Key result
Endogenous monomeric soluble Tie2 requires a >350-fold molar excess to inhibit Angpt1 signaling by 50%, whereas an engineered dimeric sTie2 ligand trap inhibits signaling at 70-fold lower concentrations.
Circulating soluble Tie2 is unlikely to systemically block Angiopoietin-1 signalling at physiological or pathological concentrations, contrary to previous hypotheses.
No immediate clinical implications; extends joint modeling-experimental methods to engineered decoy receptor design.
Angiopoietin-1 (Angpt1) is a glycoprotein ligand important for maintaining the vascular system. It signals via a receptor tyrosine kinase expressed on the surface on endothelial cells, Tie2. This receptor can undergo regulated ectodomain cleavage that releases the ligand-binding domain (sTie2) into the circulation. The concentration of sTie2 is increased in a range of conditions, including peripheral arterial disease and myocardial infarction, where it has been suggested to bind and block Angpt1 resulting in vascular dysfunction. Here we use a joint mathematical modelling and experimental approach to assess the potential impact of sTie2 on the ability of Angpt1 to signal. We find that the concentrations of sTie2 relative to Angpt1 required to suppress signalling by the ligand are more than ten-fold higher than those ever seen in normal or disease conditions. In contrast to the endogenous sTie2, an engineered form of sTie2, which presents dimeric ligand binding sites, inhibits Angpt1 signalling at seventy-fold lower concentrations. While loss of Tie2 ectodomain can suppress Angpt1 signalling locally in the cells in which the receptor is lost, our study shows that the resulting increase in circulating sTie2 is unlikely to affect Angpt1 activity elsewhere in the body.
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Alawo et al. (2017) studied this question. Soluble Tie2 (sTie2) and engineered dimeric sTie2 vs. Vehicle / absence of sTie2 was evaluated on Inhibition of Angpt1-induced cellular Tie2 activation (phosphorylation of Y992). Endogenous monomeric soluble Tie2 requires a >350-fold molar excess to inhibit Angpt1 signaling by 50%, whereas an engineered dimeric sTie2 ligand trap inhibits signaling at 70-fold lower concentrations.
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