# THBS1

## Overview
THBS1 is a gene that encodes the protein thrombospondin 1, a multifunctional glycoprotein involved in various physiological processes. Thrombospondin 1 is categorized as an extracellular matrix protein and plays a crucial role in cell-to-cell and cell-to-matrix interactions. It is involved in the regulation of angiogenesis, immune response, and tissue repair, among other functions. The protein's structure includes multiple domains that facilitate its interaction with a variety of receptors and ligands, such as CD36, CD47, and integrins, which are essential for its diverse biological activities (Roberts2011THBS1; Lawler1998Thrombospondin1). Thrombospondin 1 is also implicated in pathological conditions, including cancer, cardiovascular diseases, and neurodevelopmental disorders, highlighting its significance in both health and disease (Lu2014Common; Daubon2019Deciphering).

## Structure
Thrombospondin 1 (THBS1) is a glycoprotein with a complex molecular structure that includes several distinct domains. The primary structure of THBS1 features multiple domains such as the N-terminal domain, type 1 repeats, type 2 EGF-like repeats, and a C-terminal domain. These domains contribute to its functional versatility in cell-to-cell and cell-to-matrix interactions. The secondary structure of THBS1 is characterized by the presence of beta-sheets and alpha-helices, which are common structural motifs in proteins. 

The tertiary structure of THBS1 involves the folding of these domains into a specific three-dimensional shape, which is crucial for its interaction with other proteins and ligands. The quaternary structure of THBS1 is a homotrimer, meaning it forms a complex of three identical subunits. This trimeric form is essential for its biological activity and stability.

Post-translational modifications of THBS1 include glycosylation and phosphorylation, which can influence its function and interactions. These modifications are important for the regulation of THBS1's activity in various physiological processes. The protein's ability to bind to a variety of extracellular matrix components and cell surface receptors is partly due to these structural features and modifications (Roberts2011THBS1).

## Function
Thrombospondin-1 (THBS1) is a multifunctional glycoprotein that plays a critical role in various molecular processes within healthy human cells. It is primarily involved in the regulation of angiogenesis, vascular homeostasis, and connective tissue organization. THBS1 interacts with multiple receptors and extracellular ligands, including CD36 and CD47, to mediate its functions (Kaur2023Why). In the context of hemostasis, THBS1 is a major component of platelet α-granules and is rapidly released at sites of injury, promoting platelet activation and vasoconstriction to limit bleeding. It achieves this by inhibiting nitric oxide biosynthesis and cGMP signaling, which are negative regulators of platelet activation and vascular relaxation (Kaur2023Why).

THBS1 also plays a role in immune regulation, influencing the body's response to infectious diseases by activating latent TGFβ1 to prevent chronic inflammation (Kaur2023Why). It is involved in cellular attachment, proliferation, migration, and differentiation, interacting with various cell surface proteins and extracellular matrix components (Lawler1998Thrombospondin1). THBS1's interactions with growth factors and receptors, such as TGFβ1 and VEGF, highlight its role in modulating cell proliferation and apoptosis (Adams2011The). These functions are essential for maintaining cardiovascular health and responding to environmental stresses (Kaur2023Why).

## Clinical Significance
Mutations and alterations in the THBS1 gene have been implicated in several diseases. In glioblastoma (GBM), THBS1 is involved in tumor expansion, invasion, and angiogenesis. Its expression is regulated by TGFβ1 signaling, and increased levels are associated with enhanced tumor invasion, particularly in hypoxic conditions. Inhibition of THBS1, especially in combination with anti-angiogenic treatments, has shown potential in reducing tumor mass and improving survival in mouse models (Daubon2019Deciphering).

In autism, both common and rare variants of the THBS1 gene have been associated with increased risk. These variants may affect synapse formation, highlighting the role of THBS1 in neurodevelopmental disorders (Lu2014Common).

THBS1 mutations have also been linked to familial pulmonary arterial hypertension (FPAH). Specific mutations, such as Asp362Asn, result in a loss of function, reducing the activation of latent TGF-β1 and affecting endothelial cell proliferation, which contributes to the pathogenesis of FPAH (Maloney2012Lossoffunction).

In congenital glaucoma, THBS1 missense alleles lead to extracellular matrix protein aggregation and trabecular meshwork dysfunction, contributing to elevated intraocular pressure and disease progression (Fu2022Thrombospondin).

## Interactions
Thrombospondin 1 (THBS1) is a multifunctional glycoprotein that interacts with a variety of proteins, influencing numerous biological processes. THBS1 interacts with matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9), inhibiting their activation and thus playing a regulatory role in angiogenesis (Bein2000Thrombospondin). It also binds to vascular endothelial growth factor (VEGF), mediating its uptake and clearance, and inhibiting VEGF signal transduction by decreasing VEGFR2 phosphorylation (Lawler2012Molecular).

THBS1 interacts with cell surface receptors such as CD36 and CD47. The interaction with CD36 is involved in inducing apoptosis in endothelial cells and inhibiting angiogenesis (Lawler2012Molecular). The THBS1/CD47 interaction is significant in vascularization and tumor progression, particularly in glioblastoma development (Daubon2019Deciphering). THBS1 also binds to integrins, including αvβ1, which is crucial for matrix mechanotransduction and vascular remodeling (Yamashiro2020Matrix).

In the context of cancer, THBS1 forms a complex with integrin subunit alpha V (ITGAV) and TGFβ type I receptor (TβRI), facilitating cell migration and invasion in prostate cancer cells (Mu2024The). This interaction is TGFβ-dependent and is crucial for the migration and metastasis of cancer cells (Mu2024The).


## References


[1. (Maloney2012Lossoffunction) James P. Maloney, Robert S. Stearman, Todd M. Bull, David W. Calabrese, Megan L. Tripp-Addison, Marilee J. Wick, Ulrich Broeckel, Ivan M. Robbins, Lisa A. Wheeler, Joy D. Cogan, and James E. Loyd. Loss-of-function thrombospondin-1 mutations in familial pulmonary hypertension. American Journal of Physiology-Lung Cellular and Molecular Physiology, 302(6):L541–L554, March 2012. URL: http://dx.doi.org/10.1152/ajplung.00282.2011, doi:10.1152/ajplung.00282.2011. This article has 37 citations.](https://doi.org/10.1152/ajplung.00282.2011)

[2. (Adams2011The) J. C. Adams and J. Lawler. The thrombospondins. Cold Spring Harbor Perspectives in Biology, 3(10):a009712–a009712, August 2011. URL: http://dx.doi.org/10.1101/cshperspect.a009712, doi:10.1101/cshperspect.a009712. This article has 349 citations and is from a peer-reviewed journal.](https://doi.org/10.1101/cshperspect.a009712)

[3. (Mu2024The) Yabing Mu, Anders Wallenius, Guangxiang Zang, Shaochun Zhu, Stina Rudolfsson, Karthik Aripaka, Anders Bergh, André Mateus, and Maréne Landström. The tβri promotes migration and metastasis through thrombospondin 1 and itgav in prostate cancer cells. Oncogene, September 2024. URL: http://dx.doi.org/10.1038/s41388-024-03165-3, doi:10.1038/s41388-024-03165-3. This article has 0 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1038/s41388-024-03165-3)

[4. (Yamashiro2020Matrix) Yoshito Yamashiro, Bui Quoc Thang, Karina Ramirez, Seung Jae Shin, Tomohiro Kohata, Shigeaki Ohata, Tram Anh Vu Nguyen, Sumio Ohtsuki, Kazuaki Nagayama, and Hiromi Yanagisawa. Matrix mechanotransduction mediated by thrombospondin-1/integrin/yap in the vascular remodeling. Proceedings of the National Academy of Sciences, 117(18):9896–9905, April 2020. URL: http://dx.doi.org/10.1073/pnas.1919702117, doi:10.1073/pnas.1919702117. This article has 103 citations.](https://doi.org/10.1073/pnas.1919702117)

[5. (Roberts2011THBS1) DD Roberts. Thbs1 (thrombospondin-1). Atlas of Genetics and Cytogenetics in Oncology and Haematology, February 2011. URL: http://dx.doi.org/10.4267/2042/38213, doi:10.4267/2042/38213. This article has 0 citations and is from a peer-reviewed journal.](https://doi.org/10.4267/2042/38213)

[6. (Fu2022Thrombospondin) Haojie Fu, Owen M. Siggs, Lachlan S.W. Knight, Sandra E. Staffieri, Jonathan B. Ruddle, Amy E. Birsner, Edward Ryan Collantes, Jamie E. Craig, Janey L. Wiggs, and Robert J. D’Amato. Thrombospondin 1 missense alleles induce extracellular matrix protein aggregation and tm dysfunction in congenital glaucoma. Journal of Clinical Investigation, December 2022. URL: http://dx.doi.org/10.1172/jci156967, doi:10.1172/jci156967. This article has 11 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1172/jci156967)

[7. (Daubon2019Deciphering) Thomas Daubon, Céline Léon, Kim Clarke, Laetitia Andrique, Laura Salabert, Elodie Darbo, Raphael Pineau, Sylvaine Guérit, Marlène Maitre, Stéphane Dedieu, Albin Jeanne, Sabine Bailly, Jean-Jacques Feige, Hrvoje Miletic, Marco Rossi, Lorenzo Bello, Francesco Falciani, Rolf Bjerkvig, and Andréas Bikfalvi. Deciphering the complex role of thrombospondin-1 in glioblastoma development. Nature Communications, March 2019. URL: http://dx.doi.org/10.1038/s41467-019-08480-y, doi:10.1038/s41467-019-08480-y. This article has 147 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/s41467-019-08480-y)

[8. (Lawler2012Molecular) P. R. Lawler and J. Lawler. Molecular basis for the regulation of angiogenesis by thrombospondin-1 and -2. Cold Spring Harbor Perspectives in Medicine, 2(5):a006627–a006627, January 2012. URL: http://dx.doi.org/10.1101/cshperspect.a006627, doi:10.1101/cshperspect.a006627. This article has 372 citations and is from a peer-reviewed journal.](https://doi.org/10.1101/cshperspect.a006627)

[9. (Kaur2023Why) Sukhbir Kaur and David D. Roberts. Why do humans need thrombospondin-1? Journal of Cell Communication and Signaling, 17(3):485–493, January 2023. URL: http://dx.doi.org/10.1007/s12079-023-00722-5, doi:10.1007/s12079-023-00722-5. This article has 10 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s12079-023-00722-5)

[10. (Lu2014Common) Lina Lu, Hui Guo, Yu Peng, Guanglei Xun, Yanling Liu, Zhimin Xiong, Di Tian, Yalan Liu, Wei Li, Xiaojuan Xu, Jingping Zhao, Zhengmao Hu, and Kun Xia. Common and rare variants of the thbs1 gene associated with the risk for autism. Psychiatric Genetics, 24(6):235–240, December 2014. URL: http://dx.doi.org/10.1097/ypg.0000000000000054, doi:10.1097/ypg.0000000000000054. This article has 16 citations and is from a peer-reviewed journal.](https://doi.org/10.1097/ypg.0000000000000054)

[11. (Lawler1998Thrombospondin1) J Lawler, M Sunday, V Thibert, M Duquette, E L George, H Rayburn, and R O Hynes. Thrombospondin-1 is required for normal murine pulmonary homeostasis and its absence causes pneumonia. Journal of Clinical Investigation, 101(5):982–992, March 1998. URL: http://dx.doi.org/10.1172/jci1684, doi:10.1172/jci1684. This article has 365 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1172/jci1684)

[12. (Bein2000Thrombospondin) Kiflai Bein and Michael Simons. Thrombospondin type 1 repeats interact with matrix metalloproteinase 2. Journal of Biological Chemistry, 275(41):32167–32173, October 2000. URL: http://dx.doi.org/10.1074/jbc.m003834200, doi:10.1074/jbc.m003834200. This article has 189 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m003834200)