Coregulation of Neurite Outgrowth and Cell Survival by Amphoterin and S100 Proteins through Receptor for Advanced Glycation End Products (RAGE) Activation*

By H. Huttunen, J. Kuja-Panula, G. Sorci, A. L. Agneletti, R. Donato, H. Rauvala. Journal of Biological Chemistry, 2000

611 citations recorded by the source corpus.

Amphoterin is a protein enhancing process extension and migration in embryonic neurons and in tumor cells through binding to receptor for advanced glycation end products (RAGE), a multiligand transmembrane receptor. S100 proteins, especially S100B, are abundantly expressed in the nervous system and are suggested to function as cytokines with both neurotrophic and neurotoxic 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-κB. Furthermore, activation of RAGE by amphoterin and S100B promotes cell survival through increased expression of the anti-apoptotic protein Bcl-2. However, whereas nanomolar concentrations of S100B induce trophic effects in RAGE-expressing cells, micromolar concentrations of S100B induce apoptosis in an oxidant-dependent manner. Both trophic and toxic effects are specific for cells expressing full-length RAGE since cells expressing a cytoplasmic domain deletion mutant of RAGE are unresponsive to these stimuli. These findings suggest that activation of RAGE by multiple ligands is able to promote trophic effects whereas hyperactivation of RAGE signaling pathways promotes apoptosis. We suggest that RAGE is a signal-transducing receptor for both trophic and toxic effects of S100B.

Subfields: Clinical Biochemistry, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/6e3d4156513b0f57420120857e64ce588e6bce84

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In Clinical Biochemistry

1. Kevin J. Tracey
2. Michael Lotze
3. A. Tsung
4. Timothy R. Billiar
5. D. Tang
6. R. Kang
7. H. J. Zeh

In Molecular Biology

1. Michael Lotze
2. Kevin J. Tracey
3. Bruce S. McEwen
4. D. Tang
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6. Peter J. Gianaros
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Citations in the corpus

• S100B in brain damage and neurodegeneration (2003, background): “In chick embryonal neurons, transfected N18 mouse neuroblastoma, and C6 rat glioma, the prosurvival activity of extracellular S100B and the ability of this protein to stimulate neurite outgrowth appear to depend on the nuclear translocation of Nuclear Factor B (NF B) and upregulation of the expressi”
• Understanding RAGE, the receptor for advanced glycation end products (2005, background): “, lacking the cytosolic tail) are unresponsive to these stimuli [50, 90].”
• The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion (2005, background): “HMGB1, in vitro, interacts with TLR2, TLR4, and the receptor for advanced glycation end products for HMGB1-induced activation of inflammatory signaling (12, 32, 33).”
• Intracellular and extracellular roles of S100 proteins (2003, background): “…in both neurotrophic (via activation of the Ras-mitogen activated protein [MAP] kinase-NF B pathway and the cdc42/Rac pathway) and neurotoxic (via accumulation of reactive oxygen species and persistent activation of the Ras-MAP kinase pathway) effects of S100B (Huttunen et al., 2000) (Table 5).”
• Role of advanced glycation end products in cellular signaling (2014, background): “Low concentrations lead to more beneficial events (neurite outgrowth) and high concentrations, inducing more deleterious events (inflammatory signaling) [200].”