Affinage

ADAM10

Disintegrin and metalloproteinase domain-containing protein 10 · UniProt O14672

Length
748 aa
Mass
84.1 kDa
Annotated
2026-06-09
100 papers in source corpus 40 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1996 High

    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

    PMID:8703057

    Open questions at the time
    • Did not identify the molecular substrate cleaved
    • Mechanistic link to Notch not yet biochemically defined
  2. 2002 Medium

    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

    PMID:12119356

    Open questions at the time
    • Direct cleavage versus regulatory role not fully separated
    • CD9/tetraspanin requirement not mechanistically resolved
  3. 2007 High

    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

    PMID:17301176

    Open questions at the time
    • Did not define phosphorylation control of the interaction
    • Endocytic regulation not yet addressed
  4. 2008 High

    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

    PMID:18535782 PMID:18635581

    Open questions at the time
    • Whether ADAM10 acts on receptor versus ligand initially ambiguous
    • Specificity versus ADAM17 not yet dissected
  5. 2008 High

    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

    PMID:18420943

    Open questions at the time
    • Trafficking/cofactor requirements for endothelial activity not defined
    • Activation trigger (Ca2+) mechanism not fully resolved
  6. 2014 High

    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

    PMID:24842903

    Open questions at the time
    • Structural basis for receptor selectivity not addressed
    • Role of tetraspanin cofactors in Notch cleavage not tested here
  7. 2014 High

    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

    PMID:24008925 PMID:25429624

    Open questions at the time
    • Direct kinase identity acting in vivo not confirmed
    • Link between trafficking changes and AD pathogenesis correlative
  8. 2017 High

    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

    PMID:27256961 PMID:28600292 PMID:28620033

    Open questions at the time
    • Structural mechanism of cofactor action not yet known
    • How individual TspanC8 members map to specific substrates incompletely defined
  9. 2017 High

    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

    PMID:29058717

    Open questions at the time
    • Direct ephrin-B2 cleavage site not mapped
    • Cofactor dependence in fibroblasts not addressed
  10. 2018 High

    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

    PMID:37516108

    Open questions at the time
    • Structures with other TspanC8 members not resolved
    • How substrate is recruited to the active site not visualized
  11. 2018 High

    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

    PMID:30463011

    Open questions at the time
    • Whether clustering alters catalytic state not determined
    • Generality across cell types not established
  12. 2018 High

    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

    PMID:19632330 PMID:29625583

    Open questions at the time
    • Physiological consequence of PrPc shedding in disease incompletely defined
    • Cleavage site determinants only partly mapped
  13. 2019 Medium

    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

    PMID:31792032

    Open questions at the time
    • Single-lab study
    • Trafficking adaptors mediating differential effects not identified
  14. 2019 High

    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

    PMID:31063986 PMID:31262819

    Open questions at the time
    • Upstream signals raising ADAM10 activity in HD not fully defined
    • Therapeutic window of ADAM10 modulation untested
  15. 2020 High

    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

    PMID:32193206 PMID:32363112 PMID:33800462 PMID:35398356 PMID:38225245

    Open questions at the time
    • How PS exposure mechanistically activates the protease not fully resolved
    • Relative ADAM10/ADAM17 contributions vary by substrate
  16. 2020 High

    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

    PMID:32372373 PMID:33731436

    Open questions at the time
    • Signal linking activity to internalization not identified
    • How GDE2 sequestration arises in AD unresolved
  17. 2021 High

    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

    PMID:33601422 PMID:33839455

    Open questions at the time
    • Functional role of ADAM10–piccolo interaction beyond correlation unclear
    • Whether Trop-2 cleavage requires specific TspanC8 cofactors untested
  18. 2022 Medium

    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

    PMID:33383559

    Open questions at the time
    • Single-lab finding
    • Physiological/disease consequence of AEP-mediated ADAM10 turnover unclear
  19. 2023 High

    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

    PMID:36917886 PMID:36922678 PMID:37422628

    Open questions at the time
    • How Ser436 phosphorylation alters catalysis structurally unknown
    • On-target therapeutic specificity versus ADAM17 in cancer not fully addressed
  20. 2023 High

    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

    PMID:35163191 PMID:37788087

    Open questions at the time
    • Molecular basis of pathogen selectivity not defined
    • How exosomal ADAM10 retains/regains activity unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 11 GO:0016787 hydrolase activity 5 GO:0008289 lipid binding 2
Localization
GO:0005886 plasma membrane 4 GO:0005768 endosome 3 GO:0031410 cytoplasmic vesicle 3 GO:0005794 Golgi apparatus 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-168256 Immune System 5 R-HSA-1500931 Cell-Cell communication 4 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-392499 Metabolism of proteins 3
Partners
PCLOPDZD11PLEKHA7RECKSAP97TSPAN15TSPAN33TSPAN5
Complex memberships
ADAM10–SAP97 complexADAM10–Tspan33–PDZD11–PLEKHA7–afadin junctional complexADAM10–TspanC8 tetraspanin complex

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 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. Drosophila genetic mosaic analysis, loss-of-function Science High 8703057
2002 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. Gain-of-function overexpression, protease-domain deletion mutant, morpholino antisense knockdown, Co-IP with CD9 The Journal of Cell Biology Medium 12119356
2007 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. Overexpression, in vivo mouse metastasis model, Western blot cleavage assay, DNA microarray Cancer Research Medium 17699774
2007 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. Co-IP, cell-permeable peptide interference, subcellular fractionation, NMDA receptor activation assay The Journal of Neuroscience High 17301176
2008 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. Gain-of-function overexpression, RNAi knockdown, inhibitor studies, permeability assays, transmigration assay Circulation Research High 18420943
2008 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. Conditional knockout mouse, genetic epistasis, Western blot, gene expression analysis International Immunology High 18635581
2008 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. In vitro Drosophila cell-based Notch signaling assay, overexpression, gain-of-function Cellular and Molecular Life Sciences Medium 18535782
2009 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. Transgenic mouse overexpression, Western blot, scrapie infection survival analysis Neurobiology of Disease Medium 19632330
2011 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. ADAM10 inhibitor studies in primary tubular cells, Western blot, soluble CXCL16 measurement Kidney International Medium 18480749
2011 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. Conditional knockout mouse, reciprocal bone marrow transplantation, flow cytometry Blood High 22042698
2013 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. Electrophysiology (LTP/LTD induction), Co-IP, surface biotinylation, synaptic fractionation Neurodegenerative Diseases Medium 24008925
2014 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. Genetic knockdown/knockout, ADAM inhibitor studies, Notch reporter assays Molecular and Cellular Biology High 24842903
2014 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. Co-IP, phosphorylation mutagenesis, live imaging of dendritic trafficking, subcellular fractionation, AD brain tissue analysis Cell Death & Disease High 25429624
2017 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. ADAM10 inhibitor studies, fibroblast-specific conditional knockout, in vivo fibrosis models (bleomycin), ELISA, Western blot Nature Medicine High 29058717
2017 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. Co-IP, RNAi knockdown, subcellular fractionation, flow-based transmigration assay Journal of Immunology / Biochemical Society Transactions / Platelets High 27256961 28600292 28620033
2018 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. Cryo-EM structure determination, cell-based shedding assay (N-cadherin), mutagenesis of interface Cell High 37516108
2018 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. Co-IP, biochemical pulldown, live imaging, siRNA knockdown, pore-formation assay Cell Reports High 30463011
2018 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. Neo-epitope antibody, genetic cell and murine models, biochemical shedding assay, pharmacological modulation Molecular Neurodegeneration High 29625583
2019 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. Conditional KO mouse, cell-permeable competitive peptide, electrophysiology, behavioral assays, Western blot of postsynaptic density fractions The Journal of Clinical Investigation High 31063986
2019 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. Surface biotinylation, endocytosis assays, chimeric tetraspanin constructs, flow cytometry Life Science Alliance Medium 31792032
2019 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. Conditional KO (Itgax-cre × Adam10-fl/fl), BM chimera, ex vivo culture supernatant FLT3L measurement, in vitro shedding assay with murine embryonic fibroblasts PNAS High 31262819
2020 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. Inhibitor treatment, loss-of-function mutants, flow cytometry, lysosomal inhibition, extracellular vesicle isolation, in vivo mouse tissue analysis Cellular and Molecular Life Sciences Medium 32372373
2020 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. ADAM10/17 inhibitor studies, siRNA knockdown, CD8+ T cell killing assays, Western blot of soluble PD-L1 Oncoimmunology Medium 32363112
2020 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. Cell-based shedding assays, genetic knockouts (XKR8, ADAM10), macrophage efferocytosis assay, flow cytometry Nature Communications High 38225245
2020 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. Adenoviral overexpression, siRNA knockdown, small-molecule inhibitors (GW280264X, GI254023X), Western blot The Journal of Biological Chemistry Medium 32193206
2020 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. Genetic ablation (GDE2, RECK), biochemical shedding assay, rescue experiments, synaptic protein analysis, mouse models Science Translational Medicine High 33731436
2021 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. Co-IP, mass spectrometry, N-terminal Edman degradation, ADAM10 siRNA/shRNA, in vivo xenograft metastasis assay Neoplasia High 33839455
2021 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. Immunoaffinity purification-mass spectrometry (IP-MS), Co-IP, conditional KO mouse, electron microscopy of synaptic vesicles Human Molecular Genetics High 33601422
2021 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. Podocyte-specific conditional KO, membrane proteomics, immunogold EM, anti-podocyte nephritis in vivo model, Western blot Journal of the American Society of Nephrology High 33785583
2022 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. CD4-specific conditional KO, pharmacological inhibition, soluble IL-2Rα ELISA, T cell IL-2 signaling assay The Journal of Biological Chemistry High 35398356
2022 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. Lysosomal pathway inhibitors, AEP knockout mouse, Western blot, in vitro cleavage assay Biochemical and Biophysical Research Communications Medium 33383559
2022 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. PS interaction inhibitor, ANO6 overexpression, sCD137 shedding assay, flow cytometry International Journal of Molecular Sciences Medium 33800462
2023 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. Phosphorylation mutagenesis, Co-IP, in vivo peritoneal metastasis model, Western blot of N-cadherin cleavage Oncogene Medium 36922678
2023 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. Structural characterization by antibody binding assays, cell-based Notch cleavage assay, in vivo mouse colon cancer model, in vitro catalytic activity assay Biomedicine & Pharmacotherapy Medium 36917886
2023 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. Pharmacological ADAM10 inhibition, siRNA knockdown, calcium imaging, permeability assay, extracellular vesicle proteolytic activity measurement International Journal of Molecular Sciences Medium 35163191
2023 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. Endothelium-specific conditional KO mouse, in vivo infection models with multiple pathogens, survival analysis, histology The Journal of Clinical Investigation High 37788087
2023 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. CRISPR-Cas9 in vivo screen, PDX reconstitution assay, pharmacological inhibition, flow cytometry of stem cell frequency Molecular Cancer High 37422628
1999 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. Immunofluorescence subcellular localization, subcellular fractionation, Western blot Bone Medium 10423016

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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 263 12119356
2010 The "A Disintegrin And Metalloproteases" ADAM10 and ADAM17: novel drug targets with therapeutic potential? European journal of cell biology 256 21194787
2008 ADAM10 regulates endothelial permeability and T-Cell transmigration by proteolysis of vascular endothelial cadherin. Circulation research 245 18420943
2008 The good, the bad and the ugly substrates for ADAM10 and ADAM17 in brain pathology, inflammation and cancer. Seminars in cell & developmental biology 201 18951988
2015 The alpha secretase ADAM10: A metalloprotease with multiple functions in the brain. Progress in neurobiology 182 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 130 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 112 28624438
2020 ADAM10 and ADAM17 cleave PD-L1 to mediate PD-(L)1 inhibitor resistance. Oncoimmunology 105 32363112
2016 Regulation of A disintegrin and metalloproteinase (ADAM) family sheddases ADAM10 and ADAM17: The emerging role of tetraspanins and rhomboids. Platelets 100 27256961
2018 Alpha-Secretase ADAM10 Regulation: Insights into Alzheimer's Disease Treatment. Pharmaceuticals (Basel, Switzerland) 84 29382156
2008 ADAM10 is essential for proteolytic activation of Notch during thymocyte development. International immunology 82 18635581
2016 Discovery of an enzyme and substrate selective inhibitor of ADAM10 using an exosite-binding glycosylated substrate. Scientific reports 79 28442704
2008 ADAM10 as a target for anti-cancer therapy. Current pharmaceutical biotechnology 77 18289051
2011 High ERp5/ADAM10 expression in lymph node microenvironment and impaired NKG2D ligands recognition in Hodgkin lymphomas. Blood 75 22167753
2010 Upregulation of the alpha-secretase ADAM10--risk or reason for hope? The FEBS journal 74 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
2017 Scissor sisters: regulation of ADAM10 by the TspanC8 tetraspanins. Biochemical Society transactions 60 28620033
2018 microRNA 221 Targets ADAM10 mRNA and is Downregulated in Alzheimer's Disease. Journal of Alzheimer's disease : JAD 56 29036829
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 Trop-2 cleavage by ADAM10 is an activator switch for cancer growth and metastasis. Neoplasia (New York, N.Y.) 52 33839455
2020 NKG2D Ligand Shedding in Response to Stress: Role of ADAM10. Frontiers in immunology 52 32269567
2019 Degradome of soluble ADAM10 and ADAM17 metalloproteases. Cellular and molecular life sciences : CMLS 51 31209506
2017 Regulation of the trafficking and the function of the metalloprotease ADAM10 by tetraspanins. Biochemical Society transactions 51 28687716
2017 Regulation of ADAM10 by miR-140-5p and potential relevance for Alzheimer's disease. Neurobiology of aging 48 29253717
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
2018 Structural and mechanistic aspects influencing the ADAM10-mediated shedding of the prion protein. Molecular neurodegeneration 45 29625583
2014 ADAM10 and ADAM17 have opposite roles during sprouting angiogenesis. Angiogenesis 45 25218057
2023 Structural basis for membrane-proximal proteolysis of substrates by ADAM10. Cell 44 37516108
2017 ADAM10-Interacting Tetraspanins Tspan5 and Tspan17 Regulate VE-Cadherin Expression and Promote T Lymphocyte Transmigration. Journal of immunology (Baltimore, Md. : 1950) 44 28600292
2009 Influence of ADAM10 on prion protein processing and scrapie infectiosity in vivo. Neurobiology of disease 44 19632330
2018 A Dock-and-Lock Mechanism Clusters ADAM10 at Cell-Cell Junctions to Promote α-Toxin Cytotoxicity. Cell reports 41 30463011
2016 Regulation of the α-secretase ADAM10 at transcriptional, translational and post-translational levels. Brain research bulletin 41 27060611
2011 Dual functions of cell-autonomous and non-cell-autonomous ADAM10 activity in granulopoiesis. Blood 40 22042698
2023 New insights into the function and pathophysiology of the ectodomain sheddase A Disintegrin And Metalloproteinase 10 (ADAM10). The FEBS journal 39 37218105
2021 Regulation of ADAM10 by the TspanC8 Family of Tetraspanins and Their Therapeutic Potential. International journal of molecular sciences 39 34201472
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
2020 Butein, isoliquiritigenin, and scopoletin attenuate neurodegeneration via antioxidant enzymes and SIRT1/ADAM10 signaling pathway. RSC advances 37 35498835
2019 TspanC8 tetraspanins differentially regulate ADAM10 endocytosis and half-life. Life science alliance 37 31792032
2018 Renal ADAM10 and 17: Their Physiological and Medical Meanings. Frontiers in cell and developmental biology 37 30460232
2017 Role of ADAM10 in intestinal crypt homeostasis and tumorigenesis. Biochimica et biophysica acta. Molecular cell research 36 28739265
2021 GDE2-RECK controls ADAM10 α-secretase-mediated cleavage of amyloid precursor protein. Science translational medicine 35 33731436
2018 ADAM10 controls the differentiation of the coronary arterial endothelium. Angiogenesis 35 30446855
2020 The metalloproteinase ADAM10 requires its activity to sustain surface expression. Cellular and molecular life sciences : CMLS 33 32372373
2017 Role of MicroRNA-103a Targeting ADAM10 in Abdominal Aortic Aneurysm. BioMed research international 32 28357407
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
2008 Kuz and TACE can activate Notch independent of ligand. Cellular and molecular life sciences : CMLS 30 18535782
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
2021 ADAM10 and ADAM17 regulate EGFR, c-Met and TNF RI signalling in liver regeneration and fibrosis. Scientific reports 27 34075077
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 26 30013551
2021 ADAM10 Plasma and CSF Levels Are Increased in Mild Alzheimer's Disease. International journal of molecular sciences 25 33670873
2021 Role of ADAM10 and ADAM17 in Regulating CD137 Function. International journal of molecular sciences 25 33800462
2021 ADAM10 Site-Dependent Biology: Keeping Control of a Pervasive Protease. International journal of molecular sciences 25 34067041
2018 Protein levels of ADAM10, BACE1, and PSEN1 in platelets and leukocytes of Alzheimer's disease patients. European archives of psychiatry and clinical neuroscience 25 29845446
2012 ADAM10 expression and promoter haplotype in Alzheimer's disease. Neurobiology of aging 25 22572541
2011 PAX2 regulates ADAM10 expression and mediates anchorage-independent cell growth of melanoma cells. PloS one 25 21876729
2020 Modulation of Immune Responses by Platelet-Derived ADAM10. Frontiers in immunology 24 32117229
2013 ADAM10 in synaptic physiology and pathology. Neuro-degenerative diseases 24 24008925
2024 Direct interaction of platelet with tumor cell aggravates hepatocellular carcinoma metastasis by activating TLR4/ADAM10/CX3CL1 axis. Cancer letters 23 38280480
2020 ADAM10 mediates ectopic proximal tubule development and renal fibrosis through Notch signalling. The Journal of pathology 23 32715474
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 23 31786854
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
2022 The metalloprotease ADAM10 generates soluble interleukin-2 receptor alpha (sCD25) in vivo. The Journal of biological chemistry 22 35398356
2019 Involvement of ADAM10 in acrolein-induced astrocytic inflammation. Toxicology letters 22 31639409
2018 MicroRNA-197 controls ADAM10 expression to mediate MeCP2's role in the differentiation of neuronal progenitors. Cell death and differentiation 22 30560934
2022 ADAM10-cleaved ephrin-A5 contributes to prostate cancer metastasis. Cell death & disease 21 35551177
2022 ADAM10-a "multitasker" in sepsis: focus on its posttranslational target. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 21 36565333
2023 MAP4K4 promotes ovarian cancer metastasis through diminishing ADAM10-dependent N-cadherin cleavage. Oncogene 20 36922678
2019 ADAM10 mediates malignant pleural mesothelioma invasiveness. Oncogene 20 30651596
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
2017 miR-365 targets ADAM10 and suppresses the cell growth and metastasis of hepatocellular carcinoma. Oncology reports 20 28184920
2023 Fully human monoclonal antibody targeting activated ADAM10 on colorectal cancer cells. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 19 36917886
2022 MT1-MMP and ADAM10/17 exhibit a remarkable overlap of shedding properties. The FEBS journal 19 35944080
2021 ADAM10 hyperactivation acts on piccolo to deplete synaptic vesicle stores in Huntington's disease. Human molecular genetics 19 33601422
2024 Apoptosis-mediated ADAM10 activation removes a mucin barrier promoting T cell efferocytosis. Nature communications 18 38225245
2023 Combined proteomics and CRISPR‒Cas9 screens in PDX identify ADAM10 as essential for leukemia in vivo. Molecular cancer 18 37422628
2023 Endothelial ADAM10 utilization defines a molecular pathway of vascular injury in mice with bacterial sepsis. The Journal of clinical investigation 18 37788087
2021 ADAM10-Mediated Ectodomain Shedding Is an Essential Driver of Podocyte Damage. Journal of the American Society of Nephrology : JASN 17 33785583
2018 Cosmosiin Increases ADAM10 Expression via Mechanisms Involving 5'UTR and PI3K Signaling. Frontiers in molecular neuroscience 17 29942252
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
2022 The role of A Disintegrin and Metalloproteinase (ADAM)-10 in T helper cell biology. Biochimica et biophysica acta. Molecular cell research 15 34982961
2022 Pseudomonas aeruginosa Triggered Exosomal Release of ADAM10 Mediates Proteolytic Cleavage in Trans. International journal of molecular sciences 15 35163191
2020 α-Secretase nonsense mutation (ADAM10 Tyr167*) in familial Alzheimer's disease. Alzheimer's research & therapy 15 33129344
2024 Lactate increases ADAM10 activity and reduces BACE1 activity in mouse brain. The Journal of physiology 13 39298105
2023 ADAM10 as a biomarker for Alzheimer's disease: A systematic review. Revue neurologique 13 37460331
2020 ADAM10 and ADAM17 are degraded by lysosomal pathway via asparagine endopeptidase. Biochemical and biophysical research communications 13 33383559

Missed literature

Know a paper Affinage missed for ADAM10? Flag it for the maintainers and the community.

No submissions yet.