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Gene Section
Review
ADAM17 (ADAM metallopeptidase domain 17)
Astrid Evers, Karina Reiss
Department of Dermatology and Allergology, University Hospital Schleswig Holstein, Campus Kiel,
Schittenhelmstrasse 7, Kiel D-24105, Germany (AE, KR)
Published in Atlas Database: June 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/ADAM17ID572ch2p25.html
DOI: 10.4267/2042/46070
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
metalloprotease) family which is part of the adamalysin
proteins.
The activity and function of several membrane proteins
is regulated by the proteolytic release of their
ectodomains, a process known as shedding. About 24% of the proteins on the cell surface are affected by
ectodomain shedding (Arribas and Massague, 1995).
Since there are several of functionally and structurally
diverse substrates, ADAMs are involved in various
cellular processes. They take part in the regulation of
cell adhesion, migration, development and signalling
and are also implicated in pathologic conditions such as
inflammation and cancer. The consequences of
ectodomain shedding can vary, depending on the
function of the substrate protein. Membrane-bound
precursor proteins can be released by ADAMs as
mature active molecules, for example ligands of the
EGF receptor or cytokines like TNFa (Peschon et al.,
1998; Blobel, 2005). Receptors, for example ErbB2 and
ErbB4, can also be cleaved by ADAMs and thus
become inactive or may still function as soluble decoy
receptors (Molina et al., 2001; Vecchi et al., 1998).
Contrariwise, receptors like Notch require proteolytic
cleavage to generate intracellular signalling fragments
that act as transcription factors after translocation to the
nucleus. In this case ectodomain shedding is the
prerequisite for regulated intramembrane proteolysis
(RIP) mediated by intramembrane cleaving enzymes
(Pan and Rubin, 1997; Brou et al., 2000).
Identity
Other names: ADAM18; CD156B; CSVP;
MGC71942; TACE
HGNC (Hugo): ADAM17
Location: 2p25.1
Note: There are several recommendable reviews about
ADAM17 and related proteases, for example Blobel,
2005; Arribas and Esselens, 2009; Gooz, 2010; and
Saftig and Reiss, 2011.
DNA/RNA
Description
The genomic DNA of ADAM17 extends 66505 base
pairs with 19 exons. There is only one known
transcription variant.
Transcription
The mRNA of ADAM17 (NM_003183.4) contains
3572 base pairs and the open reading frame spans from
bp 184 to bp 2658. Different isoforms due to
differential splicing are not known.
Pseudogene
No pseudogenes have been reported for ADAM17.
Protein
Note
ADAM17 belongs to the ADAM (a disintegrin and
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10)
989
ADAM17 (ADAM metallopeptidase domain 17)
Evers A, Reiss K
The structure of "a disintegrin and metalloproteases" consists of a N-terminal prodomain (aa 1-214) followed by a metalloprotease
domain (aa 223-477), a disintegrin domain (aa 484-560) with a cystein-rich region, an epidermal growth factor-like domain (EGF) (aa
571-602), a transmembrane domain (TM) (aa 672-694) and a cytoplasmic tail (aa 695-824) (Arribas and Esselens, 2009 - modified).
Amino acid specifications according to Pubmed graphics for ADAM17 (NP_003174.3).
Description
Localisation
The preproform of ADAM17 contains 824 amino acids
(134 kDa). After cleavage of the prodomain by furin or
other proprotein convertases, the mature form has a
predicted molecular weight of 98 kDa. The prodomain
serves as a chaperone and keeps the enzyme in an
inactive state during maturation in the trans-Golgi
network (Schlöndorff et al., 2000). The catalytic
domain contains the characteristic zinc binding motif
(HEXXHXXGXXH) and
three potential Nglycosylation sites. The disintegrin domain is discussed
to be involved in regulation of the catalytic activity of
ADAM17 (Li and Fan, 2004; Smith et al., 2002), but
might also be involved in interaction with integrins and
therefore mediate cell-cell adhesion or cell-matrix
interaction. The cytoplasmic tail of ADAM17 was
thought to be important in regulation of the enzyme
activity
because
of
its
potential
tyrosine
phosphorylation site, but recent studies showed that
overexpressed ADAM17 lacking its cytoplasmic
domain was able to cleave TNFalpha upon phorbolester
stimulation (Reddy et al., 2000; Horiuchi et al., 2007).
The transmembrane domain might play a role in
regulation of ADAM activity as studies with ADAMchimera with exchanged transmembrane domains and
experiments with plasma membrane modulating stimuli
indicate (Le Gall et al., 2010; Reiss et al., 2011).
ADAM17 is a type I transmembrane protein, but only
10% of the total protein can be found in the plasma
membrane on the cell surface (Schlöndorff et al.,
2000). Most of the protein is localised in the
endoplasmic reticulum and trans-Golgi network. It is
suggested that ADAM17 accumulates in cholesterol
rich departments of the plasma membrane (lipid rafts)
(Tellier et al., 2006).
Expression
Homology
ADAM17 is ubiquitously expressed in various tissues,
for example in the brain, kidney, heart and skeletal
muscles. The expression pattern changes during
embryonic development and the adult life (Black et al.,
1997).
Homologs of the human ADAM17 are found in various
species ranging from other mammalians to primitive
chordates like zebrafish. See table 1 for results of
NCBI-Blast/blastp
with
human
ADAM17
(NP_003174.3) as query sequence. Its closest relative
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10)
Function
ADAM17 knockout mice display a severe
phenotype that resembles mice lacking the epidermal
growth factor receptor (EGFR) or one of its ligands
(TGFalpha, HB-EGF or amphiregulin). Perinatal
mortality is probably due to defects in heart
development.
Because of their catalytic and their disintegrin domain,
ADAMs can have both adhesive and proteolytic
functions. ADAM17 is best studied for its proteolytic
properties and cleaves its substrates in the
juxtamembrane region. The proteins processed by
ADAM17 have different functions and therefore
proteolytic processing can either activate or abrogate
processes. For example both receptors and ligands can
be cleaved, thus signalling can be either initiated or
stopped by ADAM17.
990
ADAM17 (ADAM metallopeptidase domain 17)
Evers A, Reiss K
in the family of human ADAM metalloproteases is
ADAM10 (NP_001101.1), but there is only less than
30% amino acid sequence identity according to NCBIBlast (blastp).
Species
identity to similarity
Accession
human
to human
#
ADAM17 ADAM17
Sus scrofa
NP_00109
92%
3396.1
97%
Mus musculus
NP_03374
92%
5.4
96%
Rattus
norwegicus
NP_06470
92%
2.1
96%
Gallus gallus
NP_00100
77%
8682.1
87%
Xenopus
laevis
NP_00108
73%
9130.1
85%
Danio rerio
NP_95596
61%
7.1
74%
Drosophila
NP_73333
42%
melanogaster 4.1
59%
Inflammation
Note
The identification of ADAM17 as TNFalpha
converting enzyme suggested an important role of this
metalloprotease in inflammatory diseases with elevated
levels of soluble TNFalpha, such as rheumatoid
arthritis and inflammatory bowel disease. Indeed,
increased enzymatic activity of ADAM17 was shown
in tissues of patients with osteoarthritis (Amin, 1999)
and rheumatoid arthritis (Ohta et al., 2001).
Furthermore ADAM17 was shown to process several
factors that are involved in leukocyte recruitment to the
site of inflammation. Moreover ADAM17 regulates
leukocyte transmigration through the vascular
endothelium for example by cleaving adhesion
molecules between endothelial cells. The vascular cell
adhesion molecule (CC: TXT: V-CAM ID: 42784>) is
released by ADAM17 and functions as the ligand of the
leukocyte very late antigen 4 (VLA-4 or alpha4beta1
integrin), which is implicated in the leukocyte adhesion
to the vascular endothelium (Garton et al., 2003).
L-Selectin cleavage by ADAM17 promotes leukocyte
migration through the basal membrane after adhering to
the endothelium (Faveeuw et al., 2001; Peschon et al.,
1998). ADAM17 was also identified as the sheddase of
the tight junction molecule JAM-1 between endothelial
cells (Koenen et al., 2009). Cleavage of JAM-1
contributes to the passage of leukocytes through the
endothelial cell layer and the processed molecule
serves as a biomarker of inflammation.
Disease
- rheumatoid arthritis (see above),
- osteoarthritis (see above),
- inflammatory bowel disease (high levels of ADAM17
expression were reported in epithelial cells during the
active phase of Crohn's disease (Cesaro et al., 2009)),
- psoriasis (ADAM17 expression was upregulated in
keratinocytes, blood vessels and mast cells from
patients (Kawaguchi et al., 2005)),
- pulmonary inflammation (reduced invasion of
eosinophils in a model of acute allergic lung
inflammation after treatment with ADAM17/MMP
inhibitors (Trifilieff et al., 2002)).
Mutations
Note
So far no common germinal or somatic mutation
variants are known.
Implicated in
Cancer
Note
Various growth factors necessary for tumor progression
and growth are shed by ADAM17 and increased
shedding of EGFR ligands was observed in tissues
developing a malignant phenotype (Katakowski et al.,
2009). ADAM17 is supposed to play a role in different
malignancies: increased levels of the enzyme were
detected in gastric carcinoma (Yoshimura et al., 2002),
primary colon carcinoma (Blanchot-Jossic et al., 2005),
skin malignancies (Oh et al., 2009) and ovarian cancer
(Tanaka et al., 2005) but its role is best studied in
breast cancer (see below).
Alzheimer's disease
Breast cancer
Note
The majority of the amyloid precursor protein (APP) is
physiologically cleaved by alpha-secretase (ADAM10
or ADAM17). This cleavage leads to the generation of
a soluble non-amyloidogenic fragment (sAPPalpha),
whereas shedding of APP by beta-secretase produces
the amyloidogenic Abeta peptide (Allinson et al.,
2003). Accordingly, decreased activity of alphasecretase results in the formation of amyloid plaques.
While ADAM10 represents the most important alphasecretase, ADAM17 could contribute to APP-
Disease
It was shown that overexpression of ADAM17 in breast
cancer correlated with TGFalpha expression (BorrellPages et al., 2003), metastasis and tumor progression
(McGowan et al., 2007) and shorter survival of patients
(McGowan et al., 2008). Recent studies by Kenny and
Bissell demonstrated that the malignant phenotype of a
breast cancer cell line was reverted to a normal
phenotype using siRNA against ADAM17 (Kenny and
Bissell, 2007).
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10)
991
ADAM17 (ADAM metallopeptidase domain 17)
Evers A, Reiss K
Reddy P, Slack JL, Davis R, Cerretti DP, Kozlosky CJ, Blanton
RA, Shows D, Peschon JJ, Black RA. Functional analysis of
the domain structure of tumor necrosis factor-alpha converting
enzyme. J Biol Chem. 2000 May 12;275(19):14608-14
processing under certain conditions (Buxbaum et al.,
1998; Jorissen et al., 2010).
Kidney diseases
Schlöndorff J, Becherer JD, Blobel CP. Intracellular maturation
and localization of the tumour necrosis factor alpha convertase
(TACE). Biochem J. 2000 Apr 1;347 Pt 1:131-8
Note
In polycystic kidney disease (PDK) increased
activation of the EGF receptor leads to cyst formation
and loss of kidney function. These symptoms could be
significantly decreased by treatment with ADAM17
inhibitors (Richards et al., 1998; Dell et al., 2001).
Which EGFR ligand is responsible in this context
remains unclear, but TGFalpha knockout mice were
shown to still develop PDK (Nemo et al., 2005).
ADAM17 is also involved in chronic kidney disease
(CDK) and it is suggested that this is due to the
transactivation of EGFR through the GPCR agonist
angiotensin-II (Lautrette et al., 2005). In this process
ADAM17 is activated by the GPCR and releases
TGFalpha, which in turn activates the EGFR.
Dell KM, Nemo R, Sweeney WE Jr, Levin JI, Frost P, Avner
ED. A novel inhibitor of tumor necrosis factor-alpha converting
enzyme ameliorates polycystic kidney disease. Kidney Int.
2001 Oct;60(4):1240-8
Faveeuw C, Preece G, Ager A. Transendothelial migration of
lymphocytes across high endothelial venules into lymph nodes
is affected by metalloproteinases. Blood. 2001 Aug
1;98(3):688-95
Molina MA, Codony-Servat J, Albanell J, Rojo F, Arribas J,
Baselga J. Trastuzumab (herceptin), a humanized anti-Her2
receptor monoclonal antibody, inhibits basal and activated
Her2 ectodomain cleavage in breast cancer cells. Cancer Res.
2001 Jun 15;61(12):4744-9
Ohta S, Harigai M, Tanaka M, Kawaguchi Y, Sugiura T, Takagi
K, Fukasawa C, Hara M, Kamatani N. Tumor necrosis factoralpha (TNF-alpha) converting enzyme contributes to
production of TNF-alpha in synovial tissues from patients with
rheumatoid arthritis. J Rheumatol. 2001 Aug;28(8):1756-63
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This article should be referenced as such:
Evers A, Reiss K. ADAM17 (ADAM metallopeptidase domain
17). Atlas Genet Cytogenet Oncol Haematol. 2011;
15(12):989-993.
Cesaro A, Abakar-Mahamat A, Brest P, Lassalle S, Selva E,
Filippi J, Hébuterne X, Hugot JP, Doglio A, Galland F, Naquet
P, Vouret-Craviari V, Mograbi B, Hofman PM. Differential
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10)
993