PHOSPHORYLCHOLINE - A NOVEL 2ND MESSENGER ESSENTIAL FOR MITOGENIC ACTIVITY OF GROWTH-FACTORS

Growth factor stimulation of quiescent cells induces a series of intra cellular early and late events that ultimately lead to DNA synthesis a nd cell division. We describe here that production of phosphorylcholin e is an essential component of the late events involved in the inducti on of DNA synthesis by platelet-derived growth factor (PDGF-BB), a pro totype mitogen for fibroblasts. Moreover, phosphorylcholine itself is mitogenic when added exogenously to NIH3T3 cells, further indicating i ts role as a crucial intracellular messenger for DNA synthesis. Cholin e kinase, the first step in the route of phosphatidylcholine synthesis appears to be the critical regulatory enzyme in phosphorylcholine pro duction, indicating that regulation of choline kinase represents a key step during mitogenic stimulation. We also describe that several grow th factors (PDGF-AA, basic FGF, EGF and phorbol esters) rely on their ability to generate phosphorylcholine for their proliferating activity . In contrast, DNA synthesis induced by serum did not require phosphor ylcholine. Moreover, the requirement for phosphorylcholine production in PDGF-stimulated cells can be over-ruled by addition of insulin. Thu s, cell proliferation in NIH3T3 cells can be triggered off by alternat ive pathways and one of them involves generation of phosphorylcholine.