The p75 receptor acts as a displacement factor that releases Rho from Rho-GDI

Abstract

The neurotrophin receptor p75(NTR) is involved in the regulation of axonal elongation by neurotrophins as well as several myelin components, including Nogo, myelin-associated glycoprotein (MAG) and myelin oligodendrocyte glycoprotein (OMgp). Neurotrophins stimulate neurite outgrowth by inhibiting Rho activity, whereas myelin-derived proteins activate RhoA and thereby inhibit growth. Here we show that direct interaction of the Rho GDP dissociation inhibitor (Rho-GDI) with p75(NTR) initiates the activation of RhoA, and this interaction between p75(NTR) and Rho-GDI is strengthened by MAG or Nogo. We also found that p75(NTR) facilitates the release of prenylated RhoA from Rho-GDI. The peptide ligand that is associated with the fifth alpha helix of p75(NTR) inhibits the interaction between Rho-GDI and p75(NTR), thus silencing the action mediated by p75(NTR). This peptide has potential as a therapeutic agent against the inhibitory cues that block regeneration in the central nervous system.

BNIP-Sα induces cell rounding and apoptosis by displacing p50RhoGAP and facilitating RhoA activation via its unique motifs in the BNIP-2 and Cdc42GAP homology domain

“…Recently, several proteins were reported to interact with either RhoA protein or its regulators indicating a similar sequestration mode of action. For example, p75 neurotrophin receptor could facilitate the release of prenylated RhoA from Rho-GDI by targeting Rho-GDI (Yamashita and Tohyama, 2003). A similar observation was reported with the ERM (ezrin/radixin/moesin) protein, which could also function as a Rho-GDI displacement factor to induce activation of RhoA in Swiss 3T3 cells (Takahashi et al, 1997).…”

Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS

“…By contrast, it has also been reported that Rho only associates with p75 NTR and becomes active on binding of Mag to the receptor complex 37 . More recently, it was reported that p75 NTR interacts only indirectly with Rho by binding to and displacing Rho-GDP dissociation inhibitor (Rho-GDI), thereby activating Rho 65 .…”

Anti-cancer drug induced neurotoxicity and identification of Rho pathway signaling modulators as potential neuroprotectants

“…These studies further validate Rho signaling as an important element in the attenuation of anti-cancer drug induced neurotoxicity. Since Rho GTPases are now well established as a convergence point downstream of p75 NTR in the regulation of neurite outgrowth (Domeniconi et al, 2005;Yamashita and Tohyama, 2003;Yamashita et al, 1999;Yamauchi et al, 2004), we propose that the inhibition of p75 NTR activation of Rho GTPases is important to maintain normal neuronal morphology during anti-cancer drug exposure.…”