Angiopoietin-Tie Signaling Pathway in Endothelial Cells: A Computational Model

Figures

• 

  Figure 1. Diagram of Model Reaction Rules Ang1 (tetrameric) and Ang2 (dimeric, trimeric, and tetrameric) induce oligomerization, phosphorylation, and internalization of Tie2. Orphan receptor Tie1 binds and forms heterodimers with receptor Tie2. Internalized receptors are recycled back to the cell surface or degraded. Receptors Tie1 and Tie2 get cleaved from the surface and form soluble receptors Tie1 and Tie2. Soluble Tie2 binds to both ligands Ang1 and Ang2. See also Table S2.

• 

  Figure 2. Model Calibration Using Global Optimization (A and B) The concentration-dependent agonistic activity of (A) Ang1 and (B) Ang2. (C and D) Ang2 functions as partial agonist compared to Ang1. (E and F) Ang1 and Ang2 induce different receptor trafficking and turnover of Tie2. (G and H) Silencing orphan receptor Tie1 enhances Ang1- and Ang2-induced Tie2 activation. (I and J) Receptors Tie2 and Tie1 are constitutively shed from the cell surface and produce soluble receptors. (K) Soluble Tie2 induces concentration-dependent inhibition of Tie2 activation. Where available, data are presented as mean +/− standard error of the mean (SEM). See also Table S4.

• 

  Figure 3. VE-PTP Reduces Ang2-Induced Activation of Tie2, but Not Ang1 (A) VE-PTP is more effective in regulating Ang2-activated Tie2 compared to Ang1-activated Tie2. (B) Simulation of concentration-dependent activation of Tie2 with VE-PTP by Ang1 and concentration-dependent activation of Tie2 without VE-PTP by Ang1 compared to experimental data by Souma et al. (C) Simulation of concentration-dependent activation of Tie2 with VE-PTP by Ang2 and concentration-dependent activation of Tie2 without VE-PTP by Ang2 compared to experimental data by Souma et al. Data are presented as mean ± SEM.

• 

  Figure 4. Effect of Internalization Rate on the Effectiveness of VE-PTP (A) Ang1 induces faster internalization of Tie2 compared to Ang2. (B and C) Simulation of phosphorylated Tie2 over time following Ang1 treatment with and without VE-PTP at (B) baseline internalization rate and (C) reduced internalization rate. (D) The ratio of phosphorylated Tie2 at 30 min with and without VE-PTP increases as internalization rate increases following Ang1 treatment. (E and F) Simulation of phosphorylated Tie2 over time following Ang1 treatment with and without VE-PTP at (E) baseline internalization rate and (F) increased internalization rate. (G) The ratio of phosphorylated Tie2 at 30 min with and without VE-PTP increases as internalization rate increases following Ang2 treatment.

• 

  Figure 5. Global Parameter Sensitivity Analysis (A) Sensitive parameters for internalized Tie2 at 30 min post-stimulation and their partial rank correlation coefficient (PRCC) values. (B) Sensitive parameters for phosphorylated Tie2 at 30 min post-stimulation and their PRCC values. (C) PRCC values for all parameters on the observables of the model. Tables with all parameters (Table S1) and all observables (Table S3) are included in the Supplemental Information. See also Figure S1.

• 

  Figure 6. Inhibition of Tie2 Shedding, VE-PTP, and Tie1 Rescues Ang2-Induced Tie2 Activation (A) Diagram of regulation mechanisms of Tie2 signaling: Tie2 shedding, VE-PTP action, and Tie1 binding. (B) Effect of inhibition of VE-PTP, Tie1, and Tie2 cleavage on maximum phosphorylated Tie2 for 30 min post-stimulation. (C) Effect of combination of inhibition of VE-PTP and Tie2 cleavage on maximum phosphorylated Tie2 for 30 min post-stimulation. (D) Effect of combination of inhibition of VE-PTP and Tie1 on maximum phosphorylated Tie2 for 30 min post-stimulation. (E) Effect of combination of inhibition of Tie1 and Tie2 cleavage on maximum phosphorylated Tie2 for 30 min post-stimulation. See also Figure S2.

• 

  Figure 7. Ang1 Dissociates Tie2 from Tie1:Tie2 Heterodimer (A) Ang1, but not Ang2, stimulates dissociation of Tie1:Tie2 heterodimer. (B) The concentration of Tie1:Tie2 heterodimer over time following Ang2 treatment and Ang1 treatment compared to experimental results by Seegar et al. (C) Heterodimer concentration at 30 min decreases as kdissang1tie1tie2 increases following Ang1 treatment but does not change following Ang2 treatment. Data are presented as mean ± SEM. See also Figure S3.