THBS1 (thrombospondin-1)

	Exon/intron organization of the THBS1 gene.
Description	The THBS1 gene is 16,393 bases in size and is composed of 22 exons. Exons 2-21 encode the 5729 b mRNA.
Transcription	Egr-1 and Sp1 sites function in the transcription of THBS1 stimulated in most cell types by culture in the presence of serum (Shingu and Bornstein, 1994). Transcription is regulated by JUN (c_jun orAP1) in cooperation with the repressor Yin Yang-1 (YY1) and by TP53. USF2 and the aryl hydrocarbon receptor ( AHR) mediate glucose-induced THBS1 transcription (Wang et al., 2004; Dabir et al., 2008). ID1 represses THBS1 transcription (Volpert et al., 2002). The ATF1 transcription factor also down-regulates transcription of THBS1 through an ATF/cAMP-responsive element-binding protein binding site (Ghoneim et al., 2007). In contrast, MYC increases turnover of thrombospondin-1 mRNA (Janz et al., 2000). Transcription of THBS1 in some human cancers is suppressed through hypermethylation (Li et al., 1999; Yang et al., 2003). THBS1 expression is also regulated post-transcriptionally by micro-RNAs including MIR17HG (miR-17-92), MIR18A, MIR19A, MIR27B, MIR98, miR-194, MIR221, and MIRLET7I (let-7i-5p) (van Almen et al., 2011; Sundaram et al.,, 2011; Italiano et al., 2012; Yang et al., 2019; Miao et al., 2018; Farberov and Meidan 2018; Chen et al., 2017).
Pseudogene	None identified.

	Domain organization and localization of selected ligand binding sites in THBS1. THBS1 is a homotrimer linked via disulfide bonds.
Description	The THBS1 precursor contains 1170 amino acids; 129,412 Da. The mature secreted protein comprises residues 19-1170 after removal of the N-terminal signal peptide and assembles into a disulfide linked homotrimer. Secreted THBS1 is a glycoprotein with a molecular mass of 150-180 kDa that contains approximately 12 Asn-linked mono-, bi- tri-, and tetraantennary complex oligosaccharides and variable numbers of C-mannosylated Trp residues in the type 1 repeats, and O-fucosylation (Furukawa et al., 1989; Hofsteenge et al., 2001).
Expression	THBS1 is expressed in many tissues during embryonic development but has limited expression in the healthy adult. THBS1 is the most abundant protein in alpha granules of platelets, but normal plasma levels are very low (typically 100-200 ng/ml). Expression in other cell types and tissues is induced by wounding, ischemia, ischemia reperfusion, during tissue remodeling, in atherosclerotic lesions, rheumatoid synovium, glomerulonephritis, in response to high glucose and fat, and in the stroma of many tumors. THBS1 expression increases with aging and in age-related conditions including type 2 diabetes and cardiovascular disease. THBS1 may also play a role in hematologic conditions such as sickle cell disease. Conversely, most but not all malignant cells in tumors exhibit loss of THBS1 expression during malignant progression (Isenberg et al., 2009). This loss is due to diminished positive regulation of the THBS1 gene by suppressor genes such as TP53 and NME1 and increased negative regulation by oncogenes including RAS and MYC. THBS1 expression is induced by TGF-beta, vitamin A, progesterone, and retinoids and suppressed by nickel, ID1, and HGF (hepatocyte growth factor).
Localisation	THBS1 is secreted by many cell types in response to injury or specific cytokines, THBS1 is and present transiently in extracellular matrix but is rapidly internalized for degradation by fibroblasts and endothelial cells. THBS1 is abundant in megakaryocytes and platelets and is constitutively expressed at the dermal-epidermal boundary in skin and in subendothelial matrix of some blood vessels. However, THBS1 levels are generally low or undetectable in most healthy adult tissues.
Function	THBS1 binds to extracellular matrix ligands including fibrinogen, fibronectin, some collagens, latent and active TGFB1 (transforming growth factor-beta-1), TNFAIP6 (TSG6), heparin, plasmin, CTSG (cathepsin G), ELANE (neutrophil elastase), some MMPs, tissue factor pathway inhibitor, and heparan sulfate proteoglycans (Resovi et al., 2014). THBS1 binds to cell surface receptors including CD36, CD47, some syndecans, LRP1 (LDL receptor-related protein-1) (via CALR (calreticulin)) and the integrins ITGA5/ ITGB3 (alpha-5/beta-3), ITGA3/ ITGB1 (alpha-3/beta-1), ITGA4/ITGB1 (alpha-4/beta-1), and ITGA6/ITGB1 (alpha-6/beta-1) (Calzada and Roberts, 2005). THBS1 is a slow tight inhibitor of several proteases including plasmin, cathepsin G, and neutrophil elastase. THBS1 directly binds and activates latent TGFB1 (Murphy-Ullrich and Suto, 2018). THBS1 in a context-dependent and cell-specific manner stimulates or inhibits cell adhesion, proliferation, motility, and survival. THBS1 is a potent inhibitor of angiogenesis, but N-terminal proteolytic and recombinant parts of THBS1 have clear pro-angiogenic activities mediated by beta-1 integrins. In the immune system, THBS1 is a potent inhibitor of T cell and dendritic cell activation and mediates clearance of apoptotic cells by phagocytes (Soto-Pantoja et al., 2015). In the CNS, THBS1 secreted by astrocytes promotes synaptogenesis (Risher and Eroglu, 2012). Based on studies of Thbs1 null mice, platelet THBS1 is not essential for platelet aggregation, but THBS1 null mice have impaired excisional but improved ischemic wound repair, increased retinal angiogenesis, and are hyper-responsive to several inflammatory stimuli (Soto-Pantoja et al., 2015). time stimulates pathologic production of reactive oxygen species (ROS) by targeting NOX1. Mitochondria from CD47 null mice produce less ROS. Inhibition of H2S signaling contributes to the inhibition of T cell activation by THBS1 mediated through the CD47 receptor (Miller et al., 2015). THBS1 through interacting with CD47, plays a broader role in primary non-cancer and cancer tissue survival of genotoxic damage caused by ionizing radiation and chemotherapy (Soto-Pantoja et al., 2015; Feliz-Mosquea et al., 2018). Animals lacking either THBS1 or CD47 tolerated high-dose regional radiation with minimal soft-tissue injury or loss of bone marrow (Isenberg et al., 2008). Suppressing THBS1-CD47 signaling renders non-cancer cells and tissues resistant to radiation- and chemotherapy-mediated injury by promoting protective autophagy and enhancing anabolic metabolic repair pathways (Soto-Pantoja et al., 2012; Miller et al., 2015). Blocking the THBS1-CD47 axis also enhanced survival to lethal whole-body radiation (Soto-Pantoja et al., 2013). Conversely, interruption of THBS1-CD47 signaling increases radiation- and chemotherapy-mediated killing of cancers (Maxhimer et al., 2009; Feliz-Mosquea et al., 2018). This latter effect is mediated through activation of T and NK cell killing of tumors (Soto-Pantoja et al., 2014; Nath et al., 2019). THBS1 is also a proximate inhibitor of stem cell self-renewal (Kaur et al., 2013). Acting via its cell surface receptor CD47, THBS1 limits the expression of important self-renewal transcription factors including POU5F1 (Oct3/4), SOX2, KLF4, and MYC in nonmalignant cells (Kaur et al., 2013). However, the ability of THBS1 to limit stem cell self-renewal is lost in cancer cells where MYC is amplified or dysregulated, and loss of CD47 expression or function consequently can suppress cancer stem cells (Kaur et al., 2013; Lee et al., 2014; Kaur and Roberts, 2016).
Homology	THBS1 is a member of the thrombospondin family that also contains THBS2, THBS3, THBS4, and COMP (cartilage oligomeric matrix protein) which arose from gene duplication of a single primordial thrombospondin in insects (Adams and Lawler, 2012). The central type 1 repeats are also known as thrombospondin-repeats (TSRs) and are shared with the larger thrombospondin/properdin repeat superfamily (Adams and Tucker, 2000; Apte 2009; deLau et al., 2012). Orthologs of THBS1 are widely conserved in mammals and have also been identified in birds (Gallus gallus NP_001186382.1), amphibians (Xenopus tropicalis XP_002937245.1) and fish (Dania rerio XP_005160819.1).

	Identified mutations in thrombospondin-1 in human cancers include 187 missense (green), 41 truncating nonsense (black), 3 inframe (brown), and 2 other (purple). Data is from The Cancer Genome Atlas (TCGA) using cBioPortal tools to analyze data from 10,953 patients.
Epigenetics	Most down-regulation of THBS1 in cancers is epigenetic, resulting from promoter hypermethylation (Yang et al., 2003), altered expression of regulatory noncoding RNAs (van Almen et al., 2011; Sundaram et al., 2011; Italiano et al., 2012; Yang et al., 2019; Miao et al., 2018; Farberov and Meidan 2018; Chen et al., 2017), or altered levels of oncogenic transcription factor. Epigenetic silencing of THBS1 is associated with a poor prognosis in several cancers (Guerrero et al., 2008; Isenberg et al., 2009).
Germinal	Deep exon sequencing of THBS1 from 60,706 humans identified 4 putative loss of function mutations, which was significantly below the 37.6 expected loss of function mutations for a non-essential gene of this size (Lek et al., 2016). The resulting calculated probability that THBS1 is loss intolerant (pLI =1.0) exceeds the pLI > 0.9 cut-off, which predicts a strong selective pressure against inactivation of this gene. The basis for this apparent selective pressure against loss of THBS1 in humans remains unclear. Thbs1-/- mice are viable and fertile but exhibit defects in inflammatory responses and wound repair that may compromise their viability outside a protected laboratory environment (Lawler et al., 1998; Crawford et al., 1998; Lamy et al., 2007; Qu et al., 2018). Coding polymorphisms in THBS1 associated with altered disease risk in humans include a2210g (Asn700Ser), which is associated with premature familial myocardial infarction and small for gestational age infants. This mutation alters calcium binding to THBS1 and protein stability (Carlson et al., 2008; Hannah et al., 2004). The coding polymorphism g1678a (Thr523Ser) was identified as a genetic risk factor of cerebral thrombosis in a Chinese population (Liu et al., 2004). Several noncoding SNPs in THBS1 have been associated with cancer risk as detailed below.
Somatic	The frequency of somatic THBS1 mutation in human cancers is low. Somatic mutations have been identified at a frequency of 1.9% in The Cancer Genome Atlas (cbioprortal.org). A total of 233 mutations have been identified, most of which are missense or nonsense. However, the random distribution of these mutations indicates a lack of cancer-specific mutation hotspots. THBS1 is most frequently mutated in cutaneous melanomas (12%) followed by uterine cancers (7%), but rare or absent in other cancer types. The higher mutation rate of THBS1 in melanomas may simply reflect the high overall mutation burden of this malignancy.

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