Signaling cascades mediated by plexin-A and plexin-B, and their crosstalk with oncogenic pathways in gliomas. Plexin-As serve as coreceptors for neuropilins to transduce signals of class 3 semaphorins. Fyn is activated upon semaphorin stimulation, which phosphorylates cyclin-dependent kinase-5 (Cdk5) and in turn collapse response mediator protein (CRMP). Cdk5 also phosphorylates isoform A of phosphatidylinositol 3-kinase enhancer (PIKE-A), which is a pro-oncogenic and antiapoptotic factor that activates AKT and promotes glioma cell growth, migration, and invasion. Stimulation of plexin-B with semaphorins causes recruitment of active Rac1 to the Cdc42/Rac interactive binding (CRIB) domain in the cytoplasmic tail, leading to sequestration of Rac1-GTP from its effector p21-activated kinase (PAK) and suppression of its downstream signalings. Stimulation of plexin-B also promotes the recruitment of Rac1 to Rho GDP-dissociation inhibitor (RhoGDI) α, which sequesters Rac1 and shuttles it from the membrane to the cytosol to prevent activation. The PDZ domain binding motif at the C-terminus of plexin-B interacts with PDZ domain containing Rho guanine nucleotide exchange factors (PDZ-RhoGEF), which promotes RhoA activation. RhoA-GTP can signal to Raf and activate the MAPK pathway. The GTPase activating protein (GAP) domain in the cytoplasmic tail of plexin-A and -B is activated upon semaphorin stimulation and Rnd1 binding, leading to inactivation of R-Ras and PI3K signaling but derepression of PTEN activities.