Receptor for advanced glycation end products (RAGE)-mediated neurite outgrowth and activation of NF-kappaB require the cytoplasmic domain of the receptor but different downstream signaling pathways.
Receptor for advanced glycation end products (RAGE) mediates neurite outgrowth in vitro on amphoterin-coated substrates. Ligation of RAGE by two other ligands, advanced glycation end products or amyloid beta-peptide, is suggested to play a role in cell injury mechanisms involving cellular oxidant stress and activation of the transcription factor NF-kappaB. However, the RAGE signaling pathways in neurite outgrowth and cell injury are largely unknown. Here we show that transfection of RAGE to neuroblastoma cells induces extension of filopodia and neurites on amphoterin-coated substrates. Furthermore, ligation of RAGE in transfected cells enhances NF-kappaB-dependent transcription. Both the RAGE-mediated neurite outgrowth and activation of NF-kappaB are blocked by deletion of the cytoplasmic domain of RAGE. Moreover, dominant negative Rac and Cdc42 but not dominant negative Ras inhibit the extension of neurites induced by RAGE-amphoterin interaction. In contrast, the activation of NF-kappaB is inhibited by dominant negative Ras but not Rac or Cdc42. These data suggest that distinct signaling pathways are used by RAGE to induce neurite outgrowth and regulate gene expression through NF-kappaB.
Laboratory of Molecular Neurobiology, Institute of Biotechnology, and Department of Biosciences, Division of Biochemistry, University of Helsinki, Finland. Henri.Huttunen@helsinki.fi
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D016229:Amyloid beta-Peptides; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics; D019204:GTP-Binding Proteins / Q000235:genetics; D005786:Gene Expression Regulation; D017127:Glycation End Products, Advanced / Q000378:metabolism; D024243:HMGB1 Protein; D006609:High Mobility Group Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism*; D009447:Neuroblastoma; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion; D015398:Signal Transduction; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D020744:rac GTP-Binding Proteins
D016229:Amyloid beta-Peptides; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D017127:Glycation End Products, Advanced; D024243:HMGB1 Protein; D006609:High Mobility Group Proteins; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D019204:GTP-Binding Proteins; D020744:rac GTP-Binding Proteins