page 869) show that plexin-B1, after binding its ligand semaphorin 4D (Sema4D), forms a heterodimer with the tyrosine kinase ErbB2. This raises the intriguing possibility that the semaphorins and the EGF-like ligands of ErbB receptors may affect each other's signaling abilities.
Swiercz et al. used a number of different kinase inhibitors to block the RhoA activation seen downstream of Sema4D binding to plexin-B1. These findings revealed that one or more proteins in the ErbB family was involved. Of the four members of the ErbB family, only a dominant-negative ErbB2 mutant showed significant effects on RhoA activation. Unlike other family members, ErbB2 is not activated by a ligand. Rather it acts in trans via association with other tyrosine kinases. Likewise, Swiercz et al. found that plexin-B1 and ErbB2 form a heterodimer in which activated ErbB2 phosphorylates plexin-B1. This phosphorylation is required for plexin-B1 signaling via PDZ-RhoGEF/LARG to RhoA.
Competition experiments between Sema4D and EGF (which stimulates and activates ErbB1/ErbB2 heterodimers) resulted in an overall inhibition of plexin-B–mediated signaling by EGF. But, at the same time, Sema4D is able to activate the ErbB2 pathway, which may under some circumstances lead to tumor promotion. ▪