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THBS2 (thrombospondin-2)

Written2006-01Elizabeth M. Perruccio, David D. Roberts
National Institutes of Health, Bldg. 10, Rm. 2A33, 10 Center Dr. MSC1500, Bethesda, MD 20892-1500, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)TSP2
Other aliasTSP2,
CISP (corticotropin-induced secreted protein)
HGNC (Hugo) THBS2
LocusID (NCBI) 7058
Atlas_Id 42549
Location 6q27  [Link to chromosome band 6q27]
Location_base_pair Starts at 169215780 and ends at 169254114 bp from pter ( according to hg19-Feb_2009)  [Mapping THBS2.png]
Local_order Telomeric to SMOC2 (SPARC related modular calcium binding 2), centromeric to LOC442278
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
COL3A1 (2q32.2) / THBS2 (6q27)PMP22 (17p12) / THBS2 (6q27)THBS2 (6q27) / NME4 (16p13.3)
THBS2 (6q27) / THBS2 (6q27)

DNA/RNA

 
  Intron-exon organization of the THBS2 gene.
Description The THBS2 gene is 38,261 bases in size and is composed of 23 exons. Exons 3-22 encode the 5,808 base mRNA.
Transcription Unlike TSP1, TSP2 is less-to-moderately responsive to serum in mouse NIH3T3 and Swiss 3T3 cells respectively. Transcription of THBS2 in some human cancers is suppressed through hypermethylation. TSP2 mRNA is upregulated by Rac1-induced reactive oxygen species, Hox A5, ACTH, TGFb, cerivastatin and in-vitro, by increasing cell confluency. Downregulation of TSP2 mRNA occurs by inhibiting TGFb-dependent p38 MAPK pathway or perturbing the Smad pathway by dexamethasone, ATF3 overexpression, human papilloma virus positive cells, cytomegalovirus infected cells, tissue factor overexpressing sarcoma cells. The oncogene c-myb affects TSP 2 expression via a post-transcriptional regulation of its mRNA stability. Potential transcription factor binding sites have been described for: NF-kB, NF-Y,p53, Myc-CF1, Sp1, CF-1,GATA and AP-1.
Pseudogene none described

Protein

 
  Domain organization and localization of selected ligand binding sites in TSP2. TSP2 is a homotrimer linked via disulfide bonds. In most cases, sequences recognized by TSP2 receptors are inferred from mutagenesis of the corresponding sequences in TSP1 and supported by peptide inhibitions studies using the TSP2 sequences.
Description The TSP2 precursor contains 1172 amino acids; 129,955 Da. The mature secreted protein comprises residues 19-1172 and assembles into a disulfide linked homotrimer. Secreted TSP2 is a glycoprotein with a molecular mass of 150-160 kDa that contains approximately 7 potential Asn-linked oligosaccharide attachment sites and variable numbers of C-mannosylated Trp residues in the type 1 repeats. An X-ray crystal structure for the C-terminal regions of TSP2 revealed that the type 3 repeats when replete with Ca wrap around the globular G domain.
Expression TSP2 is expressed in many tissues during embryonic development, in the healthy adult and in various tumor stromal environments. Predominant expression is found in the connective tissue compartment and based on EST profiling, expression is highest in bone. Mice lacking thrombospondin 2 show an atypical pattern of endocortical and periosteal bone formation in response to mechanical loading. Expression is induced during the later stages of wound repair, during tissue remodeling, in rheumatoid synovium, ovarian follicle development, in wound keratocytes, hypertrophied heart, by ACTH, cAMP analogs and adenylate cyclase activators in bovine adrenocortical cells, in aged mice. Downregulation has been observed in fetal Leydig cells of mice overexpressing human chorionic gonadotropin/ luteinizing hormone, herpes simplex 1 infected cells, and in Cyclosporin A-induced gingival overgrowths.
TSP2 expression has been reported in some tumors including invasive breast carcinoma, metastatic malignant melanoma, malignant pleural effusions, cervix of pregnant mice, ischemic brain, aggressive ovarian tumor, gastric cancer, renal cell carcinoma, endometrial cancer, colorectal cancer, chemically-induced skin cancer, osteoclastoma, in ACTH-dependent aldosterone producing adenomas, esophageal cancer. Down regulation of TSP2 was reported in ovarian serous papillary carcinoma, salivary gland carcinoma, invasive cervical cancer, and non-small cell lung cancer.
Localisation TSP2 is secreted but is present only transiently in extracellular matrix and is rapidly internalized for degradation by fibroblasts after binding to the cell surface. Degradation is similar to TSP1 removal in that it is LRP- and HSPG-dependent and has similar kinetics. Given its pericellular distribution, TSP2, like TSP1, can modulate cell-matrix interactions and cell behavior.
Function TSP2 binds to extracellular matrix ligands including, transforming growth factor-beta-1, histidine rich glycoprotein, TSG6, heparin, matrix metalloproteinase-2, and heparan sulfate proteoglycans. TSP2 binds to cell surface receptors including CD36, CD47, LDL receptor-related protein-1 (via calreticulin) and the integrins alpha-V/beta-3, alpha-4/beta-1, and alpha-6/beta-1. In contrast to TSP1, TSP2 does not activate latent TGF-beta-1 but similarly to TSP1, TSP2 contains EGF-like modules that bind calcium in a cooperative manner. TSP2 in a context-dependent and cell-specific manner stimulates or inhibits cell adhesion, proliferation, motility, and survival. TSP2 is a potent inhibitor of angiogenesis mediated by the TSP2 receptor CD36. However, its N-terminal region exhibits pro-angiogenic activities mediated by beta-1 integrins . By way of alpha-4/beta-1, TSP2, like TSP1, modulates T cell behavior in-vitro. TSP2 stimulates chemotaxis, MMP gene expression, and activation-dependent adhesion of T cells. In a model of rheumatoid synovium, cell-based TSP2 therapy had an anti-inflammatory role in-vivo and depleted the tissue of infiltrating T cells. In the CNS, TSP2 secreted by astrocytes promotes synaptogenesis.

TSP2 null mice are viable and fertile but display connective tissue abnormalities associated with a defect in collagen fibrillogenesis that manifests as fragile skin, lax tendons and ligaments. Several defects have been reported in responses of TSP2 null mice to specific stresses. Nulls have an enhanced cutaneous inflammatory response, increased endosteal bone density, increased vascular density in dermis, adipose and thymus, a prolonged bleeding time. Fibroblasts isolated from TSP2 nulls are defective in adhesion. In response-to-injury models, TSP2 null mice have an increased vascularity of wounds with a concomitant increase in activity of MMP2 and MMP9 and demonstrate enhanced wound repair.

Homology TSP2 is a member of the thrombospondin family that also contains thrombospondin-1, thrombospondin-3, thrombospondin-4, and cartilage oligomeric matrix protein (COMP). The central type 1 repeats are also known as thrombospondin-repeats and are shared with the larger thrombospondin/properdin repeat superfamily.

Mutations

Germinal t3949g substitution in the 3'-untranslated region is associated with a reduced risk of premature myocardial infarcts
Somatic LOH in markers proximal to THBS2 were reported in salivary carcinomas, but disruption of the THBS2 gene has not been confirmed to date.

Implicated in

Note
  
Entity various cancers
Disease Loss of TSP2 expression is associated with local invasive behavior, tumor neovascularization, and metastasis.
Prognosis Decreased TSP2 expression has been correlated with malignant progression and angiogenesis in some but not all cancers. In a study of 37 gliomas, a lack of TSP2 expression was significantly associated with higher histological grade (P = 0.0019) and increased vessel counts and density (p < 0.0001). In a study of 61 colon cancers, those expressing TSP2 showed a lower incidence of hepatic metastasis than those not expressing TSP2 (p = 0.02). TSP2 negative/VEGF-189 positive colon cancers showed significantly increased vessel counts and density in the stroma (P < 0.0001). Finally, in a study of 10 normal cervix and 78 invasive cervical cancer samples, TSP2 mRNA expression in normal cervix was significantly higher than that in cervical cancer (p = 0.032). Microvessel counts were marginally increased in the cervical cancer patients lacking TSP2 mRNA expression (p = 0.062). To date, the numbers of specimens examined for each of these cancers are too small to evaluate the independent prognostic value of TSP2 expression.
Conversely, TSP2 was strongly expressed in a series of melanoma metastases, but not in primary tumors, and in 55 endometrial cancer specimens TSP2 expression was significantly higher in malignancies exhibiting cervical and lymph-vascular space involvement (p=0.029 and p=0.009, respectively).
Oncogenesis Somatic mutation of THBS2 has not been clearly established in human cancers, but loss of TSP2 expression due to hypermethylation of its promoter was reported in a study of endometrial carcinomas. LOH in 6q15-27 between D6S297 and D6S1590 was reported in a study of salivary gland carcinomas and associated in 8 of 9 cases with loss of TSP2 expression.

Transgenic mouse models support the tumor suppressor activity of THBS2. Tumor progression of chemically-induced skin cancer is accelerated in TSP2 null mice, and there is an increased rate of lymph node metastases. The correlated increase in vessel density and size in these nulls also supports a suppressive role for TSP2. Tumor growth and angiogenesis are delayed and decreased when TSP2 is overexpressed in this model. Mouse models have also been used to explore therapeutic use of TSP2 to limit tumor growth and angiogenesis. These utilize a cell-based approach wherein TSP2 cDNA is transfected into a variety of cells including: glioblastoma, fibrosarcoma, squamous cell carcinoma and breast carcinoma cells. In turn, these TSP2 overexpressing cells when injected subcutaneously into immunodeficient mice exhibit decreased tumor growth and angiogenesis.

  

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Citation

This paper should be referenced as such :
Perruccio, EM ; Roberts, DD
THBS2 (thrombospondin-2)
Atlas Genet Cytogenet Oncol Haematol. 2006;10(3):161-165.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/THBS2ID42549ch6q27.html


External links

Nomenclature
HGNC (Hugo)THBS2   11786
Cards
AtlasTHBS2ID42549ch6q27
Entrez_Gene (NCBI)THBS2  7058  thrombospondin 2
AliasesTSP2
GeneCards (Weizmann)THBS2
Ensembl hg19 (Hinxton)ENSG00000186340 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000186340 [Gene_View]  chr6:169215780-169254114 [Contig_View]  THBS2 [Vega]
ICGC DataPortalENSG00000186340
TCGA cBioPortalTHBS2
AceView (NCBI)THBS2
Genatlas (Paris)THBS2
WikiGenes7058
SOURCE (Princeton)THBS2
Genetics Home Reference (NIH)THBS2
Genomic and cartography
GoldenPath hg38 (UCSC)THBS2  -     chr6:169215780-169254114 -  6q27   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)THBS2  -     6q27   [Description]    (hg19-Feb_2009)
EnsemblTHBS2 - 6q27 [CytoView hg19]  THBS2 - 6q27 [CytoView hg38]
Mapping of homologs : NCBITHBS2 [Mapview hg19]  THBS2 [Mapview hg38]
OMIM188061   603932   
Gene and transcription
Genbank (Entrez)AA853383 AA853654 AI130835 AK292429 AL603377
RefSeq transcript (Entrez)NM_003247
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)THBS2
Cluster EST : UnigeneHs.371147 [ NCBI ]
CGAP (NCI)Hs.371147
Alternative Splicing GalleryENSG00000186340
Gene ExpressionTHBS2 [ NCBI-GEO ]   THBS2 [ EBI - ARRAY_EXPRESS ]   THBS2 [ SEEK ]   THBS2 [ MEM ]
Gene Expression Viewer (FireBrowse)THBS2 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)7058
GTEX Portal (Tissue expression)THBS2
Human Protein AtlasENSG00000186340-THBS2 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP35442   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP35442  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP35442
Splice isoforms : SwissVarP35442
PhosPhoSitePlusP35442
Domaine pattern : Prosite (Expaxy)EGF_2 (PS01186)    EGF_3 (PS50026)    TSP1 (PS50092)    TSP3 (PS51234)    TSP_CTER (PS51236)    VWFC_1 (PS01208)    VWFC_2 (PS50184)   
Domains : Interpro (EBI)ConA-like_dom    EGF-like_Ca-bd_dom    EGF-like_CS    EGF-like_dom    EGF_dom    Laminin_G    Thrombospondin-2    Thrombospondin_3-like_rpt    Thrombospondin_3_rpt    Thrombospondin_C    TSP1_rpt    TSP_type-3_rpt    VWF_dom   
Domain families : Pfam (Sanger)EGF_3 (PF12947)    EGF_CA (PF07645)    TSP_1 (PF00090)    TSP_3 (PF02412)    TSP_C (PF05735)    VWC (PF00093)   
Domain families : Pfam (NCBI)pfam12947    pfam07645    pfam00090    pfam02412    pfam05735    pfam00093   
Domain families : Smart (EMBL)EGF (SM00181)  EGF_CA (SM00179)  TSP1 (SM00209)  TSPN (SM00210)  VWC (SM00214)  
Conserved Domain (NCBI)THBS2
DMDM Disease mutations7058
Blocks (Seattle)THBS2
PDB (SRS)1YO8    2RHP   
PDB (PDBSum)1YO8    2RHP   
PDB (IMB)1YO8    2RHP   
PDB (RSDB)1YO8    2RHP   
Structural Biology KnowledgeBase1YO8    2RHP   
SCOP (Structural Classification of Proteins)1YO8    2RHP   
CATH (Classification of proteins structures)1YO8    2RHP   
SuperfamilyP35442
Human Protein Atlas [tissue]ENSG00000186340-THBS2 [tissue]
Peptide AtlasP35442
HPRD01766
IPIIPI00018769   IPI01009846   IPI00642455   
Protein Interaction databases
DIP (DOE-UCLA)P35442
IntAct (EBI)P35442
FunCoupENSG00000186340
BioGRIDTHBS2
STRING (EMBL)THBS2
ZODIACTHBS2
Ontologies - Pathways
QuickGOP35442
Ontology : AmiGOcalcium ion binding  protein binding  extracellular region  basement membrane  extracellular space  cell adhesion  heparin binding  negative regulation of angiogenesis  platelet alpha granule  positive regulation of synapse assembly  
Ontology : EGO-EBIcalcium ion binding  protein binding  extracellular region  basement membrane  extracellular space  cell adhesion  heparin binding  negative regulation of angiogenesis  platelet alpha granule  positive regulation of synapse assembly  
Pathways : KEGGPhagosome    PI3K-Akt signaling pathway    Focal adhesion    ECM-receptor interaction    Malaria   
REACTOMEP35442 [protein]
REACTOME PathwaysR-HSA-5173214 [pathway]   
NDEx NetworkTHBS2
Atlas of Cancer Signalling NetworkTHBS2
Wikipedia pathwaysTHBS2
Orthology - Evolution
OrthoDB7058
GeneTree (enSembl)ENSG00000186340
Phylogenetic Trees/Animal Genes : TreeFamTHBS2
HOVERGENP35442
HOGENOMP35442
Homologs : HomoloGeneTHBS2
Homology/Alignments : Family Browser (UCSC)THBS2
Gene fusions - Rearrangements
Fusion : MitelmanTHBS2/NME4 [6q27/16p13.3]  
Fusion: TCGATHBS2 6q27 NME4 16p13.3 BRCA
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerTHBS2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)THBS2
dbVarTHBS2
ClinVarTHBS2
1000_GenomesTHBS2 
Exome Variant ServerTHBS2
ExAC (Exome Aggregation Consortium)ENSG00000186340
GNOMAD BrowserENSG00000186340
Genetic variants : HAPMAP7058
Genomic Variants (DGV)THBS2 [DGVbeta]
DECIPHERTHBS2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisTHBS2 
Mutations
ICGC Data PortalTHBS2 
TCGA Data PortalTHBS2 
Broad Tumor PortalTHBS2
OASIS PortalTHBS2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICTHBS2  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDTHBS2
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 THBS2
DgiDB (Drug Gene Interaction Database)THBS2
DoCM (Curated mutations)THBS2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)THBS2 (select a term)
intoGenTHBS2
NCG5 (London)THBS2
Cancer3DTHBS2(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM188061    603932   
Orphanet
MedgenTHBS2
Genetic Testing Registry THBS2
NextProtP35442 [Medical]
TSGene7058
GENETestsTHBS2
Target ValidationTHBS2
Huge Navigator THBS2 [HugePedia]
snp3D : Map Gene to Disease7058
BioCentury BCIQTHBS2
ClinGenTHBS2
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD7058
Chemical/Pharm GKB GenePA36498
Clinical trialTHBS2
Miscellaneous
canSAR (ICR)THBS2 (select the gene name)
Probes
Litterature
PubMed81 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineTHBS2
EVEXTHBS2
GoPubMedTHBS2
iHOPTHBS2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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