Functional dichotomy of neutral and acidic sphingomyelinases in tumor necrosis factor signaling.

Ceramide produced by sphingomyelinases (SMases) has been recognized as an important second messenger in growth factor receptor signaling. Tumor necrosis factor (TNF), through binding to the 55 kDa TNF receptor (TNF-R55), rapidly activates two distinct types of SMase, a membrane-associated neutral (N-)SMase, and an endosomal acidic (A)-SMase. N-SMase and A-SMase are activated independently by different cytoplasmic domains of TNF-R55. Each type of SMase specifically couples to select pathways of TNF signaling. Ceramide generated by N-SMase directs the activation of proline-directed serine/threonine protein kinase(s) and phospholipase A2. In contrast, A-SMase triggers the activation of NF-kappa B. No apparent crosstalk was detected between N-SMase and A-SMase pathways, indicating that ceramide action depends on the topology of its production. These results suggest that N-SMase and A-SMase control important yet dissociable and nonoverlapping pathways of TNF receptor signal transduction.