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

Makinde T, Agrawal DK - J. Cell. Mol. Med. (2008)

Bottom Line: 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.Ang-1 has an anti-inflammatory effect, when co-localized with vascular endothelial growth factor (VEGF) in the vasculature.In this article, we have summarized and critically reviewed the pathophysiological role of Ang-1-Tie2 signalling pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE 68178, USA.

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.

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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.
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fig01: 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.

Mentions: Tie2 is a 140 kD tyrosine kinase receptor with immunoglobulin and epidermal growth factor (EGF) homology domain-2. The extracellular region contains three EGF-like domain modules that are flanked by two immunoglobulin (Ig)-like domains, and three fibronectin type III repeats (Fig. 1) [11, 19]. The two Ig-like domains harbour the Ang-binding site. Investigations have also suggested a third Ig-like domain, which folds together with the three EGFs into a compact, arrowhead-shaped structure [37, 38]. The binding site is contained in the globular head domain. A stalk that acts as a spacer between the head and the cell surface is formed by the three fibronectin type III repeats. The cytoplasmic domain contains tyrosine kinase domains, made up of phos-phorylation and protein interaction sites [11]. New Ets-related factor-2 (NERF2) and E74-like factor-1 (ELF-1), which are members of the Ets family of transcription factors, can bind to the Tie2 gene promoter to induce transcription of the gene [18, 39]. Ang-1 can induce expression of NERF2 under hypoxic condition, although level of Ang-2 is greater than Ang-1 under this condition. Ang-2 can act as a Tie2 agonist under hypoxic conditions and in the presence of VEGF [18, 40]. Other factors, such as IL-11, VEGF and hypoxia, can also regulate Tie1 and Tie2 expression (Table 1) [16–18, 41, 42].


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

Makinde T, Agrawal DK - J. Cell. Mol. Med. (2008)

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.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4401129&req=5

fig01: 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.
Mentions: Tie2 is a 140 kD tyrosine kinase receptor with immunoglobulin and epidermal growth factor (EGF) homology domain-2. The extracellular region contains three EGF-like domain modules that are flanked by two immunoglobulin (Ig)-like domains, and three fibronectin type III repeats (Fig. 1) [11, 19]. The two Ig-like domains harbour the Ang-binding site. Investigations have also suggested a third Ig-like domain, which folds together with the three EGFs into a compact, arrowhead-shaped structure [37, 38]. The binding site is contained in the globular head domain. A stalk that acts as a spacer between the head and the cell surface is formed by the three fibronectin type III repeats. The cytoplasmic domain contains tyrosine kinase domains, made up of phos-phorylation and protein interaction sites [11]. New Ets-related factor-2 (NERF2) and E74-like factor-1 (ELF-1), which are members of the Ets family of transcription factors, can bind to the Tie2 gene promoter to induce transcription of the gene [18, 39]. Ang-1 can induce expression of NERF2 under hypoxic condition, although level of Ang-2 is greater than Ang-1 under this condition. Ang-2 can act as a Tie2 agonist under hypoxic conditions and in the presence of VEGF [18, 40]. Other factors, such as IL-11, VEGF and hypoxia, can also regulate Tie1 and Tie2 expression (Table 1) [16–18, 41, 42].

Bottom Line: 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.Ang-1 has an anti-inflammatory effect, when co-localized with vascular endothelial growth factor (VEGF) in the vasculature.In this article, we have summarized and critically reviewed the pathophysiological role of Ang-1-Tie2 signalling pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE 68178, USA.

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.

Show MeSH
Related in: MedlinePlus