Thrombospondins (TSPs) are a family of secreted

glycoprotein Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...

s with

antiangiogenic An angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels (angiogenesis). Some angiogenesis inhibitors are endogenous and a normal part of the body's control and others are obtained exogenously through pharmaceutical d ...

functions. Due to their dynamic role within the

extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix (ICM), is a network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and bio ...

they are considered

matricellular proteins A matricellular protein is a dynamically expressed non-structural protein that is present in the extracellular matrix (ECM). Rather than serving as stable structural elements in the ECM, these proteins are rapidly turned over and have regulatory rol ...

. The first member of the family,

thrombospondin 1 Thrombospondin 1, abbreviated as THBS1, is a protein that in humans is 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 ...

(THBS1), was discovered in 1971 by Nancy L. Baenziger.

Types

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

astrocyte Astrocytes (from Ancient Greek , , "star" and , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of en ...

s during brain development, which promotes the development of new

synapse In the nervous system, a synapse is a structure that allows a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or a target effector cell. Synapses can be classified as either chemical or electrical, depending o ...

Thrombospondin 1

Thrombospondin 1 (TSP-1) is encoded by

THBS1 Thrombospondin 1, abbreviated as THBS1, is a protein that in humans is 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 ...

. It was first isolated from

platelets Platelets or thrombocytes () are a part of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a blood clot. Platelets have no cell nucleus; they are fragments of cyto ...

that had been stimulated with thrombin, and so was designated 'thrombin-sensitive protein'. Since its first recognition, functions for TSP-1 have been found in multiple biological processes including angiogenesis, apoptosis, activation of

TGF-beta Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other ...

and Immune regulation. As such, TSP-1 is designated a multifunctional protein. TSP-1 has multiple receptors, among which

CD36 CD36 (cluster of differentiation 36), also known as platelet glycoprotein 4, fatty acid translocase (FAT), scavenger receptor class B member 3 (SCARB3), and glycoproteins 88 (GP88), IIIb (GPIIIB), or IV (GPIV) is a protein that in humans is enco ...

CD47 CD47 (Cluster of Differentiation 47) 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 al ...

and

integrins Integrins are transmembrane receptors that help 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, ...

are of particular note. TSP-1 is

, 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 Thrombospondin 1, abbreviated as THBS1, is a protein that in humans is 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 ...

bind to

, leading to the expression of

FAS ligand Fas ligand (FasL, also known as CD95L or Apo-1L) is a type-II transmembrane protein in the tumor necrosis factor (TNF) superfamily. It binds to the Fas receptor (CD95) to induce apoptosis, and also activates non-apoptotic pathways such as NF-κB ...

(FasL), which activates its specific, ubiquitous receptor, Fas. This leads to the activation of

caspase Caspases (cysteine-aspartic proteases, cysteine aspartases or cysteine-dependent aspartate-directed proteases) are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cyste ...

s and

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

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

is extremely large (~ monomer), not very abundant and exerts multiple actions, its clinical usefulness is questionable. However, small-molecules based on a CD36-binding peptide sequence from

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. In 2005, ABT-510 was evaluated in phase II clinical trials for the treatment of several types of cancer.

Human proteins containing this domain

ADAMTS1 A disintegrin and metalloproteinase with thrombospondin motifs 1 is an enzyme that in humans is encoded by the ''ADAMTS1'' gene. Structure This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin moti ...

;

ADAMTS10 A disintegrin and metalloproteinase with thrombospondin motifs 10 is an enzyme that in humans is encoded by the ''ADAMTS10'' gene. This gene belongs to the ADAMTS (a disintegrin and metalloproteinase domain with thrombospondin type-1 motifs) fami ...

; ADAMTS12;

ADAMTS13 ADAMTS13 (''a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13'')—also known as ''von Willebrand factor-cleaving protease'' (VWFCP)—is a zinc-containing metalloprotease enzyme that cleaves von Willebrand factor ...

;

ADAMTS14 ADAMTS14 encodes a member of the ADAMTS protein family. Family members share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. Individual ...

; ADAMTS15; ADAMTS16;

ADAMTS17 ADAM metallopeptidase with thrombospondin type 1 motif, 17 is a protein that in humans is encoded by the ADAMTS17 gene. Function This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein ...

; ADAMTS18; ADAMTS19;

ADAMTS2 A disintegrin and metalloproteinase with thrombospondin motifs 2 (ADAM-TS2) also known as procollagen I N-proteinase (PC I-NP) is an enzyme that in humans is encoded by the ''ADAMTS2'' gene. Gene The ADAMTS2 gene is located on the long (q) ar ...

; ADAMTS20;

ADAMTS3 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. Structure This gene encodes a member ...

;

ADAMTS4 A disintegrin and metalloproteinase with thrombospondin motifs 4 is an enzyme that in humans is encoded by the ''ADAMTS4'' gene. This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein fam ...

;

ADAMTS5 A disintegrin and metalloproteinase with thrombospondin motifs 5 also known as ADAMTS5 is an enzyme that in humans is encoded by the ''ADAMTS5'' gene. Function ADAMTS5 is a member of the ADAMTS (a disintegrin and metalloproteinase with thrombo ...

; ADAMTS6;

ADAMTS7 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 degra ...

;

ADAMTS8 A disintegrin and metalloproteinase with thrombospondin motifs 8 is an enzyme that in humans is encoded by the ''ADAMTS8'' gene. Function This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) ...

;

ADAMTS9 A disintegrin and metalloproteinase with thrombospondin motifs 9 is an enzyme that in humans is encoded by the ''ADAMTS9'' gene. This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein fam ...

; ADAMTSL1; ADAMTSL2; ADAMTSL3; ADAMTSL4; ADAMTSL5;

BAI1 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. Function Angiogenesis is controlled by a local balance between stimulators and inhi ...

;

BAI2 Brain-specific angiogenesis inhibitor 2 is a protein that in humans is encoded by the ''BAI2'' gene. It is a member of the adhesion-GPCR family of receptors. BAI1 Brain-specific angiogenesis inhibitor 1 is a protein that in humans is encoded ...

;

BAI3 Brain-specific angiogenesis inhibitor 3 is a protein that in humans is encoded by the ''BAI3'' gene. BAI1, a p53-target gene, encodes brain-specific angiogenesis inhibitor, a seven-span transmembrane protein and is thought to be a member of the ...

; C6; C7; C8A; C8B; C9; C9orf8; C9orf94; CFP;

CILP Cartilage intermediate layer protein 1 is a protein that in humans is encoded by the ''CILP'' gene. Major alterations in the composition of the cartilage extracellular matrix occur in joint disease, such as osteoarthrosis. The synthesis of cart ...

; CILP2;

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 (see also CCN intercellular signaling protein). CTGF has important roles in man ...

;

CYR61 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. CYR61 is a secreted, extracellular matrix (ECM)-associated signaling protein of the CCN family ...

;

HMCN1 Hemicentin-1 is a protein that in humans is encoded by the ''HMCN1'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed ...

;

LIBC The C standard library, sometimes referred to as libc, is the standard library for the C programming language, as specified in the ISO C standard.ISO/ IEC (2018). '' ISO/IEC 9899:2018(E): Programming Languages - C §7'' Starting from the origina ...

; NOV; PAPLN;

RSPO1 R-spondin-1 is a secreted protein that in humans is encoded by the ''RSPO1'' gene, found on chromosome 1. In humans, it interacts with WNT4 in the process of female sex development. Loss of function can cause female to male sex reversal. Furthe ...

; RSPO3;

SEMA5A Semaphorin-5A is a protein that in humans is encoded by the ''SEMA5A'' gene. Members of the semaphorin protein family, such as SEMA5A, are involved in axonal guidance during neural development. Semaphorin 5A also plays a role in autism, reduci ...

; SEMA5B; SPON1; SPON2;

SSPO SCO-spondin is a protein that in humans is encoded by the ''SSPO'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed t ...

;

; THBS2; THSD1; THSD3; THSD7A; THSD7B; UNC5A; UNC5B; UNC5C; UNC5D; WISP1;

WISP2 WNT1-inducible-signaling pathway protein 2, or WISP-2 (also named CCN5) is a matricellular protein that in humans is encoded by the ''WISP2'' gene. Function The CCN family of proteins regulates diverse cellular functions, including cell adhes ...

; WISP3;

References

External links

* * , , , , {{Gene, COMP (also known as "THBS5") Protein domains