R-Ras fills another GAP in semaphorin signalling

Plexins are cell-surface receptors for the semaphorin family of neuronal guidance cues. Following semaphorin binding, the plexin cytoplasmic region initiates poorly understood signal-transduction events that lead to modifications of the cytoskeleton. Recent findings shed new light on the signalling network downstream of semaphorins and plexins by demonstrating that one of the plexins, plexin-B1, possesses an intrinsic GTPase-activating protein (GAP) activity towards R-Ras. Inactivation of R-Ras by the plexin-B1 GAP domains is required for plexin-B1-mediated effects on the cytoskeleton. These results indicate that plexins not only bind to but also regulate directly the activity of some of their downstream effectors.

Introduction

During nervous-system development, neurons extend axonal processes that use molecular gradients in their outside environment for navigating to their target structures. These gradients are composed of axon-guidance molecules (see Glossary) and are detected by a sensory structure at the leading tip of each axon: the growth cone. High-affinity receptors at the cell surface of the growth cone enable extending axons to sample a vast number of different axon-guidance molecules. Following ligand binding, these receptors activate intracellular signalling cascades that, in turn, modulate cytoskeletal dynamics. Ultimately, these cytoskeletal changes lead to alterations in growth-cone motility and growth-cone steering.

The semaphorins comprise a large family of axon-guidance molecules. Many semaphorins function as axon repellents (i.e. growth-cone-collapse proteins), influencing axon steering, axon fasciculation and axon branching in vivo [1]. Thus far, all repulsive semaphorin signalling has been attributed to receptor complexes that contain plexins as obligatory signal-transducing subunits 2, 3. The cytoplasmic region of plexins is required for semaphorin signalling but it displays no homology to known catalytic domains. Several intracellular proteins have been implicated in plexin-mediated axon repulsion, some of which interact physically with the plexin cytoplasmic domain [4]. However, it remains largely unknown how these cues are activated by plexin receptors and how they work together to form a functional signalling network.

The plexin cytoplasmic region shows sequence similarity to a group of Ras-family-specific GTPase-activating proteins (GAPs) [4]. This observation supports the exciting possibility that plexins might directly regulate the activity of GTPases. However, since their original identification in 1995 [5], no intrinsic GAP activity has been demonstrated for plexins. Inspired by recent experimental and methodological advances, Oinuma et al. have reported on the identification of this long-sought activity [6]. The work of Oinuma et al. provides novel mechanistic insight into plexin signalling and helps to further the knowledge of how semaphorin signalling pathways intersect with other signalling cascades.