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Information on EC 3.4.24.B10 - ADAM12 endopeptidase and Organism(s) Homo sapiens
for references in articles please use BRENDA:EC3.4.24.B10preliminary BRENDA-supplied EC number
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3.4.24.B10 ADAM12 endopeptidaseSpecify your search results
Word Map
- 3.4.24.B10
-
adams
- pregnancy
-
trimester
- integrins
- metalloproteinases
- myoblasts
- papp-a
-
pregnancy-associated
- preeclampsia
-
first-trimester
- ectodomain
- thrombospondin
- protein-a
- hb-egf
-
egf-like
-
metalloprotease-disintegrins
-
gestation-specific
-
nuchal
-
disintegrin-like
- timp-3
-
adamts-7
-
invadopodia
- medicine
-
metalloproteinase-12
-
beta-hcg
- prodomain
-
second-trimester
- igfbp-5
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Synonyms
adam12, adam 12, adam-12, adamts-12, adam12-s, adam12s, adam12-l, meltrin alpha, adam12l, a disintegrin and metalloprotease 12, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
a disintegrin and metalloprotease 12
a disintegrin and metalloprotease-12
a disintegrin and metalloproteinase domain 12
ADAM 12
ADAM-12
ADAM12
ADAM12-L
ADAM12-S
ADAMTS-12
M12.212
meltrin alpha
ADAM12
-
-
ADAM12
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
proteolysis of proteins
the metalloprotease domain is catalytically active, Glu351 is essential for activity
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of peptide bond
CAS REGISTRY NUMBER
COMMENTARY
182372-11-8
-
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
5-Fam-FFLAQA(homophenylalanine)RSK-NH2 + H2O
5-Fam-FFLAQA + (homophenylalanine)RSK-NH2
best substrate
-
-
?
5-Fam-HADLAQA(homophenylalanine)RSK-NH2 + H2O
5-Fam-HADLAQA + (homophenylalanine)RSK-NH2
-
-
-
?
5-Fam-HALAQA(homophenylalanine)RSK-NH2 + H2O
5-Fam-HALAQA + (homophenylalanine)RSK-NH2
-
-
-
?
5-Fam-LAQA(homophenylalanine)RSK-NH2 + H2O
5-Fam-LAQA + (homophenylalanine)RSK-NH2
-
-
-
?
basigin + H2O
soluble basigin fragment + ?
the enzyme binds basigin and cleaves it in the juxta membrane region, thereby releasing a soluble basigin fragment to the extracellular space
-
-
?
dabcyl-LAQA(homo)PheRSK(5FAM)-NH2 + H2O
?
-
a 5-carboxamido-fluorescein labelled substrate
-
-
?
Dabcyl-LAQA(homophenylalanine)RSK(5-FAM)-NH2 + H2O
Dabcyl-LAQA + (homophenylalanine)RSK(5-FAM)-NH2
-
-
-
?
insulin-like growth factor binding protein-3 + H2O
?
-
-
-
-
?
insulin-like growth factor binding protein-3 + H2O
?
-
-
-
?
insulin-like growth factor binding protein-3 + H2O
?
enzyme plays a role in degradation of insulin-like growth factor binding protein-3 in the blood of pregnant women
-
?
insulin-like growth factor binding protein-3 + H2O
?
in serum of pregnant women
-
?
protein + H2O
peptides
-
key enzyme in the ectodomain shedding of membrane-anchored heparin-binding epidermal growth factor, i.e. proHB-EGF, leading to epidermal growth factor-like receptor transactivation
-
?
additional information
?
-
enzyme complexes alpha2-macroglobulin
-
?
additional information
?
-
enzyme complexes alpha2-macroglobulin
-
?
additional information
?
-
no activity with insulin-like growth factor binding proteins-1, -2, -4 and -6
-
?
additional information
?
-
-
no activity with insulin-like growth factor binding proteins-1, -2, -4 and -6
-
?
additional information
?
-
-
ADAM12 prevents degradation of transforming growth factor-beta type II receptor
-
-
?
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
basigin + H2O
soluble basigin fragment + ?
the enzyme binds basigin and cleaves it in the juxta membrane region, thereby releasing a soluble basigin fragment to the extracellular space
-
-
?
insulin-like growth factor binding protein-3 + H2O
?
enzyme plays a role in degradation of insulin-like growth factor binding protein-3 in the blood of pregnant women
-
?
insulin-like growth factor binding protein-3 + H2O
?
in serum of pregnant women
-
?
protein + H2O
peptides
-
key enzyme in the ectodomain shedding of membrane-anchored heparin-binding epidermal growth factor, i.e. proHB-EGF, leading to epidermal growth factor-like receptor transactivation
-
?
additional information
?
-
enzyme complexes alpha2-macroglobulin
-
?
additional information
?
-
enzyme complexes alpha2-macroglobulin
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Ca2+
Cu2+
activates, dependent on, multistep activation mechanism involving both furin cleavage and copper binding
Zn2+
Zn2+
activates, dependent on, enzyme contains a catalytically active zinc-binding domain
Zn2+
highly conserved zinc-binding motif HEXXHXXGXXH, the metalloprotease domain is the catalytically active site, the Met-turn is essential for the structural integrity of the zinc-binding site, Glu351 is essential for activity
Zn2+
-
addition of ZnCl2 at concentrations below 0.05 mM increases the activity of ADAM12-S by approximately 30%
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(2R)-N4-hydroxy-N1-[(1S)-1-(1H-indol-3-ylmethyl)-2-(methylamino)-2-oxoethyl]-2-(2-methylpropyl)butanediamide
-
IC50: 5930 nM
(4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl)-L-phenylglycine-N-methylamide
-
KB-R7785, 0.001mmol/l
4-[[[6-cyano-1-[(1-methyl-1H-imidazol-5-yl)methyl]-1,2,3,4,6,7-hexahydroquinolin-3-yl](pyridin-2-ylsulfonyl)amino]methyl]-N,N-dimethylpiperidine-1-carboxamide
-
Co2+
-
0.01 mM Co2+ inhibits the activity by 80%, while increasing concentrations rescue the lost activity
N-TIMP-1
N-terminal domain of TIMP-1, tissue inhibitor of metalloproteinase
-
N-TIMP-1TACE
mutant (V4S/V69L/T98L/TIMP-3-ABloop) of N-TIMP-1, tissue inhibitor of metalloproteinase
-
N-TIMP-1[T98L]
mutant of N-TIMP-1, tissue inhibitor of metalloproteinase
-
N-TIMP-1[TIMP-2-ABloop]
mutant of N-TIMP-1, tissue inhibitor of metalloproteinase
-
N-TIMP-1[TIMP-3-ABloop]
mutant of N-TIMP-1, tissue inhibitor of metalloproteinase
-
N-TIMP-1[V4A]
mutant of N-TIMP-1, tissue inhibitor of metalloproteinase
-
N-TIMP-1[V4S]
mutant of N-TIMP-1, tissue inhibitor of metalloproteinase
-
N-TIMP-2
N-terminal domain of TIMP-2, tissue inhibitor of metalloproteinase
-
N-TIMP-2-deltaABloop
mutant of N-TIMP-2, tissue inhibitor of metalloproteinase
-
N-TIMP-2TACE
mutant (S2T/A70S/V71L/TIMP-3-ABloop) of N-TIMP-2, tissue inhibitor of metalloproteinase
-
N-TIMP-2TACE[F34G]
mutant of N-TIMP-2TACE, tissue inhibitor of metalloproteinase
-
N-TIMP-2TACE[L100E]
mutant of N-TIMP-2TACE, tissue inhibitor of metalloproteinase
-
N-[(2E)-3-(2-fluorophenyl)-2-[(phenylcarbonyl)amino]prop-2-enoyl]valine
-
IC50: 40.5 nM
N-[(2E)-3-(3-bromophenyl)-2-[(furan-2-ylcarbonyl)amino]prop-2-enoyl]glycine
-
IC50: 16.7 nM
N-[(2E)-3-(4-bromofuran-2-yl)-2-[[(5-bromofuran-2-yl)carbonyl]amino]prop-2-enoyl]alanine
-
IC50: 24.8 nM
N-[(2E)-3-furan-2-yl-2-[(furan-2-ylcarbonyl)amino]prop-2-enoyl]alanine
-
IC50: 42.3 nM
tissue inhibitor of metalloproteinase-3
i.e. TIMP-3, possible physiological inhibitor of the enzyme
-
1,10-phenanthroline
-
total inhibition when incubated with gelatin at 37 °C for either 2 or 18 h
EDTA
-
total inhibition when incubated with gelatin at 37 °C for either 2 or 18 h
marimastat
-
1 mM, partial inhibition when incubated with gelatin at 37 °C for either 2 or 18 h
N-TIMP-3
N-terminal domain of TIMP-3, tissue inhibitor of metalloproteinase
-
Zn2+
-
when concentrations exceed 0.05 mM, activity is negatively affected, and at a concentration of 0.5 mM Zn2+, substrate degradation is only just detectable
additional information
-
N-TIMP-3 variants that lack MMP inhibitory activity but retain the ability to inhibit ADAM17/TACE fail to inhibit ADAM12
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
PACSIN3
-
protein that interacts with the enzyme via its proline-rich region, amino acid residues 829-840, at the cytoplasmic domain, interaction is necessary for the upregulation of proHB-EGF shedding
-
stanolone
-
regulation in a bell-shaped, dose-dependent manner, maximal, 5fold increase in activity at 0.000001 mM
transforming growth factor beta
-
ADAM-12m expression in osteoarthritic chondrocytes is selectively enhanced by transforming growth factor beta
-
additional information
IGF-I and IGF-II are not stimulating, the enzyme is IGF-independent
-
additional information
-
IGF-I and IGF-II are not stimulating, the enzyme is IGF-independent
-
additional information
-
no changes in expression after stimulation with tumor necrosis factor alpha, interleukin-1alpha, basic fibroblast growth factor, heparin-binding epidermal growth factor, insulin-like growth factor-1, or vascular endothelial growth factor 165
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.00593
(2R)-N4-hydroxy-N1-[(1S)-1-(1H-indol-3-ylmethyl)-2-(methylamino)-2-oxoethyl]-2-(2-methylpropyl)butanediamide
Homo sapiens
-
IC50: 5930 nM
0.0000405
N-[(2E)-3-(2-fluorophenyl)-2-[(phenylcarbonyl)amino]prop-2-enoyl]valine
Homo sapiens
-
IC50: 40.5 nM
0.0000167
N-[(2E)-3-(3-bromophenyl)-2-[(furan-2-ylcarbonyl)amino]prop-2-enoyl]glycine
Homo sapiens
-
IC50: 16.7 nM
0.0000248
N-[(2E)-3-(4-bromofuran-2-yl)-2-[[(5-bromofuran-2-yl)carbonyl]amino]prop-2-enoyl]alanine
Homo sapiens
-
IC50: 24.8 nM
0.0000423
N-[(2E)-3-furan-2-yl-2-[(furan-2-ylcarbonyl)amino]prop-2-enoyl]alanine
Homo sapiens
-
IC50: 42.3 nM
0.000025
batimastat
Homo sapiens
with 5-Fam-HALAQA(homophenylalanine)RSK-NH2 as substrate, at pH 8.0 and 22°C
0.000028
batimastat
Homo sapiens
with 5-Fam-FFLAQA(homophenylalanine)RSK-NH2 as substrate, at pH 8.0 and 22°C
0.0011
GM6001
Homo sapiens
with 5-Fam-HALAQA(homophenylalanine)RSK-NH2 as substrate, at pH 8.0 and 22°C
0.0021
GM6001
Homo sapiens
with 5-Fam-FFLAQA(homophenylalanine)RSK-NH2 as substrate, at pH 8.0 and 22°C
0.00043
marimastat
Homo sapiens
with 5-Fam-FFLAQA(homophenylalanine)RSK-NH2 as substrate, at pH 8.0 and 22°C
0.00067
marimastat
Homo sapiens
with 5-Fam-HALAQA(homophenylalanine)RSK-NH2 as substrate, at pH 8.0 and 22°C
0.0006
MMP inhibitor III
Homo sapiens
with 5-Fam-HALAQA(homophenylalanine)RSK-NH2 as substrate, at pH 8.0 and 22°C
0.0011
MMP inhibitor III
Homo sapiens
with 5-Fam-FFLAQA(homophenylalanine)RSK-NH2 as substrate, at pH 8.0 and 22°C
0.00012
MMP inhibitor V
Homo sapiens
with 5-Fam-FFLAQA(homophenylalanine)RSK-NH2 as substrate, at pH 8.0 and 22°C
0.00018
MMP inhibitor V
Homo sapiens
with 5-Fam-HALAQA(homophenylalanine)RSK-NH2 as substrate, at pH 8.0 and 22°C
0.0015
MMP-3 inhibitor VIII
Homo sapiens
with 5-Fam-HALAQA(homophenylalanine)RSK-NH2 as substrate, at pH 8.0 and 22°C
0.0028
MMP-3 inhibitor VIII
Homo sapiens
with 5-Fam-FFLAQA(homophenylalanine)RSK-NH2 as substrate, at pH 8.0 and 22°C
0.00035
TAPI-0
Homo sapiens
with 5-Fam-HALAQA(homophenylalanine)RSK-NH2 as substrate, at pH 8.0 and 22°C
0.0004
TAPI-0
Homo sapiens
with 5-Fam-FFLAQA(homophenylalanine)RSK-NH2 as substrate, at pH 8.0 and 22°C
0.001
TAPI-1
Homo sapiens
with 5-Fam-FFLAQA(homophenylalanine)RSK-NH2 as substrate, at pH 8.0 and 22°C
0.0014
TAPI-1
Homo sapiens
with 5-Fam-HALAQA(homophenylalanine)RSK-NH2 as substrate, at pH 8.0 and 22°C
0.0014
TAPI-2
Homo sapiens
with 5-Fam-FFLAQA(homophenylalanine)RSK-NH2 as substrate, at pH 8.0 and 22°C
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.4
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
6.5 - 8.5
enzyme is active at neutral and alkaline pH, but inactive below pH 6.5
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
652051, 652478, 653225, 667133, 667947, 668496, 668501, 668620, 668997, 669293, 669528, 669952, 670208, 670683, 677883, 678344, 680191, 681003, 690386
-
-
-
SwissProt
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
strong reactivity in outer root sheath of catagen and telogen hair follicles
-
ADAM-12 is produced during allergic reaction by airway epithelial cells and might increase neutrophil recruitment within airway mucosa
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
metabolism
up-regulation of ADAM12L induces the Akt Ser-473 phosphorylation-dependent survival pathway via stimulation of beta1 integrins and activation of phosphoinositide 3-kinase, and promotes kinase activity from integrin-linked kinase immunoprecipitates
physiological function
malfunction
down-regulation of ADAM12L in hepatic stellate cells leads to cytoskeletal disorganization and loss of adhesion
malfunction
enzyme knockdown greatly enhances interleukin-17-secreting cell differentiation, more potently then inhibiting transforming growth factor beta signals
malfunction
enzyme loss impedes spontaneous fusion of primary cytotrophoblasts
malfunction
enzyme downregulation in breast cancer cell lines results in reduction of pro-angiogenic factors and endothelial cell recruitment
malfunction
enzyme knockdown reduces cell migration and invasion, decreases anoikis resistance, and compromises mammosphere formation. Enzyme knockdown lowers the basal activation level of epidermal growth factor receptor pathway
physiological function
-
may play an important role in the apoptosis of hair follicle keratinocytes
physiological function
-
ADAM12 transmembrane and secreted isoforms promote breast tumor growth. The tumor-promoting activity of ADAM12-S is a function of its proteolytic activity. Only the secreted isoform enhances the ability of tumor cells to migrate and invade in vitro and results in a higher incidence of local and distant metastasis in vivo
physiological function
-
ADAMTS-12, independent of its proteolytic activity, plays a specific, non-redundant role in trophoblast invasion. ADAMTS-12 regulates cell-extracellular matrix adhesion and invasion through a mechanism involving the alphavbeta3 integrin heterodimer
physiological function
ADAMTS-12 is involved in several pathophysiological conditions, including intervertebral disc degeneration, tumorigenesis and angioinhibitory effects, pediatric stroke, gonad differentiation, trophoblast invasion, and genetic linkage to schizophrenia and asthma, with special focus on its role in arthritis and inflammation. The enzyme is also involved in the processes of chondrocyte differentiation and cartilage development
physiological function
the enzyme controls trophoblast fusion through E-cadherin ectodomain shedding and remodeling of intercellular boundaries
physiological function
the enzyme plays a regulatory role in Th17 cell differentiation or function
physiological function
breast cancer cell populations with high enzyme levels have elevated expression of cancer stem cell markers and an increased ability to form mammospheres. The enzyme actively supports the cancer stem cell phenotype in claudin-low breast cancer cells via modulation of the epidermal growth factor receptor pathway
physiological function
overexpression of isoform ADAM12-L in breast cancer cells following 5-fluorouracil treatment results in the acquisition of resistance to 5-fluorouracil. ADAM12-L overexpression also results in increased levels of p-Akt but not p-ERK. These alterations enhanced breast cancer cell growth and invasive abilities
physiological function
tumor-associated enzyme promotes angiogenesis. The enzyme induces migration and tube formation in endothelial cells. Enzyme expression in breast tumor cells correlates with a significant upregulation of proangiogenic factors such as VEGF and matrix metalloproteinase 9 and downregulation of antiangiogenic factors such as thrombospondin-1 and tissue inhibitor of metalloproteinases-2. Enzyme expression correlates with STAT3 activation in breast tumor cells
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). ADA12_HUMAN
909
0
99542
Swiss-Prot
Chloroplast (Reliability: 2)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
120000
27000
68000
90000
92000
96000
x * 68000, processed recombinant enzyme, SDS-PAGE, x * 96000, recombinant enzyme proform, SDS-PAGE
27000
x * 27000, prodomain after cleavage of the proform with furin, SDS-PAGE, x * 68000, recombinant processed enzyme form, SDS-PAGE, x * 92000, recombinant soluble enzyme proform, SDS-PAGGE
68000
the 68 kDa band represents the metalloprotease, disintegrin, cysteine-rich, and epidermal growth factor-like domains, SDS-PAGE
68000
x * 27000, prodomain after cleavage of the proform with furin, SDS-PAGE, x * 68000, recombinant processed enzyme form, SDS-PAGE, x * 92000, recombinant soluble enzyme proform, SDS-PAGGE
68000
x * 68000, processed recombinant enzyme, SDS-PAGE, x * 96000, recombinant enzyme proform, SDS-PAGE
68000
x * 68000, processed recombinant mutant enzyme, SDS-PAGE, x * 92000, unprocessed recombinant mutant enzyme, SDS-PAGE
92000
x * 27000, prodomain after cleavage of the proform with furin, SDS-PAGE, x * 68000, recombinant processed enzyme form, SDS-PAGE, x * 92000, recombinant soluble enzyme proform, SDS-PAGGE
92000
x * 68000, processed recombinant mutant enzyme, SDS-PAGE, x * 92000, unprocessed recombinant mutant enzyme, SDS-PAGE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
?
x * 27000, prodomain after cleavage of the proform with furin, SDS-PAGE, x * 68000, recombinant processed enzyme form, SDS-PAGE, x * 92000, recombinant soluble enzyme proform, SDS-PAGGE
?
x * 68000, processed recombinant enzyme, SDS-PAGE, x * 96000, recombinant enzyme proform, SDS-PAGE
?
x * 68000, processed recombinant mutant enzyme, SDS-PAGE, x * 92000, unprocessed recombinant mutant enzyme, SDS-PAGE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phosphoprotein
-
c-Src kinase activity regulates ADAM12-L phosphorylation (tyrosine phosphorylation) and the c-Src-ADAM12-L interaction, the cytoplasmic tail of ADAM12-L has two Src SH3-binding sites, the high-affinity c-Src binding site is important for its cellular localization with c-Src to actin-rich structures at the cell periphery
proteolytic modification
proteolytic modification
autocleavage occurs near the junction of the prodomain and the catalytic domain upon inactivation of cysteine residues C179 and in presence of Cu2+ which is further promoted in presence of ascorbate, multistep activation mechanism involving both furin cleavage and copper binding
proteolytic modification
the cysteine-switch of the prodomain maintaines the zymogen in a latent state, enzyme is synthesized as a catalytically inactive zymogen, in vivo cleavage by a furin-like endopeptidase, activation is chemically possible with N-ethylmaleimide, but not with Hg2+
proteolytic modification
the cysteine-switch of the prodomain maintaines the zymogen in a latent state, enzyme is synthesized as a catalytically inactive zymogen, in vivo cleavage by a furin-like endopeptidase, autoactivation is possible with N-ethylmaleimide
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C179A
C179H
site-directed mutagenesis, exchange of the cysteine-switch residue of the prodomain, still active in complex formation with alpha2-macroglobulin
C179H/E351Q
site-directed mutagenesis, exchange of the cysteine-switch residue of the prodomain results in a no longer latent but inactive zymogen
C179S
E351Q
G48R
naturally occuring mutation, statistically significant association between this polymorphism and patellofemoral osteoarthritis in male patients
L792F
the mutant with wild type activity is not associated with breast cancer
additional information
C179A
site-directed mutagenesis, exchange of the cysteine-switch residue of the prodomain results in a no longer latent but inactive zymogen
C179A
site-directed mutagenesis, exchange of the cysteine-switch residue of the prodomain, still active in complex formation with alpha2-macroglobulin
C179S
site-directed mutagenesis, exchange of the cysteine-switch residue of the prodomain results in a no longer latent but inactive zymogen
C179S
site-directed mutagenesis, exchange of the cysteine-switch residue of the prodomain the glutamic acid residue and of the zinc binding domain involved in catalytic activity, inactive to form complexes with alpha2-macroglobulin, results in a no longer latent but inactive zymogen
C179S
site-directed mutagenesis, mutant behaves identical to the wild-type concerning metal ions, therfore the cysteine-switch and activation by copper are 2 different components of enzyme activation
E351Q
site-directed mutagenesis, exchange of the glutamic acid residue of the zinc binding domain involved in catalytic activity, inactive to form complexes with alpha2-macroglobulin
additional information
elimination of the cysteine-switch by a point mutation in the propeptide has no effect on copper activation, whereas mutation of an unpaired cysteine residue in the catalytic domain resulted in a mutant form of ADAM 12-S that is insensitiv to copper
additional information
KR207NG mutation prevents cleavage of the prodomain by furin, construction of enzyme mutants where the prodomain or the metalloprotease domain or both are eliminated or exchanged for an Ig kappa-chain leader sequence, secretion to the medium, inactive mutant
additional information
-
KR207NG mutation prevents cleavage of the prodomain by furin, construction of enzyme mutants where the prodomain or the metalloprotease domain or both are eliminated or exchanged for an Ig kappa-chain leader sequence, secretion to the medium, inactive mutant
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
ADAM-12 concentration is not changed following three repeated -20°C to room temperature freeze-thaw cycles, in serum at 30°C a 10% change in concentration is observed after 14.8 hours. In serum at room temperature a 10% change in concentration is observed after 19.9 hours. In serum at refrigerator temperature a 10% change in concentration is observed after 51.0 hours. In whole blood at 30°C 64.0% is observed after 3 days. In whole blood at room temperature 81.5% is observed after 3 days. In whole blood at refrigerator temperature 96.6% is observed after 3 days.
-
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
anion exchange column chromatography and concanavalin A column chromatography
gelatin-Sepharose chromatography, cation exchange chromatography, and concanavalin A- or heparin-Sepharose affinity chromatography
-
partial, soluble recombinant protein from 293-EBNA cell and COS-1 cell medium
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in HEK-293T cells, hepatic stellate cells, rhabdomyosarcoma cells, C2C12 cells, COS7 cells, and MvLu1 cells
-
expression of the soluble enzyme in COS-1 cells and in 293-EBNA cell line, coexpression of soluble enzyme and insulin-like growth factor-binding protein-3 in a Saccharomyces cerevisiae two hybrid expression system
expression of the soluble secreted enzyme form ADAM 12-S in cell line 293-EBNA
transient expression in COS-7 cells of an enzyme mutant where the signal peptide, prodomain and metalloprotease domain are exchanged for an Ig kappa-chain leader sequence, secretion to the medium
transient expression in COS-7 cells of the enzyme mutants, secretion to the medium
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
5-fluorouracil induces expression of the enzyme isoform ADAM12-L but not ADAM12-S in breast cancer cells and in recurrent breast cancer tissues
a significant decrease in ADAMTS-12 mRNA levels is detected in extravillous cytotrophoblasts cultured in the presence of transforming growth factor-beta1 (1 ng/ml) for 24 - 48 h
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ADAM12 is dynamically upregulated and under the transcriptional control of protein kinase A
ADAM12 mRNA expression is elevated 10-30fold in malignant breast tissue and metastatic lymph nodes
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ADAM12-L mRNA expression is an independent prognostic factor in resected p-stage I lung adenocarcinoma, and is significantly correlated with tumor differentiation stage and postoperative cancer recurrence
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ADAMTS-12 mRNA levels in extravillous cytotrophoblasts are significantly higher than those detected in JEG-3 cell. Interleukin-1beta causes a continuous and significant increase in ADAMTS-12 mRNA levels in extravillous cytotrophoblasts over time in culture
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
specific isoform ADAM12-L inhibition can optimize 5-fluorouracil-based chemotherapy of breast cancer
medicine
the enzyme is a predictor of chemoresistance in estrogen receptor-negative tumors
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Loechel, F.; Fox, J.W.; Murphy, G.; Albrechtsen, R.; Wewer, U.M.
ADAM 12-S cleaves IGFBP-3 and IGFBP-5 and is inhibited by TIMP-3
Biochem. Biophys. Res. Commun.
278
511-515
2000
Homo sapiens (O43184), Homo sapiens
Loechel, F.; Wewer, U.M.
Activation of ADAM 12 protease by copper
FEBS Lett.
506
65-68
2001
Homo sapiens (O43184)
Loechel, F.; Gilpin, B.J.; Engvall, E.; Albrechtsen, R.; Wewer, U.M.
Human ADAM 12 (meltrin alpha) is an active metalloprotease
J. Biol. Chem.
273
16993-16997
1998
Homo sapiens (O43184), Homo sapiens
Loechel, F.; Overgaard, M.T.; Oxvig, C.; Albrechtsen, R.; Wewer, U.M.
Regulation of human ADAM 12 protease by the prodomain. Evidence for a functional cysteine switch
J. Biol. Chem.
274
13427-13433
1999
Homo sapiens (O43184), Homo sapiens
Shi, Z.; Xu, W.; Loechel, F.; Wewer, U.M.; Murphy, L.J.
ADAM 12, a disintegrin metalloprotease, interacts with insulin-like growth factor-binding protein-3
J. Biol. Chem.
275
18574-18580
2000
Homo sapiens (O43184), Homo sapiens
Eto, K.; Puzon-McLaughlin, W.; Sheppard, D.; Sehara-Fujisawa, A.; Zhang, X.P.; Takada, Y.
RGD-independent binding of integrin alpha9beta1 to the ADAM-12 and -15 disintegrin domains mediates cell-cell interaction
J. Biol. Chem.
275
34922-34930
2000
Homo sapiens
Mori, S.; Tanaka, M.; Nanba, D.; Nishiwaki, E.; Ishiguro, H.; Higashiyama, S.; Matsuura, N.
PACSIN3 binds ADAM12/meltrin alpha and up-regulates ectodomain shedding of heparin-binding epidermal growth factor-like growth factor
J. Biol. Chem.
278
46029-46034
2003
Homo sapiens
McCulloch, D.R.; Harvey, M.; Herington, A.C.
The expression of the ADAMs proteases in prostate cancer cell lines and their regulation by dihydrotestosterone
Mol. Cell. Endocrinol.
167
11-21
2000
Homo sapiens
Kodama, T.; Ikeda, E.; Okada, A.; Ohtsuka, T.; Shimoda, M.; Shiomi, T.; Yoshida, K.; Nakada, M.; Ohuchi, E.; Okada, Y.
ADAM12 is selectively overexpressed in human glioblastomas and is associated with glioblastoma cell proliferation and shedding of heparin-binding epidermal growth factor
Am. J. Pathol.
165
1743-1753
2004
Homo sapiens
Oh, M.; Im, I.; Lee, Y.J.; Kim, Y.H.; Yoon, J.H.; Park, H.G.; Higashiyama, S.; Kim, Y.C.; Park, W.J.
Structure-based virtual screening and biological evaluation of potent and selective ADAM12 inhibitors
Bioorg. Med. Chem. Lett.
14
6071-6074
2004
Homo sapiens
Zhao, Z.; Gruszczynska-Biegala, J.; Cheuvront, T.; Yi, H.; von der Mark, H.; von der Mark, K.; Kaufman, S.J.; Zolkiewska, A.
Interaction of the disintegrin and cysteine-rich domains of ADAM12 with integrin alpha7beta1
Exp. Cell Res.
298
28-37
2004
Homo sapiens
Thodeti, C.K.; Froehlich, C.; Nielsen, C.K.; Holck, P.; Sundberg, C.; Kveiborg, M.; Mahalingam, Y.; Albrechtsen, R.; Couchman, J.R.; Wewer, U.M.
Hierarchy of ADAM12 binding to integrins in tumor cells
Exp. Cell Res.
309
438-450
2005
Homo sapiens
Thodeti, C.K.; Froehlich, C.; Nielsen, C.K.; Takada, Y.; Faessler, R.; Albrechtsen, R.; Wewer, U.M.
ADAM12-mediated focal adhesion formation is differently regulated by beta1 and beta3 integrins
FEBS Lett.
579
5589-5595
2005
Homo sapiens
Carl-McGrath, S.; Lendeckel, U.; Ebert, M.; Roessner, A.; Roecken, C.
The disintegrin-metalloproteinases ADAM9, ADAM12, and ADAM15 are upregulated in gastric cancer
Int. J. Oncol.
26
17-24
2005
Homo sapiens
Roy, R.; Wewer, U.M.; Zurakowski, D.; Pories, S.E.; Moses, M.A.
ADAM 12 cleaves extracellular matrix proteins and correlates with cancer status and stage
J. Biol. Chem.
279
51323-51330
2004
Homo sapiens
Wewer, U.M.; Moergelin, M.; Holck, P.; Jacobsen, J.; Lydolph, M.C.; Johnsen, A.H.; Kveiborg, M.; Albrechtsen, R.
ADAM12 is a four-leafed clover: the excised prodomain remains bound to the mature enzyme
J. Biol. Chem.
281
9418-9422
2006
Homo sapiens
Bernstein, H.G.; Keilhoff, G.; Bukowska, A.; Ziegeler, A.; Funke, S.; Dobrowolny, H.; Kanakis, D.; Bogerts, B.; Lendeckel, U.
ADAM (a disintegrin and metalloprotease) 12 is expressed in rat and human brain and localized to oligodendrocytes
J. Neurosci. Res.
75
353-360
2004
Homo sapiens, Rattus norvegicus
Lafuste, P.; Sonnet, C.; Chazaud, B.; Dreyfus, P.A.; Gherardi, R.K.; Wewer, U.M.; Authier, F.J.
ADAM12 and alpha9beta1 integrin are instrumental in human myogenic cell differentiation
Mol. Biol. Cell
16
861-870
2005
Homo sapiens
Malinin, N.L.; Wright, S.; Seubert, P.; Schenk, D.; Griswold-Prenner, I.
Amyloid-beta neurotoxicity is mediated by FISH adapter protein and ADAM12 metalloprotease activity
Proc. Natl. Acad. Sci. USA
102
3058-3063
2005
Homo sapiens
Okada, A.; Mochizuki, S.; Yatabe, T.; Kimura, T.; Shiomi, T.; Fujita, Y.; Matsumoto, H.; Sehara-Fujisawa, A.; Iwamoto, Y.; Okada, Y.
ADAM-12 (meltrin alpha) is involved in chondrocyte proliferation via cleavage of insulin-like growth factor binding protein 5 in osteoarthritic cartilage
Arthritis Rheum.
58
778-789
2008
Homo sapiens
Jacobsen, J.; Visse, R.; Sorensen, H.P.; Enghild, J.J.; Brew, K.; Wewer, U.M.; Nagase, H.
Catalytic properties of ADAM12 and its domain deletion mutants
Biochemistry
47
537-547
2008
Homo sapiens
Froehlich, C.; Albrechtsen, R.; Dyrskjot, L.; Rudkjaer, L.; Orntoft, T.F.; Wewer, U.M.
Molecular profiling of ADAM12 in human bladder cancer
Clin. Cancer Res.
12
7359-7368
2006
Homo sapiens (O43184), Homo sapiens
Kveiborg, M.; Albrechtsen, R.; Couchman, J.R.; Wewer, U.M.
Cellular roles of ADAM12 in health and disease
Int. J. Biochem. Cell Biol.
40
1685-1702
2008
Homo sapiens, Mus musculus
Atfi, A.; Dumont, E.; Colland, F.; Bonnier, D.; Lhelgoualch, A.; Prunier, C.; Ferrand, N.; Clement, B.; Wewer, U.M.; Theret, N.
The disintegrin and metalloproteinase ADAM12 contributes to TGF-beta signaling through interaction with the type II receptor
J. Cell Biol.
178
201-208
2007
Homo sapiens
Estrella, C.; Rocks, N.; Paulissen, G.; Quesada-Calvo, F.; Noel, A.; Vilain, E.; Lassalle, P.; Tillie-Leblond, I.; Cataldo, D.; Gosset, P.
Role of a disintegrin and metalloprotease-12 in neutrophil recruitment induced by airway epithelium
Am. J. Respir. Cell Mol. Biol.
41
449-458
2009
Homo sapiens
Kveiborg, M.; Jacobsen, J.; Lee, M.H.; Nagase, H.; Wewer, U.M.; Murphy, G.
Selective inhibition of ADAM12 catalytic activity through engineering of tissue inhibitor of metalloproteinase 2 (TIMP-2)
Biochem. J.
430
79-86
2010
Homo sapiens (O43184)
Oh, S.T.; Cho, B.K.; Schramme, A.; Gutwein, P.; Tilgen, W.; Reichrath, J.
Hair-cycle dependent differential expression of ADAM 10 and ADAM 12: An immunohistochemical analysis in human hair follicles in situ
Dermato-endocrinology
1
46-53
2009
Homo sapiens
Stautz, D.; Sanjay, A.; Hansen, M.T.; Albrechtsen, R.; Wewer, U.M.; Kveiborg, M.
ADAM12 localizes with c-Src to actin-rich structures at the cell periphery and regulates Src kinase activity
Exp. Cell Res.
316
55-67
2010
Homo sapiens
Mino, N.; Miyahara, R.; Nakayama, E.; Takahashi, T.; Takahashi, A.; Iwakiri, S.; Sonobe, M.; Okubo, K.; Hirata, T.; Sehara, A.; Date, H.
A disintegrin and metalloprotease 12 (ADAM12) is a prognostic factor in resected pathological stage I lung adenocarcinoma
J. Surg. Oncol.
100
267-272
2009
Homo sapiens
Kerna, I.; Kisand, K.; Tamm, A.E.; Lintrop, M.; Veske, K.; Tamm, A.O.
Missense single nucleotide polymorphism of the ADAM12 gene is associated with radiographic knee osteoarthritis in middle-aged Estonian cohort
Osteoarthritis Cartilage
17
1093-1098
2009
Homo sapiens (O43184), Homo sapiens
Cowans, N.J.; Stamatopoulou, A.; Jaakohuhta, S.; Spencer, K.
ADAM-12 stability in first trimester maternal serum
Prenat. Diagn.
30
555-560
2010
Homo sapiens
Roy, R.; Rodig, S.; Bielenberg, D.; Zurakowski, D.; Moses, M.A.
ADAM12 transmembrane and secreted isoforms promote breast tumor growth: a distinct role for ADAM12-S protein in tumor metastasis
J. Biol. Chem.
286
20758-20768
2011
Homo sapiens
Beristain, A.; Zhu, H.; Leung, P.
Regulated expression of ADAMTS-12 in human trophoblastic cells: A role for ADAMTS-12 in epithelial cell invasion?
PLoS ONE
6
e18473
2011
Homo sapiens
Kotzsch, A.; Skovgaard, T.; Buus, U.; Andersen, S.; Devkota, K.; Berthelsen, J.
A substrate-optimized electrophoretic mobility shift assay for ADAM12
Anal. Biochem.
452
34-42
2014
Homo sapiens (O43184)
Aghababaei, M.; Hogg, K.; Perdu, S.; Robinson, W.P.; Beristain, A.G.
ADAM12-directed ectodomain shedding of E-cadherin potentiates trophoblast fusion
Cell Death Differ.
22
1970-1984
2015
Homo sapiens (O43184)
Wei, J.; Richbourgh, B.; Jia, T.; Liu, C.
ADAMTS-12: a multifaced metalloproteinase in arthritis and inflammation
Mediators Inflamm.
2014
649718
2014
Homo sapiens (O43184)
Leyme, A.; Bourd-Boittin, K.; Bonnier, D.; Falconer, A.; Arlot-Bonnemains, Y.; Theret, N.
Identification of ILK as a new partner of the ADAM12 disintegrin and metalloprotease in cell adhesion and survival
Mol. Biol. Cell
23
3461-3472
2012
Homo sapiens (O43184), Homo sapiens
Stautz, D.; Wewer, U.M.; Kveiborg, M.
Functional analysis of a breast cancer-associated mutation in the intracellular domain of the metalloprotease ADAM12
PLoS ONE
7
e37628
2012
Homo sapiens (O43184)
Zhou, A.X.; El Hed, A.; Mercer, F.; Kozhaya, L.; Unutmaz, D.
The metalloprotease ADAM12 regulates the effector function of human Th17 cells
PLoS ONE
8
e81146
2013
Homo sapiens (O43184), Homo sapiens
Albrechtsen, R.; Wewer Albrechtsen, N.J.; Gnosa, S.; Schwarz, J.; Dyrskjot, L.; Kveiborg, M.
Identification of ADAM12 as a novel basigin sheddase
Int. J. Mol. Sci.
20
E1957
2019
Homo sapiens (O43184), Homo sapiens
Duhachek-Muggy, S.; Qi, Y.; Wise, R.; Alyahya, L.; Li, H.; Hodge, J.; Zolkiewska, A.
Metalloprotease-disintegrin ADAM12 actively promotes the stem cell-like phenotype in claudin-low breast cancer
Mol. Cancer
16
32
2017
Homo sapiens (O43184), Homo sapiens
Roy, R.; Dagher, A.; Butterfield, C.; Moses, M.A.
ADAM12 is a novel regulator of tumor angiogenesis via STAT3 signaling
Mol. Cancer Res.
15
1608-1622
2017
Homo sapiens (O43184), Homo sapiens
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