Network topology of the minimal model for VEGFR-2 activation and downstream signaling. Color code distinguishes the 3 modules for VEGFR-2 (green), Akt (violet), and PLC-γ (pink) activation. A VEGFR-2 monomer is engaged by a bivalent molecule of VEGF to produce the VEGF–VEGFR-2 complex, which in turn promotes the recruitment of another VEGFR-2 monomer resulting in receptor dimerization and transphosphorylation.^1,18,19  The phosphorylated receptor triggers downstream signals. Akt activation moves through 3 GK modules, all characterized by a specific substrate (PI3K, PIP2, and Akt-PIP3 complex), which is interconverted from an unphosphorylated to a phosphorylated state and vice versa by a kinase and a phosphatase, respectively.^20-22  PLC-γ activation consists of a single GK module where the kinase is activated VEGFR-2 and the phosphatase an unidentified PTP,²³  (PTP′). For details on GK modules, see supplemental Section 1.2. For the graphical notation, see supplemental Section 1.6.