FIGURE 9:

Cell-cell–mediated Akt dynamics regulates MAP kinase signaling thresholds necessary for capillary-like network formation. (A) Dynamic reciprocity of Akt and Erk activity in ECs cocultured with vSMCs correlates with endothelial migration and branching morphogenesis. (B) We propose that Akt down-regulation and concurrent Erk up-regulation are induced by direct cell–cell contact between endothelial and mural cells through a VEGFR2-dependent mechanism. Direct heterotypic cell–cell contact activates an unknown endothelial E3 ubiquitin ligase that targets Akt for proteasomal degradation. Mural cell–induced Akt degradation potentiates the Erk activation that is necessary for endothelial migration and capillary-like network formation.