THBS2 (thrombospondin-2)

2006-01-01   Elizabeth M. Perruccio , David D. Roberts 

National Institutes of Health, Bldg. 10, Rm. 2A33, 10 Center Dr. MSC1500, Bethesda, MD 20892-1500, USA

Identity

HGNC
LOCATION
6q27
LOCUSID
ALIAS
TSP2
FUSION GENES

DNA/RNA

Atlas Image
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

Proteins

Atlas Image
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

Entity name
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.

Bibliography

Pubmed IDLast YearTitleAuthors
116874832001Thrombospondins: multifunctional regulators of cell interactions.Adams JC et al
150941092004The thrombospondins.Adams JC et al
92490611997Analysis of the promoter and transcription start sites of the human thrombospondin 2 gene (THBS2).Adolph KW et al
149964332004Thrombospondin 2 levels are increased in aged mice: consequences for cutaneous wound healing and angiogenesis.Agah A et al
160071232005Fetal but not adult Leydig cells are susceptible to adenoma formation in response to persistently high hCG level: a study on hCG overexpressing transgenic mice.Ahtiainen P et al
119435892002Corneal stromal cells (keratocytes) express thrombospondins 2 and 3 in wound repair phenotype.Armstrong DJ et al
127140432003Thrombospondins 1 and 2 function as inhibitors of angiogenesis.Armstrong LC et al
149759382004Proteomic analysis of exosomes isolated from human malignant pleural effusions.Bard MP et al
96949061998Myb-dependent regulation of thrombospondin 2 expression. Role of mRNA stability.Bein K et al
110276392000Angiogenesis modulators expression in culture cell lines positives for HPV-16 oncoproteins.Bequet-Romero M et al
90124631997Thrombospondin-1 and -2 messenger RNA expression in normal, benign, and neoplastic human breast tissues: correlation with prognostic factors, tumor angiogenesis, and fibroblastic desmoplasia.Bertin N et al
150941262004The role of thrombospondins 1 and 2 in the regulation of cell-matrix interactions, collagen fibril formation, and the response to injury.Bornstein P et al
157772392005Novel integrin antagonists derived from thrombospondins.Calzada MJ et al
161868192005Structure of the calcium-rich signature domain of human thrombospondin-2.Carlson CB et al
104913031999Expression of members of the thrombospondin family by human skeletal tissues and cultured cells.Carron JA et al
157613882005Suppression of thrombospondin 1 and 2 production by herpes simplex virus 1 infection in cultured keratocytes.Choudhary A et al
125314312003Molecular mechanism of the anti-cancer activity of cerivastatin, an inhibitor of HMG-CoA reductase, on aggressive human breast cancer cells.Denoyelle C et al
119377582002Gene expression profiling in silico: relative expression of candidate angiogenesis associated genes in renal cell carcinomas.Gerritsen ME et al
156162242005Thrombospondin and vascular endothelial growth factor are cyclically expressed in an inverse pattern during bovine ovarian follicle development.Greenaway J et al
162902552006Mice lacking thrombospondin 2 show an atypical pattern of endocortical and periosteal bone formation in response to mechanical loading.Hankenson KD et al
123581362002Thrombospondin expression in aldosterone-producing adenomas.Hatakeyama H et al
113871982001Thrombospondin-2 plays a protective role in multistep carcinogenesis: a novel host anti-tumor defense mechanism.Hawighorst T et al
153478402004Regulation of VEGF-A, VEGFR-I, thrombospondin-1, -2, and -3 expression in a human pituitary cell line (HP75) by TGFbeta1, bFGF, and EGF.Horiguchi H et al
115200672001Gene expression profiling in human esophageal cancers using cDNA microarray.Kan T et al
104483071999Thrombospondin-2 (TSP2) expression is inversely correlated with vascularity in glioma.Kazuno M et al
128248792003Loss of heterozygosity on chromosome 6q correlates with decreased thrombospondin-2 expression in human salivary gland carcinomas.Kishi M et al
115556002001Thrombospondin-1 and -2 messenger RNA expression in invasive cervical cancer: correlation with angiogenesis and prognosis.Kodama J et al
150095162004Decreased expressions of thrombospondin 2 in cyclosporin A-induced gingival overgrowth.Koh JT et al
145616592004Thrombospondin 2 deficiency in pregnant mice results in premature softening of the uterine cervix.Kokenyesi R et al
123537042002Differential expression of thrombospondin 2 in primary and metastatic malignant melanoma.Kunz M et al
117812362002Increased and prolonged inflammation and angiogenesis in delayed-type hypersensitivity reactions elicited in the skin of thrombospondin-2--deficient mice.Lange-Asschenfeldt B et al
150941192004Tumor progression: the effects of thrombospondin-1 and -2.Lawler J et al
111726042001Comparative study of angiostatic and anti-invasive gene expressions as prognostic factors in gastric cancer.Lee JH et al
125117712003Differential regulation of thrombospondin-1 and thrombospondin-2 after focal cerebral ischemia/reperfusion.Lin TN et al
159050802005Transdifferentiation-dependent expression of alpha-SMA in hepatic stellate cells does not involve TGF-beta pathways leading to coinduction of collagen type I and thrombospondin-2.Lindert S et al
128610252003Thrombospondin 2 regulates cell proliferation induced by Rac1 redox-dependent signaling.Lopes N et al
96768561998Thrombospondin 2 gene expression is correlated with decreased vascularity in non-small cell lung cancer.Oshika Y et al
155794512004Thrombospondin 2 functions as an endogenous regulator of angiogenesis and inflammation in rheumatoid arthritis.Park YW et al
83826991993Corticotropin-induced secreted protein, an ACTH-induced protein secreted by adrenocortical cells, is structurally related to thrombospondins.Pellerin S et al
113140512001Transcription factor ATF3 partially transforms chick embryo fibroblasts by promoting growth factor-independent proliferation.Perez S et al
123908842002Expression and localization of thrombospondin-1 and -2 and their cell-surface receptor, CD36, during rat follicular development and formation of the corpus luteum.Petrik JJ et al
163795942005A role for Hox A5 in regulating angiogenesis and vascular patterning.Rhoads K et al
129232372003Impaired angiogenesis in aging is associated with alterations in vessel density, matrix composition, inflammatory response, and growth factor expression.Sadoun E et al
153053712004Gene expression profiles in primary ovarian serous papillary tumors and normal ovarian epithelium: identification of candidate molecular markers for ovarian cancer diagnosis and therapy.Santin AD et al
152841912004Thrombospondin-2 is essential for myocardial matrix integrity: increased expression identifies failure-prone cardiac hypertrophy.Schroen B et al
114458432001Thrombospondin-1 and -2 messenger RNA expression in normal and neoplastic endometrial tissues: correlation with angiogenesis and prognosis.Seki N et al
157489992005The antiangiogenic effect of thrombospondin-2 is mediated by CD36 and modulated by histidine-rich glycoprotein.Simantov R et al
150941172004Coronary artery disease and the thrombospondin single nucleotide polymorphisms.Stenina OI et al
106113081999Thrombospondin-2: a potent endogenous inhibitor of tumor growth and angiogenesis.Streit M et al
119298172002Systemic inhibition of tumor growth and angiogenesis by thrombospondin-2 using cell-based antiangiogenic gene therapy.Streit M et al
127963962003Frequent HOXA11 and THBS2 promoter methylation, and a methylator phenotype in endometrial adenocarcinoma.Whitcomb BP et al
105688311999Expression of angiostatic factors in colorectal cancer.Yoshida Y et al
75218871994Tissue factor controls the balance of angiogenic and antiangiogenic properties of tumor cells in mice.Zhang Y et al
98267241998Cellular gene expression altered by human cytomegalovirus: global monitoring with oligonucleotide arrays.Zhu H et al
115303352001Thrombospondins and tumor angiogenesis.de Fraipont F et al

Other Information

Locus ID:

NCBI: 7058
MIM: 188061
HGNC: 11786
Ensembl: ENSG00000186340

Variants:

dbSNP: 7058
ClinVar: 7058
TCGA: ENSG00000186340
COSMIC: THBS2

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000186340ENST00000366787P35442
ENSG00000186340ENST00000435791Q5RI53
ENSG00000186340ENST00000617924P35442
ENSG00000186340ENST00000649844A0A3B3ITK0

Expression (GTEx)

0
100
200
300
400
500
600

Pathways

PathwaySourceExternal ID
Focal adhesionKEGGko04510
ECM-receptor interactionKEGGko04512
Focal adhesionKEGGhsa04510
ECM-receptor interactionKEGGhsa04512
MalariaKEGGko05144
MalariaKEGGhsa05144
PhagosomeKEGGko04145
PhagosomeKEGGhsa04145
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
O-linked glycosylationREACTOMER-HSA-5173105
O-glycosylation of TSR domain-containing proteinsREACTOMER-HSA-5173214
DiseaseREACTOMER-HSA-1643685
Diseases of glycosylationREACTOMER-HSA-3781865
Signal TransductionREACTOMER-HSA-162582
Signaling by PDGFREACTOMER-HSA-186797
Diseases associated with O-glycosylation of proteinsREACTOMER-HSA-3906995
Defective B3GALTL causes Peters-plus syndrome (PpS)REACTOMER-HSA-5083635

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
161868192005Structure of the calcium-rich signature domain of human thrombospondin-2.43
129096442003Recognition of the N-terminal modules of thrombospondin-1 and thrombospondin-2 by alpha6beta1 integrin.41
184551302008A functional polymorphism in THBS2 that affects alternative splicing and MMP binding is associated with lumbar-disc herniation.39
184551302008A functional polymorphism in THBS2 that affects alternative splicing and MMP binding is associated with lumbar-disc herniation.39
287014762017Detection of early pancreatic ductal adenocarcinoma with thrombospondin-2 and CA19-9 blood markers.38
151217692004Large scale association analysis for identification of genes underlying premature coronary heart disease: cumulative perspective from analysis of 111 candidate genes.35
171829692007Increased cortical expression of two synaptogenic thrombospondins in human brain evolution.35
120580572002Thrombospondin 2 inhibits microvascular endothelial cell proliferation by a caspase-independent mechanism.32
180325852008Thrombospondins use the VLDL receptor and a nonapoptotic pathway to inhibit cell division in microvascular endothelial cells.32

Citation

Elizabeth M. Perruccio ; David D. Roberts

THBS2 (thrombospondin-2)

Atlas Genet Cytogenet Oncol Haematol. 2006-01-01

Online version: http://atlasgeneticsoncology.org/gene/42549/thbs2