A TALE OF PROTEIN KINASE C: MEMBRANE LIPID MEDIATORS FOR CELL SIGNALING AND REGULATION
YASUTOMI NISHIZUKA
Membrane lipid constituents such as glycolipids and sphingolipids were classically views as biologically inert entities that provide a semipermeable barrier between exterior and interior compartments within and between cells. The discovery of protein kinase C (PKC) nearly 20 years ago opened an entirely new facet of research in the field of signal transduction, because a lipid product, diacylglycerol that is derived from signal-induced breakdown of membrane phospholipids, particularly inositol phospholipid, was found to trigger the activation of this emzyme. Subsequent finding of PKC as the major cellular target of tumor-promoting phorbol esters has established the importance of this enzyme in cell signaling and regulation. It became clear soon that PKC comprizes multiple discrete isoforms having related structures.
Recently, vast repertoire of lipids such as arachidonic acid and phosphatidylinositol-3,4,5-trisphosphate, that are produced in the membrane upon cell stimulation by various biologically active substances and stresses, are also shown to act as mediators for the activation of the PKC family as well as many other signaling proteins. Identification of several functional domains within each signaling protein and elucidation of the mode of interaction of these domains with membrane lipid mediators and with other protein molecules, for instance anchoring proteins and "scaffold proteins", may facilitate our understanding of how each protein Kinase is activated and targeted to selective intracellular compartments such as plasma membranes, Golgi and nucleus, where the enzyme plays a unique regulatory role by phosphorylating its specific substrate proteins.
This talk will summarize briefly some of our recent works, including dynamic aspects of liqid mediators, targeting of each isoform to specific intracellular compartments, cross-talks and interaction of PKC isoform with other signaling pathways, and some thrapeutic applications.