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ADAMTS15 (ADAM Metallopeptidase With Thrombospondin Type 1 Motif, 15)

Written2014-02Santiago 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)

(Note : for Links provided by Atlas : click)

Identity

Alias_namesa disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motif
Other alias
HGNC (Hugo) ADAMTS15
LocusID (NCBI) 170689
Atlas_Id 45587
Location 11q24.3  [Link to chromosome band 11q24]
Location_base_pair Starts at 130448974 and ends at 130476645 bp from pter ( according to hg19-Feb_2009)  [Mapping ADAMTS15.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

DNA/RNA

Description 8 exons, spans approximately 27.66 Kb of genomic DNA in the centromere-to-telomere orientation. The translation initiation codon is located to exon 1, and the stop codon to exon 8.

Protein

Description The open reading fame encodes a 950 amino acid protein, with an estimated molecular weight of 103,2 kDa. ADAMTS-15 shares a structural multidomain complex architecture with the rest of the 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 activiy 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 disintegrin-like domain, a central thrombospondin-1 (TSP-1) motif, a cysteine-rich domain, a spacer region and two more TSP-1 domains (Cal et al., 2002).
 
  Domain organization of ADAMTS-15. Pro: prodomain; TSP: thrombospondin type-1 domains.
Expression ADAMTS15 cDNA was originally cloned from both, a human liver and kidney fetal cDNA library (Cal et al., 2002). Later on, in the search for proteinases and proteinase inhibitors in articular cartilage from femoral heads of patients with end-stage osteoarthritis (OA) Kevorkian et al. found high levels of ADAMTS-15 expression in samples from both, OA patients as well as normal controls (Kevorkian et al., 2004). In relation with ADAMTS-15 participation in tumor progression its expression has been described in either normal cells or cells adjacent or marginal to cancer tissue in samples from colon adenocarcinoma as well as in samples from head and neck squamous cell carcinoma (Viloria et al., 2009; Stokes et al., 2010). Additionally ADAMTS-15 presence has also been detected in some breast and prostate cancer cell lines (Molokwu et al., 2010).
Localisation Extracellular, mostly pericellular.
Function Few studies describe ADAMTS-15 function beyond those describing its participation in cancer and osteoartritic processes. Regarding cancer, ADAMTS-15 has recently emerged as a putative tumor suppresor gene since it is downregulated in breast cancer, and functionally inactivated through specific mutations in colorectal cancer (Porter et al., 2004; Porter et al., 2006; Viloria et al., 2009). In addition, aberrant expression of ADAMTS-15 is implicated in prostate cancer progression (Molokwu et al., 2010). The latest apparently results from the relationship between ADAMTS-15 expression and versican degradation. Thus, ADAMTS-15 seems to be acting as a versican-degrading enzyme whose accumulation potentially contributes to prostate cancer pathology (Cross et al., 2005). In this regard, versican seems to be one of the targets of ADAMTS-15 proteolityc activity which involves this protein in processes such as cancer or skeletal muscle fiber formation (Croos et al., 2005; Stupka et al., 2013; Dancevic et al., 2013).
Homology ADAMTS-15 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-15 is, among all the members, closely related to ADAMTS-1 which suggested its involvement in angiogenic processes (Cal et al., 2002).
The ADAMTS15 gene is conserved in chimpanzee (Refseq: XM_522253), macaque (Refseq: XM_001113698), dog (Refseq: XM_005620295), cow (Refseq: NM_001192390), mouse (Refseq: NM_001024139), rat (Refseq: NM_001106810), chicken (Refseq: XM_417874), and zebrafish (Refseq: XM_001341842).

Mutations

Somatic ADAMTS15 was identified as one of the so-called CAN genes found to be mutated in a small set of colorectal cancers (Sjöblom et al., 2006). Two heterozigous somatic mutations were described out of eleven human cancer samples (cDNA: 2309A>G, cDNA: 2632T>G). Functional relevance of mutations found in colorectal cancer were described for a deleterious single base mutation 24544ΔG affecting the two carboxy-terminal thrombospondin motifs of ADAMTS-15 (Viloria et al., 2009). The derived truncated form of ADAMTS-15 (ADAMTS15_G849fs) is barely found in the pericellular space of the cell being mostly liberated to the culture media. Functional studies revealed ADAMTS15_G849fs not showing the anti-tumoral properties of full length ADAMTS-15. In the same study, three other mutations where identified, a base pair mutation affecting the second TSP-1 domain (24616C>T), a silent base pair change (13777C>T) and another base deletion generating a completely truncated form of ADAMTS-15 (366Δ) (Viloria et al., 2009).

Implicated in

Note
  
Entity Various cancers
Note ADAMTS-15 has recently emerged as a putative tumor suppresor gene since it is downregulated in breast cancer, and functionally inactivated through specific mutations in colorectal cancer (Porter et al., 2006; López-Otín et al., 2009; Viloria et al., 2009). In addition, aberrant expression of ADAMTS-15 is implicated in prostate cancer progression (Cross et al., 2005; Molokwu et al., 2010). The first indication regarding a potential protective role for ADAMTS15 derived from the observation that low ADAMTS15 expression levels coupled to high ADAMTS8 levels conferred poor prognosis to breast cancer patients (Porter et al., 2006). Moreover, ADAMTS15 was identified as one of the so-called CAN genes found to be mutated in a small set of colorectal cancers (Sjöblom et al., 2006). Functional support to the putative relevance of ADAMTS-15 as a tumor suppresor protease was described after finding four additional mutations in ADAMTS-15 gene sequence in human colon carcinomas (Viloria et al., 2009). Two of the new mutations resulted in the generation of truncated forms of ADAMTS-15, one of them lacking the last two thrombospondin domains whereas the other originating a complete ADAMTS-15 knock-down. Functional analysis revealed that the presence of the two last thrombospondin domains is important for the pericellular loacalization of ADAMTS-15 and affects the anti-tumoral function of full length ADAMTS-15 (Viloria et al., 2009; Dancevic et al., 2013). More recently, ADAMTS-15 has been described as a head and neck squamous cell carcinoma (HNSCC)-associated proteinase since its expression is elevated (together with ADAMTS-1 and ADAMTS-8) in areas surrounding HNSCC tumor microenvironment (Demircan et al., 2009; Stokes et al., 2010). In addition, these three members of the ADAMTS family have elevated expression levels in HNSCC tumor versus normal tissue and in HNSCC derived cell lines vs normal keratinocytes (Stokes et al., 2010). ADAMTS-15 has also been indirectly involved in androgen-mediated prostate cancer growth and proliferation, function that depends on ADAMTS-15 versicanolytic activity (Cross et al., 2005; Molokwu et al., 2010). Molokwu et al identified one androgen-responsive element (ARE) in ADAMTS-15 promoter and 12 more AREs in its gene sequence. In the same article the authors demonstrated ADAMTS-15 reduction both, at mRNA and protein levels, in the presence of dihidrotestorone (DHT). ADAMTS-15 down-regulation in prostate cancer resulted in high versican levels which is a poor prognosis indicator in these type of tumors (Ricciardelli et al., 1998; Luo et al., 2002; Molokwu et al., 2010).
  
  
Entity Colon cancer
Note ADAMTS15 expression inversely correlates with histopathologic differentiation grade in human colorectal carcinomas when analyzing ADAMTS-15 inmunostaining in normal colon epithelia, well-differentiated tumors, moderately differentiated tumors, and poorly differentiated colorectal carcinomas (Viloria et al., 2009).
  
  
Entity Head and neck squamous carcinoma (HNSCC)
Note ADAMTS15 mRNA levels, together with those of other ADAMTS members (ADAMTS1, ADAMTS4, ADAMTS5, ADAMTS8, ADAMTS9), were reduced in HNSCC primary tumors compared with paired non-cancerous tissues (Demircan et al., 2009). Regarding tumor microenvironment ADAMTS15 expression is elevated in adjacent and margin tissue when compared with tumor center tissue (Stokes et al., 2010).
  
  
Entity Breast cancer
Note ADAMTS15 elevated expression correlates with favorable outcome in patients with breast cancer (Porter et al., 2006).
  

Bibliography

Cloning, expression analysis, and structural characterization of seven novel human ADAMTSs, a family of metalloproteinases with disintegrin and thrombospondin-1 domains.
Cal S, Obaya AJ, Llamazares M, Garabaya C, Quesada V, Lopez-Otin C.
Gene. 2002 Jan 23;283(1-2):49-62.
PMID 11867212
 
The expression and regulation of ADAMTS-1, -4, -5, -9, and -15, and TIMP-3 by TGFbeta1 in prostate cells: relevance to the accumulation of versican.
Cross NA, Chandrasekharan S, Jokonya N, Fowles A, Hamdy FC, Buttle DJ, Eaton CL.
Prostate. 2005 May 15;63(3):269-75.
PMID 15599946
 
Biosynthesis and expression of a disintegrin-like and metalloproteinase domain with thrombospondin-1 repeats-15: a novel versican-cleaving proteoglycanase.
Dancevic CM, Fraser FW, Smith AD, Stupka N, Ward AC, McCulloch DR.
J Biol Chem. 2013 Dec 27;288(52):37267-76. doi: 10.1074/jbc.M112.418624. Epub 2013 Nov 12.
PMID 24220035
 
Increased mRNA expression of ADAMTS metalloproteinases in metastatic foci of head and neck cancer.
Demircan K, Gunduz E, Gunduz M, Beder LB, Hirohata S, Nagatsuka H, Cengiz B, Cilek MZ, Yamanaka N, Shimizu K, Ninomiya Y.
Head Neck. 2009 Jun;31(6):793-801. doi: 10.1002/hed.21045.
PMID 19260128
 
Expression profiling of metalloproteinases and their inhibitors in cartilage.
Kevorkian L, Young DA, Darrah C, Donell ST, Shepstone L, Porter S, Brockbank SM, Edwards DR, Parker AE, Clark IM.
Arthritis Rheum. 2004 Jan;50(1):131-41.
PMID 14730609
 
Protective roles of matrix metalloproteinases: from mouse models to human cancer.
Lopez-Otin C, Palavalli LH, Samuels Y.
Cell Cycle. 2009 Nov 15;8(22):3657-62. Epub 2009 Dec 1. (REVIEW)
PMID 19844170
 
Gene expression signature of benign prostatic hyperplasia revealed by cDNA microarray analysis.
Luo J, Dunn T, Ewing C, Sauvageot J, Chen Y, Trent J, Isaacs W.
Prostate. 2002 May 15;51(3):189-200.
PMID 11967953
 
Androgen regulates ADAMTS15 gene expression in prostate cancer cells.
Molokwu CN, Adeniji OO, Chandrasekharan S, Hamdy FC, Buttle DJ.
Cancer Invest. 2010 Aug;28(7):698-710. doi: 10.3109/07357907.2010.489538.
PMID 20590445
 
The ADAMTS metalloproteinases.
Porter S, Clark IM, Kevorkian L, Edwards DR.
Biochem J. 2005 Feb 15;386(Pt 1):15-27. (REVIEW)
PMID 15554875
 
Dysregulated expression of adamalysin-thrombospondin genes in human breast carcinoma.
Porter S, Scott SD, Sassoon EM, Williams MR, Jones JL, Girling AC, Ball RY, Edwards DR.
Clin Cancer Res. 2004 Apr 1;10(7):2429-40.
PMID 15073121
 
ADAMTS8 and ADAMTS15 expression predicts survival in human breast carcinoma.
Porter S, Span PN, Sweep FC, Tjan-Heijnen VC, Pennington CJ, Pedersen TX, Johnsen M, Lund LR, Romer J, Edwards DR.
Int J Cancer. 2006 Mar 1;118(5):1241-7.
PMID 16152618
 
Elevated levels of versican but not decorin predict disease progression in early-stage prostate cancer.
Ricciardelli C, Mayne K, Sykes PJ, Raymond WA, McCaul K, Marshall VR, Horsfall DJ.
Clin Cancer Res. 1998 Apr;4(4):963-71.
PMID 9563891
 
The consensus coding sequences of human breast and colorectal cancers.
Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE.
Science. 2006 Oct 13;314(5797):268-74. Epub 2006 Sep 7.
PMID 16959974
 
Expression profiles and clinical correlations of degradome components in the tumor microenvironment of head and neck squamous cell carcinoma.
Stokes A, Joutsa J, Ala-Aho R, Pitchers M, Pennington CJ, Martin C, Premachandra DJ, Okada Y, Peltonen J, Grenman R, James HA, Edwards DR, Kahari VM.
Clin Cancer Res. 2010 Apr 1;16(7):2022-35. doi: 10.1158/1078-0432.CCR-09-2525. Epub 2010 Mar 21.
PMID 20305301
 
Versican processing by a disintegrin-like and metalloproteinase domain with thrombospondin-1 repeats proteinases-5 and -15 facilitates myoblast fusion.
Stupka N, Kintakas C, White JD, Fraser FW, Hanciu M, Aramaki-Hattori N, Martin S, Coles C, Collier F, Ward AC, Apte SS, McCulloch DR.
J Biol Chem. 2013 Jan 18;288(3):1907-17. doi: 10.1074/jbc.M112.429647. Epub 2012 Dec 11.
PMID 23233679
 
Genetic inactivation of ADAMTS15 metalloprotease in human colorectal cancer.
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Citation

This paper should be referenced as such :
S Cal, AJ Obaya
ADAMTS15 (ADAM Metallopeptidase With Thrombospondin Type 1 Motif, 15)
Atlas Genet Cytogenet Oncol Haematol. 2014;18(9):655-658.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/ADAMTS15ID45587ch11q24.html


External links

Nomenclature
HGNC (Hugo)ADAMTS15   16305
Cards
AtlasADAMTS15ID45587ch11q24
Entrez_Gene (NCBI)ADAMTS15  170689  ADAM metallopeptidase with thrombospondin type 1 motif 15
Aliases
GeneCards (Weizmann)ADAMTS15
Ensembl hg19 (Hinxton)ENSG00000166106 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000166106 [Gene_View]  chr11:130448974-130476645 [Contig_View]  ADAMTS15 [Vega]
ICGC DataPortalENSG00000166106
TCGA cBioPortalADAMTS15
AceView (NCBI)ADAMTS15
Genatlas (Paris)ADAMTS15
WikiGenes170689
SOURCE (Princeton)ADAMTS15
Genetics Home Reference (NIH)ADAMTS15
Genomic and cartography
GoldenPath hg38 (UCSC)ADAMTS15  -     chr11:130448974-130476645 +  11q24.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)ADAMTS15  -     11q24.3   [Description]    (hg19-Feb_2009)
EnsemblADAMTS15 - 11q24.3 [CytoView hg19]  ADAMTS15 - 11q24.3 [CytoView hg38]
Mapping of homologs : NCBIADAMTS15 [Mapview hg19]  ADAMTS15 [Mapview hg38]
OMIM607509   
Gene and transcription
Genbank (Entrez)AJ315733 AK130067 BC109114 W70305
RefSeq transcript (Entrez)NM_139055
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)ADAMTS15
Cluster EST : UnigeneHs.534221 [ NCBI ]
CGAP (NCI)Hs.534221
Alternative Splicing GalleryENSG00000166106
Gene ExpressionADAMTS15 [ NCBI-GEO ]   ADAMTS15 [ EBI - ARRAY_EXPRESS ]   ADAMTS15 [ SEEK ]   ADAMTS15 [ MEM ]
Gene Expression Viewer (FireBrowse)ADAMTS15 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)170689
GTEX Portal (Tissue expression)ADAMTS15
Human Protein AtlasENSG00000166106-ADAMTS15 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ8TE58   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ8TE58  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ8TE58
Splice isoforms : SwissVarQ8TE58
Catalytic activity : Enzyme3.4.24.- [ Enzyme-Expasy ]   3.4.24.-3.4.24.- [ IntEnz-EBI ]   3.4.24.- [ BRENDA ]   3.4.24.- [ KEGG ]   
PhosPhoSitePlusQ8TE58
Domaine pattern : Prosite (Expaxy)ADAM_MEPRO (PS50215)    TSP1 (PS50092)    ZINC_PROTEASE (PS00142)   
Domains : Interpro (EBI)ADAM_Cys-rich    ADAM_spacer1    MetalloPept_cat_dom    Pept_M12B_ADAM-TS8    Peptidase_M12B    Peptidase_M12B_ADAM-TS    Peptidase_M12B_N    TSP1_rpt   
Domain families : Pfam (Sanger)ADAM_spacer1 (PF05986)    Pep_M12B_propep (PF01562)    Reprolysin (PF01421)    TSP_1 (PF00090)   
Domain families : Pfam (NCBI)pfam05986    pfam01562    pfam01421    pfam00090   
Domain families : Smart (EMBL)ACR (SM00608)  TSP1 (SM00209)  
Conserved Domain (NCBI)=/A>/T@>ADAMTS15
DMDM Disease mutations170689
Blocks (Seattle)ADAMTS15
SuperfamilyQ8TE58
Human Protein Atlas [tissue]ENSG00000166106-ADAMTS15 [tissue]
Peptide AtlasQ8TE58
HPRD06330
IPIIPI00152637   
Protein Interaction databases
DIP (DOE-UCLA)Q8TE58
IntAct (EBI)Q8TE58
FunCoupENSG00000166106
BioGRIDADAMTS15
STRING (EMBL)ADAMTS15
ZODIACADAMTS15
Ontologies - Pathways
QuickGOQ8TE58
Ontology : AmiGOmetalloendopeptidase activity  proteinaceous extracellular matrix  extracellular space  proteolysis  heparin binding  zinc ion binding  cell surface  extracellular matrix binding  
Ontology : EGO-EBImetalloendopeptidase activity  proteinaceous extracellular matrix  extracellular space  proteolysis  heparin binding  zinc ion binding  cell surface  extracellular matrix binding  
REACTOMEQ8TE58 [protein]
REACTOME PathwaysR-HSA-5173214 [pathway]   
NDEx NetworkADAMTS15
Atlas of Cancer Signalling NetworkADAMTS15
Wikipedia pathwaysADAMTS15
Orthology - Evolution
OrthoDB170689
GeneTree (enSembl)ENSG00000166106
Phylogenetic Trees/Animal Genes : TreeFamADAMTS15
HOVERGENQ8TE58
HOGENOMQ8TE58
Homologs : HomoloGeneADAMTS15
Homology/Alignments : Family Browser (UCSC)ADAMTS15
Gene fusions - Rearrangements
Tumor Fusion PortalADAMTS15
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerADAMTS15 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)ADAMTS15
dbVarADAMTS15
ClinVarADAMTS15
1000_GenomesADAMTS15 
Exome Variant ServerADAMTS15
ExAC (Exome Aggregation Consortium)ENSG00000166106
GNOMAD BrowserENSG00000166106
Genetic variants : HAPMAP170689
Genomic Variants (DGV)ADAMTS15 [DGVbeta]
DECIPHERADAMTS15 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisADAMTS15 
Mutations
ICGC Data PortalADAMTS15 
TCGA Data PortalADAMTS15 
Broad Tumor PortalADAMTS15
OASIS PortalADAMTS15 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICADAMTS15  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDADAMTS15
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch ADAMTS15
DgiDB (Drug Gene Interaction Database)ADAMTS15
DoCM (Curated mutations)ADAMTS15 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)ADAMTS15 (select a term)
intoGenADAMTS15
NCG5 (London)ADAMTS15
Cancer3DADAMTS15(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM607509   
Orphanet
DisGeNETADAMTS15
MedgenADAMTS15
Genetic Testing Registry ADAMTS15
NextProtQ8TE58 [Medical]
TSGene170689
GENETestsADAMTS15
Target ValidationADAMTS15
Huge Navigator ADAMTS15 [HugePedia]
snp3D : Map Gene to Disease170689
BioCentury BCIQADAMTS15
ClinGenADAMTS15
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD170689
Chemical/Pharm GKB GenePA24541
Clinical trialADAMTS15
Miscellaneous
canSAR (ICR)ADAMTS15 (select the gene name)
Probes
Litterature
PubMed13 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineADAMTS15
EVEXADAMTS15
GoPubMedADAMTS15
iHOPADAMTS15
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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