"Co-IP, RNAi knockdown, subcellular fractionation, flow-based transmigration assay\",\n      \"journal\": \"Journal of Immunology / Biochemical Society Transactions / Platelets\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IPs, functional knockdown assays with substrate-specific readouts, replicated across multiple labs and TspanC8 members\",\n      \"pmids\": [\"28600292\", \"28620033\", \"27256961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cryo-EM structure of a vFab-ADAM10-Tspan15 complex shows that Tspan15 binding relieves ADAM10 autoinhibition and positions the enzyme active site ~20 Å from the plasma membrane, functioning as a molecular measuring stick for membrane-proximal substrate cleavage. Cell-based N-cadherin shedding assays confirmed that the ADAM10-Tspan15 interface determines preferred cleavage site selection.\",\n      \"method\": \"Cryo-EM structure determination, cell-based shedding assay (N-cadherin), mutagenesis of interface\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure combined with functional cell-based validation and mutagenesis, rigorous mechanistic study\",\n      \"pmids\": [\"37516108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ADAM10 is clustered at epithelial cell-cell junctions by a dock-and-lock mechanism: Tspan33 docks ADAM10 to junctions by binding PLEKHA7 (via PDZD11), and ADAM10's cytoplasmic C-terminus is locked at junctions through binding afadin. Junctionally clustered ADAM10 supports efficient S. aureus α-toxin pore formation; disruption of the PLEKHA7-PDZD11 complex inhibits ADAM10 junctional clustering and promotes toxin pore removal via actin/macropinocytosis.\",\n      \"method\": \"Co-IP, biochemical pulldown, live imaging, siRNA knockdown, pore-formation assay\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple Co-IP interactions defined, live imaging of clustering, functional pore-formation readout, mechanistically complete\",\n      \"pmids\": [\"30463011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ADAM10 is the exclusive sheddase of PrPc in the nervous system; glycosylation state and type of membrane anchorage of PrPc severely affect its shedding by ADAM10; pharmacological inhibition/stimulation can modulate PrP shedding.\",\n      \"method\": \"Neo-epitope antibody, genetic cell and murine models, biochemical shedding assay, pharmacological modulation\",\n      \"journal\": \"Molecular Neurodegeneration\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic models combined with neo-epitope antibody detection and pharmacological modulation, multiple orthogonal approaches\",\n      \"pmids\": [\"29625583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ADAM10 activity levels are elevated at postsynaptic densities in Huntington's disease mouse cortex and striatum, causing excessive cleavage of N-cadherin (N-CAD). Heterozygous conditional deletion of ADAM10 or competitive TAT-Pro-ADAM10 peptide in R6/2 HD mice reduces N-CAD proteolysis, ameliorates cognitive deficits, and reduces synapse loss.\",\n      \"method\": \"Conditional KO mouse, cell-permeable competitive peptide, electrophysiology, behavioral assays, Western blot of postsynaptic density fractions\",\n      \"journal\": \"The Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic and pharmacological rescue with multiple functional readouts (biochemical, electrophysiological, behavioral), two HD mouse models\",\n      \"pmids\": [\"31063986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TspanC8 tetraspanins differentially regulate ADAM10 endocytosis and half-life: Tspan5 promotes faster ADAM10 endocytosis, while Tspan15 stabilizes ADAM10 at the cell surface (and ADAM10 stabilizes Tspan15 reciprocally). The cytoplasmic domains of these tetraspanins mediate their opposite effects on ADAM10 trafficking.\",\n      \"method\": \"Surface biotinylation, endocytosis assays, chimeric tetraspanin constructs, flow cytometry\",\n      \"journal\": \"Life Science Alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical approaches and chimeric mutants, single lab\",\n      \"pmids\": [\"31792032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cell-autonomous ADAM10 in dendritic cells (cDC2s) mediates shedding of FLT3L from cDC2 surfaces; ADAM10 deletion in DCs reduces serum FLT3L, retains membrane-bound FLT3L on cDC2s, and blocks cDC2 development and survival in spleen. In vitro studies confirmed FLT3L as a direct ADAM10 substrate.\",\n      \"method\": \"Conditional KO (Itgax-cre × Adam10-fl/fl), BM chimera, ex vivo culture supernatant FLT3L measurement, in vitro shedding assay with murine embryonic fibroblasts\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, BM chimera epistasis, in vitro substrate validation, multiple consistent readouts\",\n      \"pmids\": [\"31262819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss of ADAM10 proteolytic activity (by inhibition or loss-of-function mutation) causes removal of mature ADAM10 from the cell surface via increased internalization, lysosomal degradation, and release in extracellular vesicles; recovery requires de novo synthesis. ADAM10 activity is thus required for its own surface maintenance in vitro and in vivo.\",\n      \"method\": \"Inhibitor treatment, loss-of-function mutants, flow cytometry, lysosomal inhibition, extracellular vesicle isolation, in vivo mouse tissue analysis\",\n      \"journal\": \"Cellular and Molecular Life Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple complementary approaches (inhibitor, mutant, in vivo), single lab\",\n      \"pmids\": [\"32372373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ADAM10 and ADAM17 cleave PD-L1 from the surface of tumor cells and extracellular vesicles, generating an active soluble PD-L1 fragment that induces apoptosis in CD8+ T cells and impairs tumor cell killing by CD8+ T cells.\",\n      \"method\": \"ADAM10/17 inhibitor studies, siRNA knockdown, CD8+ T cell killing assays, Western blot of soluble PD-L1\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic inhibition with functional immune readout, single lab\",\n      \"pmids\": [\"32363112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Apoptosis-induced phosphatidylserine (PS) flipping to the outer leaflet (via XKR8 scramblase) activates ADAM10, which sheds a specific subset of transmembrane mucins from apoptotic T cells, reducing the glycocalyx barrier and enhancing macrophage efferocytic uptake.\",\n      \"method\": \"Cell-based shedding assays, genetic knockouts (XKR8, ADAM10), macrophage efferocytosis assay, flow cytometry\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic knockouts, mechanistic link between PS flipping and ADAM10 activation, functional efferocytosis readout\",\n      \"pmids\": [\"38225245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ADAM10 and ADAM17 mediate constitutive and TNF-α-induced shedding of endomucin (EMCN) from endothelial cell surfaces; ADAM10 alone mediates TNF-α-induced C-terminal fragment generation.\",\n      \"method\": \"Adenoviral overexpression, siRNA knockdown, small-molecule inhibitors (GW280264X, GI254023X), Western blot\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA and pharmacological inhibition with substrate-specific Western blot readout, single lab\",\n      \"pmids\": [\"32193206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GDE2 stimulates ADAM10-mediated APP cleavage (alpha-secretase) by shedding and inactivating RECK, a GPI-anchored inhibitor of ADAM10. In Alzheimer's disease, membrane-tethered RECK is highly elevated and GDE2 is abnormally sequestered inside neurons; RECK reduction rescues reduced sAPPα, increased Aβ, and synaptic protein loss caused by GDE2 ablation.\",\n      \"method\": \"Genetic ablation (GDE2, RECK), biochemical shedding assay, rescue experiments, synaptic protein analysis, mouse models\",\n      \"journal\": \"Science Translational Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistatic genetic rescue experiments, multiple KO models, biochemical pathway validation, functional synaptic readout\",\n      \"pmids\": [\"33731436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ADAM10 physically interacts with Trop-2 (co-immunoprecipitation, mass spectrometry) and colocalizes at the cell membrane; ADAM10 cleaves Trop-2 between R87 and T88 in its extracellular thyroglobulin domain, activating cancer cell growth and metastasis.\",\n      \"method\": \"Co-IP, mass spectrometry, N-terminal Edman degradation, ADAM10 siRNA/shRNA, in vivo xenograft metastasis assay\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — substrate identification by Edman degradation and mutagenesis, Co-IP interaction, in vivo functional validation\",\n      \"pmids\": [\"33839455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ADAM10 hyperactivity in Huntington's disease brain co-immunoprecipitates with piccolo (PCLO), a presynaptic scaffolding protein; reduced ADAM10/PCLO interaction in HD brain is associated with depleted synaptic vesicle density. Conditional heterozygous ADAM10 deletion in HD mice normalizes ADAM10/PCLO complex formation and synaptic vesicle density.\",\n      \"method\": \"Immunoaffinity purification-mass spectrometry (IP-MS), Co-IP, conditional KO mouse, electron microscopy of synaptic vesicles\",\n      \"journal\": \"Human Molecular Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — IP-MS plus Co-IP plus genetic rescue with EM ultrastructural readout, two complementary approaches\",\n      \"pmids\": [\"33601422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ADAM10 mediates antibody-induced podocyte injury by cleaving N- and P-cadherin ectodomains, decreasing their injury-related surface levels and activating downstream Wnt signaling; podocyte-specific ADAM10-deficient mice are protected from anti-podocyte nephritis.\",\n      \"method\": \"Podocyte-specific conditional KO, membrane proteomics, immunogold EM, anti-podocyte nephritis in vivo model, Western blot\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — podocyte-specific conditional KO with in vivo nephritis model, proteomics substrate identification, EM localization\",\n      \"pmids\": [\"33785583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ADAM10 is mainly responsible for constitutive shedding of IL-2Rα (CD25), generating a soluble decoy receptor that inhibits IL-2 signaling in T cells; mice with CD4-specific deletion of ADAM10 show reduced steady-state soluble IL-2Rα serum levels.\",\n      \"method\": \"CD4-specific conditional KO, pharmacological inhibition, soluble IL-2Rα ELISA, T cell IL-2 signaling assay\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with in vivo serum readout, pharmacological confirmation, functional IL-2 signaling consequence\",\n      \"pmids\": [\"35398356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ADAM10 and ADAM17 are degraded via the lysosomal pathway; the lysosomal cysteine protease asparagine endopeptidase (AEP) directly cleaves ADAM10/17, and AEP knockout increases ADAM10/17 levels in the brain.\",\n      \"method\": \"Lysosomal pathway inhibitors, AEP knockout mouse, Western blot, in vitro cleavage assay\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro cleavage assay plus genetic KO confirmation, single lab\",\n      \"pmids\": [\"33383559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ADAM10 shedding activity is blocked by phosphatidylserine (PS) interaction inhibition; the phospholipid scramblase Anoctamin-6 (ANO6) traffics PS to the outer membrane to modify ADAM10 function, and ANO6 overexpression increases stimulated shedding of CD137.\",\n      \"method\": \"PS interaction inhibitor, ANO6 overexpression, sCD137 shedding assay, flow cytometry\",\n      \"journal\": \"International Journal of Molecular Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological and overexpression approaches, functional shedding readout, single lab\",\n      \"pmids\": [\"33800462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MAP4K4 phosphorylates ADAM10 at Ser436, suppressing ADAM10-mediated N-cadherin cleavage, leading to N-cadherin stabilization and enhanced ovarian cancer peritoneal metastasis; MAP4K4 inhibition abrogates peritoneal metastases.\",\n      \"method\": \"Phosphorylation mutagenesis, Co-IP, in vivo peritoneal metastasis model, Western blot of N-cadherin cleavage\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — phosphosite mutagenesis with substrate cleavage readout and in vivo validation, single lab\",\n      \"pmids\": [\"36922678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Anti-ADAM10 monoclonal antibody 1H5 binds the substrate-binding cysteine-rich domain of ADAM10 and recognizes an activated ADAM10 conformation on tumor cells; 1H5 inhibits Notch cleavage and colon cancer proliferation in vitro and in mouse models, while paradoxically augmenting ADAM10 catalytic activity toward small peptide substrates.\",\n      \"method\": \"Structural characterization by antibody binding assays, cell-based Notch cleavage assay, in vivo mouse colon cancer model, in vitro catalytic activity assay\",\n      \"journal\": \"Biomedicine & Pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structural/functional antibody characterization with in vivo validation, single lab\",\n      \"pmids\": [\"36917886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Pseudomonas aeruginosa infection activates ADAM10 in epithelial cells via Exotoxin A-induced calcium influx, leading to E-cadherin cleavage, increased permeability, and epithelial integrity loss; ADAM10 is also released in exosomes that mediate proteolytic cleavage in trans.\",\n      \"method\": \"Pharmacological ADAM10 inhibition, siRNA knockdown, calcium imaging, permeability assay, extracellular vesicle proteolytic activity measurement\",\n      \"journal\": \"International Journal of Molecular Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic knockdown with functional readouts, mechanistic calcium imaging, single lab\",\n      \"pmids\": [\"35163191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Endothelial ADAM10 is essential for pathogenesis of S. aureus, P. aeruginosa, and S. pneumoniae sepsis (but not group B streptococci or C. albicans): endothelium-specific ADAM10 knockout mice are protected from lethal sepsis by the first three pathogens, demonstrating a pathogen-selective role of endothelial ADAM10 in microvascular injury and thrombus formation.\",\n      \"method\": \"Endothelium-specific conditional KO mouse, in vivo infection models with multiple pathogens, survival analysis, histology\",\n      \"journal\": \"The Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — endothelium-specific conditional KO, multiple pathogens tested, in vivo survival endpoint, rigorous pathogen-selective design\",\n      \"pmids\": [\"37788087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CRISPR-Cas9 screens in patient-derived xenograft (PDX) leukemia models identified ADAM10 as essential for leukemia survival in vivo; reconstitution assays confirmed the relevance of ADAM10 sheddase activity. Pharmacological ADAM10 targeting reduced PDX leukemia burden, cell homing to bone marrow, and stem cell frequency.\",\n      \"method\": \"CRISPR-Cas9 in vivo screen, PDX reconstitution assay, pharmacological inhibition, flow cytometry of stem cell frequency\",\n      \"journal\": \"Molecular Cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo CRISPR screen validated by reconstitution and pharmacological inhibition, multiple leukemia types\",\n      \"pmids\": [\"37422628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"ADAM10 protein is present in the trans-Golgi network and on the plasma membrane in osteoblast-like cells; trans-Golgi network ADAM10 appears in multiple processing forms not seen in the plasma membrane fraction (58 kDa and 56 kDa isoforms), suggesting interdomain processing during trafficking.\",\n      \"method\": \"Immunofluorescence subcellular localization, subcellular fractionation, Western blot\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct subcellular fractionation and immunofluorescence, consistent localization data\",\n      \"pmids\": [\"10423016\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADAM10 is a transmembrane zinc metalloprotease that cleaves the ectodomains of over 100 substrates (including Notch receptors, APP, VE-cadherin, N-cadherin, HB-EGF, ephrin-B2, PrPc, L1-CAM, PD-L1, IL-2Rα, FLT3L, and Trop-2) close to the plasma membrane in a process termed ectodomain shedding; its activity is structurally enabled and substrate-targeted by direct interaction with TspanC8 tetraspanins (Tspan5/10/14/15/17/33), which relieve ADAM10 autoinhibition and position its active site ~20 Å from the membrane, while SAP97/PKC-dependent trafficking governs its delivery to postsynaptic membranes, AP2-mediated endocytosis regulates its synaptic surface levels, and GDE2-mediated inactivation of the GPI-anchored inhibitor RECK controls its α-secretase activity toward APP.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ADAM10 is a transmembrane zinc metalloprotease that executes ectodomain shedding — proteolytic release of the extracellular domains of membrane proteins close to the plasma membrane — controlling processes from neurogenesis and Notch signaling to endothelial barrier function, immunity, and tumor progression [#0, #5, #15]. It is an essential, ligand-induced activator of Notch receptors, performing the S2 cleavage required for canonical NOTCH1, NOTCH2, and NOTCH3 signaling, a role distinct from and not substituted by ADAM17 [#5, #11]. ADAM10 has a broad substrate repertoire spanning adhesion molecules (VE-cadherin, N-cadherin, E-cadherin, N-/P-cadherin, L1-CAM), growth/survival ligands (HB-EGF, ephrin-B2, FLT3L), immune regulators (PD-L1, IL-2Rα/CD25, CXCL16), the prion protein PrPc, and the tumor antigen Trop-2 [#1, #2, #4, #13, #17, #20, #22, #26, #28, #29], with cleavage frequently coupled to downstream γ-secretase processing or signaling outputs such as Wnt and EGFR/Ras/Erk activation [#1, #4, #28]. Its maturation, surface delivery, subcellular targeting, and substrate selectivity are governed by TspanC8 tetraspanins (Tspan5/10/14/15/17/33), which are required for ER exit and enzymatic maturation and which relieve ADAM10 autoinhibition; the cryo-EM structure of the ADAM10–Tspan15 complex shows the tetraspanin acts as a molecular measuring stick positioning the active site ~20 Å from the membrane [#14, #15, #19]. At epithelial junctions ADAM10 is clustered by a dock-and-lock mechanism involving Tspan33–PDZD11–PLEKHA7 docking and afadin locking, which licenses bacterial α-toxin pore formation [#16]. In neurons, SAP97 binds ADAM10 via its SH3 domain and, under PKC phosphorylation control, traffics it from dendritic Golgi outposts to postsynaptic membranes, where NMDA-receptor activity and synaptic plasticity (LTP/LTD, with AP2-mediated endocytosis) tune its α-secretase cleavage of APP [#3, #10, #12]. ADAM10 activity is further set by membrane lipid context (phosphatidylserine exposure via XKR8/ANO6), by the GPI-anchored inhibitor RECK acting downstream of GDE2, by phosphorylation (MAP4K4 at Ser436), and by its own activity-dependent surface maintenance and lysosomal/AEP-mediated turnover [#21, #23, #25, #30, #31, #32]. Dysregulated ADAM10 drives disease: excessive postsynaptic N-cadherin cleavage contributes to Huntington's disease synaptic pathology [#18, #27], its shedding activity promotes cancer metastasis and leukemia survival [#2, #26, #36], and endothelial ADAM10 is required for lethal sepsis caused by specific bacterial pathogens [#35].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established the founding biological role of the ADAM10 ortholog: that a metalloprotease-disintegrin is genetically required for neurogenesis through cell-cell signaling, framing ADAM10 as a regulator of intercellular signal reception rather than a bulk proteolytic enzyme.\",\n      \"evidence\": \"Drosophila kuzbanian genetic mosaic loss-of-function analysis\",\n      \"pmids\": [\"8703057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the molecular substrate cleaved\", \"Mechanistic link to Notch not yet biochemically defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Connected ADAM10 to receptor tyrosine kinase signaling by showing it sheds HB-EGF to transactivate EGFR downstream of GPCRs, demonstrating that ectodomain shedding relays signals between receptor systems.\",\n      \"evidence\": \"Overexpression, protease-domain deletion, antisense knockdown, and CD9 Co-IP in cell models\",\n      \"pmids\": [\"12119356\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct cleavage versus regulatory role not fully separated\", \"CD9/tetraspanin requirement not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified the SAP97 SH3-domain interaction as the trafficking mechanism delivering ADAM10 to postsynaptic membranes and coupling NMDA-receptor activity to α-secretase cleavage of APP, defining how ADAM10 is spatially targeted in neurons.\",\n      \"evidence\": \"Reciprocal Co-IP, cell-permeable interfering peptides, fractionation, NMDA receptor activation\",\n      \"pmids\": [\"17301176\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define phosphorylation control of the interaction\", \"Endocytic regulation not yet addressed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated that ADAM10 is the essential S2 sheddase for Notch activation in vivo, placing it genetically epistatic to Notch1 in T cell development and confirming the kuzbanian-Notch link in mammals.\",\n      \"evidence\": \"Conditional Adam10 knockout in mouse thymocytes with genetic epistasis and downstream target analysis\",\n      \"pmids\": [\"18635581\", \"18535782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ADAM10 acts on receptor versus ligand initially ambiguous\", \"Specificity versus ADAM17 not yet dissected\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended ADAM10 substrate scope to endothelial junctions, showing VE-cadherin shedding controls vascular permeability and leukocyte transmigration and feeds into γ-secretase processing.\",\n      \"evidence\": \"Overexpression, RNAi, inhibitors, permeability and transmigration assays in HUVECs\",\n      \"pmids\": [\"18420943\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trafficking/cofactor requirements for endothelial activity not defined\", \"Activation trigger (Ca2+) mechanism not fully resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved Notch substrate specificity by showing all three canonical Notch receptors strictly depend on ADAM10 (not ADAM17) for ligand-induced S2 cleavage, cementing ADAM10 as the dedicated canonical Notch sheddase.\",\n      \"evidence\": \"Genetic knockdown/knockout, ADAM inhibitors, Notch reporter assays with ADAM17 negative control\",\n      \"pmids\": [\"24842903\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for receptor selectivity not addressed\", \"Role of tetraspanin cofactors in Notch cleavage not tested here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the regulatory logic of synaptic ADAM10 trafficking, showing a PKC phosphorylation site in the SAP97 SH3 domain controls Golgi-outpost-to-synapse delivery and is altered in Alzheimer's disease brain.\",\n      \"evidence\": \"Phosphosite mutagenesis, Co-IP, live dendritic imaging, AD brain tissue analysis\",\n      \"pmids\": [\"25429624\", \"24008925\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct kinase identity acting in vivo not confirmed\", \"Link between trafficking changes and AD pathogenesis correlative\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified TspanC8 tetraspanins as obligate ADAM10 cofactors required for ER exit, enzymatic maturation, and substrate-selective subcellular targeting, explaining how one protease achieves diverse, location-specific shedding.\",\n      \"evidence\": \"Reciprocal Co-IP, RNAi knockdown, fractionation, substrate-specific transmigration readouts across multiple TspanC8 members\",\n      \"pmids\": [\"28600292\", \"28620033\", \"27256961\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural mechanism of cofactor action not yet known\", \"How individual TspanC8 members map to specific substrates incompletely defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established ADAM10 as a therapeutically relevant sheddase in fibrosis by showing TGF-β1-induced ephrin-B2 shedding drives myofibroblast activation and that ADAM10 inhibition prevents lung fibrosis.\",\n      \"evidence\": \"Inhibitor studies, fibroblast-specific KO, bleomycin fibrosis models, human IPF fibroblasts\",\n      \"pmids\": [\"29058717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ephrin-B2 cleavage site not mapped\", \"Cofactor dependence in fibroblasts not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided the structural mechanism for membrane-proximal cleavage, showing Tspan15 relieves ADAM10 autoinhibition and positions the active site ~20 Å from the membrane as a molecular measuring stick.\",\n      \"evidence\": \"Cryo-EM of vFab–ADAM10–Tspan15 complex with N-cadherin shedding assays and interface mutagenesis\",\n      \"pmids\": [\"37516108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures with other TspanC8 members not resolved\", \"How substrate is recruited to the active site not visualized\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a dock-and-lock junctional clustering mechanism (Tspan33–PDZD11–PLEKHA7 docking, afadin locking) that concentrates ADAM10 at epithelial junctions and is exploited by bacterial α-toxin.\",\n      \"evidence\": \"Co-IP, pulldowns, live imaging, siRNA, pore-formation assays\",\n      \"pmids\": [\"30463011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether clustering alters catalytic state not determined\", \"Generality across cell types not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established ADAM10 as the exclusive nervous-system PrPc sheddase and showed substrate glycosylation and membrane anchorage govern shedding efficiency.\",\n      \"evidence\": \"Neo-epitope antibody, genetic cell and murine models, pharmacological modulation\",\n      \"pmids\": [\"29625583\", \"19632330\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological consequence of PrPc shedding in disease incompletely defined\", \"Cleavage site determinants only partly mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed TspanC8 members differentially set ADAM10 surface dynamics — Tspan5 accelerating endocytosis, Tspan15 stabilizing surface ADAM10 — through their cytoplasmic domains, linking cofactor identity to enzyme half-life.\",\n      \"evidence\": \"Surface biotinylation, endocytosis assays, chimeric tetraspanin constructs, flow cytometry\",\n      \"pmids\": [\"31792032\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Trafficking adaptors mediating differential effects not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated cell-autonomous ADAM10 shedding of FLT3L controls dendritic cell development, and that ADAM10 hyperactivity drives Huntington's disease synaptic pathology via excess N-cadherin cleavage, extending ADAM10 into immune homeostasis and neurodegeneration.\",\n      \"evidence\": \"Conditional KOs, BM chimeras, in vitro shedding, competitive TAT-peptide rescue, electrophysiology and behavior in HD mice\",\n      \"pmids\": [\"31262819\", \"31063986\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals raising ADAM10 activity in HD not fully defined\", \"Therapeutic window of ADAM10 modulation untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Expanded the immune and apoptotic substrate repertoire, showing ADAM10 sheds PD-L1, IL-2Rα/CD25, endomucin, and apoptotic-cell mucins, with PS exposure (XKR8/ANO6) acting as a lipid switch activating ADAM10.\",\n      \"evidence\": \"Inhibitors, siRNA, conditional KOs, genetic knockouts of XKR8, efferocytosis and T cell signaling/killing assays\",\n      \"pmids\": [\"32363112\", \"35398356\", \"32193206\", \"38225245\", \"33800462\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PS exposure mechanistically activates the protease not fully resolved\", \"Relative ADAM10/ADAM17 contributions vary by substrate\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined two regulatory layers of ADAM10 turnover: activity-dependent surface maintenance via internalization/lysosomal degradation/EV release, and GDE2-mediated inactivation of the inhibitor RECK that tunes α-secretase APP cleavage relevant to Alzheimer's disease.\",\n      \"evidence\": \"Inhibitor/LOF mutant analysis with EV isolation, plus epistatic GDE2/RECK genetic rescue with synaptic readouts\",\n      \"pmids\": [\"32372373\", \"33731436\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal linking activity to internalization not identified\", \"How GDE2 sequestration arises in AD unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified Trop-2 as a direct ADAM10 substrate (cleaved between R87/T88) promoting tumor growth/metastasis and showed ADAM10 hyperactivity disrupts the presynaptic ADAM10–piccolo complex and synaptic vesicle density in Huntington's disease.\",\n      \"evidence\": \"Co-IP/MS, Edman degradation, siRNA/shRNA, xenograft metastasis; IP-MS, Co-IP, conditional KO rescue, synaptic vesicle EM\",\n      \"pmids\": [\"33839455\", \"33601422\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of ADAM10–piccolo interaction beyond correlation unclear\", \"Whether Trop-2 cleavage requires specific TspanC8 cofactors untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established that ADAM10 is itself proteolytically regulated, with lysosomal asparagine endopeptidase (AEP) directly cleaving ADAM10/17 to control its brain levels.\",\n      \"evidence\": \"Lysosomal inhibitors, AEP knockout mouse, in vitro cleavage assay\",\n      \"pmids\": [\"33383559\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding\", \"Physiological/disease consequence of AEP-mediated ADAM10 turnover unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed phosphoregulation of substrate selectivity (MAP4K4 phosphorylation at Ser436 suppressing N-cadherin cleavage to drive metastasis) and validated ADAM10 as an essential, druggable dependency in PDX leukemia.\",\n      \"evidence\": \"Phosphosite mutagenesis, Co-IP, peritoneal metastasis model; in vivo CRISPR screen, PDX reconstitution, pharmacological inhibition\",\n      \"pmids\": [\"36922678\", \"37422628\", \"36917886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Ser436 phosphorylation alters catalysis structurally unknown\", \"On-target therapeutic specificity versus ADAM17 in cancer not fully addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a pathogen-selective role for endothelial ADAM10 in lethal sepsis and demonstrated infection-triggered, Ca2+-driven E-cadherin cleavage plus exosomal ADAM10 acting in trans, linking ADAM10 to host-pathogen barrier disruption.\",\n      \"evidence\": \"Endothelium-specific conditional KO with multiple pathogens and survival endpoints; pharmacological/siRNA inhibition with calcium imaging and EV proteolytic assays\",\n      \"pmids\": [\"37788087\", \"35163191\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of pathogen selectivity not defined\", \"How exosomal ADAM10 retains/regains activity unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the dozens of ADAM10 substrates, cofactors, and regulatory inputs are integrated into a unified code that selects which substrate is cleaved where and when remains unresolved.\",\n      \"evidence\": \"No single study reconstitutes substrate selection across TspanC8 identity, localization, lipid context, and phosphorylation\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No comprehensive map of TspanC8-member to substrate pairing\", \"Structural basis of substrate recognition beyond Tspan15/N-cadherin unknown\", \"Quantitative rules governing competing-substrate selection in vivo undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 4, 5, 11, 13, 15, 17, 22, 26, 28, 29]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [5, 11, 15, 17, 26]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [23, 31]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 16, 21, 37]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [12, 37]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [21, 22, 34]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [10, 19, 21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 5, 6, 11, 20]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 5, 11, 28]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 20, 22, 29, 23]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [15, 21, 30]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [18, 25, 35, 36]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [4, 16, 28, 34]}\n    ],\n    \"complexes\": [\n      \"ADAM10–TspanC8 tetraspanin complex\",\n      \"ADAM10–Tspan33–PDZD11–PLEKHA7–afadin junctional complex\",\n      \"ADAM10–SAP97 complex\"\n    ],\n    \"partners\": [\n      \"TSPAN15\",\n      \"TSPAN5\",\n      \"TSPAN33\",\n      \"SAP97\",\n      \"PLEKHA7\",\n      \"PDZD11\",\n      \"PCLO\",\n      \"RECK\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}