Ceramide in apoptosis. Several direct targets of ceramide have been identified, including Cathepsin D and the serine/threonine protein phosphatases PP1 and PP2A. These phosphatases act on several substrates such as the retinoblastoma gene product Rb, Bcl-2, PKC, Akt, and SR proteins. Increasingly, these pathways seem to be compartmentalized. In particular, Cathepsin D is activated by ceramide generated in lysosome membranes leading to activation of the proapoptotic protein Bid. Mitochondrial membrane potential can also be altered by these pathways, probably through disparate signal cascades affecting various Bcl-2 family members. Apoptosis induction through JNK activation is mediated by ceramide-dependent signaling by MKK4. These downstream effects can lead to changes in growth arrest, senescence, and apoptosis.