Fig. 6.

A general model of Sema3/PlxnD1-mediated repulsion. A, In the absence of ligand-mediated activation PlxnD1 is in a conformation that enables its association with GTP-bound Rnd2 but prevents its interaction with active, GTP-bound Rac and R-Ras. Thus, GTP-bound Rac is able to bind to PAK (p21-activated kinase) to stimulate the assembly of actin filaments to support cell migration while active GTP-bound Ras promotes integrin-mediated adhesion to the extracellular matrix (ECM) and mediates additional downstream signaling events. B, Upon binding of its Sema3 ligand, PlxnD1 undergoes a conformational change and binds the active forms of both Rac and R-Ras GTPases. By sequestering Rac, PlxnD1 leads to the inactivation of PAK and the collapse of the actin-based cytoskeleton leading to retraction and/or turning responses. PlxnD1 inactivates R-Ras GTPases by either enhancing GTP hydrolysis (as shown) or by sequestering them resulting in the loss of integrin-based adhesion to the ECM (Ito et al., 2006; Oinuma et al., 2004a; Oinuma et al., 2006; Rohm et al., 2000; Sakurai et al., 2010; Uesugi et al., 2008) and likely reducing as well other R-Ras mediated signaling events.