SIGNAL-TRANSDUCTION THROUGH THE SPHINGOMYELIN PATHWAY

The sphingomyelin pathway is a new signal transduction system initiate d by hydrolysis of plasma membrane sphingomyelin to ceramide by the ac tin of a neutral sphingomyelinase. Ceramide serine/threonine protein k inase termed ceramide-activated protein kinase. This kinase belongs to a family of proline-directed protein kinases that recognize substrate s containing the minimal motif, X-Thr/Ser-ProX, where the phosphoaccep tor site is followed on the carboxyl terminus by a proline residue and X may be any amino acid. Three lines of evidence, rapid kinetics of a ctivation of the sphingomyelin pathway by tumor necrosis factor (TNF)a lpha, the ability of cell-permeable ceramide analogs to bypass recepto r activation and mimic the effect of TNFalpha, and reconstitution of t his cascade in a cell-free system, support the concept that the sphing omyelin pathway serves to signal TNFalpha-induced monocytic differenti ation. Hence, the sphingomyelin pathway may represent a signaling syst em analogous to more well-defined systems such as the cyclic adenosine monophosphate and phosphoinositide pathways.