Thrombospondin 1

Last updated
THBS1
Protein THBS1 PDB 1lsl.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases THBS1 , THBS, THBS-1, TSP, TSP-1, TSP1, thrombospondin 1
External IDs OMIM: 188060 MGI: 98737 HomoloGene: 31142 GeneCards: THBS1
Orthologs
SpeciesHumanMouse
Entrez

7057

21825

Ensembl

ENSG00000137801

ENSMUSG00000040152

UniProt

P07996

P35441

RefSeq (mRNA)

NM_003246

NM_011580
NM_001313914

RefSeq (protein)

NP_003237

n/a

Location (UCSC) Chr 15: 39.58 – 39.6 Mb Chr 2: 117.94 – 117.96 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Thrombospondin 1, abbreviated as THBS1, is a protein that in humans is encoded by the THBS1 gene. [5] [6]

Thrombospondin 1 is a subunit of a disulfide-linked homotrimeric protein. This protein is an adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions. This protein can bind to fibrinogen, fibronectin, laminin, collagens types V and VII and integrins alpha-V/beta-1. This protein has been shown to play roles in platelet aggregation, angiogenesis, and tumorigenesis. [7] [8]

Function

The thrombospondin-1 protein is a member of the thrombospondin family. It is a multi-domain matrix glycoprotein that has been shown to be a natural inhibitor of neovascularization and tumorigenesis in healthy tissue. Both positive and negative modulation of endothelial cell adhesion, motility, and growth have been attributed to TSP1. This should not be surprising considering that TSP1 interacts with at least 12 cell adhesion receptors, including CD36, αv integrins, β1 integrins, syndecan, and integrin-associated protein (IAP or CD47). It also interacts with numerous proteases involved in angiogenesis, including plasminogen, urokinase, matrix metalloproteinase, thrombin, cathepsin, and elastase.

Thrombospondin-1 binds to the reelin receptors, ApoER2 and VLDLR, thereby affecting neuronal migration in the rostral migratory stream. [9]

The various functions of the TSRs have been attributed to several recognition motifs. Characterization of these motifs has led to the use of recombinant proteins that contain these motifs; these recombinant proteins are deemed useful in cancer therapy. The TSP-1 3TSR (a recombinant version of the THBS1 antiangiogenic domain containing all three thrombosopondin-1 type 1 repeats) can activate transforming growth factor beta 1 (TGFβ1) and inhibit endothelial cell migration, angiogenesis, and tumor growth. [10]

Structure

Thrombospondin's activity has been mapped to several domains, in particular the amino-terminal heparin-binding domain, the procollagen domain, the properdin-like type I repeats, and the globular carboxy-terminal domain. The protein also contains type II repeats with epidermal growth factor-like homology and type III repeats that contain an RGD sequence. [11]

N-terminus

The N-terminal heparin-binding domain of TSP1, when isolated as a 25kDa fragment, has been shown to be a potent inducer of cell migration at high concentrations. However, when the heparin-binding domain of TSP1 is cleaved, the remaining anti-angiogenic domains have been shown to have decreased anti-angiogenic activity at low concentrations where increased endothelial cell (EC) migration occurs. This may be explained in part by the ability of the heparin-binding domain to mediate attachment of TSP1 to cells, allowing the other domains to exert their effects. The separate roles that the heparin-binding region of TSP1 plays at high versus low concentrations may be in part responsible for regulating the two-faced nature of TSP1 and giving it a reputation of being both a positive and negative regulator of angiogenesis. [12]

Procollagen domain

Both the procollagen domain and the type I repeats of TSP1 have been shown to inhibit neovascularization and EC migration. However, it is unlikely that the mechanisms of action of these fragments are the same. The type I repeats of TSP1 are capable of inhibiting EC migration in a Boyden chamber assay after a 3-4 hour exposure, whereas a 36- to 48-hour exposure period is necessary for inhibition of EC migration with the procollagen domain. [12] Whereas the chorioallantoic membrane (CAM) assay shows the type I repeats of TSP1 to be antiangiogenic, it also shows that the procollagen sequence lacks anti-angiogenic activity. This may be in part because the animo-terminal end of TSP1 differs more than the carboxy-terminal end across species, but may also suggest different mechanisms of action. [13]

TSP1 contains three type I repeats, only the second two of which have been found to inhibit angiogenesis. The type I repeat motif is more effective than the entire protein at inhibiting angiogenesis and contains not one but two regions of activity. The amino-terminal end contains a tryptophan-rich motif that blocks fibroblast growth factor (FGF-2 or bFGF) driven angiogenesis. This region has also been found to prevent FGF-2 binding ECs, suggesting that its mechanism of action may be to sequester FGF-2. The second region of activity, the CD36 binding region of TSP1, can be found on the carboxy-terminal half of the type I repeats. [13] It has been suggested that activating the CD36 receptor causes an increase in ECs sensitivity to apoptotic signals. [14] [15] Type I repeats have also been shown to bind to heparin, fibronectin, TGF-β, and others, potentially antagonizing the effects of these molecules on ECs. [16] However, CD36 is generally considered to be the dominant inhibitory signaling receptor for TSP1, and EC expression of CD36 is restricted to microvascular ECs.

Soluble type I repeats have been shown to decrease EC numbers by inhibiting proliferation and promoting apoptosis. Attachment of endothelial cells to fibronectin partially reverses this phenomenon. However this domain is not without a two-faced nature of its own. Bound protein fragments of the type I repeats have been shown to serve as attachment factors for both ECs and melanoma cells. [17]

C-terminus

The carboxy-terminal domain of TSP1 is believed to mediate cellular attachment and has been found to bind to another important receptor for TSP1, IAP (or CD47). [18] This receptor is considered necessary for nitric oxide-stimulated TSP1-mediated vascular cell responses and cGMP signaling. [19] Various domains of and receptors for TSP1 have been shown to have pro-adhesive and chemotactic activities for cancer cells, suggesting that this molecule may have a direct effect on cancer cell biology independent of its anti-angiogenic properties. [20] [21]

Cancer treatment

One study has suggested that, by blocking TSP1 from binding to its cell surface receptor (CD47) normal tissue confers high resistance to cancer radiation therapy and assists in tumor death. [22]

Interactions

Thrombospondin 1 has been shown to interact with:

Related Research Articles

Integrin Instance of a defined set in Homo sapiens with Reactome ID (R-HSA-374573)

Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, organization of the intracellular cytoskeleton, and movement of new receptors to the cell membrane. The presence of integrins allows rapid and flexible responses to events at the cell surface.

Angiogenesis Blood vessel formation, when new vessels emerge from existing vessels

Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting. Vasculogenesis is the embryonic formation of endothelial cells from mesoderm cell precursors, and from neovascularization, although discussions are not always precise. The first vessels in the developing embryo form through vasculogenesis, after which angiogenesis is responsible for most, if not all, blood vessel growth during development and in disease.

Fibronectin Protein involved in cell adhesion, cell growth, cell migration and differentiation

Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collagen, fibrin, and heparan sulfate proteoglycans.

Angiomotin Protein-coding gene in the species Homo sapiens

Angiomotin (AMOT) is a protein that in humans is encoded by the AMOT gene. It belongs to the motin family of angiostatin binding proteins, which includes angiomotin, angiomotin-like 1 (AMOTL1) and angiomotin-like 2 (AMOTL2) characterized by coiled-coil domains at N-terminus and consensus PDZ-binding domain at the C-terminus. Angiomotin is expressed predominantly in endothelial cells of capillaries as well as angiogenic tissues such as placenta and solid tumor.

Thrombospondin

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. The first member of the family, thrombospondin 1 (THBS1), was discovered in 1971 by Nancy L. Baenziger.

Endostatin

Endostatin is a naturally occurring, 20-kDa C-terminal fragment derived from type XVIII collagen. It is reported to serve as an anti-angiogenic agent, similar to angiostatin and thrombospondin.

Transforming growth factor beta Cytokine

Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms and many other signaling proteins. TGFB proteins are produced by all white blood cell lineages.

Angiopoietin Protein family

Angiopoietin is part of a family of vascular growth factors that play a role in embryonic and postnatal angiogenesis. Angiopoietin signaling most directly corresponds with angiogenesis, the process by which new arteries and veins form from preexisting blood vessels. Angiogenesis proceeds through sprouting, endothelial cell migration, proliferation, and vessel destabilization and stabilization. They are responsible for assembling and disassembling the endothelial lining of blood vessels. Angiopoietin cytokines are involved with controlling microvascular permeability, vasodilation, and vasoconstriction by signaling smooth muscle cells surrounding vessels. There are now four identified angiopoietins: ANGPT1, ANGPT2, ANGPTL3, ANGPT4.

Endoglin Protein-coding gene in the species Homo sapiens

Endoglin (ENG) is a type I membrane glycoprotein located on cell surfaces and is part of the TGF beta receptor complex. It is also commonly referred to as CD105, END, FLJ41744, HHT1, ORW and ORW1. It has a crucial role in angiogenesis, therefore, making it an important protein for tumor growth, survival and metastasis of cancer cells to other locations in the body.

CTGF

CTGF, also known as CCN2 or connective tissue growth factor, is a matricellular protein of the CCN family of extracellular matrix-associated heparin-binding proteins. CTGF has important roles in many biological processes, including cell adhesion, migration, proliferation, angiogenesis, skeletal development, and tissue wound repair, and is critically involved in fibrotic disease and several forms of cancers.

Heparin-binding EGF-like growth factor

Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF family of proteins that in humans is encoded by the HBEGF gene.

MMP2

72 kDa type IV collagenase also known as matrix metalloproteinase-2 (MMP-2) and gelatinase A is an enzyme that in humans is encoded by the MMP2 gene. The MMP2 gene is located on chromosome 16 at position 12.2.

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.

LRP1 Mammalian protein found in Homo sapiens

Low density lipoprotein receptor-related protein 1 (LRP1), also known as alpha-2-macroglobulin receptor (A2MR), apolipoprotein E receptor (APOER) or cluster of differentiation 91 (CD91), is a protein forming a receptor found in the plasma membrane of cells involved in receptor-mediated endocytosis. In humans, the LRP1 protein is encoded by the LRP1 gene. LRP1 is also a key signalling protein and, thus, involved in various biological processes, such as lipoprotein metabolism and cell motility, and diseases, such as neurodegenerative diseases, atherosclerosis, and cancer.

Brain-specific angiogenesis inhibitor 1 Protein-coding gene in the species Homo sapiens

Brain-specific angiogenesis inhibitor 1 is a protein that in humans is encoded by the BAI1 gene. It is a member of the adhesion-GPCR family of receptors.

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.

αVβ3 is a type of integrin that is a receptor for vitronectin. It consists of two components, integrin alpha V and integrin beta 3 (CD61), and is expressed by platelets. Furthermore, it is a receptor for phagocytosis on macrophages or dendritic cells.

Angiogenesis is the process of forming new blood vessels from existing blood vessels. It is a highly complex process involving extensive interplay between cells, soluble factors, and the extracellular matrix (ECM). Angiogenesis is critical during normal physiological development, but it also occurs in adults during inflammation, wound healing, ischemia, and in pathological conditions such as rheumatoid arthritis, hemangioma, and tumor growth. Proteolysis has been indicated as one of the first and most sustained activities involved in the formation of new blood vessels. Numerous proteases including matrix metalloproteases (MMPs), a disintegrin and metalloprotease domain (ADAM), a disintegrin and metalloprotease domain with throbospondin motifs (ADAMTS), and cysteine and serine proteases are involved in angiogenesis. This article focuses on the important and diverse roles that these proteases play in the regulation of angiogenesis.

Von Willebrand factor, type C is a protein domain is found in various blood plasma proteins: complement factors B, C2, CR3 and CR4; the integrins (I-domains); collagen types VI, VII, XII and XIV; and other extracellular proteins.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000137801 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000040152 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Wolf FW, Eddy RL, Shows TB, Dixit VM (Apr 1990). "Structure and chromosomal localization of the human thrombospondin gene" (PDF). Genomics. 6 (4): 685–91. doi:10.1016/0888-7543(90)90505-O. hdl: 2027.42/28657 . PMID   2341158.
  6. ↑ Jaffe E, Bornstein P, Disteche CM (May 1990). "Mapping of the thrombospondin gene to human chromosome 15 and mouse chromosome 2 by in situ hybridization". Genomics. 7 (1): 123–6. doi:10.1016/0888-7543(90)90528-3. PMID   2335352.
  7. ↑ "Entrez Gene: THBS1 thrombospondin 1".
  8. ↑ Atanasova, VS; Russell, RJ; Webster, TG; Cao, Q; Agarwal, P; Lim, YZ; Krishnan, S; Fuentes, I; Guttmann-Gruber, C; McGrath, JA; Salas-Alanis, JC; Fertala, A; South, AP (July 2019). "Thrombospondin-1 Is a Major Activator of TGF-β Signaling in Recessive Dystrophic Epidermolysis Bullosa Fibroblasts". The Journal of Investigative Dermatology. 139 (7): 1497–1505.e5. doi: 10.1016/j.jid.2019.01.011 . PMID   30684555.
  9. ↑ Blake SM, Strasser V, Andrade N, Duit S, Hofbauer R, Schneider WJ, Nimpf J (Nov 2008). "Thrombospondin-1 binds to ApoER2 and VLDL receptor and functions in postnatal neuronal migration". The EMBO Journal. 27 (22): 3069–80. doi:10.1038/emboj.2008.223. PMC   2585172 . PMID   18946489.
  10. ↑ Lopez-Dee ZP, Chittur SV, Patel B, Stanton R, Wakeley M, Lippert B, Menaker A, Eiche B, Terry R, Gutierrez LS (2012). "Thrombospondin-1 type 1 repeats in a model of inflammatory bowel disease: transcript profile and therapeutic effects". PLOS ONE. 7 (4): e34590. Bibcode:2012PLoSO...734590L. doi: 10.1371/journal.pone.0034590 . PMC   3318003 . PMID   22509329.
  11. ↑ Forslöw A, Liu Z, Sundqvist KG (Jan 2007). "Receptor communication within the lymphocyte plasma membrane: a role for the thrombospondin family of matricellular proteins". Cellular and Molecular Life Sciences. 64 (1): 66–76. doi:10.1007/s00018-006-6255-8. PMID   17160353. S2CID   1394973.
  12. 1 2 Tolsma SS, Volpert OV, Good DJ, Frazier WA, Polverini PJ, Bouck N (Jul 1993). "Peptides derived from two separate domains of the matrix protein thrombospondin-1 have anti-angiogenic activity". The Journal of Cell Biology. 122 (2): 497–511. doi:10.1083/jcb.122.2.497. PMC   2119646 . PMID   7686555.
  13. 1 2 Iruela-Arispe ML, Lombardo M, Krutzsch HC, Lawler J, Roberts DD (Sep 1999). "Inhibition of angiogenesis by thrombospondin-1 is mediated by 2 independent regions within the type 1 repeats". Circulation. 100 (13): 1423–31. doi: 10.1161/01.cir.100.13.1423 . PMID   10500044.
  14. ↑ Guo N, Krutzsch HC, Inman JK, Roberts DD (May 1997). "Thrombospondin 1 and type I repeat peptides of thrombospondin 1 specifically induce apoptosis of endothelial cells". Cancer Research. 57 (9): 1735–42. PMID   9135017.
  15. ↑ Sid B, Sartelet H, Bellon G, El Btaouri H, Rath G, Delorme N, Haye B, Martiny L (Mar 2004). "Thrombospondin 1: a multifunctional protein implicated in the regulation of tumor growth". Critical Reviews in Oncology/Hematology. 49 (3): 245–58. doi:10.1016/j.critrevonc.2003.09.009. PMID   15036264.
  16. ↑ Guo N, Zabrenetzky VS, Chandrasekaran L, Sipes JM, Lawler J, Krutzsch HC, Roberts DD (Jul 1998). "Differential roles of protein kinase C and pertussis toxin-sensitive G-binding proteins in modulation of melanoma cell proliferation and motility by thrombospondin 1". Cancer Research. 58 (14): 3154–62. PMID   9679984.
  17. ↑ Prater CA, Plotkin J, Jaye D, Frazier WA (Mar 1991). "The properdin-like type I repeats of human thrombospondin contain a cell attachment site". The Journal of Cell Biology. 112 (5): 1031–40. doi:10.1083/jcb.112.5.1031. PMC   2288870 . PMID   1999454.
  18. ↑ Kosfeld MD, Frazier WA (Aug 1992). "Identification of active peptide sequences in the carboxyl-terminal cell binding domain of human thrombospondin-1". The Journal of Biological Chemistry. 267 (23): 16230–6. doi: 10.1016/S0021-9258(18)41990-4 . PMID   1644809.
  19. ↑ Isenberg JS, Ridnour LA, Dimitry J, Frazier WA, Wink DA, Roberts DD (Sep 2006). "CD47 is necessary for inhibition of nitric oxide-stimulated vascular cell responses by thrombospondin-1". The Journal of Biological Chemistry. 281 (36): 26069–80. doi: 10.1074/jbc.M605040200 . PMID   16835222.
  20. ↑ Chandrasekaran S, Guo NH, Rodrigues RG, Kaiser J, Roberts DD (Apr 1999). "Pro-adhesive and chemotactic activities of thrombospondin-1 for breast carcinoma cells are mediated by alpha3beta1 integrin and regulated by insulin-like growth factor-1 and CD98". The Journal of Biological Chemistry. 274 (16): 11408–16. doi: 10.1074/jbc.274.16.11408 . PMID   10196234.
  21. ↑ Taraboletti G, Roberts DD, Liotta LA (Nov 1987). "Thrombospondin-induced tumor cell migration: haptotaxis and chemotaxis are mediated by different molecular domains". The Journal of Cell Biology. 105 (5): 2409–15. doi:10.1083/jcb.105.5.2409. PMC   2114831 . PMID   3680388.
  22. ↑ Maxhimer JB, Soto-Pantoja DR, Ridnour LA, Shih HB, Degraff WG, Tsokos M, Wink DA, Isenberg JS, Roberts DD (Oct 2009). "Radioprotection in normal tissue and delayed tumor growth by blockade of CD47 signaling". Science Translational Medicine. 1 (3): 3ra7. doi:10.1126/scitranslmed.3000139. PMC   2811586 . PMID   20161613.*Lay summary in: "'Holy Grail' Of Cancer Therapy: Researchers Find Way To Protect Healthy Cells From Radiation Damage". sciencedaily.com. October 21, 2009.
  23. ↑ Wang S, Herndon ME, Ranganathan S, Godyna S, Lawler J, Argraves WS, Liau G (Mar 2004). "Internalization but not binding of thrombospondin-1 to low density lipoprotein receptor-related protein-1 requires heparan sulfate proteoglycans". Journal of Cellular Biochemistry. 91 (4): 766–76. doi:10.1002/jcb.10781. PMID   14991768. S2CID   12198474.
  24. ↑ Mikhailenko I, Krylov D, Argraves KM, Roberts DD, Liau G, Strickland DK (Mar 1997). "Cellular internalization and degradation of thrombospondin-1 is mediated by the amino-terminal heparin binding domain (HBD). High affinity interaction of dimeric HBD with the low density lipoprotein receptor-related protein". The Journal of Biological Chemistry. 272 (10): 6784–91. doi: 10.1074/jbc.272.10.6784 . PMID   9045712.
  25. ↑ Godyna S, Liau G, Popa I, Stefansson S, Argraves WS (Jun 1995). "Identification of the low density lipoprotein receptor-related protein (LRP) as an endocytic receptor for thrombospondin-1". The Journal of Cell Biology. 129 (5): 1403–10. doi:10.1083/jcb.129.5.1403. PMC   2120467 . PMID   7775583.
  26. ↑ Bein K, Simons M (Oct 2000). "Thrombospondin type 1 repeats interact with matrix metalloproteinase 2. Regulation of metalloproteinase activity". The Journal of Biological Chemistry. 275 (41): 32167–73. doi: 10.1074/jbc.M003834200 . PMID   10900205.
  27. ↑ Silverstein RL, Leung LL, Harpel PC, Nachman RL (Nov 1984). "Complex formation of platelet thrombospondin with plasminogen. Modulation of activation by tissue activator". The Journal of Clinical Investigation. 74 (5): 1625–33. doi:10.1172/JCI111578. PMC   425339 . PMID   6438154.
  28. ↑ DePoli P, Bacon-Baguley T, Kendra-Franczak S, Cederholm MT, Walz DA (Mar 1989). "Thrombospondin interaction with plasminogen. Evidence for binding to a specific region of the kringle structure of plasminogen". Blood. 73 (4): 976–82. doi: 10.1182/blood.V73.4.976.976 . PMID   2522013.
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