ADAM10

UniProt ID: O14672
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

ADAM10 encodes a single-pass type I transmembrane zinc metalloprotease of the ADAM family. The mature enzyme acts mainly at the cell surface, Golgi-derived vesicles, synaptic membranes, adherens junctions, and tetraspanin-enriched membrane domains, where it cleaves extracellular juxtamembrane regions of many membrane proteins. Its core roles are membrane-protein ectodomain shedding and alpha-secretase processing, including non-amyloidogenic cleavage of APP, S2 cleavage of Notch receptors, and processing of adhesion molecules, growth-factor and cytokine precursors, immune receptors, and other signaling substrates. ADAM10 localization, maturation, endocytosis, and substrate selectivity are regulated by tetraspanins, clathrin/AP2-dependent trafficking, and substrate-specific adaptor contexts.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0004222 metalloendopeptidase activity
IBA
GO_REF:0000033 		ACCEPT
Summary: ADAM10 is a zinc-dependent metalloendopeptidase (EC 3.4.24.81) that hydrolyzes peptide bonds in substrate ectodomains via its HEXGHXXGXXHD catalytic motif.
Reason: This is ADAM10's core catalytic molecular function; supported by IDA/structure.
GO:0005886 plasma membrane
IBA
GO_REF:0000033 		ACCEPT
Summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
Reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
GO:0006509 membrane protein ectodomain proteolysis
IBA
GO_REF:0000033 		ACCEPT
Summary: ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more).
Reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
GO:0007219 Notch signaling pathway
IBA
GO_REF:0000033 		ACCEPT
Summary: ADAM10 performs the S2 cleavage of Notch receptors, the obligatory ectodomain-shedding step that licenses gamma-secretase and Notch signal transduction.
Reason: Notch S2 cleavage is a canonical, essential ADAM10 function; IBA/ISS-supported.
GO:0097060 synaptic membrane
IBA
GO_REF:0000033 		ACCEPT
Summary: ADAM10 is enriched at synaptic membranes where it cleaves APP and synaptic adhesion/cadherin substrates, contributing to synapse structure and plasticity.
Reason: Synaptic membrane localization is a bona fide functional site; IBA/IDA-supported.
GO:0000139 Golgi membrane
IEA
GO_REF:0000044 		ACCEPT
Summary: ADAM10 resides in the Golgi apparatus membrane as it traffics through the secretory pathway toward the cell surface.
Reason: Golgi membrane localization is part of its biosynthetic transit; EXP-supported.
GO:0004222 metalloendopeptidase activity
IEA
GO_REF:0000002 		ACCEPT
Summary: ADAM10 is a zinc-dependent metalloendopeptidase (EC 3.4.24.81) that hydrolyzes peptide bonds in substrate ectodomains via its HEXGHXXGXXHD catalytic motif.
Reason: This is ADAM10's core catalytic molecular function; supported by IDA/structure.
GO:0005737 cytoplasm
IEA
GO_REF:0000044 		KEEP AS NON CORE
Summary: A cytoplasmic pool of ADAM10 (largely immature enzyme near fibrillar structures) is reported, but cytoplasm is not where the protease acts.
Reason: Immature/cytoplasmic pool; not the catalytic compartment.
GO:0005886 plasma membrane
IEA
GO_REF:0000120 		ACCEPT
Summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
Reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
GO:0005912 adherens junction
IEA
GO_REF:0000044 		KEEP AS NON CORE
Summary: ADAM10 is clustered at adherens/zonula adherens junctions via AFDN-TSPAN33-PLEKHA7 docking, positioning it to cleave junctional cadherins like E-/VE-cadherin.
Reason: Junctional localization supports specific cadherin shedding; pleiotropic, non-core.
GO:0006508 proteolysis
IEA
GO_REF:0000002 		ACCEPT
Summary: ADAM10 carries out proteolysis of its membrane-protein substrates, the biological process directly enacted by its metalloendopeptidase activity.
Reason: Core process directly reflecting its enzymatic action.
GO:0008237 metallopeptidase activity
IEA
GO_REF:0000120 		ACCEPT
Summary: ADAM10 hydrolyzes peptide bonds as a zinc-requiring metallopeptidase, the activity underlying all of its ectodomain-shedding events.
Reason: Correct parent of its catalytic activity; experimentally supported, core.
GO:0030136 clathrin-coated vesicle
IEA
GO_REF:0000044 		ACCEPT
Summary: ADAM10 localizes to clathrin-coated vesicles, reflecting AP2-dependent endocytosis that internalizes surface enzyme and regulates its availability.
Reason: Clathrin-coated vesicle pool tied to AP2-mediated endocytic regulation.
GO:0030424 axon
IEA
GO_REF:0000044 		KEEP AS NON CORE
Summary: ADAM10 is detected in axons (by similarity to mouse O35598), consistent with neuronal expression but not central to its core sheddase mechanism.
Reason: Secondary neuronal localization inferred by similarity; non-core.
GO:0030425 dendrite
IEA
GO_REF:0000044 		KEEP AS NON CORE
Summary: ADAM10 is found in dendrites, in line with its synaptic roles, but dendritic localization itself is a secondary distribution rather than a core feature.
Reason: Secondary neuronal compartment inferred by similarity; non-core.
GO:0005515 protein binding
IPI
PMID:19587294
Tetraspanin12 regulates ADAM10-dependent cleavage of amyloid... 		MARK AS OVER ANNOTATED
Summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
Reason: Uninformative generic MF; specific partner relationships captured elsewhere.
GO:0005515 protein binding
IPI
PMID:23091066
TspanC8 tetraspanins regulate ADAM10/Kuzbanian trafficking a... 		MARK AS OVER ANNOTATED
Summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
Reason: Uninformative generic MF; specific partner relationships captured elsewhere.
GO:0005515 protein binding
IPI
PMID:23289620
Tetraspanin protein CD9 interacts with metalloprotease CD10 ... 		MARK AS OVER ANNOTATED
Summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
Reason: Uninformative generic MF; specific partner relationships captured elsewhere.
GO:0005515 protein binding
IPI
PMID:25036101
Identification of SH3 domain proteins interacting with the c... 		MARK AS OVER ANNOTATED
Summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
Reason: Uninformative generic MF; specific partner relationships captured elsewhere.
GO:0005515 protein binding
IPI
PMID:26686862
TspanC8 tetraspanins differentially regulate the cleavage of... 		MARK AS OVER ANNOTATED
Summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
Reason: Uninformative generic MF; specific partner relationships captured elsewhere.
GO:0005515 protein binding
IPI
PMID:30538620
Visualization of Alzheimer's Disease Related α-/β-/γ-Secreta... 		MARK AS OVER ANNOTATED
Summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
Reason: Uninformative generic MF; specific partner relationships captured elsewhere.
GO:0005515 protein binding
IPI
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative ... 		MARK AS OVER ANNOTATED
Summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
Reason: Uninformative generic MF; specific partner relationships captured elsewhere.
GO:0005515 protein binding
IPI
PMID:32900848
Cholesterol sensing by CD81 is important for hepatitis C vir... 		MARK AS OVER ANNOTATED
Summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
Reason: Uninformative generic MF; specific partner relationships captured elsewhere.
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		MARK AS OVER ANNOTATED
Summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
Reason: Uninformative generic MF; specific partner relationships captured elsewhere.
GO:0005515 protein binding
IPI
PMID:40205054
Multimodal cell maps as a foundation for structural and func... 		MARK AS OVER ANNOTATED
Summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
Reason: Uninformative generic MF; specific partner relationships captured elsewhere.
GO:0001701 in utero embryonic development
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: ADAM10 is essential for embryonic development (largely through Notch and cadherin substrate cleavage); this is a pleiotropic developmental requirement.
Reason: Developmental phenotype downstream of substrate cleavage; non-core.
GO:0004175 endopeptidase activity
IEA
GO_REF:0000120 		ACCEPT
Summary: ADAM10 acts as an endopeptidase, cleaving internal peptide bonds within the ectodomains of transmembrane substrates such as APP and Notch.
Reason: Endopeptidase activity is integral to its sheddase mechanism; IMP/ISS-supported.
GO:0006509 membrane protein ectodomain proteolysis
IEA
GO_REF:0000107 		ACCEPT
Summary: ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more).
Reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
GO:0007219 Notch signaling pathway
IEA
GO_REF:0000107 		ACCEPT
Summary: ADAM10 performs the S2 cleavage of Notch receptors, the obligatory ectodomain-shedding step that licenses gamma-secretase and Notch signal transduction.
Reason: Notch S2 cleavage is a canonical, essential ADAM10 function; IBA/ISS-supported.
GO:0008593 regulation of Notch signaling pathway
IEA
GO_REF:0000107 		ACCEPT
Summary: By catalyzing the rate-limiting S2 ectodomain cleavage of Notch, ADAM10 directly regulates the magnitude of Notch pathway activation.
Reason: Regulation arises directly from its catalytic Notch cleavage; core.
GO:0009986 cell surface
IEA
GO_REF:0000107 		ACCEPT
Summary: Mature ADAM10 is displayed at the cell surface where it sheds ectodomains of L1, VE-cadherin, ephrins and other transmembrane substrates.
Reason: Cell-surface display is integral to its sheddase role; IDA-supported.
GO:0014069 postsynaptic density
IEA
GO_REF:0000107 		ACCEPT
Summary: ADAM10 is targeted to the postsynaptic density, where DLG1/AP2-regulated trafficking positions it to cleave synaptic substrates during plasticity.
Reason: PSD localization is functionally relevant to its synaptic substrate cleavage.
GO:0034332 adherens junction organization
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: By shedding junctional cadherins (E-/VE-cadherin), ADAM10 remodels adherens junctions, an organizational outcome downstream of substrate cleavage.
Reason: Consequence of cadherin shedding; pleiotropic, non-core.
GO:0038004 epidermal growth factor receptor ligand maturation
IEA
GO_REF:0000107 		ACCEPT
Summary: ADAM10 sheds/matures EGFR-family ligands (e.g. HB-EGF, betacellulin), releasing active growth factor from membrane precursors to enable EGFR signaling.
Reason: Ligand-precursor shedding is a direct catalytic role of ADAM10.
GO:0046930 pore complex
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: ADAM10 is implicated in S.aureus alpha-hemolysin pore complex formation by serving as the toxin receptor, a microbial-infection context distinct from its core proteolysis.
Reason: Host-pathogen pore association; non-core component.
GO:0046931 pore complex assembly
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: By acting as the receptor for S.aureus alpha-hemolysin and clustering it at cell junctions, ADAM10 promotes assembly of cytolytic toxin pores during infection.
Reason: Microbial-infection pore-assembly role; non-core relative to its sheddase function.
GO:0070573 metallodipeptidase activity
IEA
GO_REF:0000107 		REMOVE
Summary: ADAM10 is an endopeptidase that cleaves internal bonds of large protein ectodomains, not a dipeptidase that removes C-terminal dipeptides from short peptides.
Reason: IEA-only; biologically contradicted - ADAM10 is an endopeptidase, not a dipeptidase.
GO:0090102 cochlea development
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: During organ of Corti development ADAM10 promotes pillar-cell separation by cleaving E-cadherin in an EPHA4 complex; a tissue-specific developmental role.
Reason: Organ-specific development downstream of cadherin cleavage; non-core.
GO:0097060 synaptic membrane
IEA
GO_REF:0000107 		ACCEPT
Summary: ADAM10 is enriched at synaptic membranes where it cleaves APP and synaptic adhesion/cadherin substrates, contributing to synapse structure and plasticity.
Reason: Synaptic membrane localization is a bona fide functional site; IBA/IDA-supported.
GO:0098696 regulation of neurotransmitter receptor localization to postsynaptic specialization membrane
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Through cleavage of synaptic adhesion substrates, ADAM10 influences neurotransmitter-receptor localization at the postsynaptic membrane during plasticity.
Reason: Synaptic receptor-trafficking effect downstream of shedding; non-core.
GO:0098978 glutamatergic synapse
IEA
GO_REF:0000107 		ACCEPT
Summary: ADAM10 localizes to glutamatergic synapses, where it processes synaptic adhesion molecules and APP and participates in activity-dependent plasticity.
Reason: Glutamatergic synapse is a documented functional locale for ADAM10.
GO:0099173 postsynapse organization
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: ADAM10 shapes postsynaptic organization by cleaving synaptic adhesion molecules and APP, a neuronal structural outcome of its sheddase activity.
Reason: Synaptic structural effect downstream of cleavage; non-core.
GO:0099175 regulation of postsynapse organization
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Activity-dependent ADAM10 trafficking and substrate cleavage regulate postsynaptic organization during plasticity, a downstream neuronal process.
Reason: Plasticity-linked regulatory role downstream of shedding; non-core.
GO:0140249 protein catabolic process at postsynapse
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: ADAM10 contributes to proteolytic turnover of postsynaptic substrate proteins, a localized catabolic outcome of its synaptic sheddase activity.
Reason: Localized synaptic catabolism downstream of cleavage; non-core.
GO:0140448 signaling receptor ligand precursor processing
IEA
GO_REF:0000107 		ACCEPT
Summary: ADAM10 processes membrane-bound signaling-ligand precursors (e.g. ephrins, EGFR ligands, Notch ligands) into active soluble or cleaved forms.
Reason: Precursor processing is a direct catalytic function generalizing ADAM10's shedding.
GO:1901342 regulation of vasculature development
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: ADAM10 contributes to glomerular and coronary vascular development, a pleiotropic developmental outcome of its sheddase activity on vascular substrates.
Reason: Developmental vascular role downstream of shedding; non-core.
GO:0022617 extracellular matrix disassembly
TAS
Reactome:R-HSA-1474228 		KEEP AS NON CORE
Summary: ADAM10 contributes to ECM remodeling/disassembly (Reactome collagen/ECM degradation), a downstream tissue-level consequence of its sheddase activity.
Reason: Pleiotropic ECM-remodeling role; TAS-supported, non-core.
GO:0004222 metalloendopeptidase activity
TAS
Reactome:R-HSA-4224014 		ACCEPT
Summary: ADAM10 is a zinc-dependent metalloendopeptidase (EC 3.4.24.81) that hydrolyzes peptide bonds in substrate ectodomains via its HEXGHXXGXXHD catalytic motif.
Reason: This is ADAM10's core catalytic molecular function; supported by IDA/structure.
GO:0004222 metalloendopeptidase activity
ISS
GO_REF:0000024 		ACCEPT
Summary: ADAM10 is a zinc-dependent metalloendopeptidase (EC 3.4.24.81) that hydrolyzes peptide bonds in substrate ectodomains via its HEXGHXXGXXHD catalytic motif.
Reason: This is ADAM10's core catalytic molecular function; supported by IDA/structure.
GO:1902430 negative regulation of amyloid-beta formation
IDA
PMID:33731436
GDE2-RECK controls ADAM10 α-secretase-mediated cleavage of a... 		ACCEPT
Summary: By cleaving APP within the Abeta sequence (non-amyloidogenic pathway), ADAM10 directly precludes amyloid-beta peptide generation.
Reason: Direct mechanistic consequence of alpha-secretase APP cleavage; IDA-supported, core.
GO:0004222 metalloendopeptidase activity
IDA
PMID:33731436
GDE2-RECK controls ADAM10 α-secretase-mediated cleavage of a... 		ACCEPT
Summary: ADAM10 is a zinc-dependent metalloendopeptidase (EC 3.4.24.81) that hydrolyzes peptide bonds in substrate ectodomains via its HEXGHXXGXXHD catalytic motif.
Reason: This is ADAM10's core catalytic molecular function; supported by IDA/structure.
GO:0005886 plasma membrane
IDA
PMID:33731436
GDE2-RECK controls ADAM10 α-secretase-mediated cleavage of a... 		ACCEPT
Summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
Reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
GO:0042985 negative regulation of amyloid precursor protein biosynthetic process
IDA
PMID:33731436
GDE2-RECK controls ADAM10 α-secretase-mediated cleavage of a... 		MODIFY
Summary: The IDA evidence reflects ADAM10 reducing amyloidogenic APP processing/Abeta output via alpha-secretase cleavage, not repression of APP biosynthesis per se.
Reason: Annotation conflates catabolic cleavage with biosynthesis; better captured by Abeta-formation/APP catabolic terms.
GO:0005886 plasma membrane
IDA
GO_REF:0000052 		ACCEPT
Summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
Reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
GO:0004222 metalloendopeptidase activity
IMP
PMID:28164773
Apolipoprotein E-mediated Modulation of ADAM10 in Alzheimer'... 		ACCEPT
Summary: ADAM10 is a zinc-dependent metalloendopeptidase (EC 3.4.24.81) that hydrolyzes peptide bonds in substrate ectodomains via its HEXGHXXGXXHD catalytic motif.
Reason: This is ADAM10's core catalytic molecular function; supported by IDA/structure.
GO:0000139 Golgi membrane
EXP
PMID:12475894
ADAM10-mediated cleavage of L1 adhesion molecule at the cell... 		ACCEPT
Summary: ADAM10 resides in the Golgi apparatus membrane as it traffics through the secretory pathway toward the cell surface.
Reason: Golgi membrane localization is part of its biosynthetic transit; EXP-supported.
GO:0005737 cytoplasm
EXP
PMID:30463011
A Dock-and-Lock Mechanism Clusters ADAM10 at Cell-Cell Junct... 		KEEP AS NON CORE
Summary: A cytoplasmic pool of ADAM10 (largely immature enzyme near fibrillar structures) is reported, but cytoplasm is not where the protease acts.
Reason: Immature/cytoplasmic pool; not the catalytic compartment.
GO:0005886 plasma membrane
EXP
PMID:23676497
Endocytosis of synaptic ADAM10 in neuronal plasticity and Al... 		ACCEPT
Summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
Reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
GO:0005886 plasma membrane
EXP
PMID:24990881
TREM2 mutations implicated in neurodegeneration impair cell ... 		ACCEPT
Summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
Reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
GO:0005886 plasma membrane
EXP
PMID:26686862
TspanC8 tetraspanins differentially regulate the cleavage of... 		ACCEPT
Summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
Reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
GO:0005886 plasma membrane
EXP
PMID:29430990
The metalloprotease ADAM10 (a disintegrin and metalloproteas... 		ACCEPT
Summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
Reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
GO:0005886 plasma membrane
EXP
PMID:30463011
A Dock-and-Lock Mechanism Clusters ADAM10 at Cell-Cell Junct... 		ACCEPT
Summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
Reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
GO:0004222 metalloendopeptidase activity
IDA
PMID:18355445
Ectodomain shedding of TNF-alpha is enhanced by nardilysin v... 		ACCEPT
Summary: ADAM10 is a zinc-dependent metalloendopeptidase (EC 3.4.24.81) that hydrolyzes peptide bonds in substrate ectodomains via its HEXGHXXGXXHD catalytic motif.
Reason: This is ADAM10's core catalytic molecular function; supported by IDA/structure.
GO:0006509 membrane protein ectodomain proteolysis
IDA
PMID:18355445
Ectodomain shedding of TNF-alpha is enhanced by nardilysin v... 		ACCEPT
Summary: ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more).
Reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
GO:0032760 positive regulation of tumor necrosis factor production
IDA
PMID:18355445
Ectodomain shedding of TNF-alpha is enhanced by nardilysin v... 		KEEP AS NON CORE
Summary: ADAM10 was originally identified as a pro-TNF-processing enzyme; its sheddase activity can positively influence TNF production/release.
Reason: Cytokine-output effect of shedding; non-core relative to general sheddase role.
GO:1903265 positive regulation of tumor necrosis factor-mediated signaling pathway
IDA
PMID:18355445
Ectodomain shedding of TNF-alpha is enhanced by nardilysin v... 		KEEP AS NON CORE
Summary: By releasing soluble TNF and TNF-family/receptor ectodomains, ADAM10 can enhance TNF-mediated signaling, a downstream signaling consequence.
Reason: Downstream TNF signaling effect of shedding; non-core.
GO:0042803 protein homodimerization activity
IEP
PMID:25349418
Membrane-enabled dimerization of the intrinsically disordere... 		KEEP AS NON CORE
Summary: ADAM10 can self-associate/homodimerize, which may influence its surface organization, but homodimerization is not its principal molecular function.
Reason: Ancillary oligomerization property; non-core.
GO:0042803 protein homodimerization activity
IPI
PMID:25349418
Membrane-enabled dimerization of the intrinsically disordere... 		KEEP AS NON CORE
Summary: ADAM10 can self-associate/homodimerize, which may influence its surface organization, but homodimerization is not its principal molecular function.
Reason: Ancillary oligomerization property; non-core.
GO:0005515 protein binding
IPI
PMID:31792032
TspanC8 tetraspanins differentially regulate ADAM10 endocyto... 		MARK AS OVER ANNOTATED
Summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
Reason: Uninformative generic MF; specific partner relationships captured elsewhere.
GO:0005515 protein binding
IPI
PMID:34739841
Crystal structure of the Tspan15 LEL domain reveals a conser... 		MARK AS OVER ANNOTATED
Summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
Reason: Uninformative generic MF; specific partner relationships captured elsewhere.
GO:0006509 membrane protein ectodomain proteolysis
IDA
PMID:31792032
TspanC8 tetraspanins differentially regulate ADAM10 endocyto... 		ACCEPT
Summary: ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more).
Reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
GO:0006509 membrane protein ectodomain proteolysis
IDA
PMID:34739841
Crystal structure of the Tspan15 LEL domain reveals a conser... 		ACCEPT
Summary: ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more).
Reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
GO:0016485 protein processing
ISS
GO_REF:0000024 		ACCEPT
Summary: ADAM10 proteolytically processes diverse substrate proteins, converting transmembrane precursors into cleaved/soluble products.
Reason: General proteolytic-processing role directly reflects its activity; ISS-supported.
GO:0042987 amyloid precursor protein catabolic process
ISS
GO_REF:0000024 		ACCEPT
Summary: ADAM10 is the principal alpha-secretase, cleaving APP within the amyloid-beta region to drive non-amyloidogenic APP catabolism and preclude Abeta generation.
Reason: Alpha-secretase APP cleavage is a defining ADAM10 function; IMP/ISS-supported.
GO:0004222 metalloendopeptidase activity
IDA
PMID:18676862
Tumor-associated MICA is shed by ADAM proteases. 		ACCEPT
Summary: ADAM10 is a zinc-dependent metalloendopeptidase (EC 3.4.24.81) that hydrolyzes peptide bonds in substrate ectodomains via its HEXGHXXGXXHD catalytic motif.
Reason: This is ADAM10's core catalytic molecular function; supported by IDA/structure.
GO:0010629 negative regulation of gene expression
IMP
PMID:24530397
Reciprocal effects between microRNA-140-5p and ADAM10 suppre... 		KEEP AS NON CORE
Summary: ADAM10 can indirectly modulate gene expression (e.g. via Notch/signaling substrate processing); a distal transcriptional consequence, not a direct activity.
Reason: Distal transcriptional effect of signaling cleavage; IMP-supported, non-core.
GO:0005515 protein binding
IPI
PMID:20624979
Role of a disintegrin and metalloprotease 10 in Staphylococc... 		MARK AS OVER ANNOTATED
Summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
Reason: Uninformative generic MF; specific partner relationships captured elsewhere.
GO:0005886 plasma membrane
IMP
PMID:20624979
Role of a disintegrin and metalloprotease 10 in Staphylococc... 		ACCEPT
Summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
Reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
GO:0004175 endopeptidase activity
IMP
PMID:29430990
The metalloprotease ADAM10 (a disintegrin and metalloproteas... 		ACCEPT
Summary: ADAM10 acts as an endopeptidase, cleaving internal peptide bonds within the ectodomains of transmembrane substrates such as APP and Notch.
Reason: Endopeptidase activity is integral to its sheddase mechanism; IMP/ISS-supported.
GO:0005515 protein binding
IPI
PMID:23676497
Endocytosis of synaptic ADAM10 in neuronal plasticity and Al... 		MARK AS OVER ANNOTATED
Summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
Reason: Uninformative generic MF; specific partner relationships captured elsewhere.
GO:0005515 protein binding
IPI
PMID:30463011
A Dock-and-Lock Mechanism Clusters ADAM10 at Cell-Cell Junct... 		MARK AS OVER ANNOTATED
Summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
Reason: Uninformative generic MF; specific partner relationships captured elsewhere.
GO:0005886 plasma membrane
IMP
PMID:28164773
Apolipoprotein E-mediated Modulation of ADAM10 in Alzheimer'... 		ACCEPT
Summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
Reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
GO:0006509 membrane protein ectodomain proteolysis
IMP
PMID:28164773
Apolipoprotein E-mediated Modulation of ADAM10 in Alzheimer'... 		ACCEPT
Summary: ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more).
Reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
GO:0006509 membrane protein ectodomain proteolysis
IMP
PMID:29430990
The metalloprotease ADAM10 (a disintegrin and metalloproteas... 		ACCEPT
Summary: ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more).
Reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
GO:0042987 amyloid precursor protein catabolic process
IMP
PMID:28164773
Apolipoprotein E-mediated Modulation of ADAM10 in Alzheimer'... 		ACCEPT
Summary: ADAM10 is the principal alpha-secretase, cleaving APP within the amyloid-beta region to drive non-amyloidogenic APP catabolism and preclude Abeta generation.
Reason: Alpha-secretase APP cleavage is a defining ADAM10 function; IMP/ISS-supported.
GO:0046930 pore complex
IMP
PMID:30463011
A Dock-and-Lock Mechanism Clusters ADAM10 at Cell-Cell Junct... 		KEEP AS NON CORE
Summary: ADAM10 is implicated in S.aureus alpha-hemolysin pore complex formation by serving as the toxin receptor, a microbial-infection context distinct from its core proteolysis.
Reason: Host-pathogen pore association; non-core component.
GO:0046931 pore complex assembly
IMP
PMID:30463011
A Dock-and-Lock Mechanism Clusters ADAM10 at Cell-Cell Junct... 		KEEP AS NON CORE
Summary: By acting as the receptor for S.aureus alpha-hemolysin and clustering it at cell junctions, ADAM10 promotes assembly of cytolytic toxin pores during infection.
Reason: Microbial-infection pore-assembly role; non-core relative to its sheddase function.
GO:0097060 synaptic membrane
IDA
PMID:23676497
Endocytosis of synaptic ADAM10 in neuronal plasticity and Al... 		ACCEPT
Summary: ADAM10 is enriched at synaptic membranes where it cleaves APP and synaptic adhesion/cadherin substrates, contributing to synapse structure and plasticity.
Reason: Synaptic membrane localization is a bona fide functional site; IBA/IDA-supported.
GO:0004175 endopeptidase activity
IMP
PMID:24990881
TREM2 mutations implicated in neurodegeneration impair cell ... 		ACCEPT
Summary: ADAM10 acts as an endopeptidase, cleaving internal peptide bonds within the ectodomains of transmembrane substrates such as APP and Notch.
Reason: Endopeptidase activity is integral to its sheddase mechanism; IMP/ISS-supported.
GO:0006509 membrane protein ectodomain proteolysis
IMP
PMID:24990881
TREM2 mutations implicated in neurodegeneration impair cell ... 		ACCEPT
Summary: ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more).
Reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
GO:0005515 protein binding
IPI
PMID:30312582
Astroprincin (FAM171A1, C10orf38): A Regulator of Human Cell... 		MARK AS OVER ANNOTATED
Summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
Reason: Uninformative generic MF; specific partner relationships captured elsewhere.
GO:0004175 endopeptidase activity
IMP
PMID:28855301
TREM2 shedding by cleavage at the H157-S158 bond is accelera... 		ACCEPT
Summary: ADAM10 acts as an endopeptidase, cleaving internal peptide bonds within the ectodomains of transmembrane substrates such as APP and Notch.
Reason: Endopeptidase activity is integral to its sheddase mechanism; IMP/ISS-supported.
GO:0006509 membrane protein ectodomain proteolysis
IMP
PMID:28855301
TREM2 shedding by cleavage at the H157-S158 bond is accelera... 		ACCEPT
Summary: ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more).
Reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
GO:0005515 protein binding
IPI
PMID:17301176
Synapse-associated protein-97 mediates alpha-secretase ADAM1... 		MARK AS OVER ANNOTATED
Summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
Reason: Uninformative generic MF; specific partner relationships captured elsewhere.
GO:0005788 endoplasmic reticulum lumen
TAS
Reactome:R-HSA-8952289 		KEEP AS NON CORE
Summary: Portions of nascent ADAM10 reside in the ER lumen during folding and maturation, an early secretory-pathway step rather than a site of catalysis.
Reason: Early biosynthetic compartment; non-core.
GO:0005788 endoplasmic reticulum lumen
TAS
Reactome:R-HSA-9010074 		KEEP AS NON CORE
Summary: Portions of nascent ADAM10 reside in the ER lumen during folding and maturation, an early secretory-pathway step rather than a site of catalysis.
Reason: Early biosynthetic compartment; non-core.
GO:0005788 endoplasmic reticulum lumen
TAS
Reactome:R-HSA-9010113 		KEEP AS NON CORE
Summary: Portions of nascent ADAM10 reside in the ER lumen during folding and maturation, an early secretory-pathway step rather than a site of catalysis.
Reason: Early biosynthetic compartment; non-core.
GO:0006509 membrane protein ectodomain proteolysis
IMP
PMID:20711474
ADAM10 releases a soluble form of the GPNMB/Osteoactivin ext... 		ACCEPT
Summary: ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more).
Reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
GO:0035579 specific granule membrane
TAS
Reactome:R-HSA-6799350 		KEEP AS NON CORE
Summary: ADAM10 is annotated to neutrophil specific granule membranes (Reactome neutrophil degranulation), a leukocyte-specific compartment peripheral to its core role.
Reason: Granule-membrane pool tied to neutrophil biology; non-core.
GO:0070821 tertiary granule membrane
TAS
Reactome:R-HSA-6798747 		KEEP AS NON CORE
Summary: ADAM10 is annotated to neutrophil tertiary granule membranes, reflecting its presence in granulocyte degranulation compartments rather than its core sheddase site.
Reason: Leukocyte granule compartment; non-core.
GO:0006509 membrane protein ectodomain proteolysis
IDA
PMID:18355449
Calcium-regulated intramembrane proteolysis of the RAGE rece... 		ACCEPT
Summary: ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more).
Reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
GO:0006509 membrane protein ectodomain proteolysis
IDA
PMID:18419754
The novel sorting nexin SNX33 interferes with cellular PrP f... 		ACCEPT
Summary: ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more).
Reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
GO:0005925 focal adhesion
HDA
PMID:21423176
Analysis of the myosin-II-responsive focal adhesion proteome... 		KEEP AS NON CORE
Summary: ADAM10 is detected at focal adhesions (high-throughput data); relevant in the context of S.aureus toxin-induced focal adhesion disruption but not a core site.
Reason: HDA-derived secondary localization; non-core.
GO:0016020 membrane
HDA
PMID:19946888
Defining the membrane proteome of NK cells. 		ACCEPT
Summary: ADAM10 is an integral membrane metalloprotease anchored in the lipid bilayer via a single-pass transmembrane segment.
Reason: Membrane localization is intrinsic to the type I membrane protein architecture.
GO:0009986 cell surface
IDA
PMID:23035126
The TspanC8 subgroup of tetraspanins interacts with A disint... 		ACCEPT
Summary: Mature ADAM10 is displayed at the cell surface where it sheds ectodomains of L1, VE-cadherin, ephrins and other transmembrane substrates.
Reason: Cell-surface display is integral to its sheddase role; IDA-supported.
GO:0097197 tetraspanin-enriched microdomain
IDA
PMID:23035126
The TspanC8 subgroup of tetraspanins interacts with A disint... 		ACCEPT
Summary: Mature ADAM10 partitions into tetraspanin (TspanC8)-enriched microdomains; TspanC8 partners govern its ER exit, surface compartmentalization and substrate selectivity.
Reason: TspanC8 microdomain localization is mechanistically central to ADAM10 regulation; IDA-supported.
GO:0009986 cell surface
IDA
PMID:23091066
TspanC8 tetraspanins regulate ADAM10/Kuzbanian trafficking a... 		ACCEPT
Summary: Mature ADAM10 is displayed at the cell surface where it sheds ectodomains of L1, VE-cadherin, ephrins and other transmembrane substrates.
Reason: Cell-surface display is integral to its sheddase role; IDA-supported.
GO:0097038 perinuclear endoplasmic reticulum
IDA
PMID:23091066
TspanC8 tetraspanins regulate ADAM10/Kuzbanian trafficking a... 		KEEP AS NON CORE
Summary: Immature ADAM10 accumulates in the perinuclear ER prior to TspanC8-regulated exit and maturation, representing a biosynthetic rather than functional site.
Reason: Biosynthetic ER pool; non-core localization.
GO:0070062 extracellular exosome
HDA
PMID:20458337
MHC class II-associated proteins in B-cell exosomes and pote... 		KEEP AS NON CORE
Summary: ADAM10 is detected in extracellular exosomes/released membrane vesicles, a vesicle-associated pool that can carry sheddase activity but is a peripheral distribution.
Reason: Vesicle-associated extracellular pool; non-core localization.
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-2220944 		ACCEPT
Summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
Reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-2220976 		ACCEPT
Summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
Reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-2666278 		ACCEPT
Summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
Reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-2730752 		ACCEPT
Summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
Reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-4224014 		ACCEPT
Summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
Reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-6798747 		ACCEPT
Summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
Reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-6799350 		ACCEPT
Summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
Reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-9010034 		ACCEPT
Summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
Reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-9010074 		ACCEPT
Summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
Reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-9013284 		ACCEPT
Summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
Reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
GO:0006509 membrane protein ectodomain proteolysis
IMP
PMID:18355445
Ectodomain shedding of TNF-alpha is enhanced by nardilysin v... 		ACCEPT
Summary: ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more).
Reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
GO:0006509 membrane protein ectodomain proteolysis
IMP
PMID:18373975
The role of CXCL16 and its processing metalloproteinases ADA... 		ACCEPT
Summary: ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more).
Reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
GO:0006509 membrane protein ectodomain proteolysis
IDA
PMID:18676862
Tumor-associated MICA is shed by ADAM proteases. 		ACCEPT
Summary: ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more).
Reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
GO:0004222 metalloendopeptidase activity
IMP
PMID:19114711
Substrate requirements for SPPL2b-dependent regulated intram... 		ACCEPT
Summary: ADAM10 is a zinc-dependent metalloendopeptidase (EC 3.4.24.81) that hydrolyzes peptide bonds in substrate ectodomains via its HEXGHXXGXXHD catalytic motif.
Reason: This is ADAM10's core catalytic molecular function; supported by IDA/structure.
GO:0006509 membrane protein ectodomain proteolysis
IDA
PMID:19114711
Substrate requirements for SPPL2b-dependent regulated intram... 		ACCEPT
Summary: ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more).
Reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
GO:0006509 membrane protein ectodomain proteolysis
IDA
PMID:17557115
The Fas ligand intracellular domain is released by ADAM10 an... 		ACCEPT
Summary: ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more).
Reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
GO:0006509 membrane protein ectodomain proteolysis
IMP
PMID:17965014
Regulated intramembrane proteolysis of Bri2 (Itm2b) by ADAM1... 		ACCEPT
Summary: ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more).
Reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
GO:0005515 protein binding
IPI
PMID:10527948
Evidence for an interaction of the metalloprotease-disintegr... 		MARK AS OVER ANNOTATED
Summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
Reason: Uninformative generic MF; specific partner relationships captured elsewhere.
GO:0010820 positive regulation of T cell chemotaxis
IMP
PMID:18373975
The role of CXCL16 and its processing metalloproteinases ADA... 		KEEP AS NON CORE
Summary: By shedding endothelial junctional/adhesion molecules (e.g. VE-cadherin, JAM3), ADAM10 promotes T-cell transmigration and chemotaxis.
Reason: Immune migration outcome of substrate cleavage; pleiotropic, non-core.
GO:0008284 positive regulation of cell population proliferation
IMP
PMID:18373975
The role of CXCL16 and its processing metalloproteinases ADA... 		KEEP AS NON CORE
Summary: Through Notch activation and growth-factor ligand release, ADAM10 can promote cell proliferation, a downstream consequence of its proteolysis.
Reason: Proliferation effect downstream of substrate cleavage; non-core.
GO:0030307 positive regulation of cell growth
IMP
PMID:18373975
The role of CXCL16 and its processing metalloproteinases ADA... 		KEEP AS NON CORE
Summary: By releasing growth-factor ligands (e.g. EGFR ligands) ADAM10 can promote cell growth, a downstream signaling consequence of its sheddase activity.
Reason: Growth-promotion downstream of ligand shedding; IMP-supported, non-core.
GO:0030335 positive regulation of cell migration
IMP
PMID:18373975
The role of CXCL16 and its processing metalloproteinases ADA... 		KEEP AS NON CORE
Summary: ADAM10-mediated cleavage of adhesion molecules and release of motogenic ligands can promote cell migration, a pleiotropic downstream effect.
Reason: Migration effect downstream of shedding; non-core.
GO:0005515 protein binding
IPI
PMID:15280379
ADAM binding protein Eve-1 is required for ectodomain sheddi... 		MARK AS OVER ANNOTATED
Summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
Reason: Uninformative generic MF; specific partner relationships captured elsewhere.
GO:0008237 metallopeptidase activity
IMP
PMID:12535668
Putative function of ADAM9, ADAM10, and ADAM17 as APP alpha-... 		ACCEPT
Summary: ADAM10 hydrolyzes peptide bonds as a zinc-requiring metallopeptidase, the activity underlying all of its ectodomain-shedding events.
Reason: Correct parent of its catalytic activity; experimentally supported, core.
GO:0034612 response to tumor necrosis factor
IDA
PMID:11831872
Involvement of ADAM9 in multinucleated giant cell formation ... 		KEEP AS NON CORE
Summary: ADAM10 activity is modulated within TNF responses, a context-specific cellular response rather than a defining feature of the protease.
Reason: Response-to-stimulus annotation; non-core.
GO:0042117 monocyte activation
IMP
PMID:11831872
Involvement of ADAM9 in multinucleated giant cell formation ... 		KEEP AS NON CORE
Summary: ADAM10 influences monocyte activation, an immune-cell process downstream of its shedding of cytokine receptors and adhesion/signaling substrates.
Reason: Immune-cell process secondary to sheddase activity; IMP-supported, non-core.
GO:0004222 metalloendopeptidase activity
NAS
PMID:8694785
Molecular cloning of MADM: a catalytically active mammalian ... 		ACCEPT
Summary: ADAM10 is a zinc-dependent metalloendopeptidase (EC 3.4.24.81) that hydrolyzes peptide bonds in substrate ectodomains via its HEXGHXXGXXHD catalytic motif.
Reason: This is ADAM10's core catalytic molecular function; supported by IDA/structure.
GO:0005178 integrin binding
NAS
PMID:8694785
Molecular cloning of MADM: a catalytically active mammalian ... 		KEEP AS NON CORE
Summary: ADAM10's disintegrin domain can engage integrins, a binding activity relevant to adhesion modulation but ancillary to its core proteolytic function.
Reason: Disintegrin-domain integrin binding is supplementary; NAS-supported, non-core.
GO:0007162 negative regulation of cell adhesion
NAS
PMID:8694785
Molecular cloning of MADM: a catalytically active mammalian ... 		KEEP AS NON CORE
Summary: Cleavage of adhesion molecules (L1, cadherins, JAM3) by ADAM10 reduces cell adhesion, a downstream effect of its ectodomain-shedding activity.
Reason: Adhesion modulation is a consequence of shedding; non-core.
GO:0007229 integrin-mediated signaling pathway
NAS
PMID:8694785
Molecular cloning of MADM: a catalytically active mammalian ... 		KEEP AS NON CORE
Summary: Via its disintegrin domain and integrin binding, ADAM10 can engage integrin-mediated signaling, an adhesion-linked process secondary to its core protease role.
Reason: Disintegrin/integrin signaling is ancillary; NAS-supported, non-core.
GO:0016020 membrane
NAS
PMID:8694785
Molecular cloning of MADM: a catalytically active mammalian ... 		ACCEPT
Summary: ADAM10 is an integral membrane metalloprotease anchored in the lipid bilayer via a single-pass transmembrane segment.
Reason: Membrane localization is intrinsic to the type I membrane protein architecture.
GO:0001701 in utero embryonic development
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: ADAM10 is essential for embryonic development (largely through Notch and cadherin substrate cleavage); this is a pleiotropic developmental requirement.
Reason: Developmental phenotype downstream of substrate cleavage; non-core.
GO:0007219 Notch signaling pathway
ISS
GO_REF:0000024 		ACCEPT
Summary: ADAM10 performs the S2 cleavage of Notch receptors, the obligatory ectodomain-shedding step that licenses gamma-secretase and Notch signal transduction.
Reason: Notch S2 cleavage is a canonical, essential ADAM10 function; IBA/ISS-supported.
GO:0051089 constitutive protein ectodomain proteolysis
IDA
PMID:12714508
The disintegrin-like metalloproteinase ADAM10 is involved in... 		ACCEPT
Summary: ADAM10 mediates constitutive (basal, stimulus-independent) ectodomain shedding of substrates such as prion protein and APP, alongside regulated cleavage.
Reason: Constitutive shedding is a documented core mode of ADAM10 action; IDA-supported.
GO:0004175 endopeptidase activity
ISS
GO_REF:0000024 		ACCEPT
Summary: ADAM10 acts as an endopeptidase, cleaving internal peptide bonds within the ectodomains of transmembrane substrates such as APP and Notch.
Reason: Endopeptidase activity is integral to its sheddase mechanism; IMP/ISS-supported.
GO:0005794 Golgi apparatus
IDA
PMID:12475894
ADAM10-mediated cleavage of L1 adhesion molecule at the cell... 		ACCEPT
Summary: ADAM10 transits and is detected in the Golgi apparatus, where prodomain processing by furin/PCSK7 contributes to enzyme maturation before surface delivery.
Reason: Golgi localization documented by IDA; part of the maturation/trafficking route.
GO:0005798 Golgi-associated vesicle
IDA
PMID:12475894
ADAM10-mediated cleavage of L1 adhesion molecule at the cell... 		ACCEPT
Summary: ADAM10 is found in Golgi-derived vesicles, consistent with its trafficking through and budding from the Golgi en route to the plasma membrane.
Reason: Vesicular Golgi pool documented by IDA in PubMed:12475894.
GO:0006509 membrane protein ectodomain proteolysis
IDA
PMID:12714508
The disintegrin-like metalloproteinase ADAM10 is involved in... 		ACCEPT
Summary: ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more).
Reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
GO:0007162 negative regulation of cell adhesion
IDA
PMID:12714508
The disintegrin-like metalloproteinase ADAM10 is involved in... 		KEEP AS NON CORE
Summary: Cleavage of adhesion molecules (L1, cadherins, JAM3) by ADAM10 reduces cell adhesion, a downstream effect of its ectodomain-shedding activity.
Reason: Adhesion modulation is a consequence of shedding; non-core.
GO:0007267 cell-cell signaling
NAS
PMID:12714508
The disintegrin-like metalloproteinase ADAM10 is involved in... 		KEEP AS NON CORE
Summary: By releasing soluble ligands and cleaving receptors, ADAM10 influences cell-cell signaling; this is a broad downstream readout of its proteolysis.
Reason: General signaling consequence; NAS-supported, non-core.
GO:0008237 metallopeptidase activity
IDA
PMID:12475894
ADAM10-mediated cleavage of L1 adhesion molecule at the cell... 		ACCEPT
Summary: ADAM10 hydrolyzes peptide bonds as a zinc-requiring metallopeptidase, the activity underlying all of its ectodomain-shedding events.
Reason: Correct parent of its catalytic activity; experimentally supported, core.
GO:0009986 cell surface
IDA
PMID:12475894
ADAM10-mediated cleavage of L1 adhesion molecule at the cell... 		ACCEPT
Summary: Mature ADAM10 is displayed at the cell surface where it sheds ectodomains of L1, VE-cadherin, ephrins and other transmembrane substrates.
Reason: Cell-surface display is integral to its sheddase role; IDA-supported.

Core Functions

ADAM10 is a zinc-dependent type I membrane metalloendopeptidase that performs ectodomain shedding and alpha-secretase cleavage of transmembrane substrates at the cell surface and regulated membrane compartments.

Molecular Function:
metalloendopeptidase activity
Directly Involved In:
membrane protein ectodomain proteolysis constitutive protein ectodomain proteolysis signaling receptor ligand precursor processing amyloid precursor protein catabolic process negative regulation of amyloid-beta formation Notch signaling pathway epidermal growth factor receptor ligand maturation
Cellular Locations:
plasma membrane cell surface Golgi membrane clathrin-coated vesicle tetraspanin-enriched microdomain synaptic membrane
Supporting Evidence:
  • PMID:26686862
    ADAM10 mediates the ectodomain shedding of more than 40 transmembrane proteins
  • PMID:26686862
    ADAM10-mediated cleavage of the amyloid precursor protein (APP) prevents the formation of the amyloid peptide Aβ
  • PMID:26686862
    ADAM10 is also the main protease for the cleavage of Notch receptors at a site called S2 following ligand binding
  • PMID:33731436
    ADAM10 cleaves APP to generate neuroprotective soluble APPα (sAPPα), which precludes the generation of Aβ
  • PMID:12475894
    ADAM10 is involved in L1 cleavage, which occurs at the cell surface and in the Golgi apparatus

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:10527948
Evidence for an interaction of the metalloprotease-disintegrin tumour necrosis factor alpha convertase (TACE) with mitotic arrest deficient 2 (MAD2), and of the metalloprotease-disintegrin MDC9 with a novel MAD2-related protein, MAD2beta.
PMID:11831872
Involvement of ADAM9 in multinucleated giant cell formation of blood monocytes.
PMID:12475894
ADAM10-mediated cleavage of L1 adhesion molecule at the cell surface and in released membrane vesicles.
PMID:12535668
Putative function of ADAM9, ADAM10, and ADAM17 as APP alpha-secretase.
PMID:12714508
The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell-cell adhesion.
PMID:15280379
ADAM binding protein Eve-1 is required for ectodomain shedding of epidermal growth factor receptor ligands.
PMID:17301176
Synapse-associated protein-97 mediates alpha-secretase ADAM10 trafficking and promotes its activity.
PMID:17557115
The Fas ligand intracellular domain is released by ADAM10 and SPPL2a cleavage in T-cells.
PMID:17965014
Regulated intramembrane proteolysis of Bri2 (Itm2b) by ADAM10 and SPPL2a/SPPL2b.
PMID:18355445
Ectodomain shedding of TNF-alpha is enhanced by nardilysin via activation of ADAM proteases.
PMID:18355449
Calcium-regulated intramembrane proteolysis of the RAGE receptor.
PMID:18373975
The role of CXCL16 and its processing metalloproteinases ADAM10 and ADAM17 in the proliferation and migration of human mesangial cells.
PMID:18419754
The novel sorting nexin SNX33 interferes with cellular PrP formation by modulation of PrP shedding.
PMID:18676862
Tumor-associated MICA is shed by ADAM proteases.
PMID:19114711
Substrate requirements for SPPL2b-dependent regulated intramembrane proteolysis.
PMID:19587294
Tetraspanin12 regulates ADAM10-dependent cleavage of amyloid precursor protein.
PMID:19946888
Defining the membrane proteome of NK cells.
PMID:20458337
MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis.
PMID:20624979
Role of a disintegrin and metalloprotease 10 in Staphylococcus aureus alpha-hemolysin-mediated cellular injury.
PMID:20711474
ADAM10 releases a soluble form of the GPNMB/Osteoactivin extracellular domain with angiogenic properties.
PMID:21423176
Analysis of the myosin-II-responsive focal adhesion proteome reveals a role for β-Pix in negative regulation of focal adhesion maturation.
PMID:23035126
The TspanC8 subgroup of tetraspanins interacts with A disintegrin and metalloprotease 10 (ADAM10) and regulates its maturation and cell surface expression.
PMID:23091066
TspanC8 tetraspanins regulate ADAM10/Kuzbanian trafficking and promote Notch activation in flies and mammals.
PMID:23289620
Tetraspanin protein CD9 interacts with metalloprotease CD10 and enhances its release via exosomes.
PMID:23676497
Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer's disease.
PMID:24530397
Reciprocal effects between microRNA-140-5p and ADAM10 suppress migration and invasion of human tongue cancer cells.
PMID:24990881
TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis.
PMID:25036101
Identification of SH3 domain proteins interacting with the cytoplasmic tail of the a disintegrin and metalloprotease 10 (ADAM10).
PMID:25349418
Membrane-enabled dimerization of the intrinsically disordered cytoplasmic domain of ADAM10.
PMID:26686862
TspanC8 tetraspanins differentially regulate the cleavage of ADAM10 substrates, Notch activation and ADAM10 membrane compartmentalization.
PMID:28164773
Apolipoprotein E-mediated Modulation of ADAM10 in Alzheimer's Disease.
PMID:28855301
TREM2 shedding by cleavage at the H157-S158 bond is accelerated for the Alzheimer's disease-associated H157Y variant.
PMID:29430990
The metalloprotease ADAM10 (a disintegrin and metalloprotease 10) undergoes rapid, postlysis autocatalytic degradation.
PMID:30312582
Astroprincin (FAM171A1, C10orf38): A Regulator of Human Cell Shape and Invasive Growth.
PMID:30463011
A Dock-and-Lock Mechanism Clusters ADAM10 at Cell-Cell Junctions to Promote α-Toxin Cytotoxicity.
PMID:30538620
Visualization of Alzheimer's Disease Related α-/β-/γ-Secretase Ternary Complex by Bimolecular Fluorescence Complementation Based Fluorescence Resonance Energy Transfer.
PMID:31792032
TspanC8 tetraspanins differentially regulate ADAM10 endocytosis and half-life.
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
PMID:32900848
Cholesterol sensing by CD81 is important for hepatitis C virus entry.
PMID:33731436
GDE2-RECK controls ADAM10 α-secretase-mediated cleavage of amyloid precursor protein.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:34739841
Crystal structure of the Tspan15 LEL domain reveals a conserved ADAM10 binding site.
PMID:40205054
Multimodal cell maps as a foundation for structural and functional genomics.
PMID:8694785
Molecular cloning of MADM: a catalytically active mammalian disintegrin-metalloprotease expressed in various cell types.
Reactome:R-HSA-1474228
Degradation of the extracellular matrix
Reactome:R-HSA-2220944
ADAM10/17 cleaves ligand-bound NOTCH1 PEST domain mutants to produce NEXT1 PEST domain mutants
Reactome:R-HSA-2220976
NOTCH1 HD+PEST domain mutants are cleaved by ADAM10/17 irrespective of ligand binding
Reactome:R-HSA-2666278
NOTCH1 t(7;9)(NOTCH1:M1580_K2555) is cleaved to produce NEXT1
Reactome:R-HSA-2730752
NOTCH1 HD domain mutants are cleaved to produce NEXT1 irrespective of ligand binding
Reactome:R-HSA-4224014
E-cadherin degradation by ADAM10, ADAM15
Reactome:R-HSA-6798747
Exocytosis of tertiary granule membrane proteins
Reactome:R-HSA-6799350
Exocytosis of specific granule membrane proteins
Reactome:R-HSA-8952289
FAM20C phosphorylates FAM20C substrates
Reactome:R-HSA-9010034
ADAM10:Zn2+:TSPANs cleaves APP(18-770)
Reactome:R-HSA-9010074
ADAM10:Zn2+:TSPANs translocates from ER lumen to plasma membrane
Reactome:R-HSA-9010113
ADAM10:Zn2+ binds TSPANs
Reactome:R-HSA-9013284
NOTCH3-ligand complex is cleaved to produce NEXT3

Suggested Questions for Experts

Q: How should ADAM10 substrate selectivity be represented without over-annotating every substrate-specific downstream phenotype as a separate core function?

Suggested experts: ADAM protease experts, GO proteolysis curators

Q: Which ADAM10/tetraspanin complexes determine APP alpha-secretase activity versus Notch, cadherin, immune-receptor, or toxin-related substrate cleavage in vivo?

Suggested experts: tetraspanin biology experts, APP processing experts

Q: Should pathogen-exploitation annotations such as S. aureus alpha-toxin pore formation be segregated from normal evolved ADAM10 sheddase biology in review summaries?

Suggested experts: host-pathogen annotation curators, GO biological process curators

Suggested Experiments

Experiment: Use endogenous tagged ADAM10 with substrate-specific reporters for APP, Notch, cadherin, TREM2, CX3CL1, and TNF-family substrates across defined tetraspanin backgrounds.

Hypothesis: Distinct ADAM10/tetraspanin membrane pools tune substrate choice rather than changing the core metalloprotease activity.

Type: substrate-specific sheddase reporter panel

Experiment: Compare ADAM10 Alzheimer-associated variants for maturation, cell-surface localization, APP alpha-cleavage, Notch S2 cleavage, and tetraspanin binding in human neurons.

Hypothesis: ADAM10 variants linked to Alzheimer risk reduce APP alpha-secretase activity through altered maturation or membrane-compartment localization.

Type: endogenous variant knock-in protease trafficking assay

Experiment: Quantify normal substrate shedding separately from S. aureus alpha-toxin pore formation after perturbing junctional ADAM10 docking factors.

Hypothesis: Junctional docking controls pathogen pore formation and some adhesion substrate cleavage without redefining ADAM10 core function.

Type: junctional localization and pathogen-toxin challenge assay

📚 Additional Documentation

Notes

(ADAM10-notes.md)

ADAM10 notes

Review status

  • First-pass review completed on 2026-06-19.
  • just fetch-gene-pmids human ADAM10 completed successfully; all 44 PMID-backed publication caches were present after refresh.
  • Falcon deep research was attempted with timeout 180 just deep-research-falcon human ADAM10 --fallback perplexity-lite, but the process timed out and no provider deep-research artifact was written. These notes rely on cached UniProt, GOA, and publication files.
  • just validate human ADAM10 passes cleanly.

Functional synthesis

ADAM10 is a type I membrane zinc metalloprotease and broad ectodomain sheddase. A tetraspanin-regulation study gives the cleanest high-level statement of the core function: PMID:26686862 It also captures two central substrate axes: APP PMID:26686862 and Notch PMID:26686862.

ADAM10 alpha-secretase biology is directly relevant to Alzheimer mechanisms. A full-text cached paper states PMID:33731436 and frames reduced ADAM10 activity as a shift toward beta-secretase processing. Synaptic trafficking work adds that ADAM10 resides in postsynaptic compartments and that its surface removal affects activity: PMID:23676497.

ADAM10's substrate range is much broader than APP. L1 processing supports cell-surface/Golgi/vesicle cleavage: PMID:12475894 Fractalkine/CX3CL1 processing supports constitutive shedding: PMID:12714508 TREM2 shedding, TNF-family and FasL processing, cadherin/junction substrates, and tetraspanin-dependent substrate selectivity were retained as substrate-specific consequences of the same sheddase function rather than separate core functions.

The S. aureus alpha-toxin pore annotations are biologically supported as pathogen exploitation of junctional ADAM10, not normal evolved host function: PMID:30463011 These were retained as non-core.

Annotation decisions

  • Accepted metalloendopeptidase, metallopeptidase, endopeptidase, proteolysis, membrane-protein ectodomain proteolysis, constitutive ectodomain proteolysis, signaling receptor ligand precursor processing, APP catabolic processing, negative amyloid-beta formation regulation, Notch signaling, EGFR-ligand maturation, and core membrane/Golgi/synaptic/tetraspanin-domain locations.
  • Modified negative regulation of amyloid precursor protein biosynthetic process to APP catabolic processing and negative regulation of amyloid-beta formation; ADAM10 cleaves APP rather than regulating APP biosynthesis.
  • Removed metallodipeptidase activity because ADAM10 is an endopeptidase/sheddase, not a dipeptidase.
  • Marked generic protein binding annotations as over-annotated.
  • Kept immune, adhesion, chemokine, TNF, FasL, TREM2, synaptic-organization, developmental, granule, exosome, and S. aureus alpha-toxin pore annotations as non-core substrate/context outputs.

Final action distribution: 88 ACCEPT, 42 KEEP_AS_NON_CORE, 19 MARK_AS_OVER_ANNOTATED, 1 MODIFY, 1 REMOVE.

Knowledge gaps and experiments

  • The major curation challenge is representing ADAM10 substrate specificity without turning every downstream substrate phenotype into a core function.
  • Useful experiments would combine endogenous ADAM10 variant knock-ins with substrate-specific reporters for APP, Notch, cadherins, TREM2, CX3CL1, and TNF-family substrates across defined tetraspanin backgrounds.
  • For Alzheimer biology, the highest-value assay is compartment-resolved measurement of ADAM10 maturation, synaptic/cell-surface retention, APP alpha-cleavage, and amyloid-beta suppression in human neurons.

2026-06-20 Second-Pass Review Notes

Second-pass audit confirmed the existing action calls. No annotation actions were
changed. The single REMOVE call remains appropriate for GO:0070573
metallodipeptidase activity, because ADAM10 is a membrane
metalloendopeptidase/sheddase and not a dipeptidase.

The YAML now records reference_review metadata for the main evidence anchors:
PMID:26686862 for broad ectodomain shedding, APP cleavage, Notch S2 cleavage,
and tetraspanin compartmentalization; PMID:33731436 for APP alpha-secretase
cleavage; PMID:23676497 for synaptic ADAM10 endocytosis; PMID:12475894 for L1
cleavage at cell-surface/Golgi-vesicle contexts; and PMID:30463011 for
S. aureus alpha-toxin exploitation of junctional ADAM10.

The core review remains substrate-aware but conservative: ADAM10's evolved core
function is regulated membrane-protein ectodomain shedding. Substrate-specific
outputs should be retained when directly supported, but broad downstream
developmental, immune, synaptic, pathogen, or cancer phenotypes should not be
promoted above that sheddase mechanism.

📄 View Raw YAML

 
id: O14672
gene_symbol: ADAM10
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  ADAM10 encodes a single-pass type I transmembrane zinc metalloprotease of the ADAM
  family. The mature enzyme acts mainly at the cell surface, Golgi-derived vesicles,
  synaptic membranes, adherens junctions, and tetraspanin-enriched membrane domains,
  where it cleaves extracellular juxtamembrane regions of many membrane proteins.
  Its core roles are membrane-protein ectodomain shedding and alpha-secretase processing,
  including non-amyloidogenic cleavage of APP, S2 cleavage of Notch receptors, and
  processing of adhesion molecules, growth-factor and cytokine precursors, immune
  receptors, and other signaling substrates. ADAM10 localization, maturation, endocytosis,
  and substrate selectivity are regulated by tetraspanins, clathrin/AP2-dependent
  trafficking, and substrate-specific adaptor contexts.
alternative_products:
- name: '1'
  id: O14672-1
- name: '2'
  id: O14672-2
  sequence_note: VSP_056401
existing_annotations:
- term:
    id: GO:0004222
    label: metalloendopeptidase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: ADAM10 is a zinc-dependent metalloendopeptidase (EC 3.4.24.81) that hydrolyzes peptide bonds in substrate ectodomains via its HEXGHXXGXXHD catalytic motif.
    action: ACCEPT
    reason: This is ADAM10's core catalytic molecular function; supported by IDA/structure.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
    action: ACCEPT
    reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
- term:
    id: GO:0006509
    label: membrane protein ectodomain proteolysis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: "ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more)."
    action: ACCEPT
    reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
- term:
    id: GO:0007219
    label: Notch signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: ADAM10 performs the S2 cleavage of Notch receptors, the obligatory ectodomain-shedding step that licenses gamma-secretase and Notch signal transduction.
    action: ACCEPT
    reason: Notch S2 cleavage is a canonical, essential ADAM10 function; IBA/ISS-supported.
- term:
    id: GO:0097060
    label: synaptic membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: ADAM10 is enriched at synaptic membranes where it cleaves APP and synaptic adhesion/cadherin substrates, contributing to synapse structure and plasticity.
    action: ACCEPT
    reason: Synaptic membrane localization is a bona fide functional site; IBA/IDA-supported.
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: ADAM10 resides in the Golgi apparatus membrane as it traffics through the secretory pathway toward the cell surface.
    action: ACCEPT
    reason: Golgi membrane localization is part of its biosynthetic transit; EXP-supported.
- term:
    id: GO:0004222
    label: metalloendopeptidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: ADAM10 is a zinc-dependent metalloendopeptidase (EC 3.4.24.81) that hydrolyzes peptide bonds in substrate ectodomains via its HEXGHXXGXXHD catalytic motif.
    action: ACCEPT
    reason: This is ADAM10's core catalytic molecular function; supported by IDA/structure.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: A cytoplasmic pool of ADAM10 (largely immature enzyme near fibrillar structures) is reported, but cytoplasm is not where the protease acts.
    action: KEEP_AS_NON_CORE
    reason: Immature/cytoplasmic pool; not the catalytic compartment.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
    action: ACCEPT
    reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
- term:
    id: GO:0005912
    label: adherens junction
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: ADAM10 is clustered at adherens/zonula adherens junctions via AFDN-TSPAN33-PLEKHA7 docking, positioning it to cleave junctional cadherins like E-/VE-cadherin.
    action: KEEP_AS_NON_CORE
    reason: Junctional localization supports specific cadherin shedding; pleiotropic, non-core.
- term:
    id: GO:0006508
    label: proteolysis
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: ADAM10 carries out proteolysis of its membrane-protein substrates, the biological process directly enacted by its metalloendopeptidase activity.
    action: ACCEPT
    reason: Core process directly reflecting its enzymatic action.
- term:
    id: GO:0008237
    label: metallopeptidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: ADAM10 hydrolyzes peptide bonds as a zinc-requiring metallopeptidase, the activity underlying all of its ectodomain-shedding events.
    action: ACCEPT
    reason: Correct parent of its catalytic activity; experimentally supported, core.
- term:
    id: GO:0030136
    label: clathrin-coated vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: ADAM10 localizes to clathrin-coated vesicles, reflecting AP2-dependent endocytosis that internalizes surface enzyme and regulates its availability.
    action: ACCEPT
    reason: Clathrin-coated vesicle pool tied to AP2-mediated endocytic regulation.
- term:
    id: GO:0030424
    label: axon
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: ADAM10 is detected in axons (by similarity to mouse O35598), consistent with neuronal expression but not central to its core sheddase mechanism.
    action: KEEP_AS_NON_CORE
    reason: Secondary neuronal localization inferred by similarity; non-core.
- term:
    id: GO:0030425
    label: dendrite
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: ADAM10 is found in dendrites, in line with its synaptic roles, but dendritic localization itself is a secondary distribution rather than a core feature.
    action: KEEP_AS_NON_CORE
    reason: Secondary neuronal compartment inferred by similarity; non-core.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19587294
  qualifier: enables
  review:
    summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific partner relationships captured elsewhere.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23091066
  qualifier: enables
  review:
    summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific partner relationships captured elsewhere.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23289620
  qualifier: enables
  review:
    summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific partner relationships captured elsewhere.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25036101
  qualifier: enables
  review:
    summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific partner relationships captured elsewhere.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26686862
  qualifier: enables
  review:
    summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific partner relationships captured elsewhere.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30538620
  qualifier: enables
  review:
    summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific partner relationships captured elsewhere.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific partner relationships captured elsewhere.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32900848
  qualifier: enables
  review:
    summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific partner relationships captured elsewhere.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific partner relationships captured elsewhere.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific partner relationships captured elsewhere.
- term:
    id: GO:0001701
    label: in utero embryonic development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: ADAM10 is essential for embryonic development (largely through Notch and cadherin substrate cleavage); this is a pleiotropic developmental requirement.
    action: KEEP_AS_NON_CORE
    reason: Developmental phenotype downstream of substrate cleavage; non-core.
- term:
    id: GO:0004175
    label: endopeptidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: ADAM10 acts as an endopeptidase, cleaving internal peptide bonds within the ectodomains of transmembrane substrates such as APP and Notch.
    action: ACCEPT
    reason: Endopeptidase activity is integral to its sheddase mechanism; IMP/ISS-supported.
- term:
    id: GO:0006509
    label: membrane protein ectodomain proteolysis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: "ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more)."
    action: ACCEPT
    reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
- term:
    id: GO:0007219
    label: Notch signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: ADAM10 performs the S2 cleavage of Notch receptors, the obligatory ectodomain-shedding step that licenses gamma-secretase and Notch signal transduction.
    action: ACCEPT
    reason: Notch S2 cleavage is a canonical, essential ADAM10 function; IBA/ISS-supported.
- term:
    id: GO:0008593
    label: regulation of Notch signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: By catalyzing the rate-limiting S2 ectodomain cleavage of Notch, ADAM10 directly regulates the magnitude of Notch pathway activation.
    action: ACCEPT
    reason: Regulation arises directly from its catalytic Notch cleavage; core.
- term:
    id: GO:0009986
    label: cell surface
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Mature ADAM10 is displayed at the cell surface where it sheds ectodomains of L1, VE-cadherin, ephrins and other transmembrane substrates.
    action: ACCEPT
    reason: Cell-surface display is integral to its sheddase role; IDA-supported.
- term:
    id: GO:0014069
    label: postsynaptic density
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: ADAM10 is targeted to the postsynaptic density, where DLG1/AP2-regulated trafficking positions it to cleave synaptic substrates during plasticity.
    action: ACCEPT
    reason: PSD localization is functionally relevant to its synaptic substrate cleavage.
- term:
    id: GO:0034332
    label: adherens junction organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: By shedding junctional cadherins (E-/VE-cadherin), ADAM10 remodels adherens junctions, an organizational outcome downstream of substrate cleavage.
    action: KEEP_AS_NON_CORE
    reason: Consequence of cadherin shedding; pleiotropic, non-core.
- term:
    id: GO:0038004
    label: epidermal growth factor receptor ligand maturation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: ADAM10 sheds/matures EGFR-family ligands (e.g. HB-EGF, betacellulin), releasing active growth factor from membrane precursors to enable EGFR signaling.
    action: ACCEPT
    reason: Ligand-precursor shedding is a direct catalytic role of ADAM10.
- term:
    id: GO:0046930
    label: pore complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    summary: ADAM10 is implicated in S.aureus alpha-hemolysin pore complex formation by serving as the toxin receptor, a microbial-infection context distinct from its core proteolysis.
    action: KEEP_AS_NON_CORE
    reason: Host-pathogen pore association; non-core component.
- term:
    id: GO:0046931
    label: pore complex assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: By acting as the receptor for S.aureus alpha-hemolysin and clustering it at cell junctions, ADAM10 promotes assembly of cytolytic toxin pores during infection.
    action: KEEP_AS_NON_CORE
    reason: Microbial-infection pore-assembly role; non-core relative to its sheddase function.
- term:
    id: GO:0070573
    label: metallodipeptidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: ADAM10 is an endopeptidase that cleaves internal bonds of large protein ectodomains, not a dipeptidase that removes C-terminal dipeptides from short peptides.
    action: REMOVE
    reason: IEA-only; biologically contradicted - ADAM10 is an endopeptidase, not a dipeptidase.
- term:
    id: GO:0090102
    label: cochlea development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: During organ of Corti development ADAM10 promotes pillar-cell separation by cleaving E-cadherin in an EPHA4 complex; a tissue-specific developmental role.
    action: KEEP_AS_NON_CORE
    reason: Organ-specific development downstream of cadherin cleavage; non-core.
- term:
    id: GO:0097060
    label: synaptic membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: ADAM10 is enriched at synaptic membranes where it cleaves APP and synaptic adhesion/cadherin substrates, contributing to synapse structure and plasticity.
    action: ACCEPT
    reason: Synaptic membrane localization is a bona fide functional site; IBA/IDA-supported.
- term:
    id: GO:0098696
    label: regulation of neurotransmitter receptor localization to postsynaptic specialization membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Through cleavage of synaptic adhesion substrates, ADAM10 influences neurotransmitter-receptor localization at the postsynaptic membrane during plasticity.
    action: KEEP_AS_NON_CORE
    reason: Synaptic receptor-trafficking effect downstream of shedding; non-core.
- term:
    id: GO:0098978
    label: glutamatergic synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: ADAM10 localizes to glutamatergic synapses, where it processes synaptic adhesion molecules and APP and participates in activity-dependent plasticity.
    action: ACCEPT
    reason: Glutamatergic synapse is a documented functional locale for ADAM10.
- term:
    id: GO:0099173
    label: postsynapse organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: ADAM10 shapes postsynaptic organization by cleaving synaptic adhesion molecules and APP, a neuronal structural outcome of its sheddase activity.
    action: KEEP_AS_NON_CORE
    reason: Synaptic structural effect downstream of cleavage; non-core.
- term:
    id: GO:0099175
    label: regulation of postsynapse organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Activity-dependent ADAM10 trafficking and substrate cleavage regulate postsynaptic organization during plasticity, a downstream neuronal process.
    action: KEEP_AS_NON_CORE
    reason: Plasticity-linked regulatory role downstream of shedding; non-core.
- term:
    id: GO:0140249
    label: protein catabolic process at postsynapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: ADAM10 contributes to proteolytic turnover of postsynaptic substrate proteins, a localized catabolic outcome of its synaptic sheddase activity.
    action: KEEP_AS_NON_CORE
    reason: Localized synaptic catabolism downstream of cleavage; non-core.
- term:
    id: GO:0140448
    label: signaling receptor ligand precursor processing
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: ADAM10 processes membrane-bound signaling-ligand precursors (e.g. ephrins, EGFR ligands, Notch ligands) into active soluble or cleaved forms.
    action: ACCEPT
    reason: Precursor processing is a direct catalytic function generalizing ADAM10's shedding.
- term:
    id: GO:1901342
    label: regulation of vasculature development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: ADAM10 contributes to glomerular and coronary vascular development, a pleiotropic developmental outcome of its sheddase activity on vascular substrates.
    action: KEEP_AS_NON_CORE
    reason: Developmental vascular role downstream of shedding; non-core.
- term:
    id: GO:0022617
    label: extracellular matrix disassembly
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1474228
  qualifier: involved_in
  review:
    summary: ADAM10 contributes to ECM remodeling/disassembly (Reactome collagen/ECM degradation), a downstream tissue-level consequence of its sheddase activity.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic ECM-remodeling role; TAS-supported, non-core.
- term:
    id: GO:0004222
    label: metalloendopeptidase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4224014
  qualifier: enables
  review:
    summary: ADAM10 is a zinc-dependent metalloendopeptidase (EC 3.4.24.81) that hydrolyzes peptide bonds in substrate ectodomains via its HEXGHXXGXXHD catalytic motif.
    action: ACCEPT
    reason: This is ADAM10's core catalytic molecular function; supported by IDA/structure.
- term:
    id: GO:0004222
    label: metalloendopeptidase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: ADAM10 is a zinc-dependent metalloendopeptidase (EC 3.4.24.81) that hydrolyzes peptide bonds in substrate ectodomains via its HEXGHXXGXXHD catalytic motif.
    action: ACCEPT
    reason: This is ADAM10's core catalytic molecular function; supported by IDA/structure.
- term:
    id: GO:1902430
    label: negative regulation of amyloid-beta formation
  evidence_type: IDA
  original_reference_id: PMID:33731436
  qualifier: involved_in
  review:
    summary: By cleaving APP within the Abeta sequence (non-amyloidogenic pathway), ADAM10 directly precludes amyloid-beta peptide generation.
    action: ACCEPT
    reason: Direct mechanistic consequence of alpha-secretase APP cleavage; IDA-supported, core.
- term:
    id: GO:0004222
    label: metalloendopeptidase activity
  evidence_type: IDA
  original_reference_id: PMID:33731436
  qualifier: enables
  review:
    summary: ADAM10 is a zinc-dependent metalloendopeptidase (EC 3.4.24.81) that hydrolyzes peptide bonds in substrate ectodomains via its HEXGHXXGXXHD catalytic motif.
    action: ACCEPT
    reason: This is ADAM10's core catalytic molecular function; supported by IDA/structure.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:33731436
  qualifier: is_active_in
  review:
    summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
    action: ACCEPT
    reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
- term:
    id: GO:0042985
    label: negative regulation of amyloid precursor protein biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:33731436
  qualifier: involved_in
  review:
    summary: The IDA evidence reflects ADAM10 reducing amyloidogenic APP processing/Abeta output via alpha-secretase cleavage, not repression of APP biosynthesis per se.
    action: MODIFY
    reason: Annotation conflates catabolic cleavage with biosynthesis; better captured by Abeta-formation/APP catabolic terms.
    proposed_replacement_terms:
    - id: GO:1902430
      label: negative regulation of amyloid-beta formation
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
    action: ACCEPT
    reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
- term:
    id: GO:0004222
    label: metalloendopeptidase activity
  evidence_type: IMP
  original_reference_id: PMID:28164773
  qualifier: enables
  review:
    summary: ADAM10 is a zinc-dependent metalloendopeptidase (EC 3.4.24.81) that hydrolyzes peptide bonds in substrate ectodomains via its HEXGHXXGXXHD catalytic motif.
    action: ACCEPT
    reason: This is ADAM10's core catalytic molecular function; supported by IDA/structure.
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: EXP
  original_reference_id: PMID:12475894
  qualifier: located_in
  review:
    summary: ADAM10 resides in the Golgi apparatus membrane as it traffics through the secretory pathway toward the cell surface.
    action: ACCEPT
    reason: Golgi membrane localization is part of its biosynthetic transit; EXP-supported.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:30463011
  qualifier: located_in
  review:
    summary: A cytoplasmic pool of ADAM10 (largely immature enzyme near fibrillar structures) is reported, but cytoplasm is not where the protease acts.
    action: KEEP_AS_NON_CORE
    reason: Immature/cytoplasmic pool; not the catalytic compartment.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: EXP
  original_reference_id: PMID:23676497
  qualifier: located_in
  review:
    summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
    action: ACCEPT
    reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: EXP
  original_reference_id: PMID:24990881
  qualifier: located_in
  review:
    summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
    action: ACCEPT
    reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: EXP
  original_reference_id: PMID:26686862
  qualifier: located_in
  review:
    summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
    action: ACCEPT
    reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: EXP
  original_reference_id: PMID:29430990
  qualifier: located_in
  review:
    summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
    action: ACCEPT
    reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: EXP
  original_reference_id: PMID:30463011
  qualifier: located_in
  review:
    summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
    action: ACCEPT
    reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
- term:
    id: GO:0004222
    label: metalloendopeptidase activity
  evidence_type: IDA
  original_reference_id: PMID:18355445
  qualifier: enables
  review:
    summary: ADAM10 is a zinc-dependent metalloendopeptidase (EC 3.4.24.81) that hydrolyzes peptide bonds in substrate ectodomains via its HEXGHXXGXXHD catalytic motif.
    action: ACCEPT
    reason: This is ADAM10's core catalytic molecular function; supported by IDA/structure.
- term:
    id: GO:0006509
    label: membrane protein ectodomain proteolysis
  evidence_type: IDA
  original_reference_id: PMID:18355445
  qualifier: involved_in
  review:
    summary: "ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more)."
    action: ACCEPT
    reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
- term:
    id: GO:0032760
    label: positive regulation of tumor necrosis factor production
  evidence_type: IDA
  original_reference_id: PMID:18355445
  qualifier: involved_in
  review:
    summary: ADAM10 was originally identified as a pro-TNF-processing enzyme; its sheddase activity can positively influence TNF production/release.
    action: KEEP_AS_NON_CORE
    reason: Cytokine-output effect of shedding; non-core relative to general sheddase role.
- term:
    id: GO:1903265
    label: positive regulation of tumor necrosis factor-mediated signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:18355445
  qualifier: involved_in
  review:
    summary: By releasing soluble TNF and TNF-family/receptor ectodomains, ADAM10 can enhance TNF-mediated signaling, a downstream signaling consequence.
    action: KEEP_AS_NON_CORE
    reason: Downstream TNF signaling effect of shedding; non-core.
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IEP
  original_reference_id: PMID:25349418
  qualifier: enables
  review:
    summary: ADAM10 can self-associate/homodimerize, which may influence its surface organization, but homodimerization is not its principal molecular function.
    action: KEEP_AS_NON_CORE
    reason: Ancillary oligomerization property; non-core.
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IPI
  original_reference_id: PMID:25349418
  qualifier: enables
  review:
    summary: ADAM10 can self-associate/homodimerize, which may influence its surface organization, but homodimerization is not its principal molecular function.
    action: KEEP_AS_NON_CORE
    reason: Ancillary oligomerization property; non-core.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31792032
  qualifier: enables
  review:
    summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific partner relationships captured elsewhere.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34739841
  qualifier: enables
  review:
    summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific partner relationships captured elsewhere.
- term:
    id: GO:0006509
    label: membrane protein ectodomain proteolysis
  evidence_type: IDA
  original_reference_id: PMID:31792032
  qualifier: involved_in
  review:
    summary: "ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more)."
    action: ACCEPT
    reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
- term:
    id: GO:0006509
    label: membrane protein ectodomain proteolysis
  evidence_type: IDA
  original_reference_id: PMID:34739841
  qualifier: involved_in
  review:
    summary: "ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more)."
    action: ACCEPT
    reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
- term:
    id: GO:0016485
    label: protein processing
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: ADAM10 proteolytically processes diverse substrate proteins, converting transmembrane precursors into cleaved/soluble products.
    action: ACCEPT
    reason: General proteolytic-processing role directly reflects its activity; ISS-supported.
- term:
    id: GO:0042987
    label: amyloid precursor protein catabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: ADAM10 is the principal alpha-secretase, cleaving APP within the amyloid-beta region to drive non-amyloidogenic APP catabolism and preclude Abeta generation.
    action: ACCEPT
    reason: Alpha-secretase APP cleavage is a defining ADAM10 function; IMP/ISS-supported.
- term:
    id: GO:0004222
    label: metalloendopeptidase activity
  evidence_type: IDA
  original_reference_id: PMID:18676862
  qualifier: enables
  review:
    summary: ADAM10 is a zinc-dependent metalloendopeptidase (EC 3.4.24.81) that hydrolyzes peptide bonds in substrate ectodomains via its HEXGHXXGXXHD catalytic motif.
    action: ACCEPT
    reason: This is ADAM10's core catalytic molecular function; supported by IDA/structure.
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:24530397
  qualifier: acts_upstream_of_or_within
  review:
    summary: ADAM10 can indirectly modulate gene expression (e.g. via Notch/signaling substrate processing); a distal transcriptional consequence, not a direct activity.
    action: KEEP_AS_NON_CORE
    reason: Distal transcriptional effect of signaling cleavage; IMP-supported, non-core.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20624979
  qualifier: enables
  review:
    summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific partner relationships captured elsewhere.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IMP
  original_reference_id: PMID:20624979
  qualifier: located_in
  review:
    summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
    action: ACCEPT
    reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
- term:
    id: GO:0004175
    label: endopeptidase activity
  evidence_type: IMP
  original_reference_id: PMID:29430990
  qualifier: enables
  review:
    summary: ADAM10 acts as an endopeptidase, cleaving internal peptide bonds within the ectodomains of transmembrane substrates such as APP and Notch.
    action: ACCEPT
    reason: Endopeptidase activity is integral to its sheddase mechanism; IMP/ISS-supported.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23676497
  qualifier: enables
  review:
    summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific partner relationships captured elsewhere.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30463011
  qualifier: enables
  review:
    summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific partner relationships captured elsewhere.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IMP
  original_reference_id: PMID:28164773
  qualifier: located_in
  review:
    summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
    action: ACCEPT
    reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
- term:
    id: GO:0006509
    label: membrane protein ectodomain proteolysis
  evidence_type: IMP
  original_reference_id: PMID:28164773
  qualifier: involved_in
  review:
    summary: "ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more)."
    action: ACCEPT
    reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
- term:
    id: GO:0006509
    label: membrane protein ectodomain proteolysis
  evidence_type: IMP
  original_reference_id: PMID:29430990
  qualifier: involved_in
  review:
    summary: "ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more)."
    action: ACCEPT
    reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
- term:
    id: GO:0042987
    label: amyloid precursor protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:28164773
  qualifier: involved_in
  review:
    summary: ADAM10 is the principal alpha-secretase, cleaving APP within the amyloid-beta region to drive non-amyloidogenic APP catabolism and preclude Abeta generation.
    action: ACCEPT
    reason: Alpha-secretase APP cleavage is a defining ADAM10 function; IMP/ISS-supported.
- term:
    id: GO:0046930
    label: pore complex
  evidence_type: IMP
  original_reference_id: PMID:30463011
  qualifier: part_of
  review:
    summary: ADAM10 is implicated in S.aureus alpha-hemolysin pore complex formation by serving as the toxin receptor, a microbial-infection context distinct from its core proteolysis.
    action: KEEP_AS_NON_CORE
    reason: Host-pathogen pore association; non-core component.
- term:
    id: GO:0046931
    label: pore complex assembly
  evidence_type: IMP
  original_reference_id: PMID:30463011
  qualifier: involved_in
  review:
    summary: By acting as the receptor for S.aureus alpha-hemolysin and clustering it at cell junctions, ADAM10 promotes assembly of cytolytic toxin pores during infection.
    action: KEEP_AS_NON_CORE
    reason: Microbial-infection pore-assembly role; non-core relative to its sheddase function.
- term:
    id: GO:0097060
    label: synaptic membrane
  evidence_type: IDA
  original_reference_id: PMID:23676497
  qualifier: located_in
  review:
    summary: ADAM10 is enriched at synaptic membranes where it cleaves APP and synaptic adhesion/cadherin substrates, contributing to synapse structure and plasticity.
    action: ACCEPT
    reason: Synaptic membrane localization is a bona fide functional site; IBA/IDA-supported.
- term:
    id: GO:0004175
    label: endopeptidase activity
  evidence_type: IMP
  original_reference_id: PMID:24990881
  qualifier: enables
  review:
    summary: ADAM10 acts as an endopeptidase, cleaving internal peptide bonds within the ectodomains of transmembrane substrates such as APP and Notch.
    action: ACCEPT
    reason: Endopeptidase activity is integral to its sheddase mechanism; IMP/ISS-supported.
- term:
    id: GO:0006509
    label: membrane protein ectodomain proteolysis
  evidence_type: IMP
  original_reference_id: PMID:24990881
  qualifier: involved_in
  review:
    summary: "ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more)."
    action: ACCEPT
    reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30312582
  qualifier: enables
  review:
    summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific partner relationships captured elsewhere.
- term:
    id: GO:0004175
    label: endopeptidase activity
  evidence_type: IMP
  original_reference_id: PMID:28855301
  qualifier: enables
  review:
    summary: ADAM10 acts as an endopeptidase, cleaving internal peptide bonds within the ectodomains of transmembrane substrates such as APP and Notch.
    action: ACCEPT
    reason: Endopeptidase activity is integral to its sheddase mechanism; IMP/ISS-supported.
- term:
    id: GO:0006509
    label: membrane protein ectodomain proteolysis
  evidence_type: IMP
  original_reference_id: PMID:28855301
  qualifier: involved_in
  review:
    summary: "ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more)."
    action: ACCEPT
    reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17301176
  qualifier: enables
  review:
    summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific partner relationships captured elsewhere.
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952289
  qualifier: located_in
  review:
    summary: Portions of nascent ADAM10 reside in the ER lumen during folding and maturation, an early secretory-pathway step rather than a site of catalysis.
    action: KEEP_AS_NON_CORE
    reason: Early biosynthetic compartment; non-core.
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9010074
  qualifier: located_in
  review:
    summary: Portions of nascent ADAM10 reside in the ER lumen during folding and maturation, an early secretory-pathway step rather than a site of catalysis.
    action: KEEP_AS_NON_CORE
    reason: Early biosynthetic compartment; non-core.
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9010113
  qualifier: located_in
  review:
    summary: Portions of nascent ADAM10 reside in the ER lumen during folding and maturation, an early secretory-pathway step rather than a site of catalysis.
    action: KEEP_AS_NON_CORE
    reason: Early biosynthetic compartment; non-core.
- term:
    id: GO:0006509
    label: membrane protein ectodomain proteolysis
  evidence_type: IMP
  original_reference_id: PMID:20711474
  qualifier: involved_in
  review:
    summary: "ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more)."
    action: ACCEPT
    reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
- term:
    id: GO:0035579
    label: specific granule membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799350
  qualifier: located_in
  review:
    summary: ADAM10 is annotated to neutrophil specific granule membranes (Reactome neutrophil degranulation), a leukocyte-specific compartment peripheral to its core role.
    action: KEEP_AS_NON_CORE
    reason: Granule-membrane pool tied to neutrophil biology; non-core.
- term:
    id: GO:0070821
    label: tertiary granule membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798747
  qualifier: located_in
  review:
    summary: ADAM10 is annotated to neutrophil tertiary granule membranes, reflecting its presence in granulocyte degranulation compartments rather than its core sheddase site.
    action: KEEP_AS_NON_CORE
    reason: Leukocyte granule compartment; non-core.
- term:
    id: GO:0006509
    label: membrane protein ectodomain proteolysis
  evidence_type: IDA
  original_reference_id: PMID:18355449
  qualifier: acts_upstream_of_or_within
  review:
    summary: "ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more)."
    action: ACCEPT
    reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
- term:
    id: GO:0006509
    label: membrane protein ectodomain proteolysis
  evidence_type: IDA
  original_reference_id: PMID:18419754
  qualifier: involved_in
  review:
    summary: "ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more)."
    action: ACCEPT
    reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
- term:
    id: GO:0005925
    label: focal adhesion
  evidence_type: HDA
  original_reference_id: PMID:21423176
  qualifier: located_in
  review:
    summary: ADAM10 is detected at focal adhesions (high-throughput data); relevant in the context of S.aureus toxin-induced focal adhesion disruption but not a core site.
    action: KEEP_AS_NON_CORE
    reason: HDA-derived secondary localization; non-core.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: ADAM10 is an integral membrane metalloprotease anchored in the lipid bilayer via a single-pass transmembrane segment.
    action: ACCEPT
    reason: Membrane localization is intrinsic to the type I membrane protein architecture.
- term:
    id: GO:0009986
    label: cell surface
  evidence_type: IDA
  original_reference_id: PMID:23035126
  qualifier: located_in
  review:
    summary: Mature ADAM10 is displayed at the cell surface where it sheds ectodomains of L1, VE-cadherin, ephrins and other transmembrane substrates.
    action: ACCEPT
    reason: Cell-surface display is integral to its sheddase role; IDA-supported.
- term:
    id: GO:0097197
    label: tetraspanin-enriched microdomain
  evidence_type: IDA
  original_reference_id: PMID:23035126
  qualifier: located_in
  review:
    summary: Mature ADAM10 partitions into tetraspanin (TspanC8)-enriched microdomains; TspanC8 partners govern its ER exit, surface compartmentalization and substrate selectivity.
    action: ACCEPT
    reason: TspanC8 microdomain localization is mechanistically central to ADAM10 regulation; IDA-supported.
- term:
    id: GO:0009986
    label: cell surface
  evidence_type: IDA
  original_reference_id: PMID:23091066
  qualifier: located_in
  review:
    summary: Mature ADAM10 is displayed at the cell surface where it sheds ectodomains of L1, VE-cadherin, ephrins and other transmembrane substrates.
    action: ACCEPT
    reason: Cell-surface display is integral to its sheddase role; IDA-supported.
- term:
    id: GO:0097038
    label: perinuclear endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:23091066
  qualifier: located_in
  review:
    summary: Immature ADAM10 accumulates in the perinuclear ER prior to TspanC8-regulated exit and maturation, representing a biosynthetic rather than functional site.
    action: KEEP_AS_NON_CORE
    reason: Biosynthetic ER pool; non-core localization.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:20458337
  qualifier: located_in
  review:
    summary: ADAM10 is detected in extracellular exosomes/released membrane vesicles, a vesicle-associated pool that can carry sheddase activity but is a peripheral distribution.
    action: KEEP_AS_NON_CORE
    reason: Vesicle-associated extracellular pool; non-core localization.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2220944
  qualifier: located_in
  review:
    summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
    action: ACCEPT
    reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2220976
  qualifier: located_in
  review:
    summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
    action: ACCEPT
    reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2666278
  qualifier: located_in
  review:
    summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
    action: ACCEPT
    reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2730752
  qualifier: located_in
  review:
    summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
    action: ACCEPT
    reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4224014
  qualifier: located_in
  review:
    summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
    action: ACCEPT
    reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798747
  qualifier: located_in
  review:
    summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
    action: ACCEPT
    reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799350
  qualifier: located_in
  review:
    summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
    action: ACCEPT
    reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9010034
  qualifier: located_in
  review:
    summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
    action: ACCEPT
    reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9010074
  qualifier: located_in
  review:
    summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
    action: ACCEPT
    reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9013284
  qualifier: located_in
  review:
    summary: ADAM10 is a single-pass type I membrane protein localized at the plasma membrane, the principal site where it cleaves substrate ectodomains in cis and in trans.
    action: ACCEPT
    reason: Cell membrane is the primary catalytic compartment; supported by EXP/IDA and structural work.
- term:
    id: GO:0006509
    label: membrane protein ectodomain proteolysis
  evidence_type: IMP
  original_reference_id: PMID:18355445
  qualifier: involved_in
  review:
    summary: "ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more)."
    action: ACCEPT
    reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
- term:
    id: GO:0006509
    label: membrane protein ectodomain proteolysis
  evidence_type: IMP
  original_reference_id: PMID:18373975
  qualifier: involved_in
  review:
    summary: "ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more)."
    action: ACCEPT
    reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
- term:
    id: GO:0006509
    label: membrane protein ectodomain proteolysis
  evidence_type: IDA
  original_reference_id: PMID:18676862
  qualifier: involved_in
  review:
    summary: "ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more)."
    action: ACCEPT
    reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
- term:
    id: GO:0004222
    label: metalloendopeptidase activity
  evidence_type: IMP
  original_reference_id: PMID:19114711
  qualifier: enables
  review:
    summary: ADAM10 is a zinc-dependent metalloendopeptidase (EC 3.4.24.81) that hydrolyzes peptide bonds in substrate ectodomains via its HEXGHXXGXXHD catalytic motif.
    action: ACCEPT
    reason: This is ADAM10's core catalytic molecular function; supported by IDA/structure.
- term:
    id: GO:0006509
    label: membrane protein ectodomain proteolysis
  evidence_type: IDA
  original_reference_id: PMID:19114711
  qualifier: involved_in
  review:
    summary: "ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more)."
    action: ACCEPT
    reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
- term:
    id: GO:0006509
    label: membrane protein ectodomain proteolysis
  evidence_type: IDA
  original_reference_id: PMID:17557115
  qualifier: involved_in
  review:
    summary: "ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more)."
    action: ACCEPT
    reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
- term:
    id: GO:0006509
    label: membrane protein ectodomain proteolysis
  evidence_type: IMP
  original_reference_id: PMID:17965014
  qualifier: involved_in
  review:
    summary: "ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more)."
    action: ACCEPT
    reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10527948
  qualifier: enables
  review:
    summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific partner relationships captured elsewhere.
- term:
    id: GO:0010820
    label: positive regulation of T cell chemotaxis
  evidence_type: IMP
  original_reference_id: PMID:18373975
  qualifier: involved_in
  review:
    summary: By shedding endothelial junctional/adhesion molecules (e.g. VE-cadherin, JAM3), ADAM10 promotes T-cell transmigration and chemotaxis.
    action: KEEP_AS_NON_CORE
    reason: Immune migration outcome of substrate cleavage; pleiotropic, non-core.
- term:
    id: GO:0008284
    label: positive regulation of cell population proliferation
  evidence_type: IMP
  original_reference_id: PMID:18373975
  qualifier: involved_in
  review:
    summary: Through Notch activation and growth-factor ligand release, ADAM10 can promote cell proliferation, a downstream consequence of its proteolysis.
    action: KEEP_AS_NON_CORE
    reason: Proliferation effect downstream of substrate cleavage; non-core.
- term:
    id: GO:0030307
    label: positive regulation of cell growth
  evidence_type: IMP
  original_reference_id: PMID:18373975
  qualifier: involved_in
  review:
    summary: By releasing growth-factor ligands (e.g. EGFR ligands) ADAM10 can promote cell growth, a downstream signaling consequence of its sheddase activity.
    action: KEEP_AS_NON_CORE
    reason: Growth-promotion downstream of ligand shedding; IMP-supported, non-core.
- term:
    id: GO:0030335
    label: positive regulation of cell migration
  evidence_type: IMP
  original_reference_id: PMID:18373975
  qualifier: involved_in
  review:
    summary: ADAM10-mediated cleavage of adhesion molecules and release of motogenic ligands can promote cell migration, a pleiotropic downstream effect.
    action: KEEP_AS_NON_CORE
    reason: Migration effect downstream of shedding; non-core.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15280379
  qualifier: enables
  review:
    summary: Bare 'protein binding' captures ADAM10's many IPI interactions (tetraspanins, AP2, substrates) but conveys no specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific partner relationships captured elsewhere.
- term:
    id: GO:0008237
    label: metallopeptidase activity
  evidence_type: IMP
  original_reference_id: PMID:12535668
  qualifier: enables
  review:
    summary: ADAM10 hydrolyzes peptide bonds as a zinc-requiring metallopeptidase, the activity underlying all of its ectodomain-shedding events.
    action: ACCEPT
    reason: Correct parent of its catalytic activity; experimentally supported, core.
- term:
    id: GO:0034612
    label: response to tumor necrosis factor
  evidence_type: IDA
  original_reference_id: PMID:11831872
  qualifier: involved_in
  review:
    summary: ADAM10 activity is modulated within TNF responses, a context-specific cellular response rather than a defining feature of the protease.
    action: KEEP_AS_NON_CORE
    reason: Response-to-stimulus annotation; non-core.
- term:
    id: GO:0042117
    label: monocyte activation
  evidence_type: IMP
  original_reference_id: PMID:11831872
  qualifier: involved_in
  review:
    summary: ADAM10 influences monocyte activation, an immune-cell process downstream of its shedding of cytokine receptors and adhesion/signaling substrates.
    action: KEEP_AS_NON_CORE
    reason: Immune-cell process secondary to sheddase activity; IMP-supported, non-core.
- term:
    id: GO:0004222
    label: metalloendopeptidase activity
  evidence_type: NAS
  original_reference_id: PMID:8694785
  qualifier: enables
  review:
    summary: ADAM10 is a zinc-dependent metalloendopeptidase (EC 3.4.24.81) that hydrolyzes peptide bonds in substrate ectodomains via its HEXGHXXGXXHD catalytic motif.
    action: ACCEPT
    reason: This is ADAM10's core catalytic molecular function; supported by IDA/structure.
- term:
    id: GO:0005178
    label: integrin binding
  evidence_type: NAS
  original_reference_id: PMID:8694785
  qualifier: enables
  review:
    summary: ADAM10's disintegrin domain can engage integrins, a binding activity relevant to adhesion modulation but ancillary to its core proteolytic function.
    action: KEEP_AS_NON_CORE
    reason: Disintegrin-domain integrin binding is supplementary; NAS-supported, non-core.
- term:
    id: GO:0007162
    label: negative regulation of cell adhesion
  evidence_type: NAS
  original_reference_id: PMID:8694785
  qualifier: involved_in
  review:
    summary: Cleavage of adhesion molecules (L1, cadherins, JAM3) by ADAM10 reduces cell adhesion, a downstream effect of its ectodomain-shedding activity.
    action: KEEP_AS_NON_CORE
    reason: Adhesion modulation is a consequence of shedding; non-core.
- term:
    id: GO:0007229
    label: integrin-mediated signaling pathway
  evidence_type: NAS
  original_reference_id: PMID:8694785
  qualifier: involved_in
  review:
    summary: Via its disintegrin domain and integrin binding, ADAM10 can engage integrin-mediated signaling, an adhesion-linked process secondary to its core protease role.
    action: KEEP_AS_NON_CORE
    reason: Disintegrin/integrin signaling is ancillary; NAS-supported, non-core.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: NAS
  original_reference_id: PMID:8694785
  qualifier: located_in
  review:
    summary: ADAM10 is an integral membrane metalloprotease anchored in the lipid bilayer via a single-pass transmembrane segment.
    action: ACCEPT
    reason: Membrane localization is intrinsic to the type I membrane protein architecture.
- term:
    id: GO:0001701
    label: in utero embryonic development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: ADAM10 is essential for embryonic development (largely through Notch and cadherin substrate cleavage); this is a pleiotropic developmental requirement.
    action: KEEP_AS_NON_CORE
    reason: Developmental phenotype downstream of substrate cleavage; non-core.
- term:
    id: GO:0007219
    label: Notch signaling pathway
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: ADAM10 performs the S2 cleavage of Notch receptors, the obligatory ectodomain-shedding step that licenses gamma-secretase and Notch signal transduction.
    action: ACCEPT
    reason: Notch S2 cleavage is a canonical, essential ADAM10 function; IBA/ISS-supported.
- term:
    id: GO:0051089
    label: constitutive protein ectodomain proteolysis
  evidence_type: IDA
  original_reference_id: PMID:12714508
  qualifier: involved_in
  review:
    summary: ADAM10 mediates constitutive (basal, stimulus-independent) ectodomain shedding of substrates such as prion protein and APP, alongside regulated cleavage.
    action: ACCEPT
    reason: Constitutive shedding is a documented core mode of ADAM10 action; IDA-supported.
- term:
    id: GO:0004175
    label: endopeptidase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: ADAM10 acts as an endopeptidase, cleaving internal peptide bonds within the ectodomains of transmembrane substrates such as APP and Notch.
    action: ACCEPT
    reason: Endopeptidase activity is integral to its sheddase mechanism; IMP/ISS-supported.
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IDA
  original_reference_id: PMID:12475894
  qualifier: located_in
  review:
    summary: ADAM10 transits and is detected in the Golgi apparatus, where prodomain processing by furin/PCSK7 contributes to enzyme maturation before surface delivery.
    action: ACCEPT
    reason: Golgi localization documented by IDA; part of the maturation/trafficking route.
- term:
    id: GO:0005798
    label: Golgi-associated vesicle
  evidence_type: IDA
  original_reference_id: PMID:12475894
  qualifier: located_in
  review:
    summary: ADAM10 is found in Golgi-derived vesicles, consistent with its trafficking through and budding from the Golgi en route to the plasma membrane.
    action: ACCEPT
    reason: Vesicular Golgi pool documented by IDA in PubMed:12475894.
- term:
    id: GO:0006509
    label: membrane protein ectodomain proteolysis
  evidence_type: IDA
  original_reference_id: PMID:12714508
  qualifier: involved_in
  review:
    summary: "ADAM10's defining process: proteolytic shedding of the ectodomains of numerous transmembrane proteins (L1, cadherins, ephrins, TREM2, cytokine receptors and more)."
    action: ACCEPT
    reason: This is the central biological role of ADAM10; strongly supported (IDA/IMP/IBA).
- term:
    id: GO:0007162
    label: negative regulation of cell adhesion
  evidence_type: IDA
  original_reference_id: PMID:12714508
  qualifier: involved_in
  review:
    summary: Cleavage of adhesion molecules (L1, cadherins, JAM3) by ADAM10 reduces cell adhesion, a downstream effect of its ectodomain-shedding activity.
    action: KEEP_AS_NON_CORE
    reason: Adhesion modulation is a consequence of shedding; non-core.
- term:
    id: GO:0007267
    label: cell-cell signaling
  evidence_type: NAS
  original_reference_id: PMID:12714508
  qualifier: involved_in
  review:
    summary: By releasing soluble ligands and cleaving receptors, ADAM10 influences cell-cell signaling; this is a broad downstream readout of its proteolysis.
    action: KEEP_AS_NON_CORE
    reason: General signaling consequence; NAS-supported, non-core.
- term:
    id: GO:0008237
    label: metallopeptidase activity
  evidence_type: IDA
  original_reference_id: PMID:12475894
  qualifier: enables
  review:
    summary: ADAM10 hydrolyzes peptide bonds as a zinc-requiring metallopeptidase, the activity underlying all of its ectodomain-shedding events.
    action: ACCEPT
    reason: Correct parent of its catalytic activity; experimentally supported, core.
- term:
    id: GO:0009986
    label: cell surface
  evidence_type: IDA
  original_reference_id: PMID:12475894
  qualifier: located_in
  review:
    summary: Mature ADAM10 is displayed at the cell surface where it sheds ectodomains of L1, VE-cadherin, ephrins and other transmembrane substrates.
    action: ACCEPT
    reason: Cell-surface display is integral to its sheddase role; IDA-supported.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10527948
  title: Evidence for an interaction of the metalloprotease-disintegrin tumour necrosis factor alpha convertase (TACE) with mitotic arrest deficient 2 (MAD2), and of the metalloprotease-disintegrin MDC9 with a novel MAD2-related protein, MAD2beta.
  findings: []
- id: PMID:11831872
  title: Involvement of ADAM9 in multinucleated giant cell formation of blood monocytes.
  findings: []
- id: PMID:12475894
  title: ADAM10-mediated cleavage of L1 adhesion molecule at the cell surface and in released membrane vesicles.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cached abstract/title verified; supports ADAM10 substrate cleavage at the cell surface and Golgi/vesicle contexts.
- id: PMID:12535668
  title: Putative function of ADAM9, ADAM10, and ADAM17 as APP alpha-secretase.
  findings: []
- id: PMID:12714508
  title: The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell-cell adhesion.
  findings: []
- id: PMID:15280379
  title: ADAM binding protein Eve-1 is required for ectodomain shedding of epidermal growth factor receptor ligands.
  findings: []
- id: PMID:17301176
  title: Synapse-associated protein-97 mediates alpha-secretase ADAM10 trafficking and promotes its activity.
  findings: []
- id: PMID:17557115
  title: The Fas ligand intracellular domain is released by ADAM10 and SPPL2a cleavage in T-cells.
  findings: []
- id: PMID:17965014
  title: Regulated intramembrane proteolysis of Bri2 (Itm2b) by ADAM10 and SPPL2a/SPPL2b.
  findings: []
- id: PMID:18355445
  title: Ectodomain shedding of TNF-alpha is enhanced by nardilysin via activation of ADAM proteases.
  findings: []
- id: PMID:18355449
  title: Calcium-regulated intramembrane proteolysis of the RAGE receptor.
  findings: []
- id: PMID:18373975
  title: The role of CXCL16 and its processing metalloproteinases ADAM10 and ADAM17 in the proliferation and migration of human mesangial cells.
  findings: []
- id: PMID:18419754
  title: The novel sorting nexin SNX33 interferes with cellular PrP formation by modulation of PrP shedding.
  findings: []
- id: PMID:18676862
  title: Tumor-associated MICA is shed by ADAM proteases.
  findings: []
- id: PMID:19114711
  title: Substrate requirements for SPPL2b-dependent regulated intramembrane proteolysis.
  findings: []
- id: PMID:19587294
  title: Tetraspanin12 regulates ADAM10-dependent cleavage of amyloid precursor protein.
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:20458337
  title: MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis.
  findings: []
- id: PMID:20624979
  title: Role of a disintegrin and metalloprotease 10 in Staphylococcus aureus alpha-hemolysin-mediated cellular injury.
  findings: []
- id: PMID:20711474
  title: ADAM10 releases a soluble form of the GPNMB/Osteoactivin extracellular domain with angiogenic properties.
  findings: []
- id: PMID:21423176
  title: Analysis of the myosin-II-responsive focal adhesion proteome reveals a role for β-Pix in negative regulation of focal adhesion maturation.
  findings: []
- id: PMID:23035126
  title: The TspanC8 subgroup of tetraspanins interacts with A disintegrin and metalloprotease 10 (ADAM10) and regulates its maturation and cell surface expression.
  findings: []
- id: PMID:23091066
  title: TspanC8 tetraspanins regulate ADAM10/Kuzbanian trafficking and promote Notch activation in flies and mammals.
  findings: []
- id: PMID:23289620
  title: Tetraspanin protein CD9 interacts with metalloprotease CD10 and enhances its release via exosomes.
  findings: []
- id: PMID:23676497
  title: Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer's disease.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached abstract/title verified; supports synaptic ADAM10 clathrin-dependent endocytosis and plasma-membrane removal.
- id: PMID:24530397
  title: Reciprocal effects between microRNA-140-5p and ADAM10 suppress migration and invasion of human tongue cancer cells.
  findings: []
- id: PMID:24990881
  title: TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis.
  findings: []
- id: PMID:25036101
  title: Identification of SH3 domain proteins interacting with the cytoplasmic tail of the a disintegrin and metalloprotease 10 (ADAM10).
  findings: []
- id: PMID:25349418
  title: Membrane-enabled dimerization of the intrinsically disordered cytoplasmic domain of ADAM10.
  findings: []
- id: PMID:26686862
  title: TspanC8 tetraspanins differentially regulate the cleavage of ADAM10 substrates, Notch activation and ADAM10 membrane compartmentalization.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached full text verified; supports broad ADAM10 ectodomain shedding, APP alpha-secretase cleavage, Notch S2 cleavage, and tetraspanin-dependent compartmentalization.
- id: PMID:28164773
  title: Apolipoprotein E-mediated Modulation of ADAM10 in Alzheimer's Disease.
  findings: []
- id: PMID:28855301
  title: TREM2 shedding by cleavage at the H157-S158 bond is accelerated for the Alzheimer's disease-associated H157Y variant.
  findings: []
- id: PMID:29430990
  title: The metalloprotease ADAM10 (a disintegrin and metalloprotease 10) undergoes rapid, postlysis autocatalytic degradation.
  findings: []
- id: PMID:30312582
  title: 'Astroprincin (FAM171A1, C10orf38): A Regulator of Human Cell Shape and Invasive Growth.'
  findings: []
- id: PMID:30463011
  title: A Dock-and-Lock Mechanism Clusters ADAM10 at Cell-Cell Junctions to Promote α-Toxin Cytotoxicity.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cached abstract/title verified; supports Staphylococcus aureus alpha-toxin pore formation as pathogen exploitation of junctional ADAM10, retained as non-core context.
- id: PMID:30538620
  title: Visualization of Alzheimer's Disease Related α-/β-/γ-Secretase Ternary Complex by Bimolecular Fluorescence Complementation Based Fluorescence Resonance Energy Transfer.
  findings: []
- id: PMID:31792032
  title: TspanC8 tetraspanins differentially regulate ADAM10 endocytosis and half-life.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:32900848
  title: Cholesterol sensing by CD81 is important for hepatitis C virus entry.
  findings: []
- id: PMID:33731436
  title: GDE2-RECK controls ADAM10 α-secretase-mediated cleavage of amyloid precursor protein.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached full text verified; supports ADAM10 alpha-secretase cleavage of APP to generate sAPPalpha and suppress amyloid-beta generation.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: PMID:34739841
  title: Crystal structure of the Tspan15 LEL domain reveals a conserved ADAM10 binding site.
  findings: []
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: PMID:8694785
  title: 'Molecular cloning of MADM: a catalytically active mammalian disintegrin-metalloprotease expressed in various cell types.'
  findings: []
- id: Reactome:R-HSA-1474228
  title: Degradation of the extracellular matrix
  findings: []
- id: Reactome:R-HSA-2220944
  title: ADAM10/17 cleaves ligand-bound NOTCH1 PEST domain mutants to produce NEXT1 PEST domain mutants
  findings: []
- id: Reactome:R-HSA-2220976
  title: NOTCH1 HD+PEST domain mutants are cleaved by ADAM10/17 irrespective of ligand binding
  findings: []
- id: Reactome:R-HSA-2666278
  title: NOTCH1 t(7;9)(NOTCH1:M1580_K2555) is cleaved to produce NEXT1
  findings: []
- id: Reactome:R-HSA-2730752
  title: NOTCH1 HD domain mutants are cleaved to produce NEXT1 irrespective of ligand binding
  findings: []
- id: Reactome:R-HSA-4224014
  title: E-cadherin degradation by ADAM10, ADAM15
  findings: []
- id: Reactome:R-HSA-6798747
  title: Exocytosis of tertiary granule membrane proteins
  findings: []
- id: Reactome:R-HSA-6799350
  title: Exocytosis of specific granule membrane proteins
  findings: []
- id: Reactome:R-HSA-8952289
  title: FAM20C phosphorylates FAM20C substrates
  findings: []
- id: Reactome:R-HSA-9010034
  title: ADAM10:Zn2+:TSPANs cleaves APP(18-770)
  findings: []
- id: Reactome:R-HSA-9010074
  title: ADAM10:Zn2+:TSPANs translocates from ER lumen to plasma membrane
  findings: []
- id: Reactome:R-HSA-9010113
  title: ADAM10:Zn2+ binds TSPANs
  findings: []
- id: Reactome:R-HSA-9013284
  title: NOTCH3-ligand complex is cleaved to produce NEXT3
  findings: []
core_functions:
- molecular_function:
    id: GO:0004222
    label: metalloendopeptidase activity
  description: >-
    ADAM10 is a zinc-dependent type I membrane metalloendopeptidase that performs
    ectodomain shedding and alpha-secretase cleavage of transmembrane substrates at
    the cell surface and regulated membrane compartments.
  directly_involved_in:
  - id: GO:0006509
    label: membrane protein ectodomain proteolysis
  - id: GO:0051089
    label: constitutive protein ectodomain proteolysis
  - id: GO:0140448
    label: signaling receptor ligand precursor processing
  - id: GO:0042987
    label: amyloid precursor protein catabolic process
  - id: GO:1902430
    label: negative regulation of amyloid-beta formation
  - id: GO:0007219
    label: Notch signaling pathway
  - id: GO:0038004
    label: epidermal growth factor receptor ligand maturation
  locations:
  - id: GO:0005886
    label: plasma membrane
  - id: GO:0009986
    label: cell surface
  - id: GO:0000139
    label: Golgi membrane
  - id: GO:0030136
    label: clathrin-coated vesicle
  - id: GO:0097197
    label: tetraspanin-enriched microdomain
  - id: GO:0097060
    label: synaptic membrane
  supported_by:
  - reference_id: PMID:26686862
    supporting_text: >-
      ADAM10 mediates the ectodomain shedding of more than 40 transmembrane proteins
  - reference_id: PMID:26686862
    supporting_text: >-
      ADAM10-mediated cleavage of the amyloid precursor protein (APP) prevents the
      formation of the amyloid peptide Aβ
  - reference_id: PMID:26686862
    supporting_text: >-
      ADAM10 is also the main protease for the cleavage of Notch receptors at a site
      called S2 following ligand binding
  - reference_id: PMID:33731436
    supporting_text: >-
      ADAM10 cleaves APP to generate neuroprotective soluble APPα (sAPPα), which precludes
      the generation of Aβ
  - reference_id: PMID:12475894
    supporting_text: >-
      ADAM10 is involved in L1 cleavage, which occurs at the cell surface and in the
      Golgi apparatus
proposed_new_terms: []
suggested_questions:
- question: >-
    How should ADAM10 substrate selectivity be represented without over-annotating
    every substrate-specific downstream phenotype as a separate core function?
  experts:
  - ADAM protease experts
  - GO proteolysis curators
- question: >-
    Which ADAM10/tetraspanin complexes determine APP alpha-secretase activity versus
    Notch, cadherin, immune-receptor, or toxin-related substrate cleavage in vivo?
  experts:
  - tetraspanin biology experts
  - APP processing experts
- question: >-
    Should pathogen-exploitation annotations such as S. aureus alpha-toxin pore formation
    be segregated from normal evolved ADAM10 sheddase biology in review summaries?
  experts:
  - host-pathogen annotation curators
  - GO biological process curators
suggested_experiments:
- description: >-
    Use endogenous tagged ADAM10 with substrate-specific reporters for APP, Notch,
    cadherin, TREM2, CX3CL1, and TNF-family substrates across defined tetraspanin
    backgrounds.
  hypothesis: >-
    Distinct ADAM10/tetraspanin membrane pools tune substrate choice rather than changing
    the core metalloprotease activity.
  experiment_type: substrate-specific sheddase reporter panel
- description: >-
    Compare ADAM10 Alzheimer-associated variants for maturation, cell-surface localization,
    APP alpha-cleavage, Notch S2 cleavage, and tetraspanin binding in human neurons.
  hypothesis: >-
    ADAM10 variants linked to Alzheimer risk reduce APP alpha-secretase activity through
    altered maturation or membrane-compartment localization.
  experiment_type: endogenous variant knock-in protease trafficking assay
- description: >-
    Quantify normal substrate shedding separately from S. aureus alpha-toxin pore
    formation after perturbing junctional ADAM10 docking factors.
  hypothesis: >-
    Junctional docking controls pathogen pore formation and some adhesion substrate
    cleavage without redefining ADAM10 core function.
  experiment_type: junctional localization and pathogen-toxin challenge assay