Does calcium contribute to the CD95 signaling pathway?

Death receptors play a crucial role in immune surveillance and cellular homeostasis, two processes circumvented by tumor cells. CD95 (also termed Fas or APO1) is a transmembrane receptor, which belongs to the tumor necrosis factor receptor superfamily, and induces a potent apoptotic signal. Initial steps of the CD95 signal take place through protein/protein interactions that bring zymogens such as caspase-8 and caspase-10 closer. Aggregation of these procaspases leads to their autoprocessing, to the release of activated caspases in the cytosol, which causes a caspase cascade, and to the transmission of the apoptotic signal. In parallel, CD95 engagement drives an increase in the intracellular calcium concentration (Ca2+)(i) whose origin and functions remain controversial. Although Ca2+ ions play a central role in apoptosis/necrosis induction, recent studies have highlighted a protective role of Ca2+ in death receptor signaling. In the light of these findings, we discuss the role of Ca2+ ions as modulators of CD95 signaling. Anti-Cancer Drugs 22:481-487 (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.