Information on EC 3.4.24.81 - ADAM10 endopeptidase

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The expected taxonomic range for this enzyme is: Coelomata

EC NUMBER
COMMENTARY
3.4.24.81
-
RECOMMENDED NAME
GeneOntology No.
ADAM10 endopeptidase
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
endopeptidase of broad specificity
show the reaction diagram
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
hydrolysis of peptide bond
-
-
-
-
additional information
-
ADAM10 mediates the epidermal growth factor-induced CD44 cleavage by the small monomeric GTPase Rac1
SYNONYMS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
a disintegrin and metalloprotease 10
-
-
a disintegrin and metalloprotease 10
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-
a disintegrin and metalloprotease 10
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a disintegrin and metalloproteinase 10
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a disintegrin and metalloproteinase 10
-
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ADAM 10
-
-
ADAM-10
-
-
-
-
ADAM-10
-
-
ADAM-10
-
disintegrin metalloprotease
ADAM10
Drosophila melanogaster Oregon R
-
-
-
ADAM10
-
a disintegrin and metalloprotease
ADAM10
-
a disintegrin and metalloproteinase
ADAM10
-
alpha-secretase
ADAM10
O14672
-
ADAM10
-
; alpha-secretase
ADAM10
-
a disintegrin and metalloprotease
ADAM10
-
a disintegrin and metalloproteinase
ADAM10
-
disintegrin-like metalloproteinase 10
CD23 metalloprotease
-
-
kuzbanian
Drosophila melanogaster Oregon R
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-
-
kuzbanian
-
-
Kuzbanian protein
-
-
-
-
mammalian disintegrin-metalloprotease
-
-
-
-
metalloproteinase 10
-
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metalloproteinase ADAM10
-
-
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metalloproteinase Kuzbanian
-
-
-
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metalloproteinase MADM
-
-
-
-
metalloproteinase-disintegrin
-
-
myelin-associated disintegrin metalloproteinase
-
-
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notch proteinase
-
-
-
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transmembrane metzinkin-protease of the a disintegrin and metalloproteinase family-10
-
-
CAS REGISTRY NUMBER
COMMENTARY
193099-09-1
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GENERAL INFORMATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
malfunction
-
mice with a dominant negative mutant of ADAM10 show lowered amounts of APPs-alpha, accompanied by an enhanced amount of plaques and learning deficiencies in the Morris water maze test
malfunction
-
knockdown of both endogenous ADAM10 and endogenous ADAM17 inhibits FcalphaR shedding, demonstrating that ADAM10 and ADAM17 are involved in the shedding of FcalphaR
malfunction
-
to determine the involvement of ADAM10 and ADAM17 in G protein coupled receptor P2Y2 nucleotide receptor-mediated EGFR activation, human salivary gland cells are transfected with small interfering RNA targeting either ADAM10 or ADAM17 mRNA. Transfection of human salivary gland cells with ADAM10 or ADAM17 siRNA partially suppress EGFR and ERK1/2 phosphorylation induced by UTP, whereas co-transfection with both ADAM10 and ADAM17 siRNA almost completely preventd UTP-induced EGFR and ERK1/2 phosphorylation
malfunction
-
ADAM10 deletion causes reduced Notch signaling in vivo. Adam10-deficient mice die at embryonic day 9.5, due to major defects in development of somites and vasculogenesis. Adam10 conditional knock-out mice die perinatally with a disrupted neocortex and a severely reduced ganglionic eminence, due to precocious neuronal differentiation resulting in an early depletion of progenitor cells; Adam10-/- mice die at embryonic day 9.5, due to major defects in development of somites and vasculogenesis. Generation of Adam10 conditional knock-out (cKO) mice using a Nestin-Cre promotor, limiting ADAM10 inactivation to neural progenitor cells (NPCs) and NPC-derived neurons and glial cells. The cKO mice die perinatally with a disrupted neocortex and a severely reduced ganglionic eminence, due to precocious neuronal differentiation resulting in an early depletion of progenitor cells. Premature neuronal differentiation is associated with aberrant neuronal migration and a disorganized laminar architecture in the neocortex. Neurospheres derived from Adam10 cKO mice have a disrupted sphere organization and segregated more neurons at the expense of astrocytes. Notch-1 processing is affected, leading to downregulation of several Notch-regulated genes in Adam10
malfunction
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deletion of ADAM10 prevents development of the entire marginal zone B cell lineage
malfunction
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B-cell specific ADAM10 deficient mice have severely diminished primary and secondary responses after T-dependent immunization, display impaired germinal center formation, have fewer follicular T helper cells, decreased follicular dendritic cell networks, and altered chemokine expression in draining lymph nodes
malfunction
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inhibition of ADAM10 activity in the intestine of mice results in a lack of compartmentalization of Paneth cells within the crypt stem cell niche
metabolism
-
ADAM10 as a major alpha-secretase in the ectodomain shedding of nectin-1
physiological function
-
regulated proteolytic processing by ADAM10 and PS/gamma-secretase is essential for the nuclear signalling of L1
physiological function
-
ADAM10 is a primary enzymes responsible for catalysing release of membrane-anchored proteins from the cell surface in metazoan organisms
physiological function
-
human mesenchymal stem cells interfere with cell–cell adhesion and enhance migration of breast cancer cells by activating ADAM10
physiological function
-
ADAM10 is a major TNF sheddase in ADAM17-deficient fibroblasts. TNF is a major pro-inflammatory cytokine with broad immune effects
physiological function
-
expression of ADAM 10 in dermal papilla cells may imply a role in the induction and development of anagen hair follicles. Expression of ADAM 10 in the outer root sheath and hair bulb assume the involvment of ADAM 10 in the downward migration of anagen hair follicles
physiological function
-
ADAM10 and TACE (EC 3.4.24.86) are the major sheddases that balance the beta-site amyloid precursor protein cleaving enzyme-driven generation of Abeta peptides. ADAM10 regulates axon withdrawal by ephrin. ADAM10 plays a role in the aetiology of Alzheimer’s disease
physiological function
-
ADAM10 and TACE (EC 3.4.24.86) are the major sheddases that balance the beta-site amyloid precursor protein cleaving enzyme-driven generation of Abeta peptides
physiological function
O35598
ADAM10 is involved in the proteolytic processing and shedding of proteins such as the amyloid precursor protein, cadherins, and the Notch receptors, thereby initiating the regulated intramembrane proteolysis of these proteins. ADAM10 performs a dual role in cells, as a metalloprotease when it is membrane-bound, and as a potential signaling protein once cleaved by ADAM9/15 and the alpha-secretase
physiological function
-
ADAM10 is required for Notch1 site 2 cleavage
physiological function
-
the enzyme is responsible for the ectodomain shedding of a number of proteins implicated in the pathogenesis of diseases ranging from cancer to Alzheimer's disease
physiological function
-
ADAM10 and ADAM17 are activated by G protein-coupled receptor P2Y2
physiological function
-
ADAM10 plays a central role in the developing brain by controlling mainly Notch-dependent pathways but likely also by reducing surface shedding of other neuronal membrane proteins including amyloid precursor protein; ADAM10 represents the most important amyloid precursor protein alpha-secretase in brain. ADAM10 plays a central role in the developing brain by controlling mainly Notch-dependent pathways but likely also by reducing surface shedding of other neuronal membrane proteins including amyloid precursor protein
physiological function
-
ADAMs 10 and 17 represent differentially regulated components of a general shedding machinery for membrane proteins such as transforming growth factor alpha, L-selectin, and tumor necrosis factor alpha
physiological function
-
although Notch1 is a substrate for both ADAM10 and ADAM17, the particular ADAM required for receptor activation is context dependent. Specifically, ADAM10 is absolutely required for Notch1 signaling induced by ligands. Noth proteases participated in signaling intrinsic to Notch1 mutations associated with leukemia
physiological function
-
ADAM10 has no direct influence on PrPc proteolytic processing in vivo. Overexpression of active ADAM10 in transgenic mice leads to a reduced amount of PrP mRNA
physiological function
-
ADAM10 cleaves ephrin from its membrane tether on the opposite cell (through its so-called sheddase activity), thereby separating the cell-cell connection and allowing the signalling complex to internalise. Ephrin-A5 shedding by ADAM10 is controlled by steric hindrance exerted by the membrane-proximal EphA3 kinase domain, which prevents the functional interaction with ADAM10 that is needed for efficient substrate (ephrin) cleavage to occur
physiological function
-
ADAM10 activity is required for insulin-like growth factor-1-induced secretion of soluble amyloid-beta precurso protein
physiological function
-
ADAM10 is the major alpha-secretase in vivo
physiological function
-
ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo. ADAM10 initiates Notch2 signaling
physiological function
-
ADAM10 is essential for the maintenance of lymphoid structure after antigen challenge
physiological function
-
annexin A1 proteolytic processing by ADAM10 into a chemotactic peptide represents a final events during apoptosis, which after the transition to secondary necrosis contributes to the recruitment of monocytes and the prevention of inflammation
physiological function
-
ADAM10 localization and activity at synapse regulate excitatory synapses through N-cadherin cleavage, influence spine morphology, subunit composition and function of synaptic AMPA receptors
physiological function
-
ADAM10 activity acts continuously at sites of EphB-ephrin-B interaction to prevent the formation of E-cadherin-mediated cell adhesion. ADAM10 metalloproteinase activity is required for EphB/ephrin-B-mediated cell sorting and E-cadherin remodelling
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
2,4-dinitrophenyl-EVHHQKLVFFAE + H2O
?
show the reaction diagram
-
-
-
-
?
2,4-dinitrophenyl-HGDQMAQKSQST + H2O
?
show the reaction diagram
-
-
-
-
?
2,4-dinitrophenyl-LPQLENVKGTED + H2O
?
show the reaction diagram
-
-
-
-
?
2,4-dinitrophenyl-RAEQQRLKSQDL + H2O
?
show the reaction diagram
-
-
-
-
?
2,4-dinitrophenyl-SPLAQAVRSSSR + H2O
?
show the reaction diagram
-
-
-
-
?
Abz-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser-Ser-Arg-Dap(dnp)-NH2 + H2O
?
show the reaction diagram
-
-
-
-
?
amyloid precursor protein + H2O
?
show the reaction diagram
-
-
-
-
?
amyloid precursor protein + H2O
?
show the reaction diagram
-
-
-
-
?
amyloid precursor protein + H2O
?
show the reaction diagram
-
ADAM10 plays a central role in the developing brain by controlling mainly Notch-dependent pathways but likely also by reducing surface shedding of other neuronal membrane proteins including amyloid precursor protein
-
-
?
amyloid precursor protein + H2O
?
show the reaction diagram
-
cleaves amyloid precursor protein in its transmembrane region alpha-secretase activity
-
-
?
amyloid precursor protein + H2O
?
show the reaction diagram
-
tetraspanin12 associates with mature ADAM10, promotes ADAM10 maturation, and enhances ADAM10 dependent cleavage of amyloid precursor protein
-
-
?
amyloid precursor-like protein 2 + H2O
soluble amyloid precursor-like protein 2 ectodomain + C-terminal fragments
show the reaction diagram
-
ADAM10 cleaves after Arg670
-
-
?
annexin A1 + H2O
?
show the reaction diagram
-
ADAM10 cleaves within the N-terminal domain after Phe7, cleavage occurs on the outer cell surface during secondary but not primary necrosis
-
-
?
beta-amyloid precursor protein
sAPP-alpha fragment + C-terminal fragment
show the reaction diagram
-
-
-
?
beta-amyloid precursor protein
sAPP-alpha fragment + C-terminal fragment
show the reaction diagram
-
-
-
-
?
beta-amyloid precursor protein
sAPP-alpha fragment + C-terminal fragment
show the reaction diagram
-
A172 cell line has alpha-secretase activity
-
?
beta-amyloid precursor protein
sAPP-alpha fragment + C-terminal fragment
show the reaction diagram
-
LoVo cell line overexpressing ADAM10 secreted a 185% of sAPP-alpha over control values
-
?
beta-amyloid precursor protein
sAPP-alpha fragment + C-terminal fragment
show the reaction diagram
-
platelet and cerebrospinal fluid have lower levels of alpha-APP in Alzheimer patients
-
-
?
beta-amyloid precursor protein + H2O
?
show the reaction diagram
-
-
-
-
?
beta-amyloid precursor protein + H2O
sAPP-alpha fragment + C-terminal fragment
show the reaction diagram
-
-
-
-
?
beta-amyloid precursor protein + H2O
sAPP-alpha fragment + C-terminal fragment
show the reaction diagram
-
-
-
-
?
beta-amyloid precursor protein + H2O
sAPP-alpha fragment of beta-amyloid precursor protein + C-terminal fragment of beta-amyloid precursor protein
show the reaction diagram
-
-
-
-
?
beta-amyloid precursor protein + H2O
sAPP-alpha fragment of beta-amyloid precursor protein + C-terminal fragment of beta-amyloid precursor protein
show the reaction diagram
-
-
-
-
?
biotin-SPLAQAVRSSSRTPS-NH2 + H2O
?
show the reaction diagram
-
-
-
-
?
Bri2 protein + H2O
?
show the reaction diagram
-
-
the ADAM10 cleavage liberates the BRICHOS domain of Bri2
-
?
C4.4A + H2O
?
show the reaction diagram
-
the proteomic identification of a novel substrate for ADAM10 and ADAM17 is presented by using SILAC (Stable Isotope Labeling by Amino acids in Cell culture), a proteomic technique based on the differential metabolic labeling of cells in different conditions. This is applied to MCF7 cells derived from an invasive mammary tumor, and the same cells expressing shRNAs that knock down ADAM10 or -17. C4.4A is a member of the Ly-6 family originally identified in a screening designed to select membrane proteins differentially expressed on metastatic pancreatic adenocarcinoma cells
-
-
?
CD23 + H2O
?
show the reaction diagram
-
-
-
-
?
CD23 + H2O
?
show the reaction diagram
-
-
-
-
?
CD46 + H2O
sCD46-ectodomain + ?
show the reaction diagram
-
-
-
-
?
cellular prion protein
N1 fragment + C-terminal fragment
show the reaction diagram
-
constitutive protein cleavage
-
?
cellular prion protein
N1 fragment + C-terminal fragment
show the reaction diagram
-
knock out line has 51% of reduction in N1 formation
-
?
collagen XVII/BP180 + H2O
?
show the reaction diagram
-
ADAM9 and ADAM10 are the most prominent collagen XVII sheddases in primary keratinocytes
-
-
?
CXCL16 + H2O
?
show the reaction diagram
-
-
-
-
?
dabcyl-LAQA(homoPhe)RSC(fluorescein)-NH2 + H2O
?
show the reaction diagram
-
-
-
-
?
dabcyl-LAQA(homoPhe)RSC(fluorescein)-NH2 + H2O
?
show the reaction diagram
-
-
-
-
?
E-cadherin + H2O
?
show the reaction diagram
-
-
-
-
?
ephrin-A2 + H2O
?
show the reaction diagram
-
-
-
-
?
ephrin-A5 + H2O
?
show the reaction diagram
-
-
-
-
?
epidermal growth factor + H2O
?
show the reaction diagram
-
-
-
-
?
epithelial cadherin + H2O
38-kDa C-terminal fragment + ?
show the reaction diagram
-
-
-
-
?
epithelial growth factor receptor
?
show the reaction diagram
-
activation of the receptor leads to cleavage of transmembrane heparin-binding site by ADAM10 in response to infection by Staphylococcus aureus
-
-
?
extracellular domain of Klotho + H2O
130000 Da Klotho fragment + 68000 Da Klotho fragment
show the reaction diagram
-
-
-
-
?
Fas ligand + H2O
soluble Fas ligand ectodomain + ?
show the reaction diagram
-
transmembrane protein
-
-
?
FcalphaR + H2O
?
show the reaction diagram
-
FcaR (CD89) is the Fc receptor for immunoglobulin A. ADAM10 and ADAM17 are involved in the shedding of FcalphaR, FcaR (CD89) is the Fc receptor for immunoglobulin A
-
-
?
gamma-protocadherin C3 + H2O
25-kDa C-terminal fragment of gamma-protocadherin C3 + ?
show the reaction diagram
-
-
-
-
?
interleukin-6 receptor + H2O
?
show the reaction diagram
-
apoptosis-induced shedding of interleukin-6 receptor is mediated by ADAM10
-
-
?
L-selectin + H2O
?
show the reaction diagram
-
-, ADAMs 10 and 17 represent differentially regulated components of a general shedding machinery for membrane proteins such as transforming growth factor alpha, L-selectin, and tumor necrosis factor alpha
-
-
?
L1 adhesion molecule
L1-200 fragment + L1-32 fragment + ?
show the reaction diagram
-
ADAM10 cleaves L1
-
?
L1 cell adhesion molecule + H2O
?
show the reaction diagram
-
-
-
-
?
L1 cell-adhesion molecule + H2O
?
show the reaction diagram
-
-, the ectodomain of L1 cell-adhesion molecule is cleaved at the plasma membrane by ADAM10. Regulated proteolytic processing by ADAM10 and PS/gamma-secretase is essential for the nuclear signalling of L1 in human carcinoma cell lines
-
-
?
N-cadherin + H2O
?
show the reaction diagram
-
treatment with the PKC activator phorbol 12-myristate 13-acetate (PMA) increases N-cadherin cleavage. And treatment of the cells with PKC-alpha inhibitor Gö6976 [12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole] or PKC-alpha short hairpin RNA significantly reduces N-cadherin cleavage
-
-
?
N-cadherin + H2O
?
show the reaction diagram
-
ADAM10/SAP97 interaction is required for ADAM10-mediated cleavage of synaptic N-cadherin
-
-
?
nectin 1 + H2O
?
show the reaction diagram
-
ADAM10 is the major secretase responsible for nectin-1 ectodomain cleavage in neurons and the brain
-
-
?
neuronal cadherin + H2O
neuronal cadherin C-terminal fragment + ?
show the reaction diagram
-
-
-
-
?
Notch1 + H2O
?
show the reaction diagram
-
-
-
-
?
Notch1 + H2O
?
show the reaction diagram
-
ADAM10 is required for site 2 cleavage of the single-pass transmembrane receptor Notch1
-
-
?
Notch1 + H2O
?
show the reaction diagram
-
ADAM10 plays a central role in the developing brain by controlling mainly Notch-dependent pathways but likely also by reducing surface shedding of other neuronal membrane proteins including amyloid precursor protein
-
-
?
Notch1 + H2O
?
show the reaction diagram
-
although Notch1 is a substrate for both ADAM10 and ADAM17, the particular ADAM required for receptor activation is context dependent. Specifically, ADAM10 is absolutely required for Notch1 signaling induced by ligands. Noth proteases participated in signaling intrinsic to Notch1 mutations associated with leukemia
-
-
?
Notch1 + H2O
?
show the reaction diagram
-
ADAM10 is required for Notch1 site 2 cleavage
-
-
?
protocadherin + H2O
?
show the reaction diagram
-
ADAM10 cleaves the extracellular domain of protocadherin
-
-
?
RAGE + H2O
?
show the reaction diagram
-
a soluble form of the receptor for advanced glycation endproducts (RAGE) is produced by proteolytic cleavage of the membrane-bound form by ADAM10
-
-
?
receptor protein tyrosine phosphatase K + H2O
?
show the reaction diagram
-
-
-
-
?
thyrotropin receptor + H2O
?
show the reaction diagram
O14672
-
-
-
?
TNF-alpha + H2O
?
show the reaction diagram
-
-
-
-
?
transforming growth factor alpha + H2O
?
show the reaction diagram
-
-, ADAMs 10 and 17 represent differentially regulated components of a general shedding machinery for membrane proteins such as transforming growth factor alpha, L-selectin, and tumor necrosis factor alpha
-
-
?
tumor necrosis factor alpha + H2O
?
show the reaction diagram
-
-, ADAMs 10 and 17 represent differentially regulated components of a general shedding machinery for membrane proteins such as transforming growth factor alpha, L-selectin, and tumor necrosis factor alpha
-
-
?
VE-cadherin + H2O
?
show the reaction diagram
-
VE-cadherin is specifically cleaved by the disintegrin and metalloprotease ADAM10 in its ectodomain, releasing a soluble fragment and generating a carboxyl-terminal membrane-bound stub, which is a substrate for a subsequent gamma-secretase cleavage
-
-
?
betacellulin + H2O
?
show the reaction diagram
-
-
-
-
?
betacellulin precursor + H2O
additional information
-
-
-
one major (26-28 kDa) soluble form + two minor (20 and 15 kDa) soluble forms + cellular remnant lacking the ectodomain (12 kDa)
-
?
L1-CAM extracellular domain + H2O
?
show the reaction diagram
-
-
-
-
?
additional information
?
-
-
TIMP1 and TIMP-3 (tissue inhibitors of metalloproteinase) interact and inhibit ADAM10
-
-
-
additional information
?
-
-
ADAM10 cleaves ephrin from its membrane tether on the opposite cell (through its so-called sheddase activity), thereby separating the cell-cell connection and allowing the signalling complex to internalise. Ephrin-A5 shedding by ADAM10 is controlled by steric hindrance exerted by the membrane-proximal EphA3 kinase domain, which prevents the functional interaction with ADAM10 that is needed for efficient substrate (ephrin) cleavage to occur
-
-
-
additional information
?
-
-
peptide libraries are used to define the cleavage site selectivity of TACE (EC 3.4.24.86) and ADAM10. The two proteases have distinct primary sequence requirements at multiple positions surrounding the cleavage site in their substrates, which allows to generate peptide substrates that are highly specific for each of these proteases. The major difference between the two protease specificities maps to the P1' position (immediately downstream of the cleavage site) of the substrate. At this position, TACE is selective for smaller aliphatic residues, whereas ADAM10 can accommodate aromatic amino acids. Using mutagenesis three residues in the S1' pockets of these enzymes are identified that dramatically influence specificity for both peptide and protein substrates
-
-
-
neuronal cadherin + H2O
?
show the reaction diagram
-
-
-
-
?
neuronal cadherin + H2O
additional information
-
-
-
40 kDa C-terminal fragment + N-terminal 95 kDa fragment
-
?
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
amyloid precursor protein + H2O
?
show the reaction diagram
-
ADAM10 plays a central role in the developing brain by controlling mainly Notch-dependent pathways but likely also by reducing surface shedding of other neuronal membrane proteins including amyloid precursor protein
-
-
?
amyloid precursor protein + H2O
?
show the reaction diagram
-
cleaves amyloid precursor protein in its transmembrane region alpha-secretase activity
-
-
?
amyloid precursor protein + H2O
?
show the reaction diagram
-
tetraspanin12 associates with mature ADAM10, promotes ADAM10 maturation, and enhances ADAM10 dependent cleavage of amyloid precursor protein
-
-
?
annexin A1 + H2O
?
show the reaction diagram
-
ADAM10 cleaves within the N-terminal domain after Phe7, cleavage occurs on the outer cell surface during secondary but not primary necrosis
-
-
?
beta-amyloid precursor protein
sAPP-alpha fragment + C-terminal fragment
show the reaction diagram
-
-
-
?
beta-amyloid precursor protein
sAPP-alpha fragment + C-terminal fragment
show the reaction diagram
-
-
-
-
?
beta-amyloid precursor protein
sAPP-alpha fragment + C-terminal fragment
show the reaction diagram
-
A172 cell line has alpha-secretase activity
-
?
beta-amyloid precursor protein
sAPP-alpha fragment + C-terminal fragment
show the reaction diagram
-
LoVo cell line overexpressing ADAM10 secreted a 185% of sAPP-alpha over control values
-
?
beta-amyloid precursor protein
sAPP-alpha fragment + C-terminal fragment
show the reaction diagram
-
platelet and cerebrospinal fluid have lower levels of alpha-APP in Alzheimer patients
-
-
?
beta-amyloid precursor protein + H2O
?
show the reaction diagram
-
-
-
-
?
beta-amyloid precursor protein + H2O
sAPP-alpha fragment of beta-amyloid precursor protein + C-terminal fragment of beta-amyloid precursor protein
show the reaction diagram
-
-
-
-
?
CD23 + H2O
?
show the reaction diagram
-
-
-
-
?
cellular prion protein
N1 fragment + C-terminal fragment
show the reaction diagram
-
constitutive protein cleavage
-
?
cellular prion protein
N1 fragment + C-terminal fragment
show the reaction diagram
-
knock out line has 51% of reduction in N1 formation
-
?
collagen XVII/BP180 + H2O
?
show the reaction diagram
-
ADAM9 and ADAM10 are the most prominent collagen XVII sheddases in primary keratinocytes
-
-
?
E-cadherin + H2O
?
show the reaction diagram
-
-
-
-
?
epithelial growth factor receptor
?
show the reaction diagram
-
activation of the receptor leads to cleavage of transmembrane heparin-binding site by ADAM10 in response to infection by Staphylococcus aureus
-
-
?
FcalphaR + H2O
?
show the reaction diagram
-
FcaR (CD89) is the Fc receptor for immunoglobulin A. ADAM10 and ADAM17 are involved in the shedding of FcalphaR
-
-
?
L-selectin + H2O
?
show the reaction diagram
-
ADAMs 10 and 17 represent differentially regulated components of a general shedding machinery for membrane proteins such as transforming growth factor alpha, L-selectin, and tumor necrosis factor alpha
-
-
?
L1 adhesion molecule
L1-200 fragment + L1-32 fragment + ?
show the reaction diagram
-
ADAM10 cleaves L1
-
?
Notch1 + H2O
?
show the reaction diagram
-
ADAM10 is required for site 2 cleavage of the single-pass transmembrane receptor Notch1
-
-
?
Notch1 + H2O
?
show the reaction diagram
-
ADAM10 plays a central role in the developing brain by controlling mainly Notch-dependent pathways but likely also by reducing surface shedding of other neuronal membrane proteins including amyloid precursor protein
-
-
?
Notch1 + H2O
?
show the reaction diagram
-
although Notch1 is a substrate for both ADAM10 and ADAM17, the particular ADAM required for receptor activation is context dependent. Specifically, ADAM10 is absolutely required for Notch1 signaling induced by ligands. Noth proteases participated in signaling intrinsic to Notch1 mutations associated with leukemia
-
-
?
transforming growth factor alpha + H2O
?
show the reaction diagram
-
ADAMs 10 and 17 represent differentially regulated components of a general shedding machinery for membrane proteins such as transforming growth factor alpha, L-selectin, and tumor necrosis factor alpha
-
-
?
tumor necrosis factor alpha + H2O
?
show the reaction diagram
-
ADAMs 10 and 17 represent differentially regulated components of a general shedding machinery for membrane proteins such as transforming growth factor alpha, L-selectin, and tumor necrosis factor alpha
-
-
?
L1 cell-adhesion molecule + H2O
?
show the reaction diagram
-
the ectodomain of L1 cell-adhesion molecule is cleaved at the plasma membrane by ADAM10. Regulated proteolytic processing by ADAM10 and PS/gamma-secretase is essential for the nuclear signalling of L1 in human carcinoma cell lines
-
-
?
additional information
?
-
-
TIMP1 and TIMP-3 (tissue inhibitors of metalloproteinase) interact and inhibit ADAM10
-
-
-
METALS and IONS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
Ca2+
-
ADAM10-mediated proteolysis of VE-cadherin is induced by Ca2+ influx
Zinc
-
ADAM10 belongs to the subgroup of metzincins within the zinc proteinases family
Zinc
-
ADAM10 belongs to the subgroup of metzincins within the zinc proteinases family. The catalytical domain of ADAM10 contains a typical zinc-binding consensus motif
Zn2+
-
dependent on
INHIBITORS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
((2R,3S)-3-(formyl-hydroxyamino)-2-(3-phenyl-1-propyl)butanoic acid)[(1S)-2,2-dimethyl-1-methylcarbamoyl-1-propyl]amide
-
compound GI254023X, IC50: 5.3
(2S)-N4-hydroxy-N1-[(1S)-1-(1H-indol-3-ylmethyl)-2-(methylamino)-2-oxoethyl]-2-isobutylsuccinamide
-
GM6001, 0.05 mM
(2S)-N4-hydroxy-N1-[(1S)-1-(1H-indol-3-ylmethyl)-2-(methylamino)-2-oxoethyl]-2-isobutylsuccinamide
-
metalloproteinase inhibitor GM6001 suppresses constitutive AX1 shedding 2.8 and 3.5fold, respectively, and PMA-induced Axl shedding 2.9 and 3.2fold, respectively
(2S)-N4-hydroxy-N1-[(1S)-1-(1H-indol-3-ylmethyl)-2-(methylamino)-2-oxoethyl]-2-isobutylsuccinamide
-
GM6001
1,10-phenanthroline
-
inhibits shedding of Eph-A5
ADAM10 prodomain Pro-A10 WT 23-213 (C-terminal His tag)
-
48 nM, specific inhibitor
-
ADAM10 prodomain Pro-A10 WT 23-213 (N-terminal His tag)
-
75 nM, specific inhibitor
-
ADAM10 prodomain ProA10 C173S 23-213 (C-terminal His tag)
-
36 nM, specific inhibitor
-
ADAM8 prodomain Pro-A8
-
25% inhibition at 0.003 mM
-
AEBSF
-
0.1 mM
atorvastatin
-
80mg/day
BB3103
-
0.01 mM inhibitory but not completely
-
decanoyl-RVKR-chloromethylketone
-
0.03 mM of this proprotein convertase inhibitor decreases the formation of the ADAM10 mature form
G1254023X
-
specific inhibitor
GI254023
-
0.005 mM
GI254023X
-
0.005 mM, with or without 0.001 mM gamma-secretase inhibitor L-685,458
GI254023X
-
0.005 mM
GI254023X
-
specific inhibitor
GI254023X
-
inhibits RAGE (receptor for advanced glycation endproducts) cleavage
GI254023X
-
ADAM10-specific inhibitor
GI254023X
-
ADAM10-selective inhibitor
GI254023X
-
-
GI254023X
-
ADAM10-specific inhibitor
GI254023X
-
specifically inhibits ADAM10
GI254023X
-
ADAM10 specific inhibitor
GM6001
-
specific inhibitor
GM6001
-
0.01 mM
GM6001
-
inhibits 50-60% of CD23 shedding
GW 280264X
-
ADAM10/17 inhibitor
GW280264
-
0.005 mM
GW280264X
-
i.e. (2R,3S)-3-(formyl-hydroxyamino)-2-2-methyl-1-propyl hexanoic acid [(1S)-5-benzyloxycarbamoylamino-1-(1,3-thiazol-2-ylcarbamoyl)-1-pentyl]amide, potent inhibitor
GW280264X
-
0.005 mM
GW280264X
-
-
GW280264X
-
ADAM10- and ADAM17-selective inhibitor
GW280264X
-
blocks both ADAM10 and ADAM17
GW280623X
-
inhibits RAGE (receptor for advanced glycation endproducts) cleavage
o-phenanthroline
-
inhibit activity 0.1 mM
pepstatin A
-
0.001 mM
rottlerin
-
protein kinase Cdelta inhibitor causes a dramatic decrease in the activation of pro-BTC shedding by calcium ionophore A23187
TACE prodomain Pro-A17
-
11% inhibition at 0.0035 mM
-
TAPI
-
0.01 mM inhibitory but not completely
TAPI-1
-
0.05 mM
TAPI-2
-
inhibits 70% of CD23 shedding
TAPI-2
-
0.05 mM
TIMP-1
-
modest inhibitory activity toward CD23 shedding
-
TIMP-1
-
tissue inhibitors of metalloproteinase 1, it is shown that the N-terminal domain of TIMP-1 is not sufficient for inhibition of ADAM10, 37% of ADAM10-mediated CD44 shedding is observed
-
TIMP-1
-
-
-
TIMP-2
-
modest inhibitory activity toward CD23 shedding
-
TIMP-3
-
modest inhibitory activity toward CD23 shedding
-
TIMP-3
-
-
-
TIMP-3
-
tissue inhibitors of metalloproteinase 3, it is shown that the N-terminal domain of TIMP-3 is not sufficient for inhibition of ADAM10, 72% of ADAM10-mediated CD44 shedding is observed
-
tissue inhibitor of metalloproteases 1
-
500 nM TIMP-1
-
tissue inhibitor of metalloproteases 3
-
500 nM TIMP-3
-
Tissue inhibitor of metalloproteinase-1
-
-
-
TNFalpha protease inhibitor
-
0.05 mM
-
Wortmannin
-
-
GW4023
-
-
-
additional information
-
serine, thiol and acidic protease inhibitors are not inhibitory
-
additional information
-
not affected by TIMP-2 and calcimycin
-
additional information
-
TMP-1 and TIMP-2 do not inhibit shedding of Klotho by ADAM10
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
(4-aminophenyl)mercuric acetate
-
-
5alpha-dihydrotestosterone
-
10 nM, in the presence of 10 or 50 ng/ml insulin-like growth factor, 1.8fold upregulation of the 100-kDa proform and 3 to 4 fold stimulation of the active 60-kDa form
A23187
-
calcium ionophore
alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrate
-
-
donepezil
-
because donepezil-treated cells show an increase in the metabolic active form of ADAM 10, this suggests that donepezil may cause a direct increase in the level of ADAM 10 in cellular membranes
Epidermal growth factor
-
50 ng/ml, 2fold stimulation of 100-kDa proform and 3fold stimulation of 60-kDa form
Insulin
-
0.001 mM, stimulates the cleavage of the extracellular domain of Klotho
-
insulin-like growth factor I
-
10 ng/ml or 50 ng/ml, in the presence of 10 nM 5alpha-dihydrotestosterone, 1.8fold upregulation of the 100-kDa proform and 3 to 4fold stimulation of the active 60-kDa form
-
interleukin-1alpha
-
2 ng/ml stimulates ADAM-10 level 2.1 fold after 16h treatment
-
ionomycin
-
0.005 mM, strongly increases the generation of epithelial cadherin 38 kDa-C-terminal fragment
phorbol 12-myristate 13-acetate
-
-
phorbol myristate acetate
-
100 nM, induces the expression of the highly processed form of ADAM10
phorbol-12 myristate 13-acetate
-
clearly enhanced epithelial cadherin shedding
S100A7
-
expression of exogenous S100A7, a biomarker protein for alzheimer’s disease known to be involved in immune responses, in primary cortico-hippocampal neuron cultures derived from Tg2576 transgenic mice embryos inhibits the generation of beta-amyloid (Abeta)1-42 and Abeta1-40 peptides, coincidental with a selective promotion of non-amyloidogenic alpha-secretase activity via promotion of ADAM10. A selective expression of human S100A7, in the brain of transgenic mice results in significant promotion of alpha-secretase activity
-
staurosporine
-
strongly increases the generation of epithelial cadherin 38 kDa-C-terminal fragment
staurosporine
-
ADAM10-mediated proteolysis of VE-cadherin is induced
tetraspanin
-
several anti-tetraspanin mAbs (CD9, CD81, CD82) increase epidermal growth factor and/or TNF-alpha secretion through a mechanism dependent on ADAM10. The effect of anti-tetraspanin mAb on TNF-alpha release is rapid, not relayed by intercellular signaling, and depends on an intact MEK/Erk1/2 pathway. It is also associated with a concentration of ADAM10 in tetraspanin-containing patches. A large fraction of ADAM10 associates with several tetraspanins
-
thyrotropin
O14672
increases dose dependently thyrotropin receptor ectodomain cleavage
-
ionomycin
-
strongly increases the generation of epithelial cadherin 38 kDa-C-terminal fragment
additional information
-
cells overexpressing ADAM10 are not responsive to phorbol ester-induced cleavage, indicating constitutive activity and not Protein kinase C induced activity
-
additional information
-
-
-
additional information
-
4-aminophenylmercuric acetate does not stimulate the shedding of beta-amyloid precursor protein
-
additional information
-
no activation by 0.1 M phorbol 12-myristate 13-acetate
-
additional information
-
no increase in the amount of gamma-Protocadherin C3 25-kDa C-terminal fragment was observed when the ADAM10 inhibitor GI254023X is added to the cells prior to PMA stimulation
-
additional information
-
not stimulated by sphingosine 1-phosphate
-
SPECIFIC ACTIVITY [µmol/min/mg]
SPECIFIC ACTIVITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
additional information
-
-
ADAM10 does not cleave angiotensin-converting enzyme
additional information
-
-
catalytic activity of wild-type and internally FLAG-tagged fusion protein is indistinguishable
pH OPTIMUM
pH MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
7.4
-
-
assay at
TEMPERATURE OPTIMUM
TEMPERATURE OPTIMUM MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
37
-
-
assay at
37
-
-
assay at
SOURCE TISSUE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
SOURCE
-
A-172 cell line has potent alpha-secretase activity, higher than HEK-293 cell line
Manually annotated by BRENDA team
-
strain U373 MG
Manually annotated by BRENDA team
-
N-Cadherin cleavage occurs at a higher level in glioblastoma cells than in non-neoplastic astrocytes
Manually annotated by BRENDA team
-
expression of ADAM 10, 12 and 17 is analyzed by immunohistochemistry in skin tissues obtained from 25 patients with different types of basal cell carcinomas. Immunoreactivity of ADAM 10, 12 and 17 is increased at the peripheral tumor margin compared with central areas of basal cell carcinomas tumor cell nests. Immunoreactivity of ADAM 10 and 12 is increased in the deep margin of invading tumor cell nests in mixed basal cell carcinomas
Manually annotated by BRENDA team
-
lower levels of ADAM10 in Alzheimer disease
Manually annotated by BRENDA team
-
there is expression of the enzyme
Manually annotated by BRENDA team
-
there is expression of the enzyme
Manually annotated by BRENDA team
-
the expression is increased 2-fold in Alzheimer disease
Manually annotated by BRENDA team
-
COS7 cell line transfected with ADAM10 produces transactivation of epidermal growth factor receptor
Manually annotated by BRENDA team
Drosophila melanogaster Oregon R
-
-
-
Manually annotated by BRENDA team
-
ADAM17-/-, Ras-Myc-immortalized murine fibroblasts. ADAM10 is a major TNF sheddase in ADAM17-deficient fibroblasts
Manually annotated by BRENDA team
-
embryonic knock out fibroblast for ADAM10
Manually annotated by BRENDA team
-
U-1242 MG, N-Cadherin cleavage occurs at a higher level in glioblastoma cells than in non-neoplastic astrocytes
Manually annotated by BRENDA team
-
embryonic wild type cell line and overexpressing ADAM10
Manually annotated by BRENDA team
-
the expression is increased 2-fold in Alzheimer disease
Manually annotated by BRENDA team
-
confirmation of ADAM10-TSPAN12 association
Manually annotated by BRENDA team
-
cell line HaCaT
Manually annotated by BRENDA team
-
epidermal hair follicle infundibulum, keratinocytes of the hair infundibulum do not show any difference as compared to keratinocytes of the normal epidermis
Manually annotated by BRENDA team
-
ADAMs9 and 10 are the most prominent collagen XVII sheddases in primary keratinocytes
Manually annotated by BRENDA team
-
there is expression of the enzyme
Manually annotated by BRENDA team
-
there is expression of the enzyme
Manually annotated by BRENDA team
-
LoVo cell line does not express furin protease has both the immature and mature form of the enzyme
Manually annotated by BRENDA team
-
there is expression of the enzyme
Manually annotated by BRENDA team
-
confirmation of ADAM10-TSPAN12 association
Manually annotated by BRENDA team
-
human mesenchymal stem cells interfere with cell–cell adhesion and enhance migration of breast cancer cells by activating ADAM10
Manually annotated by BRENDA team
-
by immunohistochemistry, ADAM10 is shown to stain human muscle fibers exclusively. Neither satellite cells nor capillaries exhibit any positive immunoreactivity. Histochemical staining with ATPase reveals a colocalization of positive ADAM10 immunoreactivity to type I fibers only, whereas the staining pattern for ADAM10 never matches with the presence of type II fibers
Manually annotated by BRENDA team
-
acinar cell during embryogenesis, endocrinic cell and exocrinic cell in adult
Manually annotated by BRENDA team
-
ADAM10 is necessary for epidermal growth factor receptor transactivation
Manually annotated by BRENDA team
-
cell line LNCaP, localized to the secretory cells of prostate glands, with additional basal cell expression in benign glands
Manually annotated by BRENDA team
-
human salivary gland cells are used
Manually annotated by BRENDA team
-
cytoplasmic expression of ADAM 10 is observed in the hair bulb keratinocytes and fibroblasts of dermal papilla in anagen I–III hair follicles. Decreased ADAM 10 expression is observed in the hair matrix keratinocytes as compared to the hair bulb keratinocytes in anagen I–III hair follicles. ADAM 10 immunoreactivity is expressed weakly in the lower portion of outer root sheath of anagen VI hair follicles, and strong ADAM 10 expression is detected in the outer root sheath of catagen and telogen hair follicles
Manually annotated by BRENDA team
-
there is expression of the enzyme
Manually annotated by BRENDA team
-
stomach epithelial cell
Manually annotated by BRENDA team
-
there is expression of the enzyme
Manually annotated by BRENDA team
additional information
-
endothelial cells of venules and arterioles do not express ADAM10
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
in untreated cells
Manually annotated by BRENDA team
-
identification of an endoplasmic reticulum retention motif within the ADAM10 intracellular C-terminal tail. Sequential deletion/mutagenesis analyses shows that an arginine-rich (723RRR) sequence is responsible for the retention of ADAM10 in the endoplasmic reticulum and its inefficient surface trafficking. Mutating the second arginine to alanine is sufficient to allow endoplasmic reticulum exit and surface expression in both heterologous cells and hippocampal neurons
Manually annotated by BRENDA team
-
most of the activity of the enzyme
Manually annotated by BRENDA team
-
the typical multidomain structure of ADAM10 as a type I integral transmembrane protein consists of a prodomain, a catalytical domain with a conserved zinc binding sequence, a cysteine-rich disintegrin-like domain, a transmembrane domain and a rather short cytoplasmic domain
Manually annotated by BRENDA team
-
transmembrane glycoprotein
Manually annotated by BRENDA team
-
in untreated cells
Manually annotated by BRENDA team
-
predominant localization of the protein at the perinuclear region and at the cell surface where it appears as punctuated dots evenly distributed at the plasma membrane
-
Manually annotated by BRENDA team
-
some activity found
Manually annotated by BRENDA team
-
treatment of the glioblastoma cells with the PKC activator phorbol 12-myristate 13-acetate (PMA) leads to the translocation of ADAM10 to the cell membrane, the site at which N-cadherin is cleaved and this translocation is significantly reduced by the PKC-alpha inhibitor Gö6976 [12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole] or PKC-alpha short hairpin RNA
Manually annotated by BRENDA team
PDB
SCOP
CATH
ORGANISM
MOLECULAR WEIGHT
MOLECULAR WEIGHT MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
45000
-
-
highly processed mature form, SDS-PAGE
60000
-
-
SDS-PAGE, active form of ADAM-10
60000
-
-
SDS-PAGE, mature active form of ADAM10
60000
-
-
processed mature form, SDS-PAGE
60000
-
-
Western blot, reducing condition, mature protein
62000
64000
-
active form, amino-terminal sequencing
68000
-
-
SDS-PAGE
68000
-
-
SDS-PAGE, metabolically active form of ADAM 10
68000
-
-
Western blot, non-reducing conditions
70000
-
-
SDS-PAGE, mature form wild-type
85000
-
-
SDS-PAGE, nonenzymatically active proenzyme of ADAM 10
85000
-
-
precursor, SDS-PAGE
85000
-
-
Western blot, reducing condition, precursor protein
98000
-
-
SDS-PAGE, immature form wild-type
100000
-
-
SDS-PAGE, proform of ADAM-10
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
glycoprotein
-
contains high-mannose as well as complex-type N-glycans. Glycosylation sites: S269, T280, S441, T553
proteolytic modification
-
the enzyme has an inactive form that is activated by cleavage
glycoprotein
-
contained high-mannose as well as complex-type N-glycans
glycoprotein
-
glycosylation sites in the catalytic and disintegrin domain contain high-mannose as well as complex type N-glycans
glycoprotein
-
ADAm10 possesses four potential N-glycosylation sites
proteolytic modification
-
ADAM10 itself is subject to ectodomain shedding via a mechanism which is inhibited by ADAM inhibitor (GW4023) and stimulated by phorbol ester treatment of cells. The treatment of cells with GW4023 causes a reciprocal accumulation of membrane-associated mature ADAM10 in both cell lysates and extracellular membrane vesicles. ADAM9 is, at least in part, responsible for the ectodomain shedding of ADAM10
proteolytic modification
-
tetraspanin overexpression enhances ADAM10 prodomain maturation, whereas TSPAN12 ablation diminishes ADAM10 maturation. TSPAN12 serves as a robust partner for ADAM10 and promotes ADAM10 maturation, thereby facilitating ADAM10-dependent proteolysis of amyloid precursor protein
proteolytic modification
-
the nascent protein itself is not functional and is produced as a zymogen. After cleavage of the signalling sequence, ADAM10 enters the secretory pathway to be processed and thereby activated by the proprotein convertases furin or PC7
glycoprotein
-
transmembrane glycoprotein
proteolytic modification
-
the nascent protein itself is not functional and is produced as a zymogen. After cleavage of the signalling sequence, ADAM10 enters the secretory pathway to be processed and thereby activated by the proprotein convertases furin or PC7
proteolytic modification
-
synthesized in an inactive form, which is proteolytically activated during its forward transport along the secretory pathway and at the plasma membrane
Crystallization/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
hanging-drop vapour diffusion
-
Purification/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
SDS-PAGE
-
Ni2+-NTA column chromatography and Superdex-75 gel filtration
-
Cloned/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
a C-terminal HA-tagged fusion protein is transfected in human ovarian cancer SKOV3 cells and human embryonic kidney HEK293 cells
-
expressed in HEK-293 cells
-
expressed in human embryonic kidney HEK293 cell line
-
a C-terminal HA-tagged fusion protein is transfected in human ovarian cancer SKOV3 cells and human embryonic kidney HEK293 cells
-
ADAM10 is expressed as a wild-type protein and as a FLAG-tagged ADAM10 fusion protein in which the tag is inserted immediately C-terminal to the proprotein convertase recognition sequence RKKR. Expression is carried out by stable transfection of a human neuroblastoma SH-SY5Y cell line. Internally tagged ADAM10 fusion protein is easily detected in Western blot analysis. Catalytic activity of wild-type and internally tagged protein is indistinguishable
-
expressed in Escherichia coli
-
expressed in HUVEC and COS-7 cells
-
expressed in Ls174T human colon cancer cells
-
expressed in MEF cells and 293-T cells
-
expression in CHO cells
-
expressed in Escherichia coli BL21(DE3)Star cells
-
expressed in U-251 cells
-
generation of ADAM10—chimeras of the extracellular domain of the human interleukin-2 receptor with the intracellular C-terminal domain of mouse ADAM10. Transfection into COS7 cells
-
produced in insect cells by baculoviral expression as truncated constructs consisting of the signal sequence, pro- and catalytic domains fused to a C-terminal His6 (hexahistidine) tag (residues 1–460 of mouse ADAM10).
-
EXPRESSION
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
ADAM10 mRNA is lowered in moderate to severe Alzheimer’s disease
-
retinoids induce gene expression of ADAM10. The vitamin A analog acitretin stimulates ADAM10 promoter activity with an EC50 of 0.0015 mM
-
amount and activity of ADAM10 is increased by application of low doses of statins
-
ADAM10 levels are significantly enhanced on germinal center B cells
-
ENGINEERING
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
S269A
-
mutant is detected at lower molecular masses than the wild-type form, which indicates that the N-glycosylation site is occupied
S441A
-
mutant is detected at lower molecular masses than the wild-type form, which indicates that the N-glycosylation site is occupied, mutant shows increased ADAM10 susceptibility to proteolysis
T280A
-
mutant is detected at lower molecular masses than the wild-type form, which indicates that the N-glycosylation site is occupied, T280A is found to accumulate in the endoplasmic reticulum as the non-processed precursor of the enzyme. Mutant exhibits only residual levels of metalloprotease activity
T553A
-
mutant is detected at lower molecular masses than the wild-type form, which indicates that the N-glycosylation site is occupied
DELTA672
-
a truncated soluble construct of ADAM10 lacking the transmembrane and cytosolic domains (truncation after Glu680), although correctly post-translationally processed and catalytically active with respect to a synthetic peptide substrate, is incapable of shedding cell-associated amyloid precursor protein (APP)
E384A
-
the point mutation which compromises the zinc-binding consensus motif, leads to a substantial decrease in amyloid precursor protein-alpha secretion
N439
-
mutation at the N-glycosylation site N439 increase ADAM10s susceptibility to proteolytical degradation
Q170H
-
significant evidence for an association of Alzheimer’s disease with the metalloproteinase with respect to two mutations: Q170H and R181G
Q170H
-
Alzheimer’s disease-associated non-synonymous mutations, Q170H and R181G. These mutations are found in 11 of 16 affected individuals (average onset age 69.5 years) from seven late-onset Alzheimer’s disease families. Each mutation is also found in one unaffected subject implying incomplete penetrance. Functionally, both mutations significantly attenuate alpha-secretase activity of ADAM10 (more than 70% decrease), and elevate Abeta levels (1.5–3.5-fold) in cell-based studies
R181G
-
significant evidence for an association of Alzheimer’s disease with the metalloproteinase with respect to two mutations: Q170H and R181G
R181G
-
Alzheimer’s disease-associated non-synonymous mutations, Q170H and R181G. These mutations are found in 11 of 16 affected individuals (average onset age 69.5 years) from seven late-onset Alzheimer’s disease families. Each mutation is also found in one unaffected subject implying incomplete penetrance. Functionally, both mutations significantly attenuate alpha-secretase activity of ADAM10 (more than 70% decrease), and elevate Abeta levels (1.5-3.5fold) in cell-based studies
S441A
-
the mutant displays higher susceptibility to proteolysis
C173S
-
mutation does not impair the inhibitory potency of the ADAM10 prodomain against ADAM10
additional information
-
ADAM10 mutant lacking the prodomain is inactive, the prodomain is probably involved in the maturation of the enzyme; consensus sequence RKKR mutated for NAQA resulting in no expression of mature protein
additional information
-
to assess the influence of ADAM10 on the gene expression profile in the brain, a microarray analysis using RNA isolated from brains of five months old mice overexpressing either ADAM10, or a dominant-negative mutant of this enzyme. Overexpression of proteolytically active ADAM10 affects several physiological pathways, such as cell communication, nervous system development, neuron projection as well as synaptic transmission. Although ADAM10 is implicated in Notch and beta-catenin signaling, no significant changes in the respective target genes are observed in adult ADAM10 transgenic mice. RT-PCR confirms a downregulation of genes coding for the inflammation-associated proteins S100a8 and S100a9 induced by moderate ADAM10 overexpression. Overexpression of the dominant-negative form dnADAM10 leads to a significant increase in the expression of the fatty acid-binding protein Fabp7, which is found in higher amounts in brains of Down syndrome patients
E385A
-
inactive
additional information
-
using siRNA to knockdown ADAM10 in highly invasive glioblastoma cell line U251 it is shown that CD44 shedding is compromised in a dose-dependent manner
additional information
-
increased ADAM10 expression is functionally associated with an increase in endothelial permeability. ADAM10 activity also contributes to the thrombin-induced decrease of endothelial cell-cell adhesion; knockdown of ADAM10 in HUVECs as well as in T cells by small interfering RNA impairs T-cell transmigration
additional information
-
RNA interference (RNAi)-induced knockdown of ADAM10 in human astroglioma cell line U373 has no influence on NRG-1 (neuregulin-1) shedding
additional information
-
a GPI-anchored form of ADAM10 lacking the cytosolic, transmembrane and a-helical juxtamembrane regions of the wild-type protein is shed in a similar manner. Mutant fusion construct consists of the first 652 residues of wild-type ADAM10 fused, via a two residue linker, to the 24 residue GPI anchor signal sequence of human carboxypeptidase M
E384A
-
the point mutation which compromises the zinc-binding consensus motif, leads to a substantial decrease in amyloid precursor protein-alpha secretion
additional information
-
in ADAM10 deficient mouse embryonic cells the constitutive release of soluble epidermal growth factor and also beta-cellulin is strongly reduced when compared with wild type controls and can be reintroduced by adding of wild type ADAM10. Overexpression of ADAM10 causes an increase in beta-cellulin shedding, whereas the overexpression of catalytically inactive ADAM10 decreases the beta-cellulin shedding; the ADAM10 knockout mouse virtually represents a phenocopy of a presenilin 1/presenilin 2 double deficient mouse and thus features many traits attributable to defective Notch signalling; the in vivo relevance of the processing of E-cadherin is supported by data from cell extracts from ADAM10 deficient mouse embryos at embryonic day 9.5, indicating that the generation is completely abolished in the knockout mice
additional information
-
mouse embryonic fibroblast cells deficient of ADAM10 are not able to produce cleaved RAGE (receptor for advanced glycation endproducts). Stable transfection of MEF deficient with a plasmid coding for mouse ADAM10 is able to rescue the phenotype
additional information
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in vivo investigations of mice overexpressing either ADAM10 or dominant negative ADAM10 show unaltered cleavage of neuregulin-1 compared to wild-type animals. As a consequence, the myelin sheath thickness of peripheral nerves is unaffected in mice with altered ADAM10 activity
additional information
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inhibition of ADAM10 expression using short interfering RNA reduces N-cadherin cleavage and decreases glioblastoma cell migration
APPLICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
molecular biology
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there is only a moderate alteration of gene expression in ADAM10 overexpressing mice. Genes coding for pro-inflammatory or pro-apoptotic proteins are not overrepresented among differentially regulated genes. Even a decrease of inflammation markers is observed. This further supports the strategy to treat alzheimer’s disease by increasing the beta-secretase activity
medicine
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Kuzbanian is required for pericardial cell and lymph gland development
molecular biology
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Kuzbanian, the ADAM10 orthologue in Drosophila melanogaster plays an important role in axon guidance by building a complex with ephrinA2, which is cleaved off from the membrane in a moment of EphA3 receptor binding
medicine
Drosophila melanogaster Oregon R
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Kuzbanian is required for pericardial cell and lymph gland development
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medicine
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cleavage by metalloproteinase ADAM10 of PrP cellular protein is constitutive and could inhibit the maintenance of the toxic core of the protein PrP scrapie in spongiform encephalopathies
medicine
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cleavage by ADAM10 of beta-amyloid precursor protein could abolish production of longer peptides and slow down or arrest Alzheimer disease
medicine
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ADAM10 participates in the response to infection by Staphylococcus aureus
medicine
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reduction of ADAM10 in Alzheimer disease could allow beta-secretase cleavage of amyloid precursor protein
medicine
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potential therapeutic target for the treatment of allergic diseases
medicine
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since C4.4A is likely involved in tumor invasion, these results indicate that the cleavage of C4.4A by ADAM10 and ADAM17 contributes to tumor progression
medicine
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ADAM 10, 12 and 17 show different expression pattern in basal cell carcinomas histologic subtypes, indicating their different role in the basal cell carcinoma pathogenesis. Overexpression of ADAM 10, 12 and 17 immunoreactivity in deep invasion area of BCC indicates that these three proteases may play an important role in the locally invasive and highly destructive growth behavior of basal cell carcinomas
medicine
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ADAM10 plays a critical role in Alzheimer’s disease. Tetraspanin12 serves as a robust partner for ADAM10 and promotes ADAM10 maturation, thereby facilitating ADAM10-dependent proteolysis of amyloid precursor protein. This mode of regulating amyloid precursor protein cleavage is of relevance to Alzheimer’s disease therapy. Promotion of TSPAN12-ADAM10-dependent functions should be therapeutically beneficial in Alzheimer’s disease, whereas inhibition of TSPAN12-ADAM functions may be beneficial in cancer
medicine
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ADAM10 as target for Alzheimer’s disease therapy
medicine
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upregulation of ADAM10 is a therapeutic target in Alzheimer’s disease
molecular biology
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ADAM10 is regulator of vascular permeability and possesses a function VE-cadherin-dependent endothelial cell functions and leukocyte transendothelial migration
molecular biology
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tetraspanins regulate the activity of ADAM10 toward several substrates. It is illustrated how membrane compartmentalization by tetraspanins can control the function of cell surface proteins such as ectoproteases
medicine
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pharmacotherapeutic target for the treatment of cerebral amyloidosis in Alzheimer disease