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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 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.
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fig02: 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.

Mentions: Tie2 signalling can be regulated in several ways. Ang-1 activation of Tie2 can lead to subsequent Tie2 internalization and degradation [93]. With half-life of about 9 hrs in unstimulated cells, Ang-1 reduces the half-life of Tie2 to about 3 hrs. However, the rate of Tie2 synthesis remained unchanged with or without Ang-1, resulting in reduction of Tie2 overtime. This could be a pre-emptive action in preventing multiple and at times contradicting signalling through this pathway. After activating Tie2, Ang-1 was not internalized but was released from the cell surface into the surrounding medium [93]. Tie2 can be inhibited by soluble Tie2s (sTie2Fc) and antagonists such as Ang-2 and Ang-1cc. sTie2Fc is a soluble form of the extracellular domain of Tie2 and has been detected in the plasma of healthy individuals [5, 40, 80]. This suggests that sTie2Fc may be a physiological regulatory mechanism of Tie2 [94]. Elevated levels of sTie2Fc have been reported in pathological conditions such as coronary heart diseases and diabetic retinopathy [95]. Several stimulators, such as VEGF, phorbol 12-myristate 13-acetate (PMA) and basic fibroblast growth factor (FGF) have been implicated in this shedding process of Tie2 that results in sTie2Fc [94, 96]. Because of this shedding process, Tie2 protein expression could be decreased without any effect on the Tie2R mRNA [94]. sTie2Fc could be as a tumour marker [97]. However, serum level of sTie2Fc do not provide any further information on tumour behaviour [98]. Ang-1-Tie2 chemotactic effect was blocked by sTie2Fc but not sTie1Fc, suggesting that sTie1Fc may not be an effective regulator of Ang-1-Tie2 signalling [80]. Tie2 expression can be regulated by Ang-1 through a feedback mechanism [99]. Tie2 also associates with a vascular endothelial protein tyrosine phosphatase, which can regulate the tyrosine kinase activity (Fig. 2) [100]. Tie2 carboxyl terminal can also participate as a negative regulator of Tie2 signalling [101]. Although Tie2 mRNA and Ang-1 expression are down-regulated under hypoxic condition, Tie2 translation is maintained [102]. This suggests a translational mechanism that proceeds despite unfavourable conditions [102].


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

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

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.
© Copyright Policy
Related In: Results  -  Collection

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

fig02: 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.
Mentions: Tie2 signalling can be regulated in several ways. Ang-1 activation of Tie2 can lead to subsequent Tie2 internalization and degradation [93]. With half-life of about 9 hrs in unstimulated cells, Ang-1 reduces the half-life of Tie2 to about 3 hrs. However, the rate of Tie2 synthesis remained unchanged with or without Ang-1, resulting in reduction of Tie2 overtime. This could be a pre-emptive action in preventing multiple and at times contradicting signalling through this pathway. After activating Tie2, Ang-1 was not internalized but was released from the cell surface into the surrounding medium [93]. Tie2 can be inhibited by soluble Tie2s (sTie2Fc) and antagonists such as Ang-2 and Ang-1cc. sTie2Fc is a soluble form of the extracellular domain of Tie2 and has been detected in the plasma of healthy individuals [5, 40, 80]. This suggests that sTie2Fc may be a physiological regulatory mechanism of Tie2 [94]. Elevated levels of sTie2Fc have been reported in pathological conditions such as coronary heart diseases and diabetic retinopathy [95]. Several stimulators, such as VEGF, phorbol 12-myristate 13-acetate (PMA) and basic fibroblast growth factor (FGF) have been implicated in this shedding process of Tie2 that results in sTie2Fc [94, 96]. Because of this shedding process, Tie2 protein expression could be decreased without any effect on the Tie2R mRNA [94]. sTie2Fc could be as a tumour marker [97]. However, serum level of sTie2Fc do not provide any further information on tumour behaviour [98]. Ang-1-Tie2 chemotactic effect was blocked by sTie2Fc but not sTie1Fc, suggesting that sTie1Fc may not be an effective regulator of Ang-1-Tie2 signalling [80]. Tie2 expression can be regulated by Ang-1 through a feedback mechanism [99]. Tie2 also associates with a vascular endothelial protein tyrosine phosphatase, which can regulate the tyrosine kinase activity (Fig. 2) [100]. Tie2 carboxyl terminal can also participate as a negative regulator of Tie2 signalling [101]. Although Tie2 mRNA and Ang-1 expression are down-regulated under hypoxic condition, Tie2 translation is maintained [102]. This suggests a translational mechanism that proceeds despite unfavourable conditions [102].

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