Lipids were originally thought to play important roles only in energy storage and membrane structure. Recent experimental evidence indicate that phospholipids also play critical roles as mediators in cell activation and signal transduction. Phospholipases are the key enzymes that regulate various signalling pathways. Inositol phospholipid-specific phospholipase C (PLC) catalyzes thehydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), to generate 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 events leading to cellular calcium mobilization by IP3 and protein kinase C (PKC) activation by DAG. In this article, we address two aspects to PLC signalling: 1. characterization, purification and molecular cloning of PLC isozymes; and 2. mitogenic and catalytic activities of PLC isozymes. In addition to reviewing published data on PLC signalling, we have included new data that examine the mitogenic activity of the PLC isozymes. PLC-β and PLC-γ induce DNA synthesis after microinjection into quiescent NIH/3T3 cells, while PLC-Iδ does not exhibit this activity. Monoclonal antibodies to PLC-γ were shown to block serum-stimulated growth of NIH/3T3 cells and several oncogenes transformed NIH/3T3 cells (fes, src, ras and mos), yet Raf transformed cells were not inhibited by antibody injection. Thus, PLC-γ signalling is required for serum- and (fes, src, ras and mos) oncogene-induced proliferation of fibroblasts.
Phospholipase C/signal transduction
