Opposing actions of angiopoietin-2 on Tie2 signaling and FOXO1 activation

Kim, Minah; Allen, Breanna M.; Korhonen, Emilia A.; Nitschké, Maximilian; Yang, Hee Won; Bałuk, Peter; Saharinen, Pipsa; Alitalo, Kari; Daly, Christopher; Thurston, Gavin; McDonald, Donald M.

doi:10.1172/jci84871

Cited by 186 publications

(212 citation statements)

References 77 publications

(166 reference statements)

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“…(61). Furthermore, the agonist activity of recombinant ANG2 can be increased by tetramer formation or the chimeric domains used to increase ANG2 solubility and stability (70,71).…”

Section: Methodsmentioning

confidence: 99%

“…(61). Furthermore, the agonist activity of recombinant ANG2 can be increased by tetramer formation or the chimeric domains used to increase ANG2 solubility and stability (70,71).LPS triggers ANG2 release and decreases ANG1-Tie2/Tie1 signaling. Recombinant ANG1, inhibition of ANG2 or increasing Tie2 activity by therapeutic antibodies or a small-molecule phosphatase inhibitor have vascular protective effects in acute inflammation and in sepsis (32,33,34,62,72,73), consistent with an agonist action of ANG1 and antagonistic action of ANG2.…”

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confidence: 99%

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Tie1 controls angiopoietin function in vascular remodeling and inflammation

Korhonen

Lampinen

Giri³

et al. 2016

Journal of Clinical Investigation

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The angiopoietin/Tie (ANG/Tie) receptor system controls developmental and tumor angiogenesis, inflammatory vascular remodeling, and vessel leakage. ANG1 is a Tie2 agonist that promotes vascular stabilization in inflammation and sepsis, whereas ANG2 is a context-dependent Tie2 agonist or antagonist. A limited understanding of ANG signaling mechanisms and the orphan receptor Tie1 has hindered development of ANG/Tie-targeted therapeutics. Here, we determined that both ANG1 and ANG2 binding to Tie2 increases Tie1-Tie2 interactions in a β 1 integrin-dependent manner and that Tie1 regulates ANG-induced Tie2 trafficking in endothelial cells. Endothelial Tie1 was essential for the agonist activity of ANG1 and autocrine ANG2. Deletion of endothelial Tie1 in mice reduced Tie2 phosphorylation and downstream Akt activation, increased FOXO1 nuclear localization and transcriptional activation, and prevented ANG1-and ANG2-induced capillary-to-venous remodeling. However, in acute endotoxemia, the Tie1 ectodomain that is responsible for interaction with Tie2 was rapidly cleaved, ANG1 agonist activity was decreased, and autocrine ANG2 agonist activity was lost, which led to suppression of Tie2 signaling. Tie1 cleavage also occurred in patients with hantavirus infection. These results support a model in which Tie1 directly interacts with Tie2 to promote ANG-induced vascular responses under noninflammatory conditions, whereas in inflammation, Tie1 cleavage contributes to loss of ANG2 agonist activity and vascular stability. The Journal of Clinical Investigation R E S E A R C H A R T I C L E3 4 9 6 jci.org Volume 126 Number 9 September 2016We found that angiopoietins promoted a direct interaction of Tie1 and Tie2 and that this interaction was regulated by integrin β 1 . ANG1-and ANG2-induced Tie2 activation and vascular remodeling were reduced or absent in mice where Tie1 was deleted in vascular endothelial cells. Tie1 deletion also attenuated ANG1-induced Akt activation and nuclear exclusion of FOXO1. We found that Tie1 was suppressed via ectodomain cleavage during acute inflammation and that this was associated with reduced agonistic activity of ANG2 and decreased Tie2 signaling. These results indicate that the agonist action of ANG2 is attenuated in inflammation and that Tie1 is an essential component of the angiopoietin signaling system that has potential for therapeutic targeting in disease. ResultsAngiopoietins induce direct interaction of Tie1 and Tie2. To investigate the dynamics of the Tie receptors in angiopoietin signaling, we transfected HUVECs with retroviral vectors expressing full-length (FL) Tie1 and Tie2, tagged on the C terminus with mCherry and GFP, respectively. Stimulation of FL-Tie2-GFP and FL-Tie1-mCherry expressing endothelial cells with COMP-Ang1 (CAng1) (49) or with recombinant human ANG2 induced colocalization of Tie1 and Tie2 in endothelial cell-cell junctions ( Figure 1A and Supplemental Video 1; supplemental material available online with this article; doi:10.1172/JCI84923DS1) (44,45,50). To investigat...

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“…(61). Furthermore, the agonist activity of recombinant ANG2 can be increased by tetramer formation or the chimeric domains used to increase ANG2 solubility and stability (70,71).…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Tie1 controls angiopoietin function in vascular remodeling and inflammation

Korhonen

Lampinen

Giri³

et al. 2016

Journal of Clinical Investigation

Self Cite

202

279

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“…Both in cultured ECs and in conditional Tie1-knockout mice, endothelial expression of Tie1 was required for the agonist effects of both ANG1 and autocrine ANG2 on Tie2 activation and vascular remodeling. Furthermore, in support of the Kim et al study (36), Korhonen and colleagues also have shown that endotoxemia-induced cleavage of the Tie1 ectodomain reduces ANG2-mediated Tie2 phosphorylation, decreases downstream AKT activation, and increases nuclear localization of FOXO1. Based on these findings, Korhonen and colleagues propose a model in which Tie1 interacts with Tie2 at baseline to promote angiopoietin signaling, but is cleaved in the setting of inflammation, resulting in loss of ANG2 agonist activity and thereby promoting adverse vascular remodeling and leakiness.…”

Section: Remaining Questions and Implications For Therapymentioning

confidence: 65%

“…Using inhibitory antibodies targeting ANG2 and Tie2 along with powerful mouse models, Kim et al demonstrated that ANG2 antagonism of Tie2 promotes loss of vascular integrity during infection with Mycoplasma pulmonis (36). Moreover, compromised vascular integrity was further exacerbated by antibody-mediated inhibition of Tie2 activation.…”

Section: The Effect Of Inflammationmentioning

confidence: 99%

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Tie1: an orphan receptor provides context for angiopoietin-2/Tie2 signaling

Mueller¹,

Kontos²

2016

Journal of Clinical Investigation

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Angiopoietin‐Tie signaling in kidney diseases: an updated review

Zhang

Chen

et al. 2019

FEBS Letters

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Angiopoietins (Angs) are a family of vascular growth factors that share multiple cellular functions related to cell survival, proliferation, and migration. Angs play physiological and pathological roles through the Tie tyrosine kinase receptors. The Ang‐Tie signaling pathway participates in the developmental and tumor‐induced angiogenesis and is also involved in many disease settings, such as vascular diseases, systemic inflammation, and cancers. Since Angs are widely expressed in the kidney, an enormous amount of research focuses on their roles in the kidney. In this review, we describe the biological functions of the Ang‐Tie signaling pathway and summarize their roles in kidney development and maturation, acute and chronic kidney diseases, diabetic nephropathy, lupus nephropathy, hemolytic uremic syndrome, end‐stage renal diseases, and renal cell carcinoma. Understanding the molecular mechanisms of Ang‐Tie signaling may reveal potential therapeutic targets for preventing or alleviating kidney diseases.

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Opposing actions of angiopoietin-2 on Tie2 signaling and FOXO1 activation

Abstract: tributed to the design of experiments, data analysis, and interpretation of results. PB provided transgenic mice. DMM contributed to the design of experiments, data analysis, interpretation of results, and writing of the manuscript.

Cited by 186 publications

References 77 publications

Tie1 controls angiopoietin function in vascular remodeling and inflammation

Tie1 controls angiopoietin function in vascular remodeling and inflammation

Tie1: an orphan receptor provides context for angiopoietin-2/Tie2 signaling

Angiopoietin‐Tie signaling in kidney diseases: an updated review

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