Receptor for Advanced Glycation End Products (RAGE)-mediated Neurite Outgrowth and Activation of NF-κB Require the Cytoplasmic Domain of the Receptor but Different Downstream Signaling Pathways*
- From the Laboratory of Molecular Neurobiology, Institute of Biotechnology, and Department of Biosciences, Division of Biochemistry, University of Helsinki, P. O. Box 56 (Viikinkaari 5), University of Helsinki, Helsinki FIN-00014, Finland
Abstract
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 β-peptide, is suggested to play a role in cell injury mechanisms involving cellular oxidant stress and activation of the transcription factor NF-κB. 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-κB-dependent transcription. Both the RAGE-mediated neurite outgrowth and activation of NF-κB 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-κB 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-κB.
Footnotes
-
↵* This work was supported by grants from the Academy of Finland, the Sigrid Jusélius Foundation, and the Center for International Mobility Organization.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
-
↵‡ To whom correspondence should be addressed. Tel.: +358-9-70859060; Fax: +358-9-70859068; E-mail: Henri.Huttunen@helsinki.fi.
-
↵§ Both authors are in the Helsinki Graduate School in Biotechnology and Molecular Biology.
- Abbreviations:
- RAGE
-
receptor for advanced glycation end products
- AGE
-
advanced glycation end products
- HB-GAM
-
heparin-binding growth-associated molecule
- PI 3-kinase
-
phosphatidylinositol 3-kinase
- MAP kinase
-
mitogen activated protein kinase
- MEK
-
MAP or extracellular signal-related kinase kinase
- BES
-
N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid
- BSA
-
bovine serum albumin
- PBS
-
phosphate-buffered saline
- TRITC
-
tetramethylrhodamine isothiocyanate
- PAK
-
p21-activated kinase
-
- Received February 18, 1999.
- Revision received April 20, 1999.
- The American Society for Biochemistry and Molecular Biology, Inc.
