TEK tyrosine kinase is primarily expressed on endothelial cells and is most commonly referred to as TIE2. TIE2 is a receptor tyrosine kinase modulated by its ligands, angiopoietins, to regulate the development and remodeling of vascular system. It is also one of the critical pathways associated with tumor angiogenesis and familial venous malformations. Apart from the vascular system, TIE2 signaling is also associated with postnatal hematopoiesis. Despite the involvement of TIE2-angiopoietin system in several diseases, the downstream molecular events of TIE2-angiopoietin signaling are not reported in any pathway repository. Therefore, carrying out a detailed review of published literature, we have documented molecular signaling events mediated by TIE2 in response to angiopoietins and developed a network map of TIE2 signaling. The pathway information is freely available to the scientific community through NetPath, a manually curated resource of signaling pathways. We hope that this pathway resource will provide an in-depth view of TIE2-angiopoietin signaling and will lead to identification of potential therapeutic targets for TIE2-angiopoietin associated disorders. 1. Introduction Angiopoietin-TIE2 is one of the major signaling systems that regulates development and remodeling of vascular system [1, 2]. TIE2 is a member of the TIE receptor tyrosine kinase family that is preferentially expressed in endothelial cells [3]. Among the angiopoietins (angiopoietin-1, angiopoietin-2, and angiopoietin-4 in humans), angiopoietin-1 (ANGPT1) is known as a constitutive agonist of TIE2. ANGPT1/TIE2 signaling promotes endothelial cell survival, endothelium integrity, and anti-inflammatory/antiapoptotic responses supporting reduced vascular permeability [4, 5]. ANGPT2 is generally considered as antagonist as it competes with ANGPT1 for binding to TIE2, reduces vessel stability, and enhances vascular remodeling [6]. However, under specific experimental conditions, ANGPT2 has been shown to promote endothelial-cell survival, sprouting, and migration in a temporal and concentration-dependent manner [7–9]. Therefore, angiopoietin-2 (ANGPT2) is currently considered as a context dependant agonist or antagonist of TIE2 [6, 10]. Angiopoietin-4 (ANGPT4) is also known to be an agonist of TIE2 while angiopoietin-3 (ANGPT3), the mouse ortholog of angiopoietin-4, is reported to be antagonistic to TIE2 [11]. The other member of the TIE family is the orphan receptor TIE1. It heterodimerizes with TIE2 and modulates TIE2 signaling induced by ANGPT1 and ANGPT2 [12]. ANGPT1 binding to TIE2
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