Plexins are receptors for axonal guidance molecules known as semaphorins. We recently reported that the semaphorin 4D (Sema4D) receptor, Plexin-B1, induces axonal growth cone collapse by functioning as an R-Ras GTPase activating protein (GAP). Here, we report that Plexin-B1 shows GAP activity for M-Ras, another member of the Ras family of GTPases. In cortical neurons, the expression of M-Ras was upregulated during dendritic development. Knockdown of endogenous M-Ras-but not R-Ras-reduced dendritic outgrowth and branching, whereas overexpression of constitutively active M-Ras, M-Ras(Q71L), enhanced dendritic outgrowth and branching. Sema4D suppressed M-Ras activity and reduced dendritic outgrowth and branching, but this reduction was blocked by M-Ras(Q71L). M-Ras(Q71L) stimulated extracellular signal-regulated kinase (ERK) activation, inducing dendrite growth, whereas Sema4D suppressed ERK activity and down-regulation of ERK was required for a Sema4D-induced reduction of dendrite growth. Thus, we conclude that Plexin-B1 is a dual functional GAP for R-Ras and M-Ras, remodelling axon and dendrite morphology, respectively.
