RhoJ integrates attractive and repulsive cues in directional migration of endothelial cells

Abstract

During angiogenesis, VEGF acts as an attractive cue for endothelial cells (EC s), while Sema3E mediates repulsive cues. Here, we show that the small GTP ase RhoJ integrates these opposing signals in directional EC migration. In the GTP ‐bound state, RhoJ interacts with the cytoplasmic domain of PlexinD1. Upon Sema3E stimulation, RhoJ released from PlexinD1 induces cell contraction. PlexinD1‐bound RhoJ further facilitates Sema3E‐induced PlexinD1‐VEGFR 2 association, VEGFR 2 transphosphorylation at Y1214, and p38 MAPK activation, leading to reverse EC migration. Upon VEGF stimulation, RhoJ is required for the formation of the holoreceptor complex comprising VEGFR 2, PlexinD1, and neuropilin‐1, thereby preventing degradation of internalized VEGFR 2, prolonging downstream signal transductions via PLC γ, Erk, and Akt, and promoting forward EC migration. After conversion to the GDP ‐bound state, RhoJ shifts from PlexinD1 to VEGFR 2, which then terminates the VEGFR 2 signals. RhoJ deficiency in EC s efficiently suppressed aberrant angiogenesis in ischemic retina. These findings suggest that distinct Rho GTP ases may act as context‐dependent integrators of chemotactic cues in directional cell migration and may serve as candidate therapeutic targets to manipulate cell motility in disease or tissue regeneration.