Signal Transduction in Receptor for Advanced Glycation End Products (RAGE)

• Published in: The Journal of biological chemistry Vol. 287; no. 7; pp. 5133 - 5144
• Main Authors: Rai, Vivek, Maldonado, Andres Y., Burz, David S., Reverdatto, Sergey, Schmidt, Ann Marie, Shekhtman, Alexander
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.02.2012
• Subjects: Diabetes; NMR; Receptor for Advanced Glycation End Products (RAGE); Receptor Structure-Function; Signal Transduction; Receptor for Advanced Glycation End Products (RAGE); NMR; Receptor Structure-Function; Diabetes; Signal Transduction
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.277731

The receptor for advanced glycation end products (RAGE) is a multiligand cell surface macromolecule that plays a central role in the etiology of diabetes complications, inflammation, and neurodegeneration. The cytoplasmic domain of RAGE (C-terminal RAGE; ctRAGE) is critical for RAGE-dependent signal transduction. As the most membrane-proximal event, mDia1 binds to ctRAGE, and it is essential for RAGE ligand-stimulated phosphorylation of AKT and cell proliferation/migration. We show that ctRAGE contains an unusual α-turn that mediates the mDia1-ctRAGE interaction and is required for RAGE-dependent signaling. The results establish a novel mechanism through which an extracellular signal initiated by RAGE ligands regulates RAGE signaling in a manner requiring mDia1. Background: RAGE is implicated in diabetes complications, inflammation, and neurodegeneration. Results: Cytosolic domain of RAGE, ctRAGE, contains an unusual α-turn that mediates the mDia1-ctRAGE interaction and is required for RAGE-dependent signaling. Conclusion: A novel mechanism through which extracellular RAGE ligands regulate RAGE-mDia1 signaling is established. Significance: A novel binding interface as a target for suppression of RAGE ligand-stimulated signal transduction is identified.