PHOSPHOLIPASE-C SIGNALING

Recent experimental evidence indicate that phospholipids also play cri tical roles as mediators in cell activation and signal transduction. P hospholipases are the key enzymes that regulate Various signalling pat hways. Inositol phospholipid-specific phospholipase C (PLC) catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), to gen erate inositol triphosphate (IP3) and diacylglycerol (DAG) in response to several receptor-binding growth/differentiation factors, hormones, and neurotransmitters. The hydrolysis products serve as intracellular second messenger molecules which amplify the initial signalling event s leading to cellular calcium mobilization by IP3 and protein kinase C (PKC) activation by DAG. In this article, we address two aspects to P LC signalling: 1. characterization, purification and molecular cloning of PLC isozymes; and 2. mitogenic and catalytic activities of PLC iso zymes. In addition to reviewing published data on PLC signalling, we h ave included new data that examine the mitogenic activity of the PLC i sozymes. PLC-beta and PLC-gamma induce DNA synthesis after microinject ion into quiescent NIH/3T3 cells, while PLC-delta does not exhibit thi s activity. Monoclonal antibodies to PLC-gamma were shown to block ser um-stimulated growth of NIH/3T3 cells and several oncogenes transforme d NIH/3T3 cells (fes, src, ras and mos), yet Raf transformed cells wer e not inhibited by antibody injection. Thus, PLC-gamma signalling is r equired for serum- and (fes, src, ras and mps) oncogene-induced prolif eration of fibroblasts.