Plexin B mediates axon guidance in Drosophila by simultaneously inhibitingactive rac and enhancing RhoA signaling

Plexins are neuronal receptors for the repulsive axon guidance molecule Sem aphorins. Previous studies showed that Plexin B (PlexB) binds directly to t he active, GTP-bound form of the Rac GTPase. Here, we define a seven amino acid sequence in PlexB required for Rac ITP binding. The interaction of Ple xB with Rac(GTP) is necessary for Plexin-mediated axon guidance in vivo. A different region of PlexB binds to RhoA. Dosage-sensitive genetic interacti ons suggest that PlexB suppresses Rac activity and enhances RhoA activity. Biochemical evidence indicates that PlexB sequesters RacGTP from its downst ream effector PAK. These results suggest a model whereby PlexB mediates rep ulsion by coordinately regulating two small GTPases in opposite directions: PlexB binds to Rac(GTP) and downregulates its output by blocking its acces s to PAK and, at the same time, binds to and increases the output of RhoA.