Receptor for advanced glycation end products (RAGE)-mediated neurite outgrowth and activation of NF-kappa B require the cytoplasmic domain of the receptor but different downstream signaling pathways

Receptor for advanced glycation end products (RAGE) mediates neurite outgro wth in vitro on amphoterin-coated substrates. Ligation of RAGE by two other ligands, advanced glycation end products or amyloid beta-peptide, is sugge sted to play a role in cell injury mechanisms involving cellular oxidant st ress and activation of the transcription factor NF-kappa B, However, the RA GE signaling pathways in neurite outgrowth and cell injury are largely unkn own. Here we show that transfection of RAGE to neuroblastoma cells induces extension of filopodia and neurites on amphoterin-coated substrates. Furthe rmore, ligation of RAGE in transfected cells enhances NF-kappa B-dependent transcription. Both the RAGE-mediated neurite outgrowth and activation of N F-kappa B are blocked by deletion of the cytoplasmic domain of RAGE. Moreov er, dominant negative Rac and Cdc42 but not dominant negative Ras inhibit t he extension of neurites induced by RAGE-amphoterin interaction In contrast , the activation of NF-kappa B is inhibited by dominant negative Ras but no t Rac or Cdc42, These data suggest that distinct signaling pathways are use d by RAGE to induce neurite outgrowth and regulate gene expression through NF-kappa B.