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A novel pathway of cell growth regulation mediated by a PLA₂-derived phosphoinositide metabolite

Stefania Mariggiò¹, Jordi Sebastià, Beatrice Maria Filippi, Cristiano Iurisci, Cinzia Volonté^*, Susanna Amadio^*, Valentina De Falco, Massimo Santoro and Daniela Corda¹

Department of Cell Biology and Oncology, Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy;
^* Santa Lucia Foundation/CNR, Rome, Italy; and

Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università Federico II di Napoli, c/o Istituto di Endocrinologia e Oncologia Sperimentale del CNR, Naples, Italy

¹Correspondence: Department of Cell Biology and Oncology Consorzio Mario Negri Sud, Via Nazionale 8, 66030 Santa Maria Imbaro, Chieti, Italy. E-mail: mariggio@negrisud.it or corda{at}negrisud.it

ABSTRACT

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 A₂ action (the lysophosphoinositides and glycerophosphoinositols) remains to be fully elucidated. Here we demonstrate that in PCCl₃ rat thyroid cells, the intracellular levels of glycerophosphoinositol are finely modulated by ATP and norepinephrine through the P2Y metabotropic and -adrenergic receptors, respectively. The enzyme involved here is phospholipase A₂ IV (PLA₂IV), which in these cells specifically hydrolyzes phosphatidylinositol, forming lysophosphatidylinositol, glycerophosphoinositol, and arachidonic acid. This receptor-mediated activation of PLA₂IV leads to stimulation of PCCl₃ cell growth. The involvement of a PLA₂IV-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 PLA₂IV_1–522. Modulation of PCCl₃ 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 PCCl₃ 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 PLA₂-derived phosphoinositide metabolite.

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