Plasma membrane is now recognized to contain tightly packed
cholesterol/
sphingolipid-rich domains, known as
lipid or membrane rafts, which are more ordered than the surrounding
lipid bilayer.
Lipid rafts are crucial for the compartmentalization of signaling processes in the membrane, mostly involved in cell survival and immune response. However, in the last 15 years, a large body of evidence has also identified raft platforms as scaffolds for the recruitment and clustering of
death receptor Fas/CD95 and downstream signaling molecules, leading to the concept of death-promoting
lipid rafts. This raft-Fas/CD95 coclustering was first described at the early 2000s as the underlying mechanism for the proapoptotic action of the alkylphospholipid analog
edelfosine in leukemic cells, hence facilitating
protein-
protein interactions and conveying apoptotic signals independently of Fas/
CD95 ligand.
Edelfosine induces apoptosis in hematologic
cancer cells and activated T-lymphocytes. Fas/CD95 raft coclustering is also promoted by Fas/
CD95 ligand, agonistic Fas/CD95
antibodies, and additional
antitumor drugs. Thus,
death receptor recruitment in rafts is a physiologic process leading to cell demise that can be pharmacologically modulated. This redistribution and local accumulation of apoptotic molecules in membrane rafts, which are usually accompanied by displacement of survival signaling molecules, highlight how alterations in the apoptosis/survival signaling balance in specialized membrane regions modulate cell fate. Membrane rafts might also modulate apoptotic and nonapoptotic
death receptor signaling. Here, we discuss the role of
lipid rafts in Fas/CD95-mediated apoptotic cell signaling in hematologic
cancer cells and normal leukocytes, with a special emphasis on their involvement as putative therapeutic targets in
cancer and
autoimmune diseases.