Regulating small G protein signaling to coordinate axon adhesion and repulsion

Small GTPases play critical roles in diverse biological events including regulating both the cytoskeletal and adhesive properties of cells. The importance of small GTPases to these events stems from their ability to be turned on and off, respectively, by specific GEFs and GAPs. In neurons, for example, regulation of small GTPase activity by extracellular guidance cues controls axonal and dendritic process shape, extension and navigation. Here, we discuss recent findings that indicate a specific regulator of small GTPase signaling, the Plexin transmembrane GAP, is differentially controlled by specific extracellular cues to guide growing axons. In particular, Plexins are receptors for one of the largest families of axon guidance cues, Semaphorins and negatively regulate cell morphology and motility by serving as GAPs for Ras/Rap family GTPases. Recent observations reveal that Plexin's GAP activity is controlled by the cAMP-dependent protein kinase (PKA), which phosphorylates Plexin and generates a binding site for the phospho-serine/threonine binding protein 14-3-3ε. This PKA-mediated Plexin-14-3-3ε interaction prevents Plexin from associating with its GTPase substrate, and thus antagonizes Semaphorin signaling. We now further examine these interactions and how they provide a new logic by which axon guidance signaling pathways over-ride one another to steer growing axons. We also further explore how Plexin interacting proteins, including Ras, PKA and 14-3-3 may interact with the Plexin GAP domain. Our observations also further indicate that 14-3-3 proteins may have conserved roles in the regulation of GTPase activity.