Cross-talk between phosphatidylinositol 3-kinase and sphingomyelinase pathways as a mechanism for cell survival/death decisions

Peptide hormones act to regulate apoptosis through activation of multiple p ro- and anti-apoptotic signaling cascades of which lipid signaling events r epresent an important facet of the cellular rheostat that determines surviv al and death decisions. Activation of sphingomyelinase, which generates cer amide, is an intermediate in cellular stress responses and induction of apo ptosis in many systems. Conversely, phosphatidylinositol 3-kinase (PI3K) is a critical signaling molecule involved in regulating cell survival and pro liferation pathways. In the present study, we investigate cross-talk betwee n the PI3K and sphingomyelinase pathways as a mechanism for regulation of c ell survival/death decisions. We show that phorbol ester, insulin-like grow th factor 1, and a constitutively active PI3K suppress both tumor necrosis factor-induced apoptosis and ceramide generation. Conversely, inhibition of the PI3K pathway with expression of a kinase-dead PI3K both prevented surv ival signaling and enhanced tumor necrosis factor-induced ceramide generati on. The ability of exogenous sphingomyelinase to induce ceramide generation was partially suppressed by expression of constitutively active PI3K and e nhanced by inhibition of PI3K suggesting that cross-talk between PI3K and c eramide generation within cells is regulated subsequent to activation of sp hingomyelinase.