The role of the plexin-A2 receptor in Sema3A and Sema3B signal transduction.

Class 3 semaphorins are anti-angiogenic and anti-tumorigenic guidance factors that bind to neuropilins, which, in turn, associate with class A plexins to transduce semaphorin signals. To study the role of the plexin-A2 receptor in semaphorin signaling, we silenced its expression in endothelial cells and in glioblastoma cells. The silencing did not affect Sema3A signaling, which depended on neuropilin-1, plexin-A1 and plexin-A4, but completely abolished Sema3B signaling, which also required plexin-A4 and one of the two neuropilins. Interestingly, overexpression of plexin-A2 in plexin-A1- or plexin-A4-silenced cells restored responses to both semaphorins, although it nullified their ability to differentiate between them, suggesting that, when overexpressed, plexin-A2 can functionally replace other class A plexins. By contrast, although plexin-A4 overexpression restored Sema3A signaling in plexin-A1-silenced cells, it failed to restore Sema3B signaling in plexin-A2-silenced cells. It follows that the identity of plexins in functional semaphorin receptors can be flexible depending on their expression level. Our results suggest that changes in the expression of plexins induced by microenvironmental cues can trigger differential responses of different populations of migrating cells to encountered gradients of semaphorins.