Fig. 3. Sema4D exerts its biological activities responses through plexin-B1 or CD72. (a) Plexin-B1 mediates Sema4D-induced axon repulsion by coordinately regulating the activity of the Rac and Rho small GTPases. Plexin-B1 binds Rac-GTP and downregulates its activity by blocking access to PAK. Binding to the RhoGEF/PDZ-RhoGEF and LARG thereby increases the output of RhoA. During the regulation of epithelial cell invasive growth, Sema4D signals through a plexin-B1/Met receptor complex. Binding of Sema4D to plexin-B1 leads to the activation of Met. This binding event results in the phosphorylation of Met, plexin-B1 and the Met target Gab1. (b) Sema4D turns off the negative signaling of CD72. Signals from the BCR, CD40, and TLR4 are homeostatically regulated by Sema4DCD72 interactions. In the absence of Sema4D signaling, SHP-1 is associated with the ITIM of CD72. SHP-1 induces tyrosine dephosphorylation and the inactivation of several signaling effectors, including syk and lyn. Binding of Sema4D to CD72 induces the dephosphorylation of the CD72 ITIMs, resulting in the dissociation of SHP-1 from CD72.