Over 1,000 papers and reviews have been written about the role of ceramide in the production of programmed cell death or apoptosis. Ceramide is a sphingosine-based lipid-signaling molecule involved in the regulation of cellular differentiation, proliferation, and apoptosis. This diagram represents some of the current understanding of the cascades that couple ceramide to specific signaling pathways. These cascades illustrate that ceramide can be a growth stimulus or proapototic signal. The ultimate ceramide action is determined within the context of other stimuli and by the subcellular topology of its production and is cell-type specific. There are 2 forms of sphingomyelinase, acid (acid-sphingomyelinase:A-SMase) and neutral (neutral-sphingomyelinase N-SMase), that can produce ceramide. TNF-alpha can stimulate either form of sphingomyelinase as can other death receptors. Different domanis of TNF-alpha stimulate the different Smases. N-SMase stimulation is enhanced by the receptor for activated-C kinase 1 (RACK1). The activity of each form is dependent on the local intracellular pH. In the illustration the forms are seperated to reduce confusion however ceramide produced by either method can stimulate either cascade depending on the presence of specific co-factors and activators. A-SMase has been recognized as one of the required molecules to mediate proapoptotic signalling in cell death induced by a diverse array of stresses such as H2O2, Heat, UV exposure and Radiation. ROS generation in mitochondria activates caspase-3 via cooperation of cytochrome c, Aif and caspase-9 and stimulates or increases ceramide generation through A-SMase in a proaptotic activation cycle. Caspase-3 further increases its own activation by proteolytically cleaving ceramide inhibited catalase which is an inhibitor of ROS generation. Ceramide-activated protein kinase(CARK) also known as Kinase Supressor of RAS (KSR) activity is in some cases the switch point in the balance between proapoptotic and antiapoptotic signals and is also cell-type specific. In endothelial cells for example the activation of KSR is required for apoptosis. In contrast in epithelial cells activation of KSR is required for cell proliferation. An additional switch point is the availability of Bad in the cell. Activation of KSR leads to further mitocondrial stimulation or association with RAS and activation of the Raf1 cascade leading to proliferation or differentiation.
