RAGE – The Receptor of Advanced Glycation End Products

Abstract

The receptor of advanced glycation end products (RAGE) is a multi‐ligand binding protein that was initially described as an AGEs‐binding protein. Other proteins, some of them classified as danger signals or alarmins have been described as RAGE ligands. Of note, RAGE shares some of its ligands with some member of the Toll‐like receptor family. Once RAGE is engaged by any of its ligands, the receptor is able to trigger robust pro‐inflammatory cellular responses. At present, RAGE has emerged as a relevant actor in the onset and development of chronic inflammation, which underlies many human diseases.

Key Concepts

  • The receptor of advanced glycation end products is a multi‐ligand receptor.
  • RAGE variants are mainly originated by alternative splicing or proteolytic cleavage.
  • RAGE and TLRs share common ligands and signalling pathways.
  • RAGE activation is associated with activation of pro‐inflammatory signalling.
  • RAGE activation by AGEs play a key a role in the development and progression of diabetic nephropathy.
  • Most of the misfolded proteins linked to neurodegeneration act as RAGE ligands.
  • RAGE activation plays a key role in the disturbance of endothelial functions and cardiovascular homeostasis.
  • RAGE has been regarded as the bridge association between chronic inflammation and cancer.
  • RAGE activation in tumour cells promotes proliferation, invasion, angiogenesis and metastasis.

Keywords: RAGE; advanced glycation; alarmins; inflammation; cardiovascular diseases; diabetes; cancer; innate immunity; neurodenegeration

Figure 1. Structure and main isoforms of RAGE (receptor of advanced glycation end products). RAGE soluble isoforms may function as decoy receptors.
Figure 2. RAGE engagement by several ligands is able to trigger a complex intracellular signalling, where the production of ROS (reactive oxygen species) by the activation of NADPH (nicotinamide adenine dinucleotide phosphate) oxidase and the interaction of the RAGE cytoplasmic domain i with the FH1 domain of Dia‐1 are key and earlier events. The activation of several kinases leads to the activation of different pro‐inflammatory transcription factors such as NF‐kB, AP‐1 and Stat‐3. Of note, RAGE dimerisation is essential for increasing the molecular dimension of the receptor, recruiting Diaphanous 1 (DIAPH1) and thus strengthening the signalling pathways.
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Rojas, Armando, Morales, Miguel A, Araya, Paulina, and González, Ileana(Sep 2017) RAGE – The Receptor of Advanced Glycation End Products. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0027298]