Alternative Splicing of the RAGE Cytoplasmic Domain Regulates Cell Signaling and Function

The Receptor for Advanced Glycation End-products (RAGE) is a multi-ligand receptor present on most cell types. Upregulation of RAGE is seen in a number of pathological states including, inflammatory and vascular disease, dementia, diabetes and various cancers. We previously demonstrated that alternative splicing of the RAGE gene is an important mechanism which regulates RAGE signaling through the production of soluble ligand decoy isoforms. However, no studies have identified any alternative splice variants within the intracellular region of RAGE, a region critical for RAGE signaling. Herein, we have cloned and characterized a novel splice variant of RAGE that has a truncated intracellular domain (RAGE Delta ICD). RAGE Delta ICD is prevalent in both human and mouse tissues including lung, brain, heart and kidney. Expression of RAGE Delta ICD in C6 glioma cells impaired RAGE-ligand induced signaling through various MAP kinase pathways including ERK1/2, p38 and SAPK/JNK. Moreover, RAGE Delta ICD significantly affected tumor cell properties through altering cell migration, invasion, adhesion and viability in C6 glioma cells. Furthermore, C6 glioma cells expressing RAGE Delta ICD exhibited drastic inhibition on tumorigenesis in soft agar assays. Taken together, these data indicate that RAGE Delta ICD represents a novel endogenous mechanism to regulate RAGE signaling. Significantly, RAGE Delta ICD could play an important role in RAGE related disease states through down regulation of RAGE signaling.