Tie2 receptor

The Tie2 receptor is an important player in angiogenesis. The receptor protein is encoded by the TEK gene. The Tie2 protein has a unique extracellular region that contains two immunoglobulin-like domains, three epidermal growth factor (EGF)-like domains and three fibronectin type III repeats. The ligand angiopoietin-1 binds to this receptor and mediates a signaling pathway that plays a role in embryonic vascular development. Endothelial cells, which form the inner layer of blood and lymph vessels, are important regulators of vascular function and of central importance for the development of vascular diseases. In addition to the vascular endothelial growth factor(VEGF) receptor pathway, the angiopoietin (Ang)-Tie system is a second endothelial cell-specific ligand-receptor signaling system required for embryonic cardiovascular and lymphatic development. The Ang-Tie system also regulates postnatal angiogenesis, vascular remodeling, vascular permeability and inflammation to maintain vascular homeostasis in adult physiology.

The mRNA and protein of Tie2 are abundantly expressed in the lung. The associated signaling pathway also plays an important role in the development and function of the eye (Fodor LE et al. 2018). A significant association was found between the SNP rs581724 and the occurrence of allergic conjunctivitis in asthmatic children. If further studies can confirm the role of the Tie2 signaling pathway in allergic conjunctivitis, it could represent a potential new therapeutic target in the treatment of allergic conjunctivitis (Akwii RG et al. 2021).

Endothelial cells, which form the inner layer of blood and lymph vessels, are important regulators of vascular function and of central importance for the development of vascular diseases. In addition to the vascular endothelial growth factor (VEGF) receptor pathway, the angiopoietin (Ang)-Tie system is a second endothelial cell-specific ligand-receptor signaling system required for embryonic cardiovascular and lymphatic development. The Ang-Tie system also regulates postnatal angiogenesis, vascular remodeling, vascular permeability and inflammation to maintain vascular homeostasis in adult physiology.

Mutations in the TIE2 signaling pathway cause defects in vascular morphogenesis leading to venous malformations and primary congenital glaucoma.

The unique function of the ANG-TIE pathway in vascular stabilization also makes this pathway an attractive target in sepsis, organ transplantation, atherosclerosis and vascular complications of diabetes. Drugs targeting the ANG-TIE signaling pathway are in clinical development for oncology and ophthalmology applications. They are intended to complement current vascular endothelial growth factor (VEGF)-based anti-angiogenesis therapies for cancer, wet age-related macular degeneration and macular edema. The ANG-TIE system has emerged as an important area for clinical drug development in the field of oncology and neovascular eye diseases. In ongoing clinical trials, ANG-TIE-targeted drugs are being combined with other anti-angiogenic or immunotherapies. The phosphatase VE-PTP is a negative regulator of TIE2 and represents another therapeutic target.

1. Akwii RG et al. (2021) Targeting the Angiopoietin/Tie Pathway: Prospects for Treatment of Retinal and Respiratory Disorders. Drugs 81:1731-1749.
2. Eklund L et al. (2017) Angiopoietin-Tie signaling in the cardiovascular and lymphatic systems. Clin Sci (Lond) 131:87-103.
3. Fodor LE et al. (2018) Variation in the TEK gene is not associated with asthma but with allergic conjunctivitis. Int J Immunogenet 45:102-108
4. Teichert M et al. (2017) Pericyte-expressed Tie2 controls angiogenesis and vessel maturation. Nat Commun 8:16106.
5. Zhang Y et al. (2019) Angiopoietin-Tie Signaling Pathway in Endothelial Cells: A Computational Model. iScience 20:497-511.