ADAM10 (ADAM metallopeptidase domain 10)

2011-07-01   Pascal Gelebart , Hanan Armanious , Raymond Lai 

Department of Laboratory Medicine, Pathology, University of Alberta, Room 1466, 11560 University Avenue, T6G 1Z2-Edmonton, Alberta, Canada

Identity

HGNC
LOCATION
15q21.3
LOCUSID
ALIAS
AD10,AD18,CD156c,CDw156,HsT18717,MADM,RAK,kuz
FUSION GENES

DNA/RNA

Atlas Image
Figure 1. Representation of the ADAM10 gene organization.

Description

The gene spans a region of 15.36 kb and the coding part is divided into 16 exons.

Transcription

Only one type of transcript has been described. The 2247-nucleotide transcript encodes a protein of 748 amino acid residues. The first and last exons are partially untranslated.

Pseudogene

None described so far.

Proteins

Atlas Image
Figure 2. Crystal structure of ADAM10 Disintegrin and cysteine-rich domain at 2.9 A resolution. Adapted from PDB (access number: 2AO7).

Description

ADAM10 is a metalloproteinase composed of 748 residues.
Atlas Image
Figure 3. ADAM10 tissue expression profile. Adapted from GeneAtlas U113A.

Expression

ADAM10 RNA has been reported to be present in wide range of human tissue (Yanai et al., 2005). Data obtained from GeneAtlas have shown that ADAM10 transcript is the most highly expressed in myeloid, NK cells and monocytes as well as cardiomyocytes and smooth muscle cells (figure 3). At the protein level, ADAM10 has been reported in epithelials tissue of the heart, liver and kidney (Hall and Erickson, 2003).

Localisation

ADAM10 is localized at the plasma membrane. However, nuclear localization of ADAM10 has been reported in prostate cancer and in mantle cell lymphoma cells (Armanious et al., 2011).
Atlas Image
Figure 4. ADAM10 protein structure organization.

Function

ADAM10 belongs to the family of metalloproteinases (Chantry et al., 1989; Chantry and Glynn, 1990; Edwards et al., 2008). ADAM10 protein is composed of multiple functional domains that include: a prodomain, a catalytic domain, a cysteine-rich domain, a transmembraneous domain, a cytoplasmic domain and a SH3 domain (Seals and Courtneidge, 2003; Edwards et al., 2008) (see figure 4). ADAM10 is synthesized as a pro-protein and therefore needs to be cleaved to be activated (Anders et al., 2001). Two proteins, the convertase 7 and the furin, have been implicated in the activation of ADAM10 (Anders et al., 2001). To date the major function of ADAM10 appears to be attributed to its enzymatic activity as a metalloproteinase. In fact, ADAM10 is involved in the intra-membrane proteolysis process, whereby it mediates ectodomain shedding of various membrane bound receptors, adhesion molecules, growth factors and cytokines like TNF-alpha (Rosendahl et al., 1997; Lunn et al., 1997; Hikita et al., 2009; Mezyk-Kopec et al., 2009), Notch (Hartmann et al., 2002; Gibb et al., 2010), E-cadherin (Maretzky et al., 2005), Ephrin (Janes et al., 2005), HER-2 (Liu et al., 2006), CD30 (Eichenauer et al., 2007), CD44 (Anderegg et al., 2009) and IL-6 receptor to name a few. The functional role of the SH3 domains of ADAM10 has never been studied. Moreover, the recent observation that ADAM10 can be found in the nucleus of some cells raises the possibility of new and uncovers function of ADAM10 (Arima et al., 2007).
ADAM10 seems to be detrimental for embryogenesis as the knockout mice for ADAM10 die at day 9.5 of embryogenesis (Hartmann et al., 2002). The mice present several developmental defects in the nervous central system as well in the cardiovascular system. This latest observation correlates well with the fact that ADAM10 transcript is highly expressed in cardiomyocyte.
In human, ADAM10 was recently been demonstrated to be a regulator of the lymphocyte development (Gibb et al., 2011).

Mutations

Note

No mutation has been reported so far.

Implicated in

Entity name
Various cancers
Note
ADAM family members have been recently involved in malignant progression and development (Mochizuki and Okada, 2007; Rocks et al., 2008; Wagstaff et al., 2011; Duffy et al., 2009). ADAM10 has been shown to be constitutively active in a number of solid tumors, and this biochemical defect is implicated in the pathogenesis of many tumors. The following paragraphs will summarize what has been discovered about the function of ADAM10 in cancer.
Entity name
Brain tumors
Note
ADAM10 protein has been reported to be highly expressed in the human central nervous system (Kärkkäinen et al., 2000). Recently, two different studies (Kohutek et al., 2009; Formolo et al., 2011) have uncovered the function of ADAM10 in the cell migration and invasiveness process of glioblastoma cells. In fact the authors have shown that ADAM10 by mediating the cleavage of N-cadherin was found to regulate the migratory properties of glioblastoma cells (Kohutek et al., 2009). On the other hand, the protein expression of ADAM10 was found to be higher in cell with strong invasiveness capability.
Entity name
Prostate cancer
Note
Prostate cancer is one of the most frequent cancers in men. The cause of prostate cancer development is unknown but is likely to be arising from several factors. Development of prostate cancer is androgen-dependent in early stages of the disease but cell growth became androgen-independent. ADAM10 have been found to be expressed in all prostate tumor samples (Karan et al., 2003). Interestingly, McCulloch et al. have observed that ADAM10 expression was up-regulated by androgen stimulation. Those observations were confirmed in a study published by Arima et al. However, in this work they reveal that ADAM10 was predominantly localized in the nucleus of cancer cells and show that ADAM10 can co-immunoprecipitate with androgen receptor in the nucleus. Moreover, they also observed that nuclear expression of ADAM10 was correlating with several biological parameters like the Gleason score and prostate specific antigen expression. Inhibition of ADAM10 expression by a siRNA approach was able to induce a cell proliferation decrease of prostate cancer cells. This study suggests for the first time that ADAM10 may have some function in the nucleus by regulating androgen receptor function.
Entity name
Breast cancer
Note
Expressions of different members of the ADAM family have been investigated in breast cancer. Despite that some ADAM family members present differential expression between non neoplastic and breast cancer tissue, no difference was observed for ADAM10 (Lendeckel et al., 2005). Nevertheless, Liu and co-workers have recently described than ADAM10 was the principal responsible for HER2 shedding in HER2 over-expressing breast cancer. The cleavage of HER2 liberates the extracellular domain of HER2 leaving a p95 fragment containing the transmembrane domain as well as the intracellular domain. This p95 fragment presents constitutive kinase activation and its expression correlates with a poor prognosis. The author demonstrated that in conjunction with low amount of HER2 inhibitor, ADAM10 inhibition was inducing a decrease in cell proliferation.
Entity name
Colon and gastric and oral carcinomas
Note
Deregulation of ADAM10 in colon cancer development has been reported in several studies. Knösel et al. have reported that ADAM10 expression in colorectal cancer patient samples, detectable by immunohistochemistry was found to correlate with higher clinical stage.
Moreover, it has been demonstrated that xenografting of colorectal cancer cells with enforced expression of ADAM10 in nude mice induced formation of liver metastasis compared to the negative control cells, and this effect can be attributed to ADAM10-mediated cleavage and release of L1-CAM, a cell adhesion molecule (Gavert et al., 2007). Similarly to Knösel et al., ADAM10 expression was associated with gastric cancer progression and correlates with worst prognostic outcome (Wang et al., 2011). Using immunohistochemistry, it was also found that ADAM10 is over-expressed in squamous cell carcinomas of the oral cavity, as compared to the benign epithelial cells; knockdown of ADAM10 expression using siRNA in the cell lines derived from those tumors induces a significant decrease in cell growth (Ko et al., 2007).
Entity name
Melanoma, pancreatic cancer and adenoid cystic carcinoma
Note
The expression of ADAM10 has been investigated in melanoma and Lee et al. have reported that ADAM10 is over-expressed in melanoma metastasis in comparison to primary melanoma cells. Similar findings were made in pancreatic cancer, where inhibition of ADAM10 expression in pancreatic carcinoma cell lines also resulted in a significant decrease in invasiveness and migration (Gaida et al., 2010).
Entity name
Hematologic malignancies
Note
Recently, Armanious et al. have described for the first time the function of ADAM10 in non solid tumors. They have reported that ADAM10 is constitutively activated and over-expressed in different form of B-cell lymphoma like mantle cell lymphoma and diffuse large B-cell lymphoma. Moreover, the authors have described that inhibition of ADAM10 leads to a decrease of cell proliferation. On the other hand, stimulation of mantle cells with the recombinant active form of ADAM10 increases further their proliferation. Additionally, they also demonstrated, as reported previously in the literature, that ADAM10 was responsible for the release of active from of TNF-alpha that in turn was contributing to the activation of the NF-kappab pathways.

Bibliography

Pubmed IDLast YearTitleAuthors
189719592009ADAM10 is the constitutive functional sheddase of CD44 in human melanoma cells.Anderegg U et al
114812472001Regulation of the alpha-secretase ADAM10 by its prodomain and proprotein convertases.Anders A et al
177276792007Nuclear translocation of ADAM-10 contributes to the pathogenesis and progression of human prostate cancer.Arima T et al
214414652011Constitutive activation of metalloproteinase ADAM10 in mantle cell lymphoma promotes cell growth and activates the TNFα/NFκB pathway.Armanious H et al
16930751990A novel metalloproteinase originally isolated from brain myelin membranes is present in many tissues.Chantry A et al
196018312009ADAM10 as a therapeutic target for cancer and inflammation.Crawford HC et al
194083472009The role of ADAMs in disease pathophysiology.Duffy MJ et al
187622092008The ADAM metalloproteinases.Edwards DR et al
172107152007ADAM10 inhibition of human CD30 shedding increases specificity of targeted immunotherapy in vitro.Eichenauer DA et al
215746462011Secretome signature of invasive glioblastoma multiforme.Formolo CA et al
205966092010Expression of A disintegrin and metalloprotease 10 in pancreatic carcinoma.Gaida MM et al
176997742007Expression of L1-CAM and ADAM10 in human colon cancer cells induces metastasis.Gavert N et al
201569742010ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo.Gibb DR et al
212364902011The emergence of ADAM10 as a regulator of lymphocyte development and autoimmunity.Gibb DR et al
200708882010ADAM10 is expressed in human podocytes and found in urinary vesicles of patients with glomerular kidney diseases.Gutwein P et al
126542982003ADAM 10: an active metalloprotease expressed during avian epithelial morphogenesis.Hall RJ et al
123547872002The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts.Hartmann D et al
197678222009Involvement of a disintegrin and metalloproteinase 10 and 17 in shedding of tumor necrosis factor-alpha.Hikita A et al
162391462005Adam meets Eph: an ADAM substrate recognition module acts as a molecular switch for ephrin cleavage in trans.Janes PW et al
145329782003Expression of ADAMs (a disintegrin and metalloproteases) and TIMP-3 (tissue inhibitor of metalloproteinase-3) in human prostatic adenocarcinomas.Karan D et al
108605812000Metalloprotease-disintegrin (ADAM) genes are widely and differentially expressed in the adult CNS.Kärkkäinen I et al
162074762005Immunoprofiles of 11 biomarkers using tissue microarrays identify prognostic subgroups in colorectal cancer.Knösel T et al
163098262007Increase of disintergin metalloprotease 10 (ADAM10) expression in oral squamous cell carcinoma.Ko SY et al
193572852009ADAM-10-mediated N-cadherin cleavage is protein kinase C-alpha dependent and promotes glioblastoma cell migration.Kohutek ZA et al
178757012007Tissue inhibitor of metalloproteinases-1 promotes liver metastasis by induction of hepatocyte growth factor signaling.Kopitz C et al
198650982010ADAM10 is upregulated in melanoma metastasis compared with primary melanoma.Lee SB et al
155654592005Increased expression of ADAM family members in human breast cancer and breast cancer cell lines.Lendeckel U et al
166279892006Identification of ADAM10 as a major source of HER2 ectodomain sheddase activity in HER2 overexpressing breast cancer cells.Liu PC et al
90092251997Purification of ADAM 10 from bovine spleen as a TNFalpha convertase.Lunn CA et al
159585332005ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and beta-catenin translocation.Maretzky T et al
147344842004Expression of the disintegrin metalloprotease, ADAM-10, in prostate cancer and its regulation by dihydrotestosterone, insulin-like growth factor I, and epidermal growth factor in the prostate cancer cell model LNCaP.McCulloch DR et al
193461382009Identification of ADAM10 as a major TNF sheddase in ADAM17-deficient fibroblasts.Mezyk-Kopeć R et al
173552652007ADAMs in cancer cell proliferation and progression.Mochizuki S et al
182890512008ADAM10 as a target for anti-cancer therapy.Moss ML et al
179207492008Emerging roles of ADAM and ADAMTS metalloproteinases in cancer.Rocks N et al
93059251997Identification and characterization of a pro-tumor necrosis factor-alpha-processing enzyme from the ADAM family of zinc metalloproteases.Rosendahl MS et al
125140952003The ADAMs family of metalloproteases: multidomain proteins with multiple functions.Seals DF et al
197839062009Triptolide: An inhibitor of a disintegrin and metalloproteinase 10 (ADAM10) in cancer cells.Soundararajan R et al
211962702011The roles of ADAMTS metalloproteinases in tumorigenesis and metastasis.Wagstaff L et al
212592442011ADAM 10 is associated with gastric cancer progression and prognosis of patients.Wang YY et al
211719682010Inhibiting adenoid cystic carcinoma cells growth and metastasis by blocking the expression of ADAM 10 using RNA interference.Xu Q et al
153885192005Genome-wide midrange transcription profiles reveal expression level relationships in human tissue specification.Yanai I et al
96181751998Human metalloprotease-disintegrin Kuzbanian regulates sympathoadrenal cell fate in development and neoplasia.Yavari R et al

Other Information

Locus ID:

NCBI: 102
MIM: 602192
HGNC: 188
Ensembl: ENSG00000137845

Variants:

dbSNP: 102
ClinVar: 102
TCGA: ENSG00000137845
COSMIC: ADAM10

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000137845ENST00000260408O14672
ENSG00000137845ENST00000260408A0A024R5U5
ENSG00000137845ENST00000396136H3BS53
ENSG00000137845ENST00000402627B5MC71
ENSG00000137845ENST00000439637C9J9B4
ENSG00000137845ENST00000461408A0A087WYG1
ENSG00000137845ENST00000558004H0YK87
ENSG00000137845ENST00000559053H0YNC5
ENSG00000137845ENST00000561288H0YK32

Expression (GTEx)

0
5
10
15
20
25
30
35
40

Pathways

PathwaySourceExternal ID
Alzheimer's diseaseKEGGko05010
Epithelial cell signaling in Helicobacter pylori infectionKEGGko05120
Alzheimer's diseaseKEGGhsa05010
Epithelial cell signaling in Helicobacter pylori infectionKEGGhsa05120
DiseaseREACTOMER-HSA-1643685
Diseases of signal transductionREACTOMER-HSA-5663202
Signaling by NOTCH1 in CancerREACTOMER-HSA-2644603
Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation MutantREACTOMER-HSA-2660825
Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation MutantREACTOMER-HSA-2660826
Signaling by NOTCH1 HD Domain Mutants in CancerREACTOMER-HSA-2691230
Constitutive Signaling by NOTCH1 HD Domain MutantsREACTOMER-HSA-2691232
Signaling by NOTCH1 PEST Domain Mutants in CancerREACTOMER-HSA-2644602
Constitutive Signaling by NOTCH1 PEST Domain MutantsREACTOMER-HSA-2644606
Signaling by NOTCH1 HD+PEST Domain Mutants in CancerREACTOMER-HSA-2894858
Constitutive Signaling by NOTCH1 HD+PEST Domain MutantsREACTOMER-HSA-2894862
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
Signaling by NOTCHREACTOMER-HSA-157118
Signaling by NOTCH1REACTOMER-HSA-1980143
Activated NOTCH1 Transmits Signal to the NucleusREACTOMER-HSA-2122948
Signaling by NOTCH2REACTOMER-HSA-1980145
NOTCH2 Activation and Transmission of Signal to the NucleusREACTOMER-HSA-2979096
Signaling by NOTCH3REACTOMER-HSA-1980148
Signaling by NOTCH4REACTOMER-HSA-1980150
Extracellular matrix organizationREACTOMER-HSA-1474244
Degradation of the extracellular matrixREACTOMER-HSA-1474228
Collagen degradationREACTOMER-HSA-1442490
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
EPH-Ephrin signalingREACTOMER-HSA-2682334
EPH-ephrin mediated repulsion of cellsREACTOMER-HSA-3928665
Neutrophil degranulationREACTOMER-HSA-6798695

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
159585332005ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and beta-catenin translocation.217
206760562010ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons.190
206249792010Role of a disintegrin and metalloprotease 10 in Staphylococcus aureus alpha-hemolysin-mediated cellular injury.169
186035872008A soluble form of the receptor for advanced glycation endproducts (RAGE) is produced by proteolytic cleavage of the membrane-bound form by the sheddase a disintegrin and metalloprotease 10 (ADAM10).154
162391462005Adam meets Eph: an ADAM substrate recognition module acts as a molecular switch for ephrin cleavage in trans.153
203718032010The disintegrin/metalloproteinase ADAM10 is essential for the establishment of the brain cortex.124
197040102009Selective use of ADAM10 and ADAM17 in activation of Notch1 signaling.112
186768622008Tumor-associated MICA is shed by ADAM proteases.105
128324232003Cellular cholesterol depletion triggers shedding of the human interleukin-6 receptor by ADAM10 and ADAM17 (TACE).97
184209432008ADAM10 regulates endothelial permeability and T-Cell transmigration by proteolysis of vascular endothelial cadherin.88

Citation

Pascal Gelebart ; Hanan Armanious ; Raymond Lai

ADAM10 (ADAM metallopeptidase domain 10)

Atlas Genet Cytogenet Oncol Haematol. 2011-07-01

Online version: http://atlasgeneticsoncology.org/gene/44397/adam10-(adam-metallopeptidase-domain-10)