# ANGPT1

## Overview
The ANGPT1 gene encodes angiopoietin-1, a secreted glycoprotein that plays a pivotal role in vascular development and homeostasis. Angiopoietin-1 is categorized as a ligand for the receptor tyrosine kinase Tie2, which is predominantly expressed on endothelial cells. This protein is integral to maintaining vascular stability, promoting endothelial cell survival, and regulating vascular permeability. Through its interaction with the Tie2 receptor, angiopoietin-1 activates signaling pathways that enhance endothelial barrier function and inhibit inflammatory responses. The gene's significance is underscored by its involvement in various clinical conditions, such as hereditary angioedema and primary congenital glaucoma, where mutations can disrupt its function and lead to pathological vascular permeability and developmental defects (Eklund2013Angiopoietin; Bafunno2018Mutation; Thomson2017Angiopoietin1).

## Structure
The ANGPT1 protein, also known as angiopoietin-1, is a secreted glycoprotein involved in vascular stability and endothelial barrier defense. Its molecular structure includes several distinct domains. The protein features an N-terminal coiled-coil domain, which is essential for oligomerization, allowing the formation of multimeric structures crucial for its function. This domain facilitates the clustering of oligomers to form higher-order multimers, which are necessary for effective binding to the TIE2 receptor on endothelial cells (Bafunno2018Mutation; d’Apolito2019Angiopoietin‐1).

The C-terminal region of ANGPT1 contains a fibrinogen-like domain, which is responsible for binding to the TIE2 receptor, a key interaction for promoting endothelial cell survival and inhibiting vascular leakage (David2011Angiopoietin1). The protein undergoes post-translational modifications, such as glycosylation, which may influence its stability and function. ANGPT1 also has splice variant isoforms, which can affect its functional properties.

The p.A119S mutation within the coiled-coil domain has been identified as affecting the protein's ability to multimerize and bind to TIE2, leading to increased vascular permeability and a novel type of hereditary angioedema (Bafunno2018Mutation; d’Apolito2019Angiopoietin‐1).

## Function
The ANGPT1 gene encodes angiopoietin-1, a protein that plays a critical role in vascular development and maintenance. Angiopoietin-1 primarily functions by binding to the Tie2 receptor, a receptor tyrosine kinase expressed on endothelial cells. This interaction is crucial for promoting endothelial cell survival, stabilization, and anti-inflammatory responses (Eklund2013Angiopoietin; Kim2005Oligomerization). Angiopoietin-1 enhances the integrity of blood vessels by forming complexes with Tie2 at cell-cell junctions, which are essential for endothelial survival and stabilization. This signaling pathway involves the activation of Akt and inhibition of FOXO1, contributing to the maintenance of vascular integrity (Eklund2013Angiopoietin).

In addition to its role in stabilizing blood vessels, angiopoietin-1 is involved in regulating endothelial cell interactions with the extracellular matrix, promoting cell adhesion and migration (Eklund2013Angiopoietin). It also plays a significant role in reducing vascular permeability and inflammation by inhibiting NF-kB signaling and decreasing endothelial cell adhesion molecule expression (Eklund2013Angiopoietin; Thurston2000Angiopoietin1). Angiopoietin-1's ability to protect against plasma leakage without promoting angiogenesis highlights its therapeutic potential in conditions characterized by vascular leakage (Thurston2000Angiopoietin1).

## Clinical Significance
Mutations in the ANGPT1 gene have been linked to several clinical conditions, most notably hereditary angioedema (HAE) and primary congenital glaucoma (PCG). In hereditary angioedema, mutations such as p.Ala119Ser (p.A119S) disrupt the multimerization of the ANGPT1 protein and its ability to bind to the TIE2 receptor on endothelial cells. This leads to increased vascular permeability and recurrent angioedema episodes, suggesting a mechanism of haploinsufficiency (Bafunno2018Mutation; Santacroce2021The; d’Apolito2019Angiopoietin‐1). The p.A119S variant specifically results in reduced expression of VE-cadherin and β-catenin, crucial for maintaining endothelial barrier integrity (d’Apolito2019Angiopoietin‐1).

In primary congenital glaucoma, ANGPT1 mutations such as p.Q236* and p.R494* have been identified. These mutations can lead to defects in Schlemm's canal development, resulting in elevated intraocular pressure and glaucoma. The p.Q236* mutation introduces a premature stop codon, likely leading to mRNA degradation, while the p.R494* mutation may result in a truncated protein that affects stability and interaction with the TEK receptor (Thomson2017Angiopoietin1). These findings highlight the critical role of ANGPT1 in maintaining vascular stability and its potential impact on disease pathogenesis.

## Interactions
ANGPT1 (angiopoietin 1) primarily interacts with the Tie2 receptor, a receptor tyrosine kinase, to play a crucial role in vascular development and stability. This interaction involves the binding of ANGPT1 to Tie2, leading to the receptor's dimerization or multimerization and subsequent autophosphorylation at tyrosine residues. This activation initiates downstream signaling pathways, including the PI3K/AKT pathway, which promotes endothelial cell survival and maintains the endothelial barrier (Huang2010Targeting; Bilimoria2019The).

ANGPT1's interaction with Tie2 is dependent on its oligomerization and multimerization. Proper oligomerization, involving at least four subunits, is essential for effective Tie2 binding and activation. Specific cysteines in ANGPT1 are crucial for forming higher-order oligomers necessary for this interaction (Kim2005Oligomerization).

ANGPT1 also interacts with other proteins, such as integrins and angiopoietin-2 (ANGPT2). ANGPT2 can act as an antagonist or activator of Tie2, depending on the context, and shares structural similarities with ANGPT1 (Kim2005Oligomerization). ANGPT1's interaction with Tie2 is modulated by the presence of TIE1, which can negatively regulate ANGPT1-TIE2 activation (Huang2010Targeting).


## References


[1. (d’Apolito2019Angiopoietin‐1) Maria d’Apolito, Rosa Santacroce, Anna Laura Colia, Giorgia Cordisco, Angela Bruna Maffione, and Maurizio Margaglione. Angiopoietin‐1 haploinsufficiency affects the endothelial barrier and causes hereditary angioedema. Clinical & Experimental Allergy, 49(5):626–635, February 2019. URL: http://dx.doi.org/10.1111/cea.13349, doi:10.1111/cea.13349. This article has 32 citations.](https://doi.org/10.1111/cea.13349)

[2. (David2011Angiopoietin1) Sascha David, Chandra C. Ghosh, Aditi Mukherjee, and Samir M. Parikh. Angiopoietin-1 requires iq domain gtpase-activating protein 1 to activate rac1 and promote endothelial barrier defense. Arteriosclerosis, Thrombosis, and Vascular Biology, 31(11):2643–2652, November 2011. URL: http://dx.doi.org/10.1161/atvbaha.111.233189, doi:10.1161/atvbaha.111.233189. This article has 77 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1161/atvbaha.111.233189)

[3. (Eklund2013Angiopoietin) Lauri Eklund and Pipsa Saharinen. Angiopoietin signaling in the vasculature. Experimental Cell Research, 319(9):1271–1280, May 2013. URL: http://dx.doi.org/10.1016/j.yexcr.2013.03.011, doi:10.1016/j.yexcr.2013.03.011. This article has 203 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.yexcr.2013.03.011)

[4. (Bafunno2018Mutation) Valeria Bafunno, Davide Firinu, Maria D’Apolito, Giorgia Cordisco, Stefania Loffredo, Angelica Leccese, Maria Bova, Maria Pina Barca, Rosa Santacroce, Marco Cicardi, Stefano Del Giacco, and Maurizio Margaglione. Mutation of the angiopoietin-1 gene (angpt1) associates with a new type of hereditary angioedema. Journal of Allergy and Clinical Immunology, 141(3):1009–1017, March 2018. URL: http://dx.doi.org/10.1016/j.jaci.2017.05.020, doi:10.1016/j.jaci.2017.05.020. This article has 215 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.jaci.2017.05.020)

[5. (Thomson2017Angiopoietin1) Benjamin R. Thomson, Tomokazu Souma, Stuart W. Tompson, Tuncer Onay, Krishnakumar Kizhatil, Owen M. Siggs, Liang Feng, Kristina N. Whisenhunt, Tammy L. Yanovitch, Luba Kalaydjieva, Dimitar N. Azmanov, Simone Finzi, Christine E. Tanna, Alex W. Hewitt, David A. Mackey, Yasmin S. Bradfield, Emmanuelle Souzeau, Shari Javadiyan, Janey L. Wiggs, Francesca Pasutto, Xiaorong Liu, Simon W.M. John, Jamie E. Craig, Jing Jin, Terri L. Young, and Susan E. Quaggin. Angiopoietin-1 is required for schlemm’s canal development in mice and humans. Journal of Clinical Investigation, 127(12):4421–4436, November 2017. URL: http://dx.doi.org/10.1172/JCI95545, doi:10.1172/jci95545. This article has 101 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1172/JCI95545)

[6. (Kim2005Oligomerization) Kyung-Tae Kim, Han-Ho Choi, Michel O. Steinmetz, Bohumil Maco, Richard A. Kammerer, So Young Ahn, Hak-Zoo Kim, Gyun Min Lee, and Gou Young Koh. Oligomerization and multimerization are critical for angiopoietin-1 to bind and phosphorylate tie2. Journal of Biological Chemistry, 280(20):20126–20131, May 2005. URL: http://dx.doi.org/10.1074/jbc.m500292200, doi:10.1074/jbc.m500292200. This article has 126 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m500292200)

[7. (Santacroce2021The) Rosa Santacroce, Giovanna D’Andrea, Angela Bruna Maffione, Maurizio Margaglione, and Maria d’Apolito. The genetics of hereditary angioedema: a review. Journal of Clinical Medicine, 10(9):2023, May 2021. URL: http://dx.doi.org/10.3390/jcm10092023, doi:10.3390/jcm10092023. This article has 47 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/jcm10092023)

[8. (Huang2010Targeting) Hanhua Huang, Abhijit Bhat, Gary Woodnutt, and Rodney Lappe. Targeting the angpt–tie2 pathway in malignancy. Nature Reviews Cancer, 10(8):575–585, August 2010. URL: http://dx.doi.org/10.1038/nrc2894, doi:10.1038/nrc2894. This article has 352 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1038/nrc2894)

[9. (Thurston2000Angiopoietin1) Gavin Thurston, John S. Rudge, Ella Ioffe, Hao Zhou, Leorah Ross, Susan D. Croll, Nicole Glazer, Jocelyn Holash, Donald M. McDonald, and George D. Yancopoulos. Angiopoietin-1 protects the adult vasculature against plasma leakage. Nature Medicine, 6(4):460–463, April 2000. URL: http://dx.doi.org/10.1038/74725, doi:10.1038/74725. This article has 1008 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/74725)

[10. (Bilimoria2019The) Jay Bilimoria and Harprit Singh. The angiopoietin ligands and tie receptors: potential diagnostic biomarkers of vascular disease. Journal of Receptors and Signal Transduction, 39(3):187–193, May 2019. URL: http://dx.doi.org/10.1080/10799893.2019.1652650, doi:10.1080/10799893.2019.1652650. This article has 27 citations and is from a peer-reviewed journal.](https://doi.org/10.1080/10799893.2019.1652650)