Network of Signal Transduction Pathways Involving Lipids: Protein Kinase C-Dependent and -Independent Pathways

Abstract

The cellular glycerol- and sphingolipids are turning out to play not only fundamental roles in cellular and organellar membranes but also new and exciting roles in cellular regulation. The great diversity and complexity of the glycerolipids and sphingolipids present in mammalian cells had long portended important cellular functions, yet few molecular clues were uncovered until protein kinase C was discovered by Nishizuka (1986) to be regulated by sn-l,2-diacylglycerol (DAG), a second messenger derived by cleavage of phosphatidylinositol 4,5-bisphosphate (PIP₂)- Glycerolipids turned out to play two major roles in protein kinase C regulation: i) as essential phospholipid cofactors and ii) as lipid second messenger activators, DAG (Bell, 1986). In 1985, detailed structure-activity studies on protein kinase C using advanced mixed micellar methods to investigate specificity and stoichiometry of phospholipid cofactor and DAG activator function produced molecular insight into the mechanism of regulation (Hannun et al., 1985); these studies also led to the discovery that sphingosine inhibits protein kinase C activity and blocks [³H]phorbol 12,13-dibutyrate ([³H]PDBu) binding (Hannun et al., 1986). The work opened up a growing field of research involving the role of sphingolipid breakdown products in normal cellular regulation and perturbation of these normal pathways in disease and pathobiology (Hannun and Bell, 1987; 1989).