Intra and extravascular transmembrane signalling of angiopoietin-1-Tie2 receptor in health and disease

Abstract

Angiopoietin-1 (Ang-1) is the primary agonist for Tie2 tyrosine kinase receptor (Tie2), and the effect of Ang-1-Tie2 signalling is context-dependent. Deficiency in either Ang-1 or Tie2 protein leads to severe microvascular defects and subsequent embryonic lethality in murine model. Tie2 receptors are expressed in several cell types, including endothelial cells, smooth muscle cells, fibroblasts, epithelial cells, monocytes, neutrophils, eosinophils and glial cells. Ang-1-Tie2 signalling induces a chemotactic effect in smooth muscle cells, neutrophils and eosinophils, and induces differentiation of mesenchymal cells to smooth muscle cells. Additionally, this signalling pathway induces the secretion of serotonin, matrix metalloproteinases (MMPs) and plasmin. Ang-1 inhibits the secretion of tissue inhibitor of matrix metalloproteinase (TIMPs). Aberrant expression and activity of Tie2 in vascular and non-vascular cells may result in the development of rheumatoid arthritis, cancer, hypertension and psoriasis. Ang-1 has an anti-inflammatory effect, when co-localized with vascular endothelial growth factor (VEGF) in the vasculature. Thus, Ang-1 could be potentially important in the therapy of various pathological conditions such as pulmonary hypertension, arteriosclerosis and diabetic retinopathy. In this article, we have summarized and critically reviewed the pathophysiological role of Ang-1-Tie2 signalling pathway.

1

Schematic representation of Tie2 (Tie2 tyrosine kinase receptor) structure and Ang-1-Tie2 signallingsignaling. Ang-1 binding to Tie2 leads to dimerization and autophosphorylation of Tie2. Several effector molecules are recruited and activated, leading to downstream signallingsignaling. Several downstream signallingsignaling molecules have been identified. Tie2 signals primarily through the PI3-kinase (phosphatidylinositol 3-kinase) pathway. However, Tie2 can also activate other molecules, such as Grb2 (growth factor receptor-bound protein 2), ABIN-2 (A20-binding inhibitor of NF-κB-2), SHP2 (Src homology 2 (SH2)-containing protein tyrosine phosphatase), STATs (Signal transducer and activator of transcriptions), Shc-A (Src homology 2 domain containing protein), and Dok-R (Downstream-of-kinase-related protein) to elicit various downstream effects.

2

Schematic depiction of Tie2 signallingsignaling regulation. Ang-1 activation of Tie2 subsequently leads to Tie2 internalization and degradation. Tie2 activation can also be inhibited by Ang-2 competitive binding. Stimulator such as PMA (phorbol 12-myristate 13-acetate) and basic FGF (basic fibroblast growth factor) can induce Tie2R shedding, leaving the extracellular domain (sTie2RFc) in the area. sTie2Fc can compete with Tie2 for Ang-1 binding. Vascular endothelial protein phosphatase associates with Tie2 and can also regulate the activity of the tyrosine kinase domain.

3

Schematic depiction of Ang-1-Tie2 effect on various cell types. Several cells are capable expression Ang-1 and Tie2 receptors. Ang-1 is activates Tie2 receptors on these cells, leading to downstream signallingsignaling and ultimately regulation of cellular behavioursbehaviors. Some of the various known roles of Ang-1-Tie2 effects in vascular and extravascular cells have been illustrated.

4

Illustration of the relationship between Ang-1-Tie2 signallingsignaling and pathological conditions. Ang-1-Tie2 signallingsignaling induces various responses in different cells and these responses contribute to the development of various pathological conditions.