Coregulation of neurite outgrowth and cell survival by amphoterin and S100proteins through receptor for advanced glycation end products (RAGE) activation

Amphoterin is a protein enhancing process extension and migration in embryo nic neurons and in tumor cells through binding to receptor for advanced gly cation end products (RAGE), a multiligand transmembrane receptor. S100 prot eins, especially S100B, are abundantly expressed in the nervous system and are suggested to function as cytokines with both neurotrophic and neurotoxi c effects. However, the cell surface receptor for the cytokine function of S100B has not been identified. Here we show that two S100 family proteins, S100B and S100A1, activate RAGE in concert with amphoterin inducing neurite outgrowth and activation of transcription factor NF-kappaB. Furthermore, a ctivation of RAGE by amphoterin and S100B promotes cell survival through in creased expression of the anti-apoptotic protein Bcl-2. However, whereas na nomolar concentrations of S100B induce trophic effects in RAGE-expressing c ells, micromolar concentrations of S100B induce apoptosis in an oxidant-dep endent manner. Both trophic and toxic effects are specific for cells expres sing full-length RAGE since cells expressing a cytoplasmic domain deletion mutant of RAGE are unresponsive to these stimuli. These findings suggest th at activation of RAGE by multiple ligands is able to promote trophic effect s whereas hyperactivation of RAGE signaling pathways promotes apoptosis, We suggest that RAGE is a signal-transducing receptor for both trophic and to xic effects of S100B.