Thrombospondin 1

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.{{cite journal | vauthors = Blake SM, Strasser V, Andrade N, Duit S, Hofbauer R, Schneider WJ, Nimpf J | title = Thrombospondin-1 binds to ApoER2 and VLDL receptor and functions in postnatal neuronal migration | journal = The EMBO Journal | volume = 27 | issue = 22 | pages = 3069–80 | date = Nov 2008 | pmid = 18946489 | pmc = 2585172 | doi = 10.1038/emboj.2008.223 }}

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.{{cite journal | vauthors = Lopez-Dee ZP, Chittur SV, Patel B, Stanton R, Wakeley M, Lippert B, Menaker A, Eiche B, Terry R, Gutierrez LS | title = Thrombospondin-1 type 1 repeats in a model of inflammatory bowel disease: transcript profile and therapeutic effects | journal = PLOS ONE | volume = 7 | issue = 4 | pages = e34590 | year = 2012 | pmid = 22509329 | pmc = 3318003 | doi = 10.1371/journal.pone.0034590 | bibcode = 2012PLoSO...734590L | doi-access = free }}

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.{{cite journal | vauthors = Forslöw A, Liu Z, Sundqvist KG | title = Receptor communication within the lymphocyte plasma membrane: a role for the thrombospondin family of matricellular proteins | journal = Cellular and Molecular Life Sciences | volume = 64 | issue = 1 | pages = 66–76 | date = Jan 2007 | pmid = 17160353 | doi = 10.1007/s00018-006-6255-8 | s2cid = 1394973 | pmc = 11136314 }}

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.{{cite journal | vauthors = Tolsma SS, Volpert OV, Good DJ, Frazier WA, Polverini PJ, Bouck N | title = Peptides derived from two separate domains of the matrix protein thrombospondin-1 have anti-angiogenic activity | journal = The Journal of Cell Biology | volume = 122 | issue = 2 | pages = 497–511 | date = Jul 1993 | pmid = 7686555 | pmc = 2119646 | doi = 10.1083/jcb.122.2.497 }}

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. 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.{{cite journal | vauthors = Iruela-Arispe ML, Lombardo M, Krutzsch HC, Lawler J, Roberts DD | title = Inhibition of angiogenesis by thrombospondin-1 is mediated by 2 independent regions within the type 1 repeats | journal = Circulation | volume = 100 | issue = 13 | pages = 1423–31 | date = Sep 1999 | pmid = 10500044 | doi = 10.1161/01.cir.100.13.1423 | doi-access = free }}

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. It has been suggested that activating the CD36 receptor causes an increase in ECs sensitivity to apoptotic signals.{{cite journal | vauthors = Guo N, Krutzsch HC, Inman JK, Roberts DD | title = Thrombospondin 1 and type I repeat peptides of thrombospondin 1 specifically induce apoptosis of endothelial cells | journal = Cancer Research | volume = 57 | issue = 9 | pages = 1735–42 | date = May 1997 | pmid = 9135017 | url = http://cancerres.aacrjournals.org/cgi/content/abstract/57/9/1735 }}{{cite journal | vauthors = Sid B, Sartelet H, Bellon G, El Btaouri H, Rath G, Delorme N, Haye B, Martiny L | title = Thrombospondin 1: a multifunctional protein implicated in the regulation of tumor growth | journal = Critical Reviews in Oncology/Hematology | volume = 49 | issue = 3 | pages = 245–58 | date = Mar 2004 | pmid = 15036264 | doi = 10.1016/j.critrevonc.2003.09.009 }} 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.{{cite journal | vauthors = Guo N, Zabrenetzky VS, Chandrasekaran L, Sipes JM, Lawler J, Krutzsch HC, Roberts DD | title = Differential roles of protein kinase C and pertussis toxin-sensitive G-binding proteins in modulation of melanoma cell proliferation and motility by thrombospondin 1 | journal = Cancer Research | volume = 58 | issue = 14 | pages = 3154–62 | date = Jul 1998 | pmid = 9679984 | url = http://cancerres.aacrjournals.org/cgi/content/abstract/58/14/3154 }} 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.{{cite journal | vauthors = Prater CA, Plotkin J, Jaye D, Frazier WA | title = The properdin-like type I repeats of human thrombospondin contain a cell attachment site | journal = The Journal of Cell Biology | volume = 112 | issue = 5 | pages = 1031–40 | date = Mar 1991 | pmid = 1999454 | pmc = 2288870 | doi = 10.1083/jcb.112.5.1031 }}

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).{{cite journal | vauthors = Kosfeld MD, Frazier WA | title = Identification of active peptide sequences in the carboxyl-terminal cell binding domain of human thrombospondin-1 | journal = The Journal of Biological Chemistry | volume = 267 | issue = 23 | pages = 16230–6 | date = Aug 1992 | doi = 10.1016/S0021-9258(18)41990-4 | pmid = 1644809 | doi-access = free }} This receptor is considered necessary for nitric oxide-stimulated TSP1-mediated vascular cell responses and cGMP signaling.{{cite journal | vauthors = Isenberg JS, Ridnour LA, Dimitry J, Frazier WA, Wink DA, Roberts DD | title = CD47 is necessary for inhibition of nitric oxide-stimulated vascular cell responses by thrombospondin-1 | journal = The Journal of Biological Chemistry | volume = 281 | issue = 36 | pages = 26069–80 | date = Sep 2006 | pmid = 16835222 | doi = 10.1074/jbc.M605040200 | doi-access = free }} 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.{{cite journal | vauthors = Chandrasekaran S, Guo NH, Rodrigues RG, Kaiser J, Roberts DD | title = 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 | journal = The Journal of Biological Chemistry | volume = 274 | issue = 16 | pages = 11408–16 | date = Apr 1999 | pmid = 10196234 | doi = 10.1074/jbc.274.16.11408 | doi-access = free }}{{cite journal | vauthors = Taraboletti G, Roberts DD, Liotta LA | title = Thrombospondin-induced tumor cell migration: haptotaxis and chemotaxis are mediated by different molecular domains | journal = The Journal of Cell Biology | volume = 105 | issue = 5 | pages = 2409–15 | date = Nov 1987 | pmid = 3680388 | pmc = 2114831 | doi = 10.1083/jcb.105.5.2409 }}

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One study conducted in mice 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.{{cite journal | vauthors = Maxhimer JB, Soto-Pantoja DR, Ridnour LA, Shih HB, Degraff WG, Tsokos M, Wink DA, Isenberg JS, Roberts DD | title = Radioprotection in normal tissue and delayed tumor growth by blockade of CD47 signaling | journal = Science Translational Medicine | volume = 1 | issue = 3 | pages = 3ra7 | date = Oct 2009 | pmid = 20161613 | pmc = 2811586 | doi = 10.1126/scitranslmed.3000139 }}*{{lay source |template = cite web|url = https://www.sciencedaily.com/releases/2009/10/091021144246.htm |title = 'Holy Grail' Of Cancer Therapy: Researchers Find Way To Protect Healthy Cells From Radiation Damage|date = October 21, 2009 |website = sciencedaily.com }}

However, the majority of studies of cancer using mouse models, demonstrate that TSP1 inhibits tumor progression by inhibiting angiogenesis.{{cite journal |last1=Weinstat-Saslow |first1=D |title=Transfection of thrombospondin 1 complementary DNA into a human breast carcinoma cell line reduces primary tumor growth, metastatic potential, and angiogenesis |journal=Cancer Research |date=December 15, 1994 |volume=54 |issue=24 |pages=6504-6511 |pmid=7527299}}{{cite journal |last1=Hsu |first1=S |title=Inhibition of angiogenesis in human glioblastomas by chromosome 10 induction of thrombospondin-1 |journal=Cancer Research |date=December 15, 1996 |volume=56 |issue=24 |pages=5684-5691 |pmid=8971176}} Moreover, stimulating TSP1 via over-expressing prosaposin or treating with a small prosaposin-derived peptide potently inhibits and even induces regression of existing tumors in mice.{{cite journal |last1=Kang |first1=Soo-Young |title=Prosaposin inhibits tumor metastasis via paracrine and endocrine stimulation of stromal p53 and Tsp-1 |journal=PNAS |date=July 21, 2009 |volume=106 |issue=29 |pages=12115-12120 |doi=10.1073/pnas.0903120106 |pmid=19581582 |url=https://www.pnas.org/doi/10.1073/pnas.0903120106?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed|pmc=2715504 }}{{cite journal |last1=Catena |first1=Raul |title=Bone marrow-derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1 |journal=Cancer Discovery |date=May 2013 |volume=3 |issue=5 |pages=578-589 |doi=10.1158/2159-8290.CD-12-0476 |pmid=23633432 |url=https://aacrjournals.org/cancerdiscovery/article-lookup/doi/10.1158/2159-8290.CD-12-0476|pmc=3672408 }}{{cite journal |last1=Wang |first1=Suming |title=Development of a prosaposin-derived therapeutic cyclic peptide that targets ovarian cancer via the tumor microenvironment |journal=Science Translational Medicine |date=March 9, 2016 |volume=8 |issue=329 |page=329 |doi=10.1126/scitranslmed.aad5653 |pmid=26962158 |url=https://www.science.org/doi/10.1126/scitranslmed.aad5653?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed|pmc=6261358 }}

Thrombospondin 1 has been shown to interact with:

• LRP1,{{cite journal | vauthors = Wang S, Herndon ME, Ranganathan S, Godyna S, Lawler J, Argraves WS, Liau G | title = Internalization but not binding of thrombospondin-1 to low density lipoprotein receptor-related protein-1 requires heparan sulfate proteoglycans | journal = Journal of Cellular Biochemistry | volume = 91 | issue = 4 | pages = 766–76 | date = Mar 2004 | pmid = 14991768 | doi = 10.1002/jcb.10781 | s2cid = 12198474 }}{{cite journal | vauthors = Mikhailenko I, Krylov D, Argraves KM, Roberts DD, Liau G, Strickland DK | title = 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 | journal = The Journal of Biological Chemistry | volume = 272 | issue = 10 | pages = 6784–91 | date = Mar 1997 | pmid = 9045712 | doi = 10.1074/jbc.272.10.6784 | doi-access = free }}{{cite journal | vauthors = Godyna S, Liau G, Popa I, Stefansson S, Argraves WS | title = Identification of the low density lipoprotein receptor-related protein (LRP) as an endocytic receptor for thrombospondin-1 | journal = The Journal of Cell Biology | volume = 129 | issue = 5 | pages = 1403–10 | date = Jun 1995 | pmid = 7775583 | pmc = 2120467 | doi = 10.1083/jcb.129.5.1403 }}
• MMP-2,{{cite journal | vauthors = Bein K, Simons M | title = Thrombospondin type 1 repeats interact with matrix metalloproteinase 2. Regulation of metalloproteinase activity | journal = The Journal of Biological Chemistry | volume = 275 | issue = 41 | pages = 32167–73 | date = Oct 2000 | pmid = 10900205 | doi = 10.1074/jbc.M003834200 | doi-access = free }} and
• Plasmin.{{cite journal | vauthors = Silverstein RL, Leung LL, Harpel PC, Nachman RL | title = Complex formation of platelet thrombospondin with plasminogen. Modulation of activation by tissue activator | journal = The Journal of Clinical Investigation | volume = 74 | issue = 5 | pages = 1625–33 | date = Nov 1984 | pmid = 6438154 | pmc = 425339 | doi = 10.1172/JCI111578 }}{{cite journal | vauthors = DePoli P, Bacon-Baguley T, Kendra-Franczak S, Cederholm MT, Walz DA | title = Thrombospondin interaction with plasminogen. Evidence for binding to a specific region of the kringle structure of plasminogen | journal = Blood | volume = 73 | issue = 4 | pages = 976–82 | date = Mar 1989 | pmid = 2522013 | doi = 10.1182/blood.V73.4.976.976| doi-access = free }}

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Category:Thrombospondins