Angiopoietin-TIE2 Signaling
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Angiopoietin-TIE2 Signaling

The growth of new blood vessels (angiogenesis) follows a coordinated genetic program of vascular sprouting, vessel assembly, and organotypic maturation. The VEGF/VEGF Receptor and the Notch/Notch ligand pathways control early steps of the angiogenic cascade related to invasive capillary sprouting. A plethora of neurovascular guidance molecules (ephrins, slits, netrins, semaphorins) subsequently initiate 3D vessel assembly and lumen formation. Last, molecules of the angiopoietin, PDGF, and TGF-ß families regulate maturation and vascular remodeling. Among the regulators of vessel maturation, angiopoietin has a particularly central role. The angiopoietin (Ang) growth factors and the endothelial Ang/TIE receptors regulate blood and lymphatic vessel development, and vascular permeability, inflammation, angiogenic remodeling and tumor vascularization in adult tissues. The angiopoietins activate the Ang/TIE receptors in unique in trans complexes at endothelial cell–cell and cell–matrix contacts. In addition, integrins have been implicated in the regulation of AngAng/TIE signaling (Ref.1 and 2).

The Ang/TIE signaling pathway is composed of two tyrosine kinase receptors (Tie1, Tie2) and three known Tie2 ligands in humans (Ang1, Ang2, Ang4).Ang1 is a Tie2 agonist responsible for basal Tie2 phosphorylation observed in quiescent vessels and is constitutively expressed by stromal cells, such as fibroblasts and vascular supporting cells, and by nonvascular normal and tumor cells. Ang2 generally functions as an Ang1 antagonist, although in some cases it may act as a partial agonist. The balance between these proteins plays a critical role in dictating vascular phenotype (Ref.3).Ang2 binds the endothelial-specific Tie2 and acts as a negative regulator of Ang1/Tie2 signaling during angiogenesis,thereby controlling the responsiveness of ECs to exogenous cytokines. Under certain conditions Ang2 can also promote angiogenesis (Ref.1).

Angiopoietin mainly regulates two pathways that mediate cell motility, the first being through activation of the (PI3K) Pathway and the second involving Ras Pathway (Ref.4). Ang1 can promote endothelial cell survival through activation of the PI3K pathway, and similar results could be achieved with higher concentrations of Ang2. Ang2 can act as an agonist of the Tie2 receptor in the absence of Ang1 and can activate the PI3KAkt1 pathway, although with weaker potency than Ang1. Ang1 has been shown to stimulate Tie2, Akt1, and eNOS phosphorylation in HUVECs in a PI3K dependent manner. PI3K induces conversion of PIP2 (Phosphatidylinositol 4, 5-Bisphosphate) to PIP3 (Phosphatidylinositol 3, 4, 5-Trisphosphate). PIP3 formation is required for phosphorylation of Akt1 by the kinase PDK-1. Activation of the PI3K pathway contribute to Ang1 induced eNOS phosphorylation, NO production, and angiogenesis in coronary artery endothelial cells (Ref.4). Activation of Akt1/ Akt/PKB (Protein Kinase-B) also result in upregulation of Caspase9 and BCL2 Associated Death Promoter leading to a concomitant increase in cell survival. angiopoietin-1 can promote migration, sprouting, and survival of endothelial cells through activation of different signaling pathways triggered by the Tie2 tyrosine kinase receptor. SHCA adapter proteins are targets of activated tyrosine kinases and are implicated in the transmission of activation signals to the Ras/MAPK (Mitogen-Activated Protein Kinase) pathway. Upstream molecules of the Ras/MAPK pathway, GRB2 and SHP2, acts as binding partners of Tie2. Tie2 also binds DOKR, an adapter molecule structurally homologous to p62DOK and IRS3 (Insulin-Receptor Substrate-3). DOKR is able to recruit the adapter protein Nck, PAK (p21-Activated Kinase) and RASGAP (Ras-GTPase-Activating Protein) (Ref.5). Two other binding partners, and the protein phosphatase SHP2 also use this pathway to potentiate cell migration. The docking protein DOKR is recruited in a phospho-specific manner and in response to associate with Nck thereby enhancing PAK-dependent cell migration. The exact nature of, and residues involved in the Tie2-ABIN2 interaction and the hypothetical mechanism by which ABIN2 may inhibit NF-KappaBactivation is still under investigation. In contrast to Ang1, does not lead to activation of the receptor but is a naturally occurring antagonist of the receptor (Ref.4). makes mature vessels unstable by blocking the effects of Ang1. This Ang2-mediated vessel destabilization makes the vessels hypersensitive to other classes of angiogenic factors (Ref.5). A20 binding inhibitor of NF-kappaB activation-2, ABIN-2, also interacts with the endothelial receptor Tie2.ABIN-2 inhibits nuclear factor-kappaB (NF-KappaB) activity and is a possible effector of A20 regulation of NF-KappaB (Ref.6).

Angiogenesis plays an essential role in physiological processes such as embryonic development, and in pathologic conditions like wound healing, malignant tumor growth, and metastasis, rheumatoid arthritis, proliferative diabetic retinopathy, atherosclerosis, and postischemic vascularization of the myocardium. Angiogenesis is an essential component of endometrial repair and regeneration following menses. Perturbation of this process is associated with menorrhagia, a common gynecological disorder that results in excessive menstrual bleeding. In some human diseases such as in heart ischemia, this process can be used to restore the vital function of the affected organs. In other diseases such as in cancer, aberrant angiogenesis can be therapeutically blocked to prevent disease progression, induces endothelial cell sprouting, promotes blood vessel maturation during angiogenesis, and inhibits leakage from adult micro vessels (Ref.6) via the receptor. is its natural antagonist that destabilizes vessels and initiates neovascularization in the presence of VEGF. Other known endogenous inhibitors that physiologically suppress angiogenesis include angiostatin, endostatin, Interferon-Alpha, Platelet Factor-4, Prolactin, Thrombospondin, TIMP1, and (Tissue Inhibitors Of Metalloproteinase), and Troponin (Ref.7).