Thrombospondin 1
Encyclopedia
Thrombospondin 1, also known as THBS1, is a protein
that in humans in encoded by the THBS1 gene
.
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
, type V collagen and integrins alpha-V/beta-1. This protein has been shown to play roles in platelet aggregation, angiogenesis
, and tumorigenesis.
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
.
sequence.
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.
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. 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. 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. Interestingly, 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.
). This receptor is considered necessary for nitric oxide
-stimulated TSP1-mediated vascular cell responses and cGMP
signaling. 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.
) normal tissue becomes nearly immune to cancer
radiation therapy and assists in tumor
death.
with LRP1
, Plasmin
and MMP2
.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans in encoded by the THBS1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Thrombospondin 1 is a subunit of a disulfide-linked homotrimeric protein. This protein is an adhesive glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
that mediates cell-to-cell and cell-to-matrix interactions. This protein can bind to fibrinogen
Fibrinogen
Fibrinogen is a soluble plasma glycoprotein, synthesised by the liver, that is converted by thrombin into fibrin during blood coagulation. This is achieved through processes in the coagulation cascade that activate the zymogen prothrombin to the serine protease thrombin, which is responsible for...
, fibronectin
Fibronectin
Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. In addition to integrins, fibronectin also binds extracellular matrix components such as collagen, fibrin and heparan sulfate proteoglycans...
, laminin
Laminin
Laminins are major proteins in the basal lamina , a protein network foundation for most cells and organs...
, type V collagen and integrins alpha-V/beta-1. This protein has been shown to play roles in platelet aggregation, angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
, and tumorigenesis.
Function
The thrombospondin-1 protein is a member of the thrombospondinThrombospondin
Thrombospondins are secreted proteins with antiangiogenic abilities. TSP was discovered by Nancy L. Baenziger.-Types:The thrombospondins are a family of multifunctional proteins...
family. It is a multi-domain matrix glycoprotein that has been shown to be a natural inhibitor of neovascularization
Neovascularization
Neovascularization is the formation of functional microvascular networks with red blood cell perfusion. Neovascularization differs from angiogenesis in that angiogenesis is mainly characterized by the protrusion and outgrowth of capillary buds and sprouts from pre-existing blood vessels.In...
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
CD36
CD36 is an integral membrane protein found on the surface of many cell types in vertebrate animals and is also known as FAT, SCARB3, GP88, glycoprotein IV and glycoprotein IIIb . CD36 is a member of the class B scavenger receptor family of cell surface proteins...
, αv integrins, β1 integrins, syndecan
Syndecan
Syndecans are single transmembrane domain proteins that are thought to act as coreceptors, especially for G protein-coupled receptors. These core proteins carry three to five heparan sulfate and chondroitin sulfate chains, which allow for interaction with a large variety of ligands including...
, and integrin-associated protein (IAP or CD47
CD47
CD47 is a protein that in humans is encoded by the CD47 gene.- Function :CD47 is a membrane protein, which is involved in the increase in intracellular calcium concentration that occurs upon cell adhesion to extracellular matrix...
). It also interacts with numerous proteases involved in angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
, including plasminogen, urokinase
Urokinase
Urokinase , also called urokinase-type plasminogen activator , is a serine protease . Urokinase was originally isolated from human urine, but is present in several physiological locations, such as blood stream and the extracellular matrix...
, matrix metalloproteinase
Matrix metalloproteinase
Matrix metalloproteinases are zinc-dependent endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs belong to a larger family of proteases known as the metzincin superfamily....
, thrombin
Thrombin
Thrombin is a "trypsin-like" serine protease protein that in humans is encoded by the F2 gene. Prothrombin is proteolytically cleaved to form thrombin in the first step of the coagulation cascade, which ultimately results in the stemming of blood loss...
, cathepsin
Cathepsin
Cathepsins are proteases: proteins that break apart other proteins, found in many types of cells including those in all animals. There are approximately a dozen members of this family, which are distinguished by their structure, catalytic mechanism, and which proteins they cleave...
, and elastase
Elastase
In molecular biology, elastase is an enzyme from the class of proteases that break down proteins.- Forms and classification:There exist eight human genes for elastase:Bacterial forms: Organisms such as P...
.
Thrombospondin-1 binds to the reelin
Reelin
Reelin is a large secreted extracellular matrix protein that helps regulate processes of neuronal migration and positioning in the developing brain by controlling cell–cell interactions. Besides this important role in early development, reelin continues to work in the adult brain. It modulates the...
receptors, ApoER2 and VLDLR, thereby affecting neuronal migration in the rostral migratory stream
Rostral migratory stream
The rostral migratory stream is a pathway found in the brain of some animals along which neuronal precursors that originated in the subventricular zone of the brain migrate to reach the main olfactory bulb . This pathway has been studied in the rodent, rabbit, and both the squirrel and rheusus...
.
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 RGDRGD
RGD may refer to:*The Association of Registered Graphic Designers of Ontario *Rat genome database, a collection of genetic and genomic information about the rat*The Reacting Gas Dynamics Laboratory at the Massachusetts Institute of Technology...
sequence.
N-terminus
The N-terminal heparin-binding domain of TSP1, when isolated as a 25kDaKDA
KDA may refer to:* Karachi Development Authority* Kongsberg Defence & Aerospace* Kotelawala Defence Academy* Kramer Design Associates* Lithium diisopropylamide, KDA is the potassium analogue of lithium diisopropylamideOr kDa may refer to:...
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.
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 36-48 hour exposure period is necessary for inhibition of EC migration with the procollagen domain. Whereas the chorioallantroic 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.TSP1 contains three type I repeats, only the second two of which have been found to inhibit angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
. 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
Fibroblast growth factor
Fibroblast growth factors, or FGFs, are a family of growth factors involved in angiogenesis, wound healing, and embryonic development. The FGFs are heparin-binding proteins and interactions with cell-surface associated heparan sulfate proteoglycans have been shown to be essential for FGF signal...
(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. Type I repeats have also been shown to bind to heparin
Heparin
Heparin , also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule...
, fibronectin
Fibronectin
Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. In addition to integrins, fibronectin also binds extracellular matrix components such as collagen, fibrin and heparan sulfate proteoglycans...
, TGF-β
TGF beta
Transforming growth factor beta is a protein that controls proliferation, cellular differentiation, and other functions in most cells. It plays a role in immunity, cancer, heart disease, diabetes, Marfan syndrome, and Loeys–Dietz syndrome....
, and others, potentially antagonizing the effects of these molecules on ECs. 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. Interestingly, attachment of endothelial cells to fibronectin
Fibronectin
Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. In addition to integrins, fibronectin also binds extracellular matrix components such as collagen, fibrin and heparan sulfate proteoglycans...
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.
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 CD47CD47
CD47 is a protein that in humans is encoded by the CD47 gene.- Function :CD47 is a membrane protein, which is involved in the increase in intracellular calcium concentration that occurs upon cell adhesion to extracellular matrix...
). This receptor is considered necessary for nitric oxide
Endothelium-derived relaxing factor
Endothelium-derived relaxing factor is produced and released by the endothelium to promote smooth muscle relaxation. The best-characterized is nitric oxide . Some sources equate EDRF and nitric oxide....
-stimulated TSP1-mediated vascular cell responses and cGMP
Cyclic guanosine monophosphate
Cyclic guanosine monophosphate is a cyclic nucleotide derived from guanosine triphosphate . cGMP acts as a second messenger much like cyclic AMP...
signaling. 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.
Cancer treatment
By blocking TSP1 from binding to its cell surface receptor (CD47CD47
CD47 is a protein that in humans is encoded by the CD47 gene.- Function :CD47 is a membrane protein, which is involved in the increase in intracellular calcium concentration that occurs upon cell adhesion to extracellular matrix...
) normal tissue becomes nearly immune to cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
radiation therapy and assists in tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
death.
Interactions
Thrombospondin 1 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with LRP1
LRP1
Low density lipoprotein receptor-related protein 1 , also known as alpha-2-macroglobulin receptor , apolipoprotein E receptor or cluster of differentiation 91 , is a protein forming a receptor found in the plasma membrane of cells involved in receptor-mediated endocytosis...
, Plasmin
Plasmin
Plasmin is an important enzyme present in blood that degrades many blood plasma proteins, most notably, fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein is encoded by the PLG gene.- Function :...
and MMP2
MMP2
72 kDa type IV collagenase also known as matrix metalloproteinase-2 and gelatinase A is an enzyme that in humans is encoded by the MMP2 gene....
.