A novel pathway of cell growth regulation mediated by a PLA 2 α‐derived phosphoinositide metabolite

The phosphoinositides have well‐defined roles in the control of cellular functions, including cytoskeleton dynamics, membrane trafficking, and cell signaling. However, the interplay among the phosphoinositides and their diffusible derivatives that originate through phospholipase A 2 action (the lysophosphoinositides and glycerophosphoinositols) remains to be fully elucidated. Here we demonstrate that in PCCl 3 rat thyroid cells, the intracellular levels of glycerophosphoinositol are finely modulated by ATP and norepinephrine through the P2Y metabotropic and a‐adrenergic receptors, respectively. The enzyme involved here is phospholipase A 2 IVa (PLA 2 IVα), which in these cells specifically hydrolyzes phosphatidylinositol, forming lysophosphatidylinositol, glycerophosphoinositol, and arachidonic acid. This receptor‐mediated activation of PLA 2 IVα leads to stimulation of PCCl 3 cell growth. The involvement of a PLA 2 IVα‐mediated pathway is demonstrated by inhibition of the increase in intracellular glycerophosphoinositol levels and cell proliferation by specific inhibitors, RNA interference, and overexpression of the dominant‐negative PLA 2 IVα 1–522 . Modulation of PCCl 3 cell growth is not seen with inhibitors of arachidonic acid metabolism. In conclusion, these data characterize glycerophosphoinositol as a mediator of the purinergic and adrenergic regulation of PCCl 3 cell proliferation, defining a novel regulatory cascade specifically involving this soluble phosphoinositide derivative and widening the involvement of the phosphoinositides in the regulation of cell function.—Mariggiò, S., Sebastià, J., Filippi, B. M., Iurisci, C., Volonté, C., Amadio, S., De Falco, V., Santoro, M., Corda, D. A Novel pathway of cell growth regulation mediated by a PLA 2 α‐derived phosphoinositide metabolite. FASEB J. 20, E1964–E1978 (2006)