Thrombospondin

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Thrombospondin type 1 domain
PDB 1lsl EBI.jpg
Thrombospondin-1
Identifiers
SymbolTSP_1
Pfam PF00090
InterPro IPR000884
SMART SM00209
PROSITE PS50092
SCOPe 1lsl / SUPFAM

Thrombospondins (TSPs) are a family of secreted glycoproteins with antiangiogenic functions. Due to their dynamic role within the extracellular matrix they are considered matricellular proteins. [1] The first member of the family, thrombospondin 1 (THBS1), was discovered in 1971 by Nancy L. Baenziger. [2]

Contents

Types

The thrombospondins are a family of multifunctional proteins. The family consists of thrombospondins 1-5 and can be divided into 2 subgroups: A, which contains TSP-1 and -2, and B, which contains TSP-3, -4 and -5 (also designated cartilage oligomeric protein or COMP). TSP-1 and -2 are homotrimers, consisting of three identical subunits, whereas TSP-3, -4 and -5 are homopentamers.

TSP-1 and TSP-2 are produced by immature astrocytes during brain development, which promotes the development of new synapses. [3]

Thrombospondin 1

Thrombospondin 1 (TSP-1) is encoded by THBS1. It was first isolated from platelets that had been stimulated with thrombin, and so was designated 'thrombin-sensitive protein'. [2] Since its first recognition, functions for TSP-1 have been found in multiple biological processes including angiogenesis, apoptosis, activation of TGF-beta and Immune regulation. As such, TSP-1 is designated a multifunctional protein.

TSP-1 has multiple receptors, among which CD36, CD47 and integrins are of particular note.

TSP-1 is antiangiogenic, inhibiting the proliferation and migration of endothelial cells by interactions with CD36 expressed on their surface of these cells. Inhibitory peptides and fragments of TSP1 bind to CD36, leading to the expression of FAS ligand (FasL), which activates its specific, ubiquitous receptor, Fas. This leads to the activation of caspases and apoptosis of the cell. Since tumors overexpressing TSP-1 typically grow slower, exhibit less angiogenesis, and have fewer metastases, TSP1 is an attractive target for cancer treatment. Because TSP1 is extremely large (~120 kDa monomer), not very abundant and exerts multiple actions, its clinical usefulness is questionable. However, small-molecules based on a CD36-binding peptide sequence from TSP1 are being tested. One analog, ABT-510, exhibits potent proapoptotic activity in cultured cells, while clinically it is very well tolerated with therapeutic benefits reported against several malignancies. [4] In 2005, ABT-510 was evaluated in phase II clinical trials for the treatment of several types of cancer. [5]

Human proteins containing this domain

ADAMTS1; ADAMTS10; ADAMTS12; ADAMTS13; ADAMTS14; ADAMTS15; ADAMTS16; ADAMTS17; ADAMTS18; ADAMTS19; ADAMTS2; ADAMTS20; ADAMTS3; ADAMTS4; ADAMTS5; ADAMTS6; ADAMTS7; ADAMTS8; ADAMTS9; ADAMTSL1; ADAMTSL2; ADAMTSL3; ADAMTSL4; ADAMTSL5; BAI1; BAI2; BAI3; C6; C7; C8A; C8B; C9; C9orf8; C9orf94; CFP; CILP; CILP2; CTGF; CYR61; HMCN1; LIBC; NOV; PAPLN; RSPO1; RSPO3; SEMA5A; SEMA5B; SPON1; SPON2; SSPO; THBS1; THBS2; THSD1; THSD3; THSD7A; THSD7B; UNC5A; UNC5B; UNC5C; UNC5D; WISP1; WISP2; WISP3;

Related Research Articles

Thrombospondin 1 protein-coding gene in the species Homo sapiens

Thrombospondin 1, abbreviated as THBS1, is a protein that in humans is encoded by the THBS1 gene.

CYR61 protein-coding gene in the species Homo sapiens

Cysteine-rich angiogenic inducer 61 (CYR61) or CCN family member 1 (CCN1), is a matricellular protein that in humans is encoded by the CYR61 gene.

Brain-specific angiogenesis inhibitor 3 protein-coding gene in the species Homo sapiens

Brain-specific angiogenesis inhibitor 3 is a protein that in humans is encoded by the BAI3 gene.

PEDF protein-coding gene in the species Homo sapiens

Pigment epithelium-derived factor (PEDF) also known as serpin F1 (SERPINF1), is a multifunctional secreted protein that has anti-angiogenic, anti-tumorigenic, and neurotrophic functions. Found in vertebrates, this 50 kDa protein is being researched as a therapeutic candidate for treatment of such conditions as choroidal neovascularization, heart disease, and cancer. In humans, pigment epithelium-derived factor is encoded by the SERPINF1 gene.

CD47 Protein-coding gene in humans

CD47 also known as integrin associated protein (IAP) is a transmembrane protein that in humans is encoded by the CD47 gene. CD47 belongs to the immunoglobulin superfamily and partners with membrane integrins and also binds the ligands thrombospondin-1 (TSP-1) and signal-regulatory protein alpha (SIRPα). CD-47 acts as a don't eat me signal to macrophages of the immune system which has made it a potential therapeutic target in some cancers, and more recently, for the treatment of pulmonary fibrosis.

NOV (gene) protein-coding gene in the species Homo sapiens

NOV also known as CCN3 is a matricellular protein that in humans is encoded by the NOV gene.

Thrombospondin-2 protein-coding gene in the species Homo sapiens

Thrombospondin-2 is a protein that in humans is encoded by the THBS2 gene.

WNT1-inducible-signaling pathway protein 1 protein-coding gene in the species Homo sapiens

WNT1-inducible-signaling pathway protein 1 (WISP-1), also known as CCN4, is a matricellular protein that in humans is encoded by the WISP1 gene.

Thrombospondin 3 protein-coding gene in the species Homo sapiens

Thrombospondin-3 (TSP3) is a protein that in humans is encoded by the THBS3 gene.

WNT1-inducible-signaling pathway protein 3 protein-coding gene in the species Homo sapiens

WNT1-inducible-signaling pathway protein 3 is a matricellular protein that in humans is encoded by the WISP3 gene.

WNT1-inducible-signaling pathway protein 2 protein-coding gene in the species Homo sapiens

WNT1-inducible-signaling pathway protein 2, or WISP-2 is a matricellular protein that in humans is encoded by the WISP2 gene.

ADAMTS is a family of multidomain extracellular protease enzymes. 19 members of this family have been identified in humans, the first of which, ADAMTS1, was described in 1997. Known functions of the ADAMTS proteases include processing of procollagens and von Willebrand factor as well as cleavage of aggrecan, versican, brevican and neurocan, making them key remodeling enzymes of the extracellular matrix. They have been demonstrated to have important roles in connective tissue organization, coagulation, inflammation, arthritis, angiogenesis and cell migration. Homologous subfamily of ADAMTSL (ADAMTS-like) proteins, which lack enzymatic activity, has also been described. Most cases of thrombotic thrombocytopenic purpura arise from autoantibody-mediated inhibition of ADAMTS13.

ADAMTS8 protein-coding gene in the species Homo sapiens

A disintegrin and metalloproteinase with thrombospondin motifs 8 is an enzyme that in humans is encoded by the ADAMTS8 gene.

ADAMTS9 protein-coding gene in the species Homo sapiens

A disintegrin and metalloproteinase with thrombospondin motifs 9 is an enzyme that in humans is encoded by the ADAMTS9 gene.

ADAMTS10 protein-coding gene in the species Homo sapiens

A disintegrin and metalloproteinase with thrombospondin motifs 10 is an enzyme that in humans is encoded by the ADAMTS10 gene.

ADAMTS3 protein-coding gene in the species Homo sapiens

A disintegrin and metalloproteinase with thrombospondin motifs 3 is an enzyme that in humans is encoded by the ADAMTS3 gene. The protein encoded by this gene is the major procollagen II N-propeptidase.

Immunoglobulin I-set domain

I-set domains are found in several cell adhesion molecules, including vascular (VCAM), intercellular (ICAM), neural (NCAM) and mucosal addressin (MADCAM) cell adhesion molecules, as well as junction adhesion molecules (JAM). I-set domains are also present in several other diverse protein families, including several tyrosine-protein kinase receptors, the hemolymph protein hemolin, the muscle proteins titin, telokin, and twitchin, the neuronal adhesion molecule axonin-1, and the signalling molecule semaphorin 4D that is involved in axonal guidance, immune function and angiogenesis.

CCN proteins are a family of extracellular matrix (ECM)-associated proteins involved in intercellular signaling. Due to their dynamic role within the ECM they are considered matricellular proteins.

Tumstatin is a protein fragment cleaved from collagen that serves as both an antiangiogenic and proapoptotic agent. It has similar function to canstatin, endostatin, restin, and arresten, which also affect angiogenesis. Angiogenesis is the growth of new blood vessels from pre-existing blood vessels, and is important in tumor growth and metastasis. Angiogenesis is stimulated by many growth factors, the most prevalent of which is vascular endothelial growth factor (VEGF).

A disintegrin and metalloproteinase with thrombospondin motifs 7 (ADAMTS7) is an enzyme that in humans is encoded by the ADAMTS7 gene on chromosome 15. It is ubiquitously expressed in many tissues and cell types. This enzyme catalyzes the degradation of cartilage oligomeric matrix protein (COMP) degradation. ADAMTS7 has been associated with cancer and arthritis in multiple tissue types. The ADAMTS7 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.

References

  1. Morris, Aaron H.; Kyriakides, Themis R. (July 2014). "Matricellular proteins and biomaterials". Matrix Biology. 37: 183–191. doi:10.1016/j.matbio.2014.03.002. PMC   4167162 . PMID   24657843.
  2. 1 2 Baenziger NL, Brodie GN, Majerus PW (January 1971). "A Thrombin-Sensitive Protein of Human Platelet Membranes". Proc. Natl. Acad. Sci. U.S.A. 68 (1): 240–3. Bibcode:1971PNAS...68..240B. doi:10.1073/pnas.68.1.240. PMC   391203 . PMID   5276296.
  3. Christopherson KS; Ullian EM; Stokes CC; Mullowney CE; Hell JW; Agah A; Lawler J; Mosher DF; Bornstein P; Barres BA. (2005). "Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis". Cell. 120 (3): 421–33. doi:10.1016/j.cell.2004.12.020. PMID   15707899. S2CID   5772111.
  4. Haviv F, Bradley MF, Kalvin DM, et al. (April 2005). "Thrombospondin-1 mimetic peptide inhibitors of angiogenesis and tumor growth: design, synthesis, and optimization of pharmacokinetics and biological activities". Journal of Medicinal Chemistry. 48 (8): 2838–46. doi:10.1021/jm0401560. PMID   15828822.
  5. Sorbera LA, Bayes M (2005). "ABT-510: oncolytic angiogenesis inhibitor". Drugs of the Future. Prous Science. 30 (11): 1081–6. doi:10.1358/dof.2005.030.11.949588.