Semaphorin Signaling to Actin

Abstract

Modulation of the actin cytoskeleton underlies the protrusion and retraction responses of migrating neuronal growth cones. Semaphorins (Semas) are transmembrane proteins that elicit growth cone collapse, but the signaling events that affect actin dynamics when Semas engage their cell surface receptors, called plexins, remain unclear. Aizawa et al. report that Sema 3 may alter actin through the action of cofilin, an actin-binding protein that stimulates actin filament depolymerization. When dorsal root ganglion (DRG) neurons were treated with Sema 3A, sequential phoshorylation and then dephosphorylation of cofilin at the growth cone correlated with growth cone collapse. The authors suggest that serine phosphorylation of cofilin stabilizes peripheral actin filaments in the growth cone, but subsequent dephosphorylation by a phosphatase, that has yet to be identified, then reactivates cofilin, resulting in the rapid actin depolymerization that is characteristic of semaphorins. Inhibition of LIM-kinase in DRG neurons indicates that LIM-kinase is necessary, but not sufficient, for this growth cone collapse response. How plexins activate LIM-kinase remains to be determined. Interestingly, LIM-kinase activity is known to be regulated by Rac, the small GTP-binding protein that has also been implicated in gowth cone collapse by semaphorins. Driessens et al. report that activation of plexin-B1 that is overexpressed in fibroblasts results in activation of the small GTP-binding protein Rho in a Rac -dependent manner, causing actin stress fiber formation. The authors determined that activated Rac binds to the cytoplasmic domain of plexin-B1, but the significance of this interaction is not yet clear as plexin that lacks the Rac-binding region is still functional in control of the cytoskeleton. H. Aizawa, S. Wakatsuki, A. Ishii, K. Moriyama, Y. Sasaki, K. Ohashi, Y. Sekine-Aizawa, A. Sehara-Fujisawa, K. Mizuno, Y. Goshima, I. Yahara, Phosphorylation of cofilin by LIM-kinase is necessary for semaphorin 3A-induced growth cone collapse. Nature Neurosci. 4 , 367-373 (2001). [Online Journal] M. H. E. Driessens, H. Hu, C. D. Nobes, A. Self, I. Jordens, C. S. Goodman, A. Hall, Plexin-B semaphorin receptors interact directly with active Rac and regulate the actin cytoskeleton by activating Rho. Curr. Biol. 11 , 339-344 (2001). [Online Journal]