CROSS-TALK BETWEEN THE BIOACTIVE GLYCEROLIPIDS AND SPHINGOLIPIDS IN SIGNAL-TRANSDUCTION

Hydrolysis of phosphatidylcholine via receptor-mediated stimulation of phospholipase D produces phosphatidate that can be converted to lysop hosphatidate and diacylglycerol. Diacylglycerol is an activator of pro tein kinase C, whereas phosphatidate and lysophosphatidate stimulate t yrosine kinases and activate the Ras-Raf-mitogen-activated protein kin ase pathway. These three lipids can stimulate cell division. Conversel y, activation of sphingomyelinase by agonists (e.g., tumor necrosis fa ctor-alpha) causes ceramide production that inhibits cell division and produces apoptosis. If ceramides are metabolized to sphingosine and s phingosine 1-phosphate, then these lipids can stimulate phospholipase D and are also mitogenic. By contrast, ceramides inhibit the activatio n of phospholipase D by decreasing its interaction with the G-proteins , ARF and Rho, which are necessary for its activation. In whole cells, ceramides also stimulate the degradation of phosphatidate, lysophosph atidate, ceramide 1-phosphate, and sphingosine 1-phosphate through a m ultifunctional phosphohydrolase (the Mg2+-independent phosphatidate ph osphohydrolase), whereas sphingosine inhibits phosphatidate phosphohyd rolase. Tumor necrosis factor-alpha causes insulin resistance, which m ay be partly explained by ceramide production. Cell-permeable ceramide s decrease insulin-stimulated glucose uptake in 3T3-L1 adipocytes afte r 2-24 h, whereas they stimulate basal glucose uptake. These effects d o not depend on decreased tyrosine phosphorylation of the insulin rece ptor and insulin receptor substrate-1 or the interaction of insulin re ceptor substrate-1 with phosphatidylinositol 3-kinase. They appear to rely on the differential effects of ceramides on the translocation of GLUT1- and GLUT4-containing vesicles. It is concluded that there is a significant interaction and ''cross-talk'' between the sphingolipid an d glycerolipid pathways that modifies signal transduction to control v esicle movement, cell division, and cell death.