Showing papers on "TIE1 published in 2009"
TL;DR: The Tie receptors and their angiopoietin (Ang) ligands have been identified as the second vascular tissue-specific receptor Tyr kinase system and provide unique insights into the functions of this vascular signalling system.
Abstract: Angiogenesis, the growth of blood vessels, is a fundamental biological process that controls embryonic development and is also involved in numerous life-threatening human diseases. Much work in the field of angiogenesis research has centred on the vascular endothelial growth factor (VEGF)-VEGF receptor system. The Tie receptors and their angiopoietin (Ang) ligands have been identified as the second vascular tissue-specific receptor Tyr kinase system. Ang-Tie signalling is essential during embryonic vessel assembly and maturation, and functions as a key regulator of adult vascular homeostasis. The structural characteristics and the spatio-temporal regulation of the expression of receptors and ligands provide unique insights into the functions of this vascular signalling system.
1,255 citations
TL;DR: The better mechanistic understanding of the Ang/Tie system is gradually paving the way toward the rationale exploitation of this vascular signaling system as a therapeutic target for neoplastic and non-neoplastic diseases.
Abstract: The Angiopoietin/Tie system acts as a vascular specific ligand/receptor system to control endothelial cell survival and vascular maturation. The Angiopoietin family includes four ligands (Angiopoietin-1, Angiopoietin-2 and Angiopoietin-3/4) and two corresponding tyrosine kinase receptors (Tie1 and Tie2). Ang-1 and Ang-2 are specific ligands of Tie2 binding the receptor with similar affinity. Tie2 activation promotes vessel assembly and maturation by mediating survival signals for endothelial cells and regulating the recruitment of mural cells. Ang-1 acts in a paracrine agonistic manner inducing Tie2 phosphorylation and subsequent vessel stabilization. In contrast, Ang-2 is produced by endothelial cells and acts as an autocrine antagonist of Ang-1-mediated Tie2 activation. Ang-2 thereby primes the vascular endothelium to exogenous cytokines and induces vascular destabilization at higher concentrations. Ang-2 is strongly expressed in the vasculature of many tumors and it has been suggested that Ang-2 may act synergistically with other cytokines such as vascular endothelial growth factor to promote tumor-associated angiogenesis and tumor progression. The better mechanistic understanding of the Ang/Tie system is gradually paving the way toward the rationale exploitation of this vascular signaling system as a therapeutic target for neoplastic and non-neoplastic diseases.
360 citations
TL;DR: Although Ang2 is a weaker agonist than Ang1, endogenous Ang2 maintains a level of Tie2 activation that is critical to a spectrum of EC functions that may reconcile disparate reports of Ang2's effect on Tie2, impact the understanding of endogenous receptor tyrosine kinase signal transduction mechanisms, and affect how Ang2 and Tie2 are targeted under conditions such as sepsis and cancer.
Abstract: Angiopoietin 2 (Ang2) was originally shown to be a competitive antagonist for Ang1 of the receptor tyrosine kinase Tie2 in endothelial cells (ECs). Since then, reports have conflicted on whether Ang2 is an agonist or antagonist of Tie2. Here we show that Ang2 functions as an agonist when Ang1 is absent but as a dose-dependent antagonist when Ang1 is present. Exogenous Ang2 activates Tie2 and the promigratory, prosurvival PI3K/Akt pathway in ECs but with less potency and lower affinity than exogenous Ang1. ECs produce Ang2 but not Ang1. This endogenous Ang2 maintains Tie2, phosphatidylinositol 3-kinase, and Akt activities, and it promotes EC survival, migration, and tube formation. However, when ECs are stimulated with Ang1 and Ang2, Ang2 dose-dependently inhibits Ang1-induced Tie2 phosphorylation, Akt activation, and EC survival. We conclude that Ang2 is both an agonist and an antagonist of Tie2. Although Ang2 is a weaker agonist than Ang1, endogenous Ang2 maintains a level of Tie2 activation that is critical to a spectrum of EC functions. These findings may reconcile disparate reports of Ang2's effect on Tie2, impact our understanding of endogenous receptor tyrosine kinase signal transduction mechanisms, and affect how Ang2 and Tie2 are targeted under conditions such as sepsis and cancer.
337 citations
TL;DR: Targeted angiopoietin-2 inhibition with RNA aptamers or blocking antibodies is a potential anti-inflammatory and anti-vascular hyperpermeability strategy in the treatment of sepsis and ALI/ARDS.
Abstract: Background: Sepsis and acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) are life-threatening syndromes characterised by inflammation and increased vascular permeability. Amongst other factors, the angiopoietin–tyrosine kinase with immunoglobulin-like and EGF-like domains 2 (Tie2) system is involved. Objective: To explore whether the angiopoietin–Tie2 system provides suitable targets for the treatment of sepsis and ALI/ARDS. Methods: Original experimental and patient studies on angiopoietins and sepsis/endotoxemia, inflammation, lung injury, hyperpermeability, apoptosis, organ functions and vital outcomes were reviewed. Results/conclusion: The angiopoietin–Tie2 system controls the responsiveness of the endothelium to inflammatory, hyperpermeability, apoptosis and vasoreactive stimuli. Angiopoietin-2 provokes inflammation and vascular hyperpermeability, while angiopoietin-1 has a protective effect. Targeted angiopoietin-2 inhibition with RNA aptamers or blocking antibodies is a potential a...
70 citations
TL;DR: The roles of AngPTl2 and Angptl6/angiopoietin-like growth factor (AGF) in the development of MetS and CVD are focused on and the potential for these proteins to function as molecular targets for the prevention and treatment of both conditions is discussed.
Abstract: Recent major increases in obesity and related metabolic diseases (known as the metabolic syndrome (MetS)) because of sedentary lifestyles and overnutrition in developed and developing countries, are an exploding medical and social problem These conditions are associated with increased risk of cardiovascular disease (CVD), the leading cause of death Thus, it is necessary to understand the molecular basis underlying MetS and develop effective preventive and therapeutic approaches against CVD To date, 7 angiopoietin-like proteins (Angptls) that are structurally similar to angiopoietins have been identified However, none binds to the angiopoietin receptor, Tie2, or to the closely related Tie1 receptor, suggesting that these ligands function differently from angiopoietins Some Angptls potently regulate angiogenesis, similar to angiopoietins, whereas others have pleiotropic activity other than angiogenesis and function in lipid and energy metabolism In this review, we focus on the roles of Angptl2 and Angptl6/angiopoietin-like growth factor (AGF) in the development of MetS and CVD, and discuss the potential for Angptl2 and Angptl6/AGF to function as molecular targets for the prevention and treatment of both conditions
66 citations
TL;DR: It is demonstrated that Tie2 mediates the inhibitory effects of Ang1 on endothelial permeability and apoptosis and that Tie1 does not transduce anti-apoptotic or anti-permeability effects of angiopoietin-1 in endothelial cells.
36 citations
Patent•
10 Dec 2009TL;DR: In this paper, the present invention relates to amino acid sequences that are directed against proteins from the group of the Angiopoietin/Tie family such as Tie 1, Tie 2, Tie 3, Tie 4, Tie 5, Tie 6, Tie 7, Tie 8, Tie 9, Tie 10, Tie 11, Tie 12, Tie 13, Tie 14, Tie 15, Tie 16, Tie 17, Tie 18, Tie 19, Tie 20
Abstract: The present invention relates to amino acid sequences that are directed against proteins from the group of the Angiopoietin/Tie family such as Tie1, Tie2, Ang1, Ang2, Ang3, Ang4, Angptl1, Angptl12, Angptl13, Angptl14, Angptl15, Angptl16, as well as to compounds or constructs, and in particular proteins and polypeptides, that comprise or essentially consist of one or more of such amino acid sequences.
14 citations