[Frontiers in Bioscience 16, 2756-2770 , June 1, 2011]

Alternative splicing of RAGE: roles in biology and disease

Anastasia Z. Kalea1, Ann Marie Schmidt2, Barry I Hudson3

1Division of Nephrology/Hypertension, Feinberg School of Medicine, Northwestern University, IL, 2 Department of Medicine and Pharmacology, NYU Langone Medical Center, NY, 3 Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami, FL

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Rage protein structure and domains
4. Rage gene structure and organization
5. Mechanisms of mRNA diversity of RAGE
5.1. Alternative promoters
5.2. Alternative poly(A) sites
5.3. Alternative splicing of RAGE
5.3.1. Premature stop codons / NMD targeted variants
5.3.2. Altered extracellular domain variants
5.3.3. Secreted non-membranous variants 5.3.4 ... Function of RAGEv1 / esRAGE
5.3.5. Regulation of RAGEv1/esRAGE
5.3.6. RAGEv1 / esRAGE as a novel biomarker for disease
6. Conclusions
7. Acknowledgements
8. References

1. ABSTRACT

The Receptor for Advanced Glycation End-products (RAGE) is a complex, multi-ligand signaling system implicated in the pathogenesis of diabetes, cardiovascular disease and various cancers. RAGE undergoes extensive alternative splicing to produce a variety of transcripts with diverse functions, including soluble antagonists and variants with altered ligand binding domains. Studies focused on the major soluble variant (RAGEv1/esRAGE) have revealed this to function by binding RAGE-ligands and preventing activation of RAGE signaling in vascular and tumor cells. Furthermore, measurement of this variant in human serum has revealed that RAGEv1/esRAGE levels may represent a novel biomarker for RAGE-ligand related pathogenic states. Understanding the full plethora of RAGE alternative splicing and its regulation is central to elucidating the role of RAGE in biology and disease.