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Information on EC 3.4.24.81 - ADAM10 endopeptidase
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3.4.24.81 ADAM10 endopeptidaseSpecify your search results
Word Map
- 3.4.24.81
- alzheimer
- adam17
-
amyloid
- ectodomain
- sheddase
- alpha-secretase
- endothelial
- metalloproteases
-
neuroprotective
- plaque
-
amyloidogenic
-
non-amyloidogenic
- tnf
-
sh-sy5y
- synaptic
-
secretase
-
membrane-anchored
- tetraspanins
- gamma-secretase
- n-cadherin
-
presenilins
- notch1
-
intramembrane
- abeta
- cxcl16
- prpc
- prion
- amyloid-beta
- prodomains
- psen1
- beta-secretase
-
sappalpha
- hb-egf
-
beta-site
-
trans-signaling
- amphiregulin
- fractalkine
- meprin
-
disintegrin-like
-
adam17-mediated
-
app-cleaving
- betacellulin
-
nicastrin
- timp-3
- molecular biology
-
anti-amyloidogenic
- medicine
-
srage
-
notch-dependent
-
ad-like
-
juxtamembrane
- bace-1
The enzyme appears in viruses and cellular organisms
Synonyms
adam10, adam-10, adam 10, a disintegrin and metalloproteinase 10, a disintegrin and metalloprotease 10, kuzbanian, metalloproteinase adam10, metalloproteinase 10, metalloproteinase-disintegrin, a disintegrin and metalloproteinase-10, 
more
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
a disintegrin and metalloprotease 10
a disintegrin and metalloproteinase 10
ADAM-10
ADAM10
kuzbanian
Kuzbanian protein
-
-
-
-
mammalian disintegrin-metalloprotease
-
-
-
-
metalloproteinase 10
metalloproteinase ADAM10
-
-
-
-
metalloproteinase Kuzbanian
-
-
-
-
metalloproteinase MADM
-
-
-
-
myelin-associated disintegrin metalloproteinase
-
-
-
-
notch proteinase
-
-
-
-
transmembrane metzinkin-protease of the a disintegrin and metalloproteinase family-10
-
-
a disintegrin and metalloproteinase 10
-
-
ADAM-10
-
-
-
-
ADAM10
-
-
ADAM10
-
-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
endopeptidase of broad specificity
-
-
-
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of peptide bond
-
-
-
-
additional information
-
ADAM10 mediates the epidermal growth factor-induced CD44 cleavage by the small monomeric GTPase Rac1
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CAS REGISTRY NUMBER
COMMENTARY
193099-09-1
-
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
amyloid precursor-like protein 2 + H2O
soluble amyloid precursor-like protein 2 ectodomain + amyloid precursor-like protein 2 C-terminal fragments
-
ADAM10 cleaves after Arg670
-
-
?
beta-amyloid precursor protein + H2O
sAPP-alpha fragment of beta-amyloid precursor protein + C-terminal fragment of beta-amyloid precursor protein
Bri2 protein + H2O
?
-
-
the ADAM10 cleavage liberates the BRICHOS domain of Bri2
-
?
cell adhesion molecule CADM1 + H2O
?
type I transmembrane glycoprotein, endopeptidase ADAM10 mediates endogenous CADM1 shedding. The membrane-bound fragment generated by shedding is further cleaved by gammaetase and generates CADM1-intracellular domain
-
-
?
cell surface VEGF receptor Flt + H2O
?
-
release of an N-terminal extracellular fragment which can antagonize the effects of vascular endothelial growth factor, substrate can be cleaved to release an N-terminal extracellular fragment. Overexpression of ADAM10 and ADAM17, EC 3.4.24.86, increase cleavage while knockdown of ADAM10 and ADAM17 reduce N-terminal cleavage
-
?
collagen XVII/BP180 + H2O
?
-
ADAM9 and ADAM10 are the most prominent collagen XVII sheddases in primary keratinocytes
-
-
?
E(Edans)-PLAQAVRSSS[O-(beta-D-Glc-(1->3)-alpha-D-GlcNAc]-K(Dabcyl) + H2O
E(Edans)-PLAQA + VRSSS[O-(beta-D-Glc-(1->3)-alpha-D-GlcNAc]-K(Dabcyl)
-
-
-
ir
epithelial growth factor receptor
?
-
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
-
-
-
-
?
Fas ligand + H2O
soluble Fas ligand ectodomain + ?
-
transmembrane protein
-
-
?
gamma-protocadherin C3 + H2O
25-kDa C-terminal fragment of gamma-protocadherin C3 + ?
-
-
-
-
?
Glu(EDANS)-Pro-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser(glycosyl)-Ser-Lys(DABCYL) + H2O
Glu(EDANS)-Pro-Leu-Ala-Gln-Ala + Val-Arg-Ser-Ser(glycosyl)-Ser-Lys(DABCYL)
-
-
-
?
Glu(EDANS)-Pro-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser-Ser-Lys(DABCYL) + H2O
Glu(EDANS)-Pro-Leu-Ala-Gln-Ala + Val-Arg-Ser-Ser-Ser-Lys(DABCYL)
-
-
-
?
interleukin-6 receptor + H2O
?
-
apoptosis-induced shedding of interleukin-6 receptor is mediated by ADAM10
-
-
?
interleukin-6 receptor + H2O
sIL-6R fragment + C-terminal fragment
-
-
-
?
interleukin-6 receptor subunit alpha + H2O
?
-
cleavage occurs between residues LPVQ357-DSSV. Substrate shows N-linked glycosylation 7 residues apart from scissile bond
-
?
L1 adhesion molecule
L1-200 fragment + L1-32 fragment + ?
-
ADAM10 cleaves L1
-
?
meprin A + H2O
?
-
during ischemia-reperfusion-induced acute kidney injury, meprin A is shed from proximal tubule membranes. ADAM10 inhibition is sufficient to block shedding, small interfering RNA to ADAM10 inhibits shedding
-
?
meprin beta + H2O
?
-
during ischemia-reperfusion-induced acute kidney injury, meprin beta is shed from proximal tubule membranes. ADAM10 inhibition is sufficient to block shedding, small interfering RNA to ADAM10 inhibits shedding
-
?
nectin 1 + H2O
?
-
ADAM10 is the major secretase responsible for nectin-1 ectodomain cleavage in neurons and the brain
-
-
?
Notch S2 + H2O
Notch extracellular truncation fragment + ?
-
the enzyme is responsible for proteolytic cleavage at the S2 cleavage site within the extracellular juxtamembrane region of the Notch C-terminal fragment, which leads to the removal of the Notch ectodomain and the generation of a membrane-anchored Notch C-terminal fragment, termed Notch extracellular truncation
-
-
?
probetacellulin + H2O
?
-
cleavage occurs between residues CVVA31-DGNS. Substrate shows N-linked glycosylation 3 residues apart from scissile bond
-
?
proheparin-binding EGF-like growth factor + H2O
?
-
cleavage occurs between residues RKVR62-DLQE. Substrate shows O-linked glycosylation 13 residues apart from scissile bond
-
?
protocadherin + H2O
?
-
ADAM10 cleaves the extracellular domain of protocadherin
-
-
?
protransforming growth factor alpha + H2O
?
-
cleavage occurs between residues AAA39-VVSH. Substrate shows N-linked glycosylation 14 residues apart from scissile bond
-
?
syndecan-1 + H2O
?
both ADAM10 and ADAM17 contribute to SDC1 shedding
-
-
?
VE-cadherin + H2O
?
-
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
-
-
?
amyloid precursor protein + H2O
?
-
cleaves amyloid precursor protein in its transmembrane region alpha-secretase activity
-
-
?
amyloid precursor protein + H2O
?
-
tetraspanin12 associates with mature ADAM10, promotes ADAM10 maturation, and enhances ADAM10 dependent cleavage of amyloid precursor protein
-
-
?
amyloid precursor protein + H2O
?
-
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
?
-
cleaves amyloid precursor protein in its transmembrane region alpha-secretase activity
-
-
?
annexin A1 + H2O
?
-
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
-
-
-
-
?
beta-amyloid precursor protein
sAPP-alpha fragment + C-terminal fragment
-
-
-
?
beta-amyloid precursor protein
sAPP-alpha fragment + C-terminal fragment
-
A172 cell line has alpha-secretase activity
-
?
beta-amyloid precursor protein
sAPP-alpha fragment + C-terminal fragment
-
LoVo cell line overexpressing ADAM10 secreted a 185% of sAPP-alpha over control values
-
?
beta-amyloid precursor protein
sAPP-alpha fragment + C-terminal fragment
-
platelet and cerebrospinal fluid have lower levels of alpha-APP in Alzheimer patients
-
-
?
beta-amyloid precursor protein + H2O
sAPP-alpha fragment + C-terminal fragment
-
-
-
-
?
beta-amyloid precursor protein + H2O
sAPP-alpha fragment + C-terminal fragment
-
-
-
?
beta-amyloid precursor protein + H2O
sAPP-alpha fragment + C-terminal fragment
cleavage at Lys683-Leu684
-
-
?
beta-amyloid precursor protein + H2O
sAPP-alpha fragment + C-terminal fragment
-
-
-
-
?
beta-amyloid precursor protein + H2O
sAPP-alpha fragment + C-terminal fragment
-
-
-
?
beta-amyloid precursor protein + H2O
sAPP-alpha fragment of beta-amyloid precursor protein + C-terminal fragment of beta-amyloid precursor protein
-
-
-
-
?
beta-amyloid precursor protein + H2O
sAPP-alpha fragment of beta-amyloid precursor protein + C-terminal fragment of beta-amyloid precursor protein
-
-
-
-
?
C4.4A + H2O
?
-
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
-
-
?
CD84 + H2O
?
signaling lymphocyte activation molecule (SLAM) family receptor CD84
CD84 is cleaved from the surface of human platelets. ADAM10 is the principal sheddase responsible for CD84 cleavage
-
?
CD84 + H2O
?
signaling lymphocyte activation molecule (SLAM) family receptor CD84
CD84 is cleaved from the surface of murine platelets. ADAM10 is the principal sheddase responsible for CD84 cleavage
-
?
cellular prion protein
N1 fragment + C-terminal fragment
-
constitutive protein cleavage
-
?
cellular prion protein
N1 fragment + C-terminal fragment
-
constitutive protein cleavage
-
?
cellular prion protein
N1 fragment + C-terminal fragment
-
knock out line has 51% of reduction in N1 formation
-
?
E-cadherin + H2O
?
efficient cleavage of the ADAM10 substrate epithelial cadherin (E-cadherin) requires supra-cytotoxic concentrations of alpha-toxin
-
-
?
FcalphaR + H2O
?
-
FcaR (CD89) is the Fc receptor for immunoglobulin A. ADAM10 and ADAM17 are involved in the shedding of FcalphaR
-
-
?
L-selectin + H2O
?
-
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
?
-
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
?
-
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
?
-
ADAM10/SAP97 interaction is required for ADAM10-mediated cleavage of synaptic N-cadherin
-
-
?
Notch1 + H2O
?
-
ADAM10 is required for site 2 cleavage of the single-pass transmembrane receptor Notch1
-
-
?
Notch1 + H2O
?
-
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
?
-
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
-
-
?
RAGE + H2O
?
-
a soluble form of the receptor for advanced glycation endproducts (RAGE) is produced by proteolytic cleavage of the membrane-bound form by ADAM10
-
-
?
RAGE + H2O
?
-
a soluble form of the receptor for advanced glycation endproducts (RAGE) is produced by proteolytic cleavage of the membrane-bound form by ADAM10
-
-
?
transforming growth factor alpha + H2O
?
-
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
?
-
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
-
-
?
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)
-
?
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
-
-
?
additional information
?
-
the enzyme can cut normal prion proteins from the surface of neurons
-
-
?
neuronal cadherin + H2O
additional information
-
-
-
40 kDa C-terminal fragment + N-terminal 95 kDa fragment
-
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
beta-amyloid precursor protein + H2O
sAPP-alpha fragment of beta-amyloid precursor protein + C-terminal fragment of beta-amyloid precursor protein
-
-
-
-
?
collagen XVII/BP180 + H2O
?
-
ADAM9 and ADAM10 are the most prominent collagen XVII sheddases in primary keratinocytes
-
-
?
epithelial growth factor receptor
?
-
activation of the receptor leads to cleavage of transmembrane heparin-binding site by ADAM10 in response to infection by Staphylococcus aureus
-
-
?
FcalphaR + H2O
?
-
FcaR (CD89) is the Fc receptor for immunoglobulin A. ADAM10 and ADAM17 are involved in the shedding of FcalphaR
-
-
?
interleukin-6 receptor + H2O
sIL-6R fragment + C-terminal fragment
-
-
-
?
L-selectin + H2O
?
-
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 + ?
-
ADAM10 cleaves L1
-
?
L1 cell-adhesion molecule + H2O
?
-
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
-
-
?
Notch S2 + H2O
Notch extracellular truncation fragment + ?
-
the enzyme is responsible for proteolytic cleavage at the S2 cleavage site within the extracellular juxtamembrane region of the Notch C-terminal fragment, which leads to the removal of the Notch ectodomain and the generation of a membrane-anchored Notch C-terminal fragment, termed Notch extracellular truncation
-
-
?
transforming growth factor alpha + H2O
?
-
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
?
-
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
-
-
?
amyloid precursor protein + H2O
?
-
cleaves amyloid precursor protein in its transmembrane region alpha-secretase activity
-
-
?
amyloid precursor protein + H2O
?
-
tetraspanin12 associates with mature ADAM10, promotes ADAM10 maturation, and enhances ADAM10 dependent cleavage of amyloid precursor protein
-
-
?
amyloid precursor protein + H2O
?
-
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
?
-
cleaves amyloid precursor protein in its transmembrane region alpha-secretase activity
-
-
?
annexin A1 + H2O
?
-
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
-
-
-
-
?
beta-amyloid precursor protein
sAPP-alpha fragment + C-terminal fragment
-
-
-
?
beta-amyloid precursor protein
sAPP-alpha fragment + C-terminal fragment
-
A172 cell line has alpha-secretase activity
-
?
beta-amyloid precursor protein
sAPP-alpha fragment + C-terminal fragment
-
LoVo cell line overexpressing ADAM10 secreted a 185% of sAPP-alpha over control values
-
?
beta-amyloid precursor protein
sAPP-alpha fragment + C-terminal fragment
-
platelet and cerebrospinal fluid have lower levels of alpha-APP in Alzheimer patients
-
-
?
beta-amyloid precursor protein + H2O
sAPP-alpha fragment + C-terminal fragment
-
-
-
?
beta-amyloid precursor protein + H2O
sAPP-alpha fragment + C-terminal fragment
cleavage at Lys683-Leu684
-
-
?
beta-amyloid precursor protein + H2O
sAPP-alpha fragment + C-terminal fragment
-
-
-
?
cellular prion protein
N1 fragment + C-terminal fragment
-
constitutive protein cleavage
-
?
cellular prion protein
N1 fragment + C-terminal fragment
-
constitutive protein cleavage
-
?
cellular prion protein
N1 fragment + C-terminal fragment
-
knock out line has 51% of reduction in N1 formation
-
?
E-cadherin + H2O
?
efficient cleavage of the ADAM10 substrate epithelial cadherin (E-cadherin) requires supra-cytotoxic concentrations of alpha-toxin
-
-
?
Notch1 + H2O
?
-
ADAM10 is required for site 2 cleavage of the single-pass transmembrane receptor Notch1
-
-
?
Notch1 + H2O
?
-
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
?
-
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
-
-
?
additional information
?
-
-
TIMP1 and TIMP-3 (tissue inhibitors of metalloproteinase) interact and inhibit ADAM10
-
-
?
additional information
?
-
the enzyme can cut normal prion proteins from the surface of neurons
-
-
?
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Ca2+
Zinc
Zn2+
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
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INHIBITOR
ORGANISM
UNIPROT
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
2-(2,4-dioxo-3-phenyl-1,3-thiazolidin-5-yl)-N-(4-ethoxyphenyl)acetamide
-
3-[[1-[(2-(hydroxymethyl)-1-pyrrolidinyl)carbonyl]-2-methylpropyl]carbamoyl]octanohydroxamic acid
actinonin
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
-
decanoyl-RVKR-chloromethylketone
-
0.03 mM of this proprotein convertase inhibitor decreases the formation of the ADAM10 mature form
GW280623X
-
inhibits RAGE (receptor for advanced glycation endproducts) cleavage
N-(3-chloro-4-methylphenyl)-2-[2-(3-methoxybenzoyl)hydrazinyl]-2-oxoacetamide
selective, non-competitive inhibitor
rottlerin
-
protein kinase Cdelta inhibitor causes a dramatic decrease in the activation of pro-BTC shedding by calcium ionophore A23187
(2S)-N4-hydroxy-N1-[(1S)-1-(1H-indol-3-ylmethyl)-2-(methylamino)-2-oxoethyl]-2-isobutylsuccinamide
-
GM6001
(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
GI254023X
-
0.005 mM, with or without 0.001 mM gamma-secretase inhibitor L-685,458
GI254023X
-
inhibits RAGE (receptor for advanced glycation endproducts) cleavage
GI254023X
specific inhibitor, i.e. (2R,3S)-3-(formyl-hydroxyamino)-2-(3-phenyl-1-propyl) butanoic acid [(1S)-2,2-dimethyl-1 methylcarbamoyl-1-propyl] amide
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
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-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
-
additional information
-
serine, thiol and acidic protease inhibitors are not inhibitory
-
additional information
-
TMP-1 and TIMP-2 do not inhibit shedding of Klotho by ADAM10
-
additional information
-
serine, thiol and acidic protease inhibitors are not inhibitory
-
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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
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
-
phorbol myristate acetate
-
100 nM, induces the expression of the highly processed form of ADAM10
S100A7
-
expression of exogenous S100A7, a biomarker protein for alzheimers 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
-
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
increases dose dependently thyrotropin receptor ectodomain cleavage
-
ionomycin
-
0.005 mM, strongly increases the generation of epithelial cadherin 38 kDa-C-terminal fragment
ionomycin
-
strongly increases the generation of epithelial cadherin 38 kDa-C-terminal fragment
staurosporine
-
strongly increases the generation of epithelial cadherin 38 kDa-C-terminal fragment
staurosporine
-
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
-
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
-
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0085
Glu(EDANS)-Pro-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser(glycosyl)-Ser-Lys(DABCYL)
pH 7.5, 22°C
0.012
Glu(EDANS)-Pro-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser-Ser-Lys(DABCYL)
pH 7.5, 22°C
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.06
Glu(EDANS)-Pro-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser(glycosyl)-Ser-Lys(DABCYL)
pH 7.5, 22°C
0.28
Glu(EDANS)-Pro-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser-Ser-Lys(DABCYL)
pH 7.5, 22°C
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kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
8
Glu(EDANS)-Pro-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser(glycosyl)-Ser-Lys(DABCYL)
pH 7.5, 22°C
25
Glu(EDANS)-Pro-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser-Ser-Lys(DABCYL)
pH 7.5, 22°C
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.000883
N-(3-chloro-4-methylphenyl)-2-[2-(3-methoxybenzoyl)hydrazinyl]-2-oxoacetamide
at pH 7.5 and 25°C
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.07
2-(2,4-dioxo-3-phenyl-1,3-thiazolidin-5-yl)-N-(4-ethoxyphenyl)acetamide
Homo sapiens
IC50 above 0.07 mM, at pH 7.5 and 25°C
0.07
3-[[1-[(2-(hydroxymethyl)-1-pyrrolidinyl)carbonyl]-2-methylpropyl]carbamoyl]octanohydroxamic acid
Homo sapiens
IC50 above 0.07 mM, at pH 7.5 and 25°C
0.07
4-(1H-indol-3-yl)-4-oxobutanoic acid
Homo sapiens
IC50 above 0.07 mM, at pH 7.5 and 25°C
0.032
5-[(4-chlorophenyl)methyl]-5-phenylimidazolidine-2,4-dione
Homo sapiens
at pH 7.5 and 25°C
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
-
catalytic activity of wild-type and internally FLAG-tagged fusion protein is indistinguishable
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
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pI VALUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
in Drosophila, the ADAM10 orthologue kuzbanian acts act as Notch sheddase
-
-
brenda
-
644076, 644077, 644078, 667528, 668275, 668305, 668460, 669926, 669957, 670409, 670688, 677996, 679015, 679035, 679073, 679098, 679354, 680669, 680772, 680905, 682103, 682558, 696088, 696395, 696526, 697352, 697848, 697898, 699201, 699339, 699655, 700326, 700891, 707429, 708058, 708278, 708458, 708462, 708492, 708656, 708699, 709158, 712413, 719416, 719922, 720160, 720832
-
-
brenda
-
668407, 669333, 669464, 669480, 670245, 670247, 670688, 679356, 680854, 682137, 697848, 697898, 699697, 707435, 708269, 708492
-
-
brenda
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
A-172 cell line has potent alpha-secretase activity, higher than HEK-293 cell line
brenda
-
N-Cadherin cleavage occurs at a higher level in glioblastoma cells than in non-neoplastic astrocytes
brenda
-
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
brenda
-
COS7 cell line transfected with ADAM10 produces transactivation of epidermal growth factor receptor
brenda
both ADAM10 and ADAM17, EC 3.4.24.86, are present during all stages of spermatogenesis
brenda
both ADAM10 and ADAM17 contribute to SDC1 shedding and IL-8 production by HVECs in response to staphylococcal superantigen toxic shock syndrome toxin TSST-1
brenda
-
human mesenchymal stem cells interfere with cellcell adhesion and enhance migration of breast cancer cells by activating ADAM10
brenda
-
acinar cell during embryogenesis, endocrinic cell and exocrinic cell in adult
brenda
-
ADAM10 is necessary for epidermal growth factor receptor transactivation
brenda
-
cell line LNCaP, localized to the secretory cells of prostate glands, with additional basal cell expression in benign glands
brenda
both ADAM10 and ADAM17, EC 3.4.24.86, are present during all stages of spermatogenesis
brenda
both ADAM10 and ADAM17, EC 3.4.24.86, are present during all stages of spermatogenesis. Protein level and cell surface localization strongly dropp in Dark segments as compared with the rest of the segments
brenda
additional information
ADAM10 specifically localizes in the CD31+ endothelial cells in normal human cardiac tissues and in cultured primary arterial endothelial cells
brenda
-
ADAM17-/-, Ras-Myc-immortalized murine fibroblasts. ADAM10 is a major TNF sheddase in ADAM17-deficient fibroblasts
brenda
-
U-1242 MG, N-Cadherin cleavage occurs at a higher level in glioblastoma cells than in non-neoplastic astrocytes
brenda
-
in the adult intestine, ADAM10 is abundantly expressed on the basolateral cell surface of all intestinal epithelial cells
brenda
-
epidermal hair follicle infundibulum, keratinocytes of the hair infundibulum do not show any difference as compared to keratinocytes of the normal epidermis
brenda
-
ADAMs9 and 10 are the most prominent collagen XVII sheddases in primary keratinocytes
brenda
-
LoVo cell line does not express furin protease has both the immature and mature form of the enzyme
brenda
-
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
brenda
-
cytoplasmic expression of ADAM 10 is observed in the hair bulb keratinocytes and fibroblasts of dermal papilla in anagen IIII hair follicles. Decreased ADAM 10 expression is observed in the hair matrix keratinocytes as compared to the hair bulb keratinocytes in anagen IIII 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
brenda
additional information
-
endothelial cells of venules and arterioles do not express ADAM10
brenda
additional information
the enzyme is not localized in cardiomyocytes
brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
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
-
brenda
-
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
brenda
-
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
brenda
-
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
brenda
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
metabolism
physiological function
malfunction
-
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
-
knockdown of both endogenous ADAM10 and endogenous ADAM17 inhibits FcalphaR shedding, demonstrating that ADAM10 and ADAM17 are involved in the shedding of FcalphaR
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
-
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
malfunction
-
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
-
deletion of ADAM10 prevents development of the entire marginal zone B cell lineage
malfunction
-
inhibition of ADAM10 activity in the intestine of mice results in a lack of compartmentalization of Paneth cells within the crypt stem cell niche
malfunction
enzyme depletion in forebrain neurons leads to posttranslational increase of cellular prion protein levels
malfunction
enzyme inhibition selectively increases glioma sphere-forming cell, but not neural stem cell, migration out of tumourspheres towards fibronectin
malfunction
enzyme knockdown inhibits the CNE-2 nasopharyngeal carcinoma cell proliferation and migration
malfunction
enzyme knockout in cranial neural crest cells leads to embryonic death, craniofacial dysmorphia and bone defects
malfunction
-
enzyme-deficient embryos die at E 9.5 due to developmental defects in somitogenesis, neurogenesis and vasculogenesis
metabolism
-
ADAM10 as a major alpha-secretase in the ectodomain shedding of nectin-1
physiological function
-
ADAM10 and ADAM17 are activated by G protein-coupled receptor P2Y2
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
-
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 Alzheimers disease
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 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 is a major TNF sheddase in ADAM17-deficient fibroblasts. TNF is a major pro-inflammatory cytokine with broad immune effects
physiological function
-
ADAM10 is a primary enzymes responsible for catalysing release of membrane-anchored proteins from the cell surface in metazoan organisms
physiological function
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 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
-
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
-
human mesenchymal stem cells interfere with cellcell adhesion and enhance migration of breast cancer cells by activating ADAM10
physiological function
-
regulated proteolytic processing by ADAM10 and PS/gamma-secretase is essential for the nuclear signalling of L1
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 activity is required for insulin-like growth factor-1-induced secretion of soluble amyloid-beta precurso protein
physiological function
-
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
-
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
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
-
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
-
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 deficiency in ureteric bud derivatives leads to a decrease in urinary concentrating ability, polyuria, and hydronephrosis. Adam10 deficiency leads to a reduction in the percentage of aquaporin 2+ principal cells in the collecting ducts that is accompanied by a proportional increase in the percentage of intercalated cells. Foxi1, a transcription factor important for the differentiation of intercalated cells, is upregulated in the Adam10 mutants
physiological function
ADAM10 is the major ADAM metalloproteinase responsible for the constitutive and stimulated shedding of meprin beta and meprin A
physiological function
collagen binding induces ADAM10-dependent ectodomain shedding of discoidin domain receptor DDR1. DDR1 shedding is not a result of an activation of its signaling pathway, since DDR1 mutants defective in signaling are shed in an efficient manner. DDR1 and ADAM10 are in a complex on the cell surface, but shedding does not occur unless collagen binds to DDR1. ADAM10-dependent DDR1 shedding regulates the half-life of collagen-induced phosphorylation of the receptor
physiological function
endopeptidase ADAM10 selectively regulates Notch receptors and ligands in en dothelial cells and promotes Dll4 expression. ADAM10 mediates a canonical Notch dependent release of interleukin IL-6, dependent of gamma-secretase activity. The production of IL-6 through ADAM10/Notch signaling in endothelial cells requires the involvement of the phosphoinositol 3-kinase pathway
physiological function
-
loss of ADAM10 from developing and adult intestine causes lethality associated with altered intestinal morphology, reduced progenitor cell proliferation, and increased secretory cell differentiation. ADAM10 deletion leads to the replacement of intestinal cell progenitors with post-mitotic, secretory cell lineages: intermediate-like and enteroendocrine cells. ADAM10 controls these cell fate decisions by regulating Notch signaling. ADAM10 is required for survival of Lgr5+ crypt-based columnar cells
physiological function
overexpression of ADAM10 and ADAM17 increase cleavage of cell surface VEGF receptor Flt while knockdown of ADAM10 and ADAM17 reduce N-terminal cleavage suggesting that these metalloproteases are responsible for Flt1 cleavage
physiological function
Staphylococcus aureus alpha-hemolysin, a pore-forming cytotoxin, is required for full virulence in a murine sepsis model. The alpha-hemolysin binding to its receptor A-disintegrin and metalloprotease ADAM10 upregulates the receptor's metalloprotease activity on endothelial cells, causing vascular endothelial-cadherin cleavage and concomitant loss of endothelial barrier function
physiological function
upon deletion of ADAM10 in B cells, antibody responses are impaired despite normal germinal center formation in mice, implicating ADAM10 in post-germinal center and extrafollicular B cell terminal differentiation. Plasma cell numbers are normal in ADAM10 deletion mice when compared to controls. Plasma cells of the deletion strain exhibit decreased expression of transcription factors important for their function: Prdm1, Xbp1 and Irf4. Transcriptional repressor Bcl6 expression is increased in plasma cells isolated from ADAM10 deletion mice at both the mRNA and protein level
physiological function
enzyme overexpression promotes the progression and migration of nasopharyngeal carcinoma
physiological function
interaction of Cry3Aa toxin with ADAM10 metalloprotease is an essential part of the mode of action of this toxin. ADAM10 is a Cry3Aa toxin functional receptor
physiological function
the enzyme critically contributes to alpha-toxin-dependent pathology of experimental Staphylococcus aureus infections in mice
physiological function
the enzyme has deleterious effects for patients with brain tumors because it may promote the spreading of tumor cells. The level and/or activity of ADAM10 affects neuronal structures in the adult brain, in particular dendritic spines
physiological function
the enzyme is directly involved in the development of Alzheimer's disease, prion diseases, fragile X syndrome and possibly Huntington disease
physiological function
the enzyme is essential for cranial neural crest-derived maxillofacial bone development
physiological function
-
the enzyme is essential for intestinal development. Several signaling pathways that undergo ectodomain shedding by the enzyme (e.g. Notch, EGFR/ErbB, interleukin-6/sinterleukin-6R) help control intestinal injury/regenerative responses and may drive intestinal inflammation and colon cancer initiation and progression. The enzyme is associated with regulated intramembrane proteolysis activity
physiological function
the enzyme mediates a canonical Notch-dependent regulation of IL-6 through Dll4 in human endothelial cells. ADAM10/Dll4 signaling is a major signaling pathway in endothelial cells driving inflammatory events involved in inflammation and immune cell recruitment
physiological function
the enzyme promotes binding of alpha-toxin to human keratinocytes. The enzyme is required but insufficient to sensitize cells to alpha-toxin. The enzyme does not sensitize cells to Vibrio cholerae cytolysin
Show AA Sequence and Transmembrane Helices (1745 entries)
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PDB
SCOP
CATH
UNIPROT
ORGANISM
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
60000
68000
85000
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
glycoprotein
proteolytic modification
glycoprotein
-
contains high-mannose as well as complex-type N-glycans. Glycosylation sites: S269, T280, S441, T553
glycoprotein
-
glycosylation sites in the catalytic and disintegrin domain contain high-mannose as well as complex type N-glycans
glycoprotein
the enzyme has four potential N-glycosylation sites (N267, N278, N439 and N551)
proteolytic modification
-
the enzyme has an inactive form that is activated by cleavage
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
proteolytic modification
-
synthesized in an inactive form, which is proteolytically activated during its forward transport along the secretory pathway and at the plasma membrane
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
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
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PROTEIN VARIANTS
ORGANISM
UNIPROT
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
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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
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the point mutation which compromises the zinc-binding consensus motif, leads to a substantial decrease in amyloid precursor protein-alpha secretion
N439
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mutation at the N-glycosylation site N439 increase ADAM10s susceptibility to proteolytical degradation
Q170H
R181G
C173S
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mutation does not impair the inhibitory potency of the ADAM10 prodomain against ADAM10
E384A
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the point mutation which compromises the zinc-binding consensus motif, leads to a substantial decrease in amyloid precursor protein-alpha secretion
additional information
Q170H
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Alzheimers 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 Alzheimers 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 (1.53.5-fold) in cell-based studies
Q170H
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significant evidence for an association of Alzheimers disease with the metalloproteinase with respect to two mutations: Q170H and R181G
Q170H
the mutation in the pro-domain region of the ADAM10 gene reduce alpha-secretase activity of the enzyme
R181G
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Alzheimers 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 Alzheimers 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
R181G
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significant evidence for an association of Alzheimers disease with the metalloproteinase with respect to two mutations: Q170H and R181G
R181G
the mutation in the pro-domain region of the ADAM10 gene reduce alpha-secretase activity of the enzyme
additional information
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consensus sequence RKKR mutated for NAQA resulting in no expression of mature protein
additional information
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ADAM10 mutant lacking the prodomain is inactive, the prodomain is probably involved in the maturation of the enzyme
additional information
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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
additional information
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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
additional information
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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
additional information
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knockdown of ADAM10 in HUVECs as well as in T cells by small interfering RNA impairs T-cell transmigration
additional information
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RNA interference (RNAi)-induced knockdown of ADAM10 in human astroglioma cell line U373 has no influence on NRG-1 (neuregulin-1) shedding
additional information
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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
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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
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
additional information
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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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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
additional information
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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
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
SDS-PAGE
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
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
-
generation of ADAM10chimeras of the extracellular domain of the human interleukin-2 receptor with the intracellular C-terminal domain of mouse ADAM10. Transfection into COS7 cells
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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 1460 of mouse ADAM10).
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a C-terminal HA-tagged fusion protein is transfected in human ovarian cancer SKOV3 cells and human embryonic kidney HEK293 cells
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a C-terminal HA-tagged fusion protein is transfected in human ovarian cancer SKOV3 cells and human embryonic kidney HEK293 cells
-
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
amount and activity of ADAM10 is increased by application of low doses of statins
-
cultured HL-60 neutrophils exposed to tobacco smoke extract show increased enzyme content, cleavage of the molecule into its active form, and release of microvesicles carrying mature enzyme
-
enzyme levels are higher in sections from patients with anterior disk displacement with and without reduction compared to normal temporomandibular joint disks
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retinoids induce gene expression of ADAM10. The vitamin A analog acitretin stimulates ADAM10 promoter activity with an EC50 of 0.0015 mM
-
the enzyme is upregulated at injury sites and in denervated areas of the brain following brain injury
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
molecular biology
medicine
-
cleavage by ADAM10 of beta-amyloid precursor protein could abolish production of longer peptides and slow down or arrest Alzheimer disease
medicine
-
ADAM10 participates in the response to infection by Staphylococcus aureus
medicine
-
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
-
reduction of ADAM10 in Alzheimer disease could allow beta-secretase cleavage of amyloid precursor protein
medicine
-
pharmacotherapeutic target for the treatment of cerebral amyloidosis in Alzheimer disease
medicine
-
Kuzbanian is required for pericardial cell and lymph gland development
medicine
-
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
-
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
-
ADAM10 plays a critical role in Alzheimers 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 Alzheimers disease therapy. Promotion of TSPAN12-ADAM10-dependent functions should be therapeutically beneficial in Alzheimers disease, whereas inhibition of TSPAN12-ADAM functions may be beneficial in cancer
medicine
-
upregulation of ADAM10 is a therapeutic target in Alzheimers disease
medicine
Staphylococcus aureus alpha-hemolysin, a pore-forming cytotoxin, is required for full virulence in a murine sepsis model. The alpha-hemolysin binding to its receptor A-disintegrin and metalloprotease ADAM10 upregulates the receptors metalloprotease activity on endothelial cells, causing vascular endothelial-cadherin cleavage and concomitant loss of endothelial barrier function
medicine
patients with nasopharyngeal carcinoma with high expression of the enzyme have shorter overall survival rates
medicine
-
Kuzbanian is required for pericardial cell and lymph gland development
-
molecular biology
-
ADAM10 is regulator of vascular permeability and possesses a function VE-cadherin-dependent endothelial cell functions and leukocyte transendothelial migration
molecular biology
-
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
molecular biology
-
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
molecular biology
-
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 alzheimers disease by increasing the beta-secretase activity
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EXTERNAL LINKS (specific for EC-Number 3.4.24.81)
Transporter Classification Database (TCDB): 8.A.77.1.4
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Release 2023.1 (January 2023)
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