The semaphorin family of guidance cues act predominantly through plexin receptors at the surface of various cell types. The small guanosine triphosphatases (GTPases) Rho and Rac have been implicated as downstream effectors of semaphorin-plexin interactions that modulate the cytoskeleton, but details of how plexins activate these GTPases are not clear. Swiercz et al. report that ErbB-2 was required for Sema4D-induced axon growth cone collapse in primary hippocampal neurons. Plexin B family members also interacted with the transmembrane tyrosine kinase ErbB-2 in cultured mammalian fibroblasts. Expression of an ErbB-2 mutant lacking kinase activity, or treatment of cells with an ErbB-specific inhibitor, blocked Sema4D-mediated activation of RhoA and tyrosine phosphorylation of Plexin-B1. Plexin phosphorylation was required for activation of RhoA through a complex that contains a Rho guanine nucleotide exchange factor (RhoGEF) protein. Although Sema4D did not bind to ErbB-2, it induced phosphorylation of a tyrosine residue in ErbB-2 that activated a Shc-ERK signaling pathway, which suggests that semaphorins may regulate Erb signaling cascades that control cell proliferation and differentiation. ErbB-2 has no known ligand and acts through dimerization with other Erb family members. Activation of ErbB-2 (by interaction with ErbB-1) by epidermal growth factor (EGF) did not result in tyrosine phosphorylation of plexin-B1 or RhoA activation. However, Sema4D-induced plexin phosphorylation was inhibited by EGF, which suggests that ligand-bound plexin and ligand-bound ErbB-1 compete for ErbB-2. J. M. Swiercz, R. Kuner, S. Offermanns, Plexin-B1/RhoGEF-mediated RhoA activation involves the receptor tyrosine kinase ErbB-2. J. Cell Biol . 165 , 869-880 (2004). [Abstract] [Full Text]