Affinage

ADAM10

Disintegrin and metalloproteinase domain-containing protein 10 · UniProt O14672

Length
748 aa
Mass
84.1 kDa
Annotated
2026-04-28
100 papers in source corpus 38 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ADAM10 is a transmembrane zinc metalloprotease (sheddase) that cleaves the ectodomains of a broad repertoire of substrates — including Notch receptors, APP, VE-cadherin, N-cadherin, L1-CAM, CX3CL1, ephrin-B2, FLT3L, IL-2Rα, Trop-2, prion protein, and RELT — thereby governing neural development, synaptic plasticity, vascular permeability, immune cell homeostasis, and fibrosis (PMID:8703057, PMID:20371803, PMID:18420943, PMID:29058717, PMID:31262819, PMID:35398356). Its catalytic competence and substrate selectivity depend on association with TspanC8 tetraspanins (Tspan5, Tspan14, Tspan15, Tspan33): cryo-EM reveals that Tspan15 binding relieves ADAM10 autoinhibition and positions the active site ~20 Å from the membrane, while different TspanC8 partners compartmentalize ADAM10 into distinct membrane microdomains that favor different substrates (PMID:37516108, PMID:26686862, PMID:31792032). ADAM10 surface availability is controlled by dynamin-dependent endocytosis, clathrin adaptor AP2-mediated internalization during LTP, SAP97/PKC-regulated postsynaptic delivery, and an activity-dependent self-stabilization mechanism whereby catalytically inactive ADAM10 is internalized and degraded (PMID:21586144, PMID:24008925, PMID:17301176, PMID:25429624, PMID:32372373). Activation additionally requires outer-leaflet phosphatidylserine exposure sensed through a stalk-region PS-binding motif, and ADAM10 activity is negatively regulated by the GPI-anchored inhibitor RECK and by MAP4K4 phosphorylation at Ser436 (PMID:30753537, PMID:33731436, PMID:36922678).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1996 High

    Establishing that the ADAM10 ortholog Kuzbanian is genetically required upstream of Notch signaling during neurogenesis placed this metalloprotease at the heart of a conserved cell-fate decision pathway.

    Evidence Genetic mosaic analysis of Kuzbanian in Drosophila neurogenesis

    PMID:8703057

    Open questions at the time
    • Mammalian requirement not yet shown
    • Biochemical substrate (Notch ectodomain) not directly demonstrated
    • Whether ADAM10 acts on multiple Notch family members unknown
  2. 1998 Medium

    Demonstration that purified ADAM10 cleaves type IV collagen established it as a bona fide extracellular protease with matrix-degrading capacity, though the physiological relevance of this activity remained unclear.

    Evidence In vitro enzymatic assay with purified bovine ADAM10

    PMID:9571200

    Open questions at the time
    • In vivo collagenolytic role not confirmed
    • No cellular context for ECM cleavage
    • Substrate specificity determinants unknown
  3. 2002 High

    Discovery that ADAM10 cleaves pro-HB-EGF downstream of GPCR stimulation to transactivate EGFR revealed a receptor-crosstalk mechanism and identified the first growth-factor-linked substrate, with tetraspanin CD9 as an associated partner.

    Evidence Dominant-negative overexpression, knockdown, co-IP with CD9, and downstream Ras/Erk signaling assays in mammalian cells

    PMID:11786905 PMID:12119356

    Open questions at the time
    • Nature of CD9–ADAM10 interaction (direct vs. indirect) unresolved
    • How GPCR stimulation activates ADAM10 catalytically not defined
  4. 2007 High

    Identification of SAP97 as a direct trafficking partner that delivers ADAM10 to postsynaptic membranes via its SH3 domain, regulated by NMDA receptor activation, established the first mechanism for spatially controlling ADAM10-dependent APP α-secretase processing at synapses.

    Evidence Reciprocal co-IP, cell-permeable peptide disruption of SAP97–ADAM10 in vivo, subcellular fractionation, APP cleavage assays

    PMID:17301176

    Open questions at the time
    • Structural basis of SAP97–ADAM10 interaction not resolved
    • Whether SAP97 controls ADAM10 trafficking to non-neuronal substrates unknown
  5. 2008 High

    Demonstrating ADAM10-mediated VE-cadherin ectodomain shedding with subsequent γ-secretase cleavage linked ADAM10 to vascular permeability and leukocyte transmigration, expanding its role beyond neural substrates.

    Evidence RNAi, overexpression, pharmacological inhibition, endothelial permeability and T-cell transmigration assays in HUVECs

    PMID:18420943

    Open questions at the time
    • In vivo vascular phenotype of ADAM10 loss not yet shown
    • Stimulus-specific activation mechanism (Ca²⁺ dependency) not molecularly defined
  6. 2010 High

    Conditional neural knockout confirmed ADAM10 as the principal neuronal APP α-secretase and essential Notch-1 processor in vivo, with loss causing precocious differentiation, progenitor depletion, and laminar disorganization.

    Evidence Nestin-Cre conditional knockout in mice, neurosphere assays, gene expression profiling

    PMID:20371803

    Open questions at the time
    • Whether ADAM10 is the sole Notch activator in non-neural tissues unknown
    • Redundancy with ADAM17 not fully delineated
  7. 2011 Medium

    Showing that dynamin-dependent endocytosis limits ADAM10 surface residence and that LTP/LTD bidirectionally control ADAM10 trafficking (via AP2-mediated internalization and SAP97-dependent insertion, respectively) established synaptic activity as a key regulator of sheddase availability.

    Evidence Dominant-negative dynamin, surface biotinylation, co-IP of ADAM10–AP2, synaptic plasticity protocols, spine morphology analysis

    PMID:21586144 PMID:24008925

    Open questions at the time
    • Specific phosphorylation events linking synaptic stimulation to AP2 recruitment unresolved
    • Relative contributions of endocytosis vs. exocytosis to net surface ADAM10 not quantified
  8. 2014 High

    Extension of ADAM10's Notch-processing role to Notch2 and Notch3 — with ADAM17 excluded from ligand-induced activation — and demonstration that PKC phosphorylation of SAP97 modulates ADAM10 synaptic delivery refined the selectivity and regulatory logic of ADAM10 in Notch biology and synaptic trafficking.

    Evidence Knockdown/inhibitor epistasis with Notch reporters; PKC site mutagenesis with co-IP and live imaging

    PMID:24842903 PMID:25429624

    Open questions at the time
    • Whether ADAM10 processes Notch4 remains untested
    • How PKC integrates with NMDA signaling at SAP97 not defined
  9. 2015 High

    Discovery that TspanC8 tetraspanins (Tspan5, Tspan14, Tspan15, Tspan33) regulate ADAM10 surface expression and differentially steer substrate selectivity through compartmentalization into distinct membrane microdomains introduced the concept of tetraspanin-guided substrate specificity.

    Evidence Sucrose gradient fractionation, single-molecule tracking, quantitative mass spectrometry co-IP, substrate cleavage assays

    PMID:26686862

    Open questions at the time
    • Structural basis of TspanC8 selectivity unknown
    • How cells regulate TspanC8 expression to tune ADAM10 substrate choice not addressed
  10. 2017 High

    Identifying ephrin-B2 as a fibroblast ADAM10 substrate whose TGFβ1-induced shedding drives myofibroblast activation and organ fibrosis extended ADAM10's physiological reach to tissue remodeling and fibrotic disease.

    Evidence Fibroblast-specific conditional knockout, pharmacological inhibition, in vivo fibrosis models, human tissue validation

    PMID:29058717

    Open questions at the time
    • Other ADAM10 substrates contributing to fibrosis not catalogued
    • Whether ADAM10 inhibition reverses established fibrosis not tested
  11. 2018 High

    Two discoveries — that ADAM10 undergoes rapid autoproteolytic degradation upon lysis (masking its true abundance) and is the exclusive nervous-system PrPC sheddase — clarified ADAM10 biochemistry and its role in prion biology.

    Evidence Cycloheximide chase with active-site inhibitors across multiple cell types; conditional KO mice with neo-epitope PrPC antibodies

    PMID:29430990 PMID:29625583

    Open questions at the time
    • Autoproteolysis mechanism (cis vs. trans) not determined
    • Whether PrPC shedding is TspanC8-dependent not tested
  12. 2019 High

    A suite of studies established that ADAM10 activation requires outer-leaflet phosphatidylserine exposure (sensed via a stalk-region PS-binding motif), that catalytic activity stabilizes ADAM10 at the cell surface (inactive enzyme is internalized and degraded), and that CX3CL1 shedding by neuronal ADAM10 drives microglia-mediated synapse elimination.

    Evidence PS scramblase overexpression/KO (Scott syndrome cells), PS-binding motif mutagenesis; pharmacological/mutational inhibition with internalization assays and EV isolation; conditional KO and ADAM10 inhibition with in vivo synapse counting after whisker lesioning

    PMID:30753537 PMID:31209379 PMID:32372373

    Open questions at the time
    • How PS exposure is spatially coordinated with ADAM10 at the membrane not resolved
    • Structural basis of the activity-dependent self-stabilization loop unknown
    • Whether PS regulation applies to all ADAM10 substrates not tested
  13. 2019 High

    Identification of FLT3L and IL-2Rα as in vivo ADAM10 substrates on dendritic cells and T cells, respectively, positioned ADAM10 as a central regulator of immune cytokine/receptor availability.

    Evidence Itgax-Cre and CD4-Cre conditional KOs, serum cytokine/receptor measurements, MEF reconstitution substrate assays, T cell IL-2 signaling

    PMID:31262819 PMID:35398356

    Open questions at the time
    • Full immune degradome of ADAM10 not mapped
    • Whether TspanC8 partners determine immune substrate selection unknown
  14. 2019 High

    Characterization of Tspan5 vs. Tspan15 as having opposing effects on ADAM10 endocytosis (Tspan5 accelerates; Tspan15 stabilizes), mediated by their cytoplasmic tails, explained how TspanC8 identity tunes ADAM10 surface dynamics and Notch signaling output.

    Evidence Chimeric tetraspanin domain-swap constructs, endocytosis kinetics, Notch reporter assays

    PMID:31792032

    Open questions at the time
    • Which endocytic adaptors are recruited by Tspan5 cytoplasmic tail not identified
    • In vivo validation of differential trafficking effects lacking
  15. 2020 High

    Fusion protein and KO reconstitution experiments confirmed ADAM10 and Tspan15 form a catalytically active 'scissor complex' with mutual stabilization, solidifying the obligate partnership model.

    Evidence Reciprocal co-IP, ADAM10-KO cell reconstitution, ADAM10–Tspan15 fusion protein N-cadherin cleavage assays

    PMID:32111735

    Open questions at the time
    • Stoichiometry of the complex in native membranes unresolved
    • Whether all TspanC8–ADAM10 pairs are equally obligate not tested
  16. 2021 High

    Structural and upstream-regulatory insights converged: the Tspan15 LEL crystal structure identified the ADAM10-binding interface, GDE2–RECK epistasis defined a new layer of ADAM10 regulation relevant to Alzheimer's disease, and excessive ADAM10 activity at postsynaptic densities was causally linked to N-cadherin loss and cognitive decline in Huntington's disease models.

    Evidence X-ray crystallography with interface mutagenesis; GDE2-KO epistasis in mouse/human AD tissue; ADAM10 conditional deletion and inhibitor rescue in HD mice with electrophysiology

    PMID:31063986 PMID:33731436 PMID:34739841

    Open questions at the time
    • Full-length Tspan15–ADAM10 structure at atomic resolution not yet available at this time point
    • Therapeutic window for ADAM10 modulation in neurodegenerative disease not defined
    • How RECK inhibition is relieved in normal neurons unclear
  17. 2023 High

    Cryo-EM of the ADAM10–Tspan15 complex revealed that Tspan15 relieves ADAM10 autoinhibition and positions the catalytic cleft ~20 Å from the membrane, providing the structural basis for substrate-site proximity requirements and explaining TspanC8-dependent substrate selectivity.

    Evidence Cryo-EM structure determination of vFab–ADAM10–Tspan15, interface mutant N-cadherin cleavage assays

    PMID:37516108

    Open questions at the time
    • Structures with other TspanC8 partners not yet determined
    • How autoinhibition is relieved dynamically upon PS exposure or other stimuli not captured structurally
    • No structure with a bound substrate
  18. 2023 Medium

    Identification of MAP4K4-mediated Ser436 phosphorylation as a negative regulator of ADAM10 N-cadherin shedding added a kinase-level control mechanism and linked ADAM10 regulation to ovarian cancer metastasis.

    Evidence Phosphosite identification, MAP4K4 knockdown/overexpression, N-cadherin cleavage assays, in vivo peritoneal metastasis model

    PMID:36922678

    Open questions at the time
    • Whether Ser436 phosphorylation affects other substrates not tested
    • Structural consequence of Ser436 phosphorylation on ADAM10 conformation unknown
    • Single-lab finding awaiting independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include: how different TspanC8–ADAM10 complexes achieve substrate selectivity at a structural level; whether PS-dependent activation and TspanC8 regulation are mechanistically linked; and what determines the therapeutic window for ADAM10 modulation across its many physiological roles.
  • No co-structures of ADAM10 with Tspan5/Tspan14/Tspan33
  • No substrate-bound structure
  • Integrated model of PS exposure, TspanC8 identity, and kinase regulation on substrate selectivity lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 14 GO:0016787 hydrolase activity 3
Localization
GO:0005886 plasma membrane 8 GO:0005794 Golgi apparatus 2
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-112316 Neuronal System 5 R-HSA-168256 Immune System 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-1266738 Developmental Biology 2
Partners
AP2CD9DLG1RECKTSPAN14TSPAN15TSPAN5
Complex memberships
ADAM10–Tspan15 scissor complexADAM10–TspanC8 complexes

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 The Drosophila ADAM10 ortholog Kuzbanian (KUZ) is essential for Notch-dependent cell fate decisions during neurogenesis; mosaic analysis showed KUZ is required in cells receiving Notch inhibitory signals, placing it upstream of Notch signaling in neural/non-neural cell partitioning. Genetic mosaic analysis in Drosophila Science High 8703057
1998 Purified bovine ADAM10 cleaves basement membrane type IV collagen in vitro, demonstrating direct extracellular matrix proteolytic activity. In vitro enzymatic assay with purified protein; SDS-PAGE and antibody-based epitope detection Biochemical and biophysical research communications Medium 9571200
1999 ADAM10 protein localizes to the trans-Golgi network and plasma membrane in osteoblast-lineage cells, with distinct isoforms present in each compartment, suggesting processing during secretory trafficking. Immunofluorescence subcellular localization and Western blot of fractionated cells Bone Medium 10423016
2002 ADAM10 (Kuzbanian) mediates GPCR transactivation of EGFR by cleaving heparin-binding EGF (HB-EGF); bombesin receptor stimulation enhances the association of ADAM10 and HB-EGF with tetraspanin CD9, and this metalloprotease activity drives Ras/Erk activation downstream. Dominant-negative overexpression, morpholino knockdown, co-immunoprecipitation with CD9, downstream signaling assays The Journal of cell biology High 12119356
2002 ADAM10 mediates activation of mucin gene expression in lung epithelial cells downstream of platelet-activating factor receptor (GPCR) stimulation by bacterial lipoteichoic acid, acting via cleavage of pro-HB-EGF to activate EGFR; this is independent of TLR2/4. Pharmacological inhibition and genetic manipulation in epithelial cells; EGFR pathway readouts Nature medicine High 11786905
2007 SAP97 directly interacts with ADAM10 via its SH3 domain and is responsible for trafficking ADAM10 to the postsynaptic membrane; NMDA receptor activation mediates this event and positively modulates alpha-secretase activity toward APP. Disrupting ADAM10/SAP97 association in vivo with cell-permeable peptides reduces ADAM10 postsynaptic localization and decreases non-amyloidogenic APP metabolism. Co-immunoprecipitation, cell-permeable peptide interference, subcellular fractionation, activity assays The Journal of neuroscience High 17301176
2007 ADAM10 cleaves the L1-CAM extracellular domain in colon cancer cells, and ADAM10 is a target gene of beta-catenin/TCF signaling. ADAM10 overexpression enhances L1-CAM cleavage and promotes liver metastasis in mouse xenograft models. Overexpression/knockdown, in vivo xenograft metastasis assay, Western blot Cancer research Medium 17699774
2008 ADAM10 specifically cleaves VE-cadherin in its ectodomain in endothelial cells, releasing a soluble fragment and generating a C-terminal stub that is subsequently cleaved by gamma-secretase. This cleavage is induced by Ca2+ influx and staurosporine, contributes to dissolution of adherens junctions, regulates endothelial permeability, and is required for T-cell transendothelial migration. Gain-of-function overexpression, RNA interference, inhibitor studies, permeability assays, T-cell transmigration assays in HUVECs Circulation research High 18420943
2009 ADAM10 overexpression in mice reduces total cellular prion protein (PrPc) levels in brain rather than generating specific cleavage products, and increases scrapie incubation time, indicating ADAM10 controls PrPc homeostasis and indirectly influences prion infectivity in vivo. Transgenic mouse overexpression, Western blot, scrapie infection model Neurobiology of disease Medium 19632330
2010 ADAM10 is the principal APP alpha-secretase in brain neurons and is required for Notch-1 processing; conditional neural knockout causes precocious neuronal differentiation, depletes progenitor cells, disrupts neocortical laminar architecture, and downregulates Notch-target genes. Conditional knockout (Nestin-Cre), neurosphere assays, gene expression analysis The Journal of neuroscience High 20371803
2011 ADAM10 activity is regulated by dynamin-dependent endocytosis; inhibition of dynamin increases ADAM10 surface expression and its own ectodomain shedding (generating a C-terminal fragment), establishing that internalization limits ADAM10 surface availability and proteolytic function. Dominant-negative dynamin transfection, surface biotinylation, gamma-secretase inhibitor, Western blot BMC cell biology Medium 21586144
2014 ADAM10 regulates Notch2 and Notch3 signaling by performing ligand-induced ectodomain cleavage required prior to gamma-secretase intramembrane cleavage; ADAM17/TACE plays no role in ligand-induced NOTCH2 or NOTCH3 activation. Genetic knockdown, inhibitor studies, luciferase Notch reporter assays Molecular and cellular biology High 24842903
2014 SAP97-mediated ADAM10 trafficking from dendritic Golgi outposts to synaptic membranes is controlled by PKC phosphorylation of a site in the SAP97 SH3 domain, modulating SAP97-ADAM10 association and ADAM10 delivery to the synapse. Co-immunoprecipitation, phosphorylation site mutagenesis, live cell imaging, synaptic fractionation Cell death & disease High 25429624
2015 TspanC8 tetraspanins (Tspan5, Tspan14, Tspan15, Tspan33) positively regulate ADAM10 surface expression and differentially modulate ADAM10-dependent Notch activation and cleavage of APP, N-cadherin, and CD44 by compartmentalizing ADAM10 to distinct membrane microdomains. Sucrose gradient fractionation, single molecule tracking, quantitative mass spectrometry co-immunoprecipitation, substrate cleavage assays Cellular and molecular life sciences High 26686862
2016 The cleavage site distance from the plasma membrane differentially controls IL-6R proteolysis by ADAM10 versus ADAM17; deletion of a triple-serine motif that reduces membrane-to-cleavage-site distance blocks ADAM17 but not ADAM10, and increasing this distance reveals an ADAM10-specific cleavage site. Deletion mutagenesis, shedding assays, site-specific mutant constructs Scientific reports Medium 27151651
2017 ADAM10 is the major ephrin-B2 sheddase in fibroblasts; TGF-β1 increases ADAM10 expression, and ADAM10-mediated soluble ephrin-B2 generation is required for TGF-β1-induced myofibroblast activation and organ fibrosis via EphB3/EphB4 receptor signaling. Genetic fibroblast-specific knockout, pharmacological inhibition, in vivo fibrosis models, bronchoalveolar lavage analysis Nature medicine High 29058717
2018 ADAM10 is the exclusive sheddase of prion protein (PrPC) in the nervous system; glycosylation state and type of membrane-anchorage of PrPC regulate its ADAM10-dependent shedding, and shedding can be pharmacologically modulated. Conditional knockout mice, neo-epitope specific antibody, biochemical and morphological analysis of modified cellular and murine models Molecular neurodegeneration High 29625583
2018 Mature ADAM10 undergoes rapid intramolecular autoproteolytic degradation upon cell lysis, requiring its own catalytic activity; inhibition of autoproteolysis reveals that mADAM10 is more abundant than proADAM10 in cells and has a half-life of ~12 hours. Cycloheximide chase, active-site inhibitors, Western blot in multiple cell lines and primary neurons FASEB journal High 29430990
2019 ADAM10 sheddase activation requires transient cell-surface exposure of phosphatidylserine (PS); PS headgroup acts as competitive inhibitor of substrate cleavage, Anoctamin-6 (ANO6) scramblase overexpression increases PS externalization and ADAM10 activity, and a PS-binding motif in the ADAM10 stalk region is required for activity. PS scramblase overexpression/knockout (Scott syndrome patient cells), competitive inhibition assays, mutagenesis of PS-binding motif, substrate cleavage assays Journal of molecular cell biology High 30753537
2019 ADAM10 cleaves CX3CL1 (fractalkine) into a secreted form in cortical neurons; this neuron-derived soluble CX3CL1 signals through microglial CX3CR1 to drive synapse elimination following whisker lesioning, and ADAM10 inhibition phenocopies CX3CL1/CX3CR1 knockout synapse elimination defects. Single-cell RNA sequencing, conditional knockout, ADAM10 inhibition, synapse counting after whisker lesioning Nature neuroscience High 31209379
2019 ADAM10 activity is required for its own cell-surface stability; loss of proteolytic activity by inhibition or mutation induces internalization, lysosomal degradation, and release in extracellular vesicles of mature ADAM10, and in vivo ADAM10 inhibition reduces systemic ADAM10 levels. Pharmacological inhibition, loss-of-function mutations, internalization assays, lysosomal inhibitors, EV isolation, in vivo mouse experiments Cellular and molecular life sciences High 32372373
2019 ADAM10 is required for SCF/c-Kit-mediated mast cell migration; ADAM10-deficient mast cells show impaired c-Kit-mediated migration, and cytokines IL-10 and TGFβ1 reduce ADAM10 expression, while ADAM10 deletion causes mast cell hyperplasia in skin and intestine. Inducible conditional knockout (Mx1-Cre), migration assays, cytokine treatment Cellular immunology Medium 24950026
2019 ADAM10 cleaves FLT3L from cDC2 surfaces in a cell-autonomous manner, generating soluble FLT3L required for cDC2 development and survival; genetic ablation of ADAM10 in dendritic cells reduces serum FLT3L and splenic cDC2 numbers, and FLT3L is established as a direct ADAM10 substrate in MEF reconstitution experiments. Conditional knockout (Itgax-Cre), BM chimeras, ex vivo culture FLT3L shedding assay, in vitro substrate assay in MEFs PNAS High 31262819
2019 Active ADAM10 accumulates at postsynaptic densities in Huntington's disease brain and causes excessive N-cadherin cleavage; inhibition of ADAM10 or heterozygous conditional deletion rescues N-cadherin proteolysis, corrects striatal neuron electrophysiology, and ameliorates cognitive deficits in HD mouse models. Conditional ADAM10 knockout, ADAM10 synthetic inhibitor, TAT-competitive peptide, ex vivo electrophysiology, PSD fractionation, HD mouse models The Journal of clinical investigation High 31063986
2020 Tspan15 and ADAM10 form a functional scissor complex at the cell surface; endogenous Tspan15 requires ADAM10 for surface stability, ADAM10 is the principal Tspan15-interacting protein, and a synthetic ADAM10/Tspan15 fusion protein is catalytically active toward N-cadherin. Monoclonal antibody generation in ADAM10-KO cells, co-immunoprecipitation, co-localization, ADAM10-KO cell lines, fusion protein activity assay The Journal of biological chemistry High 32111735
2019 Tspan5 promotes faster ADAM10 endocytosis while Tspan15 stabilizes ADAM10 at the cell surface; cytoplasmic domains of these TspanC8 tetraspanins mediate opposite effects on ADAM10 trafficking and Notch signaling, and ADAM10 reciprocally stabilizes Tspan15 at the plasma membrane. Endocytosis assays, chimeric tetraspanin constructs, Notch reporter assays, surface expression quantification Life science alliance High 31792032
2021 GDE2 stimulates ADAM10-mediated APP cleavage by shedding and inactivating RECK, a GPI-anchored inhibitor of ADAM10; in Alzheimer's disease, membrane-tethered RECK is elevated and GDE2 is sequestered inside neurons, reducing ADAM10 alpha-secretase activity toward APP. Genetic GDE2 ablation, RECK overexpression/reduction, sAPPα/Aβ measurements, synaptic protein analysis, epistasis in mouse models Science translational medicine High 33731436
2021 ADAM10 cleaves the Trop-2 extracellular domain between R87 and T88 in tumors; co-immunoprecipitation and mass spectrometry confirm ADAM10 physically interacts with Trop-2, and this cleavage activates cancer cell growth and metastasis (R87A-T88A mutant abolishes metastasis in xenografts). Co-immunoprecipitation, mass spectrometry, Edman degradation, siRNA/shRNA, ADAM10 inhibitors, xenotransplant models, confocal time-lapse Neoplasia High 33839455
2021 Crystal structure of Tspan15 large extracellular loop (LEL) identifies a conserved ADAM10 binding site; mutations in this LEL site abolish both ADAM10 co-immunoprecipitation and N-cadherin cleavage activity in cells. X-ray crystallography, co-immunoprecipitation, cellular N-cadherin cleavage assay, site-directed mutagenesis Structure High 34739841
2022 ADAM10 is the principal constitutive sheddase of IL-2Rα (CD25) in vivo; mice with CD4-specific ADAM10 deletion show reduced steady-state sIL-2Rα serum levels, and shed sIL-2Rα functions as a decoy receptor inhibiting IL-2 signaling in T cells. CD4-specific conditional KO, in vivo serum sIL-2Rα measurement, ADAM10/17 inhibitors, T cell IL-2 signaling assays The Journal of biological chemistry High 35398356
2023 Cryo-EM structure of vFab-ADAM10-Tspan15 complex reveals that Tspan15 binding relieves ADAM10 autoinhibition and positions the enzyme active site ~20 Å from the plasma membrane; cell-based N-cadherin cleavage assays show the ADAM10-Tspan15 interface determines preferred substrate cleavage site proximity to the membrane. Cryo-EM structure determination, cell-based N-cadherin shedding assays with interface mutants Cell High 37516108
2013 LTP promotes ADAM10 endocytosis via activity-regulated association with the clathrin adaptor AP2 complex, reducing surface ADAM10; LTD promotes ADAM10 membrane insertion and activity, with SAP97 interaction required for LTD-induced ADAM10 trafficking, LTD maintenance, and spine morphology changes. Co-immunoprecipitation (ADAM10-AP2), surface biotinylation, synaptic plasticity induction, spine morphology analysis Neuro-degenerative diseases Medium 24008925
2012 ADAM10 promotes pituitary adenoma cell migration by cleaving L1-CAM (enhanced by PMA/Src/Shc signaling) and CD44 (enhanced by Ca2+ flux that disrupts calmodulin-ADAM10 interaction); knockdown of ADAM10 suppresses migration reversed by CD44 ectodomain cleavage. siRNA knockdown, overexpression, kinase inhibitors, Ca2+ flux experiments, Co-IP of calmodulin-ADAM10, migration assays Journal of molecular endocrinology Medium 22586143
2023 MAP4K4 phosphorylates ADAM10 at Ser436, suppressing ADAM10-mediated N-cadherin cleavage and stabilizing N-cadherin to promote ovarian cancer metastasis; pharmacological MAP4K4 inhibition abrogates peritoneal metastases. Transcriptomic sequencing, phosphorylation site identification, MAP4K4 knockdown/overexpression, N-cadherin cleavage assays, in vivo peritoneal metastasis model Oncogene Medium 36922678
2019 Soluble ADAM10 (sADAM10) has an altered substrate spectrum compared to membrane-bound ADAM10; N-terminomics identified fibronectin, cystatin C, sN-cadherin, PCPE-1, and sAPP as direct substrates of sADAM10 in vitro. Mass spectrometry-based N-terminomics, in vitro substrate cleavage assays Cellular and molecular life sciences Medium 31209506
2021 ADAM10 sheddase activity is essential for leukemia stem cell survival and growth in vivo; CRISPR-Cas9 loss-of-function in PDX models confirms ADAM10 as a vulnerability, and reconstitution assays confirm the relevance of sheddase activity for leukemia maintenance. Deep proteome profiling of dormant PDX leukemia stem cells, CRISPR-Cas9 screen in vivo, reconstitution assays Molecular cancer Medium 37422628
2019 ADAM10 cleaves the RELT TNF receptor extracellular domain (not ADAM17) in ameloblasts and facilitates LS8 cell migration/invasion through Matrigel, consistent with a role in enamel development. PCR screen for ADAM expression, substrate cleavage assays, Matrigel invasion assay, siRNA Scientific reports Medium 31575895
2024 Platelets increase ADAM10 expression in hepatocellular carcinoma cells via TLR4/NF-κB signaling; ADAM10 then catalyzes CX3CL1 shedding, and the released soluble CX3CL1 binds CX3CR1 to induce EMT and RhoA signaling, promoting tumor metastasis. In vitro co-culture, TLR4/ADAM10 knockdown, CX3CL1 shedding measurement, RhoA signaling assays, in vivo lung metastasis mouse model Cancer letters Medium 38280480

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 The disintegrin/metalloproteinase ADAM10 is essential for the establishment of the brain cortex. The Journal of neuroscience : the official journal of the Society for Neuroscience 296 20371803
2002 Platelet-activating factor receptor and ADAM10 mediate responses to Staphylococcus aureus in epithelial cells. Nature medicine 288 11786905
1996 KUZ, a conserved metalloprotease-disintegrin protein with two roles in Drosophila neurogenesis. Science (New York, N.Y.) 287 8703057
2002 The metalloprotease Kuzbanian (ADAM10) mediates the transactivation of EGF receptor by G protein-coupled receptors. The Journal of cell biology 262 12119356
2019 Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling. Nature neuroscience 257 31209379
2010 The "A Disintegrin And Metalloproteases" ADAM10 and ADAM17: novel drug targets with therapeutic potential? European journal of cell biology 254 21194787
2008 ADAM10 regulates endothelial permeability and T-Cell transmigration by proteolysis of vascular endothelial cadherin. Circulation research 244 18420943
2015 The alpha secretase ADAM10: A metalloprotease with multiple functions in the brain. Progress in neurobiology 181 26522965
2007 Expression of L1-CAM and ADAM10 in human colon cancer cells induces metastasis. Cancer research 175 17699774
2007 Synapse-associated protein-97 mediates alpha-secretase ADAM10 trafficking and promotes its activity. The Journal of neuroscience : the official journal of the Society for Neuroscience 159 17301176
2017 ADAM10-mediated ephrin-B2 shedding promotes myofibroblast activation and organ fibrosis. Nature medicine 127 29058717
2017 The Role of ADAM10 in Alzheimer's Disease. Journal of Alzheimer's disease : JAD 122 28409746
2017 The metalloproteinase ADAM10: A useful therapeutic target? Biochimica et biophysica acta. Molecular cell research 111 28624438
1998 The metallo-disintegrin ADAM10 (MADM) from bovine kidney has type IV collagenase activity in vitro. Biochemical and biophysical research communications 106 9571200
2015 TspanC8 tetraspanins differentially regulate the cleavage of ADAM10 substrates, Notch activation and ADAM10 membrane compartmentalization. Cellular and molecular life sciences : CMLS 105 26686862
2016 Cleavage Site Localization Differentially Controls Interleukin-6 Receptor Proteolysis by ADAM10 and ADAM17. Scientific reports 83 27151651
2018 Alpha-Secretase ADAM10 Regulation: Insights into Alzheimer's Disease Treatment. Pharmaceuticals (Basel, Switzerland) 81 29382156
2016 Discovery of an enzyme and substrate selective inhibitor of ADAM10 using an exosite-binding glycosylated substrate. Scientific reports 80 28442704
2005 Increase of disintergin metalloprotease 10 (ADAM10) expression in oral squamous cell carcinoma. Cancer letters 77 16309826
2011 High ERp5/ADAM10 expression in lymph node microenvironment and impaired NKG2D ligands recognition in Hodgkin lymphomas. Blood 74 22167753
2010 Upregulation of the alpha-secretase ADAM10--risk or reason for hope? The FEBS journal 73 20136654
2014 Regulated proteolysis of NOTCH2 and NOTCH3 receptors by ADAM10 and presenilins. Molecular and cellular biology 69 24842903
2011 Regulation of α-secretase ADAM10 expression and activity. Experimental brain research 66 21969210
2007 Modeling sporadic loss of heterozygosity in mice by using mosaic analysis with double markers (MADM). Proceedings of the National Academy of Sciences of the United States of America 64 17360552
2019 ADAM10 sheddase activation is controlled by cell membrane asymmetry. Journal of molecular cell biology 61 30753537
2016 An activated form of ADAM10 is tumor selective and regulates cancer stem-like cells and tumor growth. The Journal of experimental medicine 61 27503072
2017 Scissor sisters: regulation of ADAM10 by the TspanC8 tetraspanins. Biochemical Society transactions 58 28620033
2018 microRNA 221 Targets ADAM10 mRNA and is Downregulated in Alzheimer's Disease. Journal of Alzheimer's disease : JAD 56 29036829
2014 The association of the expression of miR-122-5p and its target ADAM10 with human breast cancer. Molecular biology reports 56 25318895
2014 SAP97-mediated ADAM10 trafficking from Golgi outposts depends on PKC phosphorylation. Cell death & disease 56 25429624
1999 Localization of ADAM10 and Notch receptors in bone. Bone 54 10423016
2021 Induction of ADAM10 by Radiation Therapy Drives Fibrosis, Resistance, and Epithelial-to-Mesenchyal Transition in Pancreatic Cancer. Cancer research 52 33526513
2020 NKG2D Ligand Shedding in Response to Stress: Role of ADAM10. Frontiers in immunology 51 32269567
2019 Degradome of soluble ADAM10 and ADAM17 metalloproteases. Cellular and molecular life sciences : CMLS 51 31209506
2021 Trop-2 cleavage by ADAM10 is an activator switch for cancer growth and metastasis. Neoplasia (New York, N.Y.) 49 33839455
2021 A genome-wide library of MADM mice for single-cell genetic mosaic analysis. Cell reports 49 34161767
2017 Regulation of the trafficking and the function of the metalloprotease ADAM10 by tetraspanins. Biochemical Society transactions 49 28687716
2017 Regulation of ADAM10 by miR-140-5p and potential relevance for Alzheimer's disease. Neurobiology of aging 48 29253717
2012 Extensions of MADM (mosaic analysis with double markers) in mice. PloS one 47 22479386
2002 MADM, a novel adaptor protein that mediates phosphorylation of the 14-3-3 binding site of myeloid leukemia factor 1. The Journal of biological chemistry 47 12176995
2011 The transcription factor PAX2 regulates ADAM10 expression in renal cell carcinoma. Carcinogenesis 46 21880579
2011 Physiological functions of the amyloid precursor protein secretases ADAM10, BACE1, and presenilin. Experimental brain research 46 22120156
2008 Characterization of CXCL16 and ADAM10 in the normal and transplanted kidney. Kidney international 46 18480749
2009 Influence of ADAM10 on prion protein processing and scrapie infectiosity in vivo. Neurobiology of disease 44 19632330
2018 Structural and mechanistic aspects influencing the ADAM10-mediated shedding of the prion protein. Molecular neurodegeneration 43 29625583
2016 Regulation of the α-secretase ADAM10 at transcriptional, translational and post-translational levels. Brain research bulletin 41 27060611
2018 Proteolytic cleavage of amyloid precursor protein by ADAM10 mediates proliferation and migration in breast cancer. EBioMedicine 40 30470613
2023 Structural basis for membrane-proximal proteolysis of substrates by ADAM10. Cell 39 37516108
2019 Inhibiting pathologically active ADAM10 rescues synaptic and cognitive decline in Huntington's disease. The Journal of clinical investigation 39 31063986
2017 miR-320a modulates cell growth and chemosensitivity via regulating ADAM10 in gastric cancer. Molecular medicine reports 39 29152656
2021 Regulation of ADAM10 by the TspanC8 Family of Tetraspanins and Their Therapeutic Potential. International journal of molecular sciences 38 34201472
2018 Levels of ADAM10 are reduced in Alzheimer's disease CSF. Journal of neuroinflammation 38 30045733
2023 New insights into the function and pathophysiology of the ectodomain sheddase A Disintegrin And Metalloproteinase 10 (ADAM10). The FEBS journal 36 37218105
2020 The tetraspanin Tspan15 is an essential subunit of an ADAM10 scissor complex. The Journal of biological chemistry 36 32111735
2018 Renal ADAM10 and 17: Their Physiological and Medical Meanings. Frontiers in cell and developmental biology 36 30460232
2017 Role of ADAM10 in intestinal crypt homeostasis and tumorigenesis. Biochimica et biophysica acta. Molecular cell research 36 28739265
2003 Modeling of enzyme-substrate complexes for the metalloproteases MMP-3, ADAM-9 and ADAM-10. Journal of computer-aided molecular design 36 14713188
2021 GDE2-RECK controls ADAM10 α-secretase-mediated cleavage of amyloid precursor protein. Science translational medicine 34 33731436
2019 TspanC8 tetraspanins differentially regulate ADAM10 endocytosis and half-life. Life science alliance 34 31792032
2017 Role of MicroRNA-103a Targeting ADAM10 in Abdominal Aortic Aneurysm. BioMed research international 32 28357407
2016 miR-448 suppressed gastric cancer proliferation and invasion by regulating ADAM10. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 32 26852749
2020 The metalloproteinase ADAM10 requires its activity to sustain surface expression. Cellular and molecular life sciences : CMLS 31 32372373
2020 ADAM10 and ADAM17 proteases mediate proinflammatory cytokine-induced and constitutive cleavage of endomucin from the endothelial surface. The Journal of biological chemistry 30 32193206
2014 ADAM10 correlates with uveal melanoma metastasis and promotes in vitro invasion. Pigment cell & melanoma research 30 25124714
2022 The development of ADAM10 endocytosis inhibitors for the treatment of Alzheimer's disease. Molecular therapy : the journal of the American Society of Gene Therapy 29 35390543
2016 Metalloproteinases ADAM10 and ADAM17 Mediate Migration and Differentiation in Glioblastoma Sphere-Forming Cells. Molecular neurobiology 29 27541285
2011 The emergence of ADAM10 as a regulator of lymphocyte development and autoimmunity. Molecular immunology 29 21236490
2018 The metalloprotease ADAM10 (a disintegrin and metalloprotease 10) undergoes rapid, postlysis autocatalytic degradation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 28 29430990
2020 The Gut-Brain Axis in Autism Spectrum Disorder: A Focus on the Metalloproteases ADAM10 and ADAM17. International journal of molecular sciences 27 33374371
2009 The effects of alpha-secretase ADAM10 on the proteolysis of neuregulin-1. The FEBS journal 27 19220854
2018 Regulation of Leukocytes by TspanC8 Tetraspanins and the "Molecular Scissor" ADAM10. Frontiers in immunology 25 30013551
2021 Role of ADAM10 and ADAM17 in Regulating CD137 Function. International journal of molecular sciences 24 33800462
2020 Modulation of Immune Responses by Platelet-Derived ADAM10. Frontiers in immunology 24 32117229
2016 The novel tumour suppressor Madm regulates stem cell competition in the Drosophila testis. Nature communications 24 26792023
2013 ADAM10 in synaptic physiology and pathology. Neuro-degenerative diseases 24 24008925
2012 ADAM10 promotes pituitary adenoma cell migration by regulating cleavage of CD44 and L1. Journal of molecular endocrinology 24 22586143
2020 ADAM10 mediates ectopic proximal tubule development and renal fibrosis through Notch signalling. The Journal of pathology 23 32715474
2014 ADAM10 regulates proliferation, invasion, and chemoresistance of bladder cancer cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 23 24935471
2019 Involvement of ADAM10 in acrolein-induced astrocytic inflammation. Toxicology letters 22 31639409
2019 miR-365 inhibits cell invasion and migration of triple negative breast cancer through ADAM10. Journal of B.U.ON. : official journal of the Balkan Union of Oncology 22 31786854
2014 Upregulation of APP, ADAM10 and ADAM17 in the denervated mouse dentate gyrus. PloS one 22 24404197
2018 MicroRNA-197 controls ADAM10 expression to mediate MeCP2's role in the differentiation of neuronal progenitors. Cell death and differentiation 21 30560934
2024 Direct interaction of platelet with tumor cell aggravates hepatocellular carcinoma metastasis by activating TLR4/ADAM10/CX3CL1 axis. Cancer letters 20 38280480
2019 Cell-autonomous FLT3L shedding via ADAM10 mediates conventional dendritic cell development in mouse spleen. Proceedings of the National Academy of Sciences of the United States of America 20 31262819
2023 MAP4K4 promotes ovarian cancer metastasis through diminishing ADAM10-dependent N-cadherin cleavage. Oncogene 19 36922678
2022 The metalloprotease ADAM10 generates soluble interleukin-2 receptor alpha (sCD25) in vivo. The Journal of biological chemistry 19 35398356
2023 Fully human monoclonal antibody targeting activated ADAM10 on colorectal cancer cells. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 18 36917886
2023 Combined proteomics and CRISPR‒Cas9 screens in PDX identify ADAM10 as essential for leukemia in vivo. Molecular cancer 18 37422628
2022 MT1-MMP and ADAM10/17 exhibit a remarkable overlap of shedding properties. The FEBS journal 18 35944080
2021 Crystal structure of the Tspan15 LEL domain reveals a conserved ADAM10 binding site. Structure (London, England : 1993) 18 34739841
2010 Ectodomain shedding of Fcalpha receptor is mediated by ADAM10 and ADAM17. Immunology 18 20059578
2018 Cosmosiin Increases ADAM10 Expression via Mechanisms Involving 5'UTR and PI3K Signaling. Frontiers in molecular neuroscience 17 29942252
2023 Endothelial ADAM10 utilization defines a molecular pathway of vascular injury in mice with bacterial sepsis. The Journal of clinical investigation 16 37788087
2022 Inhibitors of ADAM10 reduce Hodgkin lymphoma cell growth in 3D microenvironments and enhance brentuximab-vedotin effect. Haematologica 16 34109776
2021 Nmnat2 attenuates amyloidogenesis and up-regulates ADAM10 in AMPK activity-dependent manner. Aging 16 34644262
2019 ADAM10 is Expressed by Ameloblasts, Cleaves the RELT TNF Receptor Extracellular Domain and Facilitates Enamel Development. Scientific reports 16 31575895
2011 Surface expression and limited proteolysis of ADAM10 are increased by a dominant negative inhibitor of dynamin. BMC cell biology 16 21586144
2022 The role of A Disintegrin and Metalloproteinase (ADAM)-10 in T helper cell biology. Biochimica et biophysica acta. Molecular cell research 15 34982961
2020 α-Secretase nonsense mutation (ADAM10 Tyr167*) in familial Alzheimer's disease. Alzheimer's research & therapy 15 33129344
2014 ADAM10 is required for SCF-induced mast cell migration. Cellular immunology 15 24950026