Angiopoietin Signaling

The Angiopoietins are a new family of growth factors that bind specifically to the TIE2/Tek receptor tyrosine kinase. To date, four Angiopoietins (Ang1, Ang2, Ang3, Ang4) have been identified as binding partners for Tek, and behave as either agonists (Ang1 and Ang4) or context-dependent antagonists (Ang2 and Ang3) of Tek kinase activity. Angiopoietin regulates two pathways that mediate cell motility, the first being mediated through activation of PI3K and the second involving activation of Ras through phosphotyrosine-dependent recruitment of DOKR, Nck and PAK at the cell membrane. The significance of GRB2 and GRB14 binding to Tek, as well as binding of RasGAP to DOKR, are still under investigation. Upon Ang1 stimulation, the SH2 domain-containing p85 regulatory subunit of PI3K associates with the phosphorylated Tek receptor, resulting in stimulation of PI3K catalytic activity. This leads to subsequent activation of Akt and upregulation of Caspase9, BAD, eNOS and survivin, which results in an increase in cell survival. Ang1 acts either directly or through Src activation to induce conversion of PIP2 to PIP3 by PI3K. PIP3 formation is required for phosphorylation of Akt by the kinase PDK1. PI3K activates FAK leading to cell migration. Two other Tek binding partners, namely GRB7 and the protein phosphatase SHP2, also use this pathway to potentiate cell migration. The docking protein DOKR is recruited in a Tek phospho-specific manner in response to Ang1, and associates with Nck thereby enhancing PAK-dependent cell migration. The exact nature of and residues involved in the Tek-ABIN2 interaction, and the hypothetical mechanism by which ABIN2 may inhibit NF-κB activation, are still under investigation. In contrast to Ang1, Ang2 does not activate the Tek receptor, as Ang2 is a naturally occurring antagonist of Tek. Ang2 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.Angiogenesis plays an essential role in normal physiological processes such as embryonic development and wound healing, and in disease processes such as malignant tumor growth, 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 heart ischemia, this process can be used to restore the vital function of the affected organs. In other diseases such as cancer, aberrant angiogenesis can be therapeutically blocked to prevent disease progression. Ang1 induces endothelial cell sprouting, promotes blood vessel maturation during angiogenesis, and inhibits leakage from adult microvessels via the Tek receptor. Ang2 destabilizes vessels and initiates neovascularization in the presence of VEGF. Other known endogenous inhibitors that physiologically suppress angiogenesis include angiostatin, endostatin, IFN-α, platelet factor-4, prolactin, thrombospondin, TIMP1, TIMP2, TIMP3, and troponin.