Growth factor-like action of phosphatidic acid

Abstract

Phosphatidic acid (PA), an intriguing phospholipid that is rapidly produced during receptor-stimulated breakdown of phosphoinosi-tides, has often been proposed to function as a Ca²⁺ ionophore in activated cells1^1–5. The PA-ionophore hypothesis is supported by the fact that exogenously applied PA stimulates Ca²⁺ uptake in various cells4–6 and can evoke Ca²⁺-mediated physiological responses^2–5, 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 Ca²⁺ release. Furthermore, our data strengthen the notion that any Ca_i²⁺-mobilizing stimulus acting through phospholipase C may ultimately function as a growth factor.