The receptor for advanced glycation endproducts (RAGE) interacts with several ligands and is involved in various human diseases. RAGE_v1 or sRAGE, a RAGE splice variant, is secreted and contributes to the removal of RAGE ligands. Because RAGE blockade by specific antibodies directed against RAGE extracellular domains and the use of sRAGE have been proven to be beneficial in the context of pathological settings, both RAGE and sRAGE are considered as therapeutic target. Here, we show that sRAGE is also produced through regulated intramembrane proteolysis of the RAGE receptor, which is catalyzed by ADAM10 and the gamma-secretase and that calcium is an essential regulator of RAGE processing. Furthermore, RAGE intracellular domain localizes both in the cytoplasm and the nucleus and induces apoptosis when expressed in cells. These findings reveal new aspects of RAGE regulation and signaling and also provide a new interaction between RAGE and human pathologies.