Plexin D1 signals via the cytoskeletal scaffold protein filamin A

One of the major cell guidance mechanisms in the cardiovascular system involves the plexin family of transmembrane receptors and their ligands, the semaphorins. In particular, recent findings specifically implicated plexin D1 (plexD1) in this role, but its signaling mechanism is unknown. We have recently identified filamin A (FLNa) as the first known cytoplasmic binding partner of plexD1. It is also the first cytoskeletal protein found to interact directly with any plexin receptor. FLNa regulates the formation of actin networks and serves as an adaptor of numerous proteins, including Rho GTPases and integrins, both of which are major plexin effectors. Thus the association of FLNa with plexD1 may be the key to deciphering one of the major mechanisms of cardiovascular morphogenesis. FLNa consists of 24 modular domains, out of which plexD1 binds domains 10–11. Expression of this fragment in EC inhibited their migration rate, possibly by competing for plexD1 binding with endogenous FLNa, thus making more of the latter available for binding and inhibiting integrin β1. The inhibition would be expected to be independent of the plexD1 ligands sema3C and 3E. In agreement, the migration rate of the FLNa(10–11)‐expressing EC in response to VEGF was ~1/8 of the control group, and sema3E application (100 ng/ml) did not further inhibit their migration. These results provide the first insights into the signaling mechanism of plexD1.