Growth factor-like action of phosphatidic acid

Phosphatidic acid (PA), an intriguing phospholipid that is rapidly produced during receptor-stimulated breakdown of phosphoinositides, has often been proposed to function as a Ca2+ ionophore in activated cells. The PA-ionophore hypothesis is supported by the fact that exogenously applied PA stimulates Ca2+ uptake in various cells and can evoke Ca2+-mediated physiological responses, but it is not known whether PA accumulation affects cytoplasmic free Ca2+ concentration ([Ca2+]i). Here we report that PA elicits a transient rise in [Ca2+]i in cultured cells, not by stimulating Ca2+ influx, but, surprisingly, by releasing Ca2+ from intracellular stores. We further show that PA evokes growth factor-like effects in that it raises cytoplasmic pH, induces expression of the c-fos and c-myc proto-oncogenes and stimulates DNA synthesis. Our results indicate that, unlike an ionophore, PA acts by triggering the hydrolysis of phosphoinositides, with consequent formation of second messengers such as inositol trisphosphate signalling Cai2+ release. Furthermore, our data strengthen the notion that any Ca2+-mobilizing stimulus acting through phospholipase C may ultimately function as a growth factor.