Review on ADAMTS12, with data on DNA/RNA, on the protein encoded and where the gene is implicated

Cal, S

Obaya, AJ

Atlas of Genetics and Cytogenetics in Oncology and Haematology

S Cal

AJ Obaya

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ADAMTS12 (ADAM Metallopeptidase With Thrombospondin Type 1 Motif, 12)

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Gene Section 
Review 
 
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(2)  78 
INIST-CNRS 
 
OPEN ACCESS JOURNAL 
Atlas of Genetics and Cytogenetics 
in Oncology and Haematology 
ADAMTS12 (ADAM Metallopeptidase With 
Thrombospondin Type 1 Motif, 12) 
Santiago Cal, Alvaro J Obaya 
Departamento de Bioquimica y Biologia Molecular, Instituto Universitario de Oncologia (IUOPA), 
Universidad de Oviedo, 33006, Asturias, Spain (SC), Biologia Funcional, Instituto Universitario de 
Oncologia (IUOPA), Universidad de Oviedo, 33006, Asturias, Spain (AJO) 
 
Published in Atlas Database: July 2013 
Online updated version : http://AtlasGeneticsOncology.org/Genes/ADAMTS12ID575ch5p13.html 
DOI: 10.4267/2042/53078 
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. 
© 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology 
 
Abstract 
Review on ADAMTS12, with data on DNA/RNA, on 
the protein encoded and where the gene is implicated. 
Identity 
Other names: PRO4389 
HGNC (Hugo): ADAMTS12 
Location: 5p13.3 
DNA/RNA 
Description 
24 exons, spans approximately 368.66 Kb of genomic 
DNA in the telomere-to-centromere orientation.  
The translation initiation codon is located to exon 1, 
and the stop codon to exon 24. 
Transcription 
ADAMTS12 Human mRNA of 8.77 Kb as detected by 
northern-blot. 
Protein 
Description 
The open reading frame encodes a 1594 amino acid 
protein, with an estimated molecular weight of 178 
kDa. ADAMTS-12 shares a structural multidomain 
complex architecture with the rest of members of the 
ADAMTS family. This organization includes a  
signal peptide, a prodomain involved in maintaining 
enzyme latency and a catalytic domain that contains the 
consensus sequence HEXXHGXXHD involved in the 
coordination of the zinc atom necessary for catalytic 
activity of the enzyme. This sequence ends in an Asp 
residue which distinguishes ADAMTSs from other 
metalloproteases such as MMPs. Following this 
catalytic region there are several other domains 
characterized as a disintegrin-like domain, a central 
thrombospondin-1 (TSP-1) motif, a cysteine-rich 
domain, a spacer region and a variable number of TSP-
1 repeats, three in the case of ADAMTS-12. A 
structural hallmark of ADAMTS-12 is the presence of 
a second spacer region followed by four additional 
TSP-1 repeats (Figure 1) (Cal et al., 2001). 
Expression 
ADAMTS12 cDNA was originally cloned from a 
human fetal lung cDNA library and its expression was 
also detected in human fetal fibroblasts following 
treatment with TGF-β. By real-time polymerase chain 
reaction (PCR) assay ADAMTS12 expression can also 
be detected in cartilage, synovium, tendon, skeletal 
muscle and fat. ADAMTS12 was also found widely 
expressed in gastrointestinal, pancreatic and colon 
carcinomas but not in the paired normal tissues, 
suggesting that this enzyme could also participate in 
the development and/or progression of tumors from 
different origin (Cal et al., 2001; Liu et al., 2006; 
Moncada-Pazos et al., 2009). 
 
ADAMTS12 (ADAM Metallopeptidase With Thrombospondin Type 1 Motif, 12) Cal S, Obaya AJ 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(2)  79 
 
Figure 1. Domain organization of ADAMTS-12. Pro: prodomain; TSP: thrombospondin type-1 domains. 
 
 
Localisation 
Extracellular. 
Function 
Several studies performed to characterized ADAMTS-
12 function indicate its role as being a host-protective 
enzyme with antitumor properties (Llamazares et al., 
2007; Moncada-Pazos et al., 2009; El-Hour et al., 
2010; Wang et al., 2011). Additionally, ADAMTS-12 
has a role in trophoblasts invasion during placental 
development which is independent of the proteolytic 
domain (Beristain et al., 2011).  
ADAMTS-12 also participates in other pathological 
processes such as inflammation, allergen-induced 
inflammation and hyperresponsiveness, and it is also 
involved in arthritic processes (Liu, 2009; Moncada-
Pazos et al., 2012; Nah et al., 2012; Paulissen et al., 
2012).  
Furthermore, different genomic approximations have 
described how other human pathologies like asthma, 
schizophrenia or predisposition to pediatric stroke are 
related to ADAMTS12 locus (Kurz et al., 2006; Arnin 
et al., 2012; Bespalova et al., 2012). However, besides 
its participation in pathological situations little is 
known about ADAMTS-12 partners and/or substrates 
in normal or pathogenic processes. 
Homology 
The ADAMTS12 gene is conserved in chimpanzee 
(Refseq: XP_517836), macaque (Refseq: 
XM_001090049), dog (Refseq: XM_536508), cow 
(Refseq: NM_001192609), mouse (Refseq: 
NM_175501), rat (Refseq: NM_001106420), chicken 
(Refseq: XM_003642975), and zebrafish (Refseq: 
XM_001343335). 
ADAMTS-12 belongs to the A Disintegrin And 
Metalloprotease Domains with ThromboSpondin 
motifs (ADAMTS) family, which consists of 19 
secreted zinc metalloproteinases (Porter et al., 2005).  
All members of the family share the same structural 
domain design.  
ADAMTS-12 is closely related to ADAMTS-7 since 
both proteins display the C-terminal TSP residues 
separated by two spacer regions (spacer-1 and spacer-
2).  
The rest of the members contain only one spacer region 
followed by a variable number of TSP domains. 
 
 
Implicated in 
Various cancers 
Note 
Different studies have highlighted the role of 
ADAMTS12 as a tumor-suppressor gene. ADAMTS-
12 is able to alter the tumorigenic effects of hepatocyte 
growth factor (HGF) in Madin-Darby canine kidney 
(MDCK) cells (Llamazares et al., 2007). ADAMTS-12 
also prevents the formation of tubules by bovine aortic 
endothelial cells in the presence of vascular endothelial 
growth factor (VEGF). Additionally, growth of 
subcutaneous tumors induced by the human lung tumor 
cell line A549 is compromised when ADAMTS12 is 
exogenously expressed. Analysis of the epigenetic 
status of ADAMTS12 promoter has reinforced the role 
of ADAMTS-12 as an in vivo tumor-suppressor 
enzyme. In fact, ADAMTS12 is epigenetically silenced 
in tumor cells from different sources such as colon 
cancer cell lines, breast cancer cell lines, cervix cancer 
cell lines or lymphoma cell lines (Moncada-Pazos et 
al., 2009). In particular, methylation levels of 
ADAMTS12 gene promoter were very high in a colon 
cancer sample panel that included both cancer cell lines 
and tumor samples, whereas it was found not or barely 
methylated in normal cells and tissues. However and 
similar to what has been found in gastrointestinal and 
pancreatic carcinomas, ADAMTS12 expression was 
higher in colon tumor samples cells than in normal 
tissues. This apparent contradiction resides in the fact 
that ADAMTS-12 is produced by the stromal cells 
surrounding neoplastic cells and not by the tumor cells 
themselves, which was confirmed using different 
approaches. For instance, immunofluorescence 
techniques allowed the localization of this protease in 
the proximity to alpha smooth muscle actin positive 
cells, which suggests that cancer-associated fibroblasts 
could be responsible for ADAMTS12 expression. By 
contrast, ADAMTS-12 staining resulted negative in the 
case of tumor cells. ADAMTS12 expression in 
fibroblasts was verified through the use of co-cultures 
of colon fibroblasts with colon cancer cells. 
Furthermore, this expression could be associated with a 
functional effect as colon cancer cells showed minor 
growth rates and an increase in apoptosis when co-
cultured with colon fibroblasts in comparison to the 
colon tumor cell line cultured alone. Consequently,  
 
 
ADAMTS12 (ADAM Metallopeptidase With Thrombospondin Type 1 Motif, 12) Cal S, Obaya AJ 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(2)  80 
colon miofibroblast-ADAMTS12 expression could be  
part of a protective response aimed to compensate for 
the epigenetic silencing of this gene in tumor cells 
(Moncada-Pazos et al., 2009). Moreover, ADAMTS12 
expression in colorectal cancer significantly correlated 
with the tumor histological grade, depth of tumor 
invasion, lymph node metastasis, and Duke's stage. In 
fact, patients with low or no ADAMTS12 expression in 
the tumor stroma had a significantly poor overall 
survival or disease-free survival (Wang et al., 2011). 
Phenotypic analysis of the Adamts12-deficient mouse 
has confirmed the role of this metalloprotease as a 
tumor-protective enzyme (El-Hour et al., 2010).  
This mouse develops normally and does not show any 
obvious phenotype. However, different models to 
analyze the angiogenesis process in vivo, including 
malignant keratinocyte transplantation, aortic ring 
assay and Matrigel plug, supported that this protease 
exhibits anti-angiogenic properties (El-Hour et al., 
2010). Additionally, both intact ADAMTS-12 and a 
catalytically inactive form of ADAMTS-12 showed a 
similar ability to inhibit the spreading of endothelial 
cells. These data were in line with the previous results 
indicating that antitumor functions of ADAMTS-12 do 
not depend on its metalloprotease domain (Llamazares 
et al., 2007). 
However, there are some data showing that ADAMTS-
12 could also be a potential pro-tumor agent (Beristain 
et al., 2011). Thus, in placental cytotrophoblasts the 
expression of ADAMTS12 is able to exploit the same 
molecular machinery found in metastatic carcinoma 
cells. Comparing ADAMTS-family members-
expression in highly versus poorly invasive cells during 
placental development, ADAMTS12 was preferentially 
expressed by the highly invasive cytotrophoblast cell 
line EVT.  
Furthermore, TGF-β or IL-1β, are also able to 
respectively induce or restrain ADAMTS12 expression 
in these cells as they also did in colon fibroblasts. 
Analyzing the domains involved in this process 
demonstrated how the metalloprotease domain does not 
fulfill a relevant role in this pro-invasive phenotype 
(Beristain et al., 2011).  
In summary, there are several studies suggesting 
ADAMTS-12 as being involved in tumor progression.  
Nowadays, more data indicate this protein as a new 
member of the growing type of metalloproteases 
showing tumor-suppressor properties (Lopez-Otin and 
Matrisian, 2007). However, some data indicate a 
different role for this gene specifically regarding 
cellular invasion, which suggest that ADAMTS-12-
function in tumor progression might depend on 
different interactions occurring within the extracellular 
microenvironment. 
Inflammation 
Note 
Loss-of-function of Adamts-12 enhances mouse  
 
susceptibility to inflammatory processes (Moncada-
Pazos et al., 2012). In this sense, it has been shown 
how Adamts12 deficiency is responsible for increase 
inflammation in mice that was not limited to a certain 
tissue as it was a common phenomenon affecting 
several organs. Different experimental conditions to 
induce colitis, endotoxic sepsis, pancreatitis or 
allergen-induced lung inflammation demonstrated that 
absence of ADAMTS-12 resulted in a more severe 
inflammation phenotype as well as a delayed recovery 
from these anomalies. These changes were 
accompanied by an increase in inflammatory markers 
and, at the same time, the clinical symptoms observed 
in Adamts12-deficient mice were also concomitant 
with neutrophilia or eosinophilia and mast cells 
recruitment in affected tissues (Moncada-Pazos et al., 
2012; Paulissen et al., 2012). In vitro culture of human 
neutrophils indicated that the presence of ADAMTS-12 
might be a player in inducing neutrophil clearance, a 
required step for the resolution of an inflammation 
process. 
Arthritis 
Note 
ADAMTS-12 shows aggrecan-degrading activity, 
similarly to aggrecanases ADAMTS-4 and ADAMTS-
5, and to other members of the family such as 
ADAMTS-1, ADAMTS-9, ADAMTS-15, ADAMTS-
16 and ADAMTS-18 (Lin and Liu, 2010). 
Nevertheless, the ability of ADAMTS-12 to degrade 
aggrecan is reduced and it has only been reported to 
occur in vitro (Llamazares et al., 2007). Although 
barely detectable in adult tissues real-time polymerase 
chain reaction (PCR) assay revealed ADAMTS12 
expression in cartilage, synovium, tendon, skeletal 
muscle and fat (Liu et al., 2006). In vitro experiments 
have also been used to demonstrate ADAMTS-12 
proteolytic activity towards cartilage oligomeric matrix 
protein (COMP), other component of cartilage. This, 
together with ADAMTS-12 aggrecanolytic activity, 
may indicate a role of ADAMTS-12 in arthritic 
diseases (Liu et al., 2006). In this regard, profiling 
analysis demonstrated a significant upregulation of 
ADAMTS-12 in cartilage from patients with 
osteoarthritis when compared with normal cartilage 
(Kevorkian et al., 2004). Thus, ADAMTS-7 and 
ADAMTS-12, apart from the known aggrecanases 
ADAMTS-4 and -5, seem to be important players in 
the degradation of components of cartilaginous tissue 
during arthritic processes (Liu, 2009). In relation to 
potential endogenous inhibitors, it has been described 
that α2-macroglobulin and the granulin-epithelin 
precursor, a growth factor highly expressed in 
chondrocytes, can interact with  
ADAMTS-12, leading to an inhibition of its COMP-
degrading activity (Luan et al., 2008; Guo et al., 2010). 
 
 
ADAMTS12 (ADAM Metallopeptidase With Thrombospondin Type 1 Motif, 12) Cal S, Obaya AJ 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(2)  81 
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This article should be referenced as such: 
Cal S, Obaya AJ. ADAMTS12 (ADAM Metallopeptidase With 
Thrombospondin Type 1 Motif, 12). Atlas Genet Cytogenet 
Oncol Haematol. 2014; 18(2):78-81. 


ADAMTS12 (ADAM Metallopeptidase With Thrombospondin Type 1 Motif, 12)

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