A novel pathway of cell growth regulation mediated by a PLA2alpha-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 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 alpha-adrenergic receptors, respectively. The enzyme involved here is phospholipase A2 IValpha (PLA2 IValpha), which in these cells specifically hydrolyzes phosphatidylinositol, forming lysophosphatidylinositol, glycerophosphoinositol, and arachidonic acid. This receptor-mediated activation of PLA2 IValpha leads to stimulation of PCCl3 cell growth. The involvement of a PLA2 IValpha-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 PLA2 IValpha(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
Stefania
S
Department of Cell Biology and Oncology, Consorzio Mario Negri Sud, Via Nazionale 8, 66030 Santa Maria Imbaro, Chieti, Italy. mariggio@negrisud.it
Sebastià
Jordi
J
Filippi
Beatrice Maria
BM
Iurisci
Cristiano
C
Volonté
Cinzia
C
Amadio
Susanna
S
De Falco
Valentina
V
Santoro
Massimo
M
Corda
Daniela
D
D000818:Animals; D016466:CHO Cells; D002454:Cell Differentiation; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D005819:Genetic Markers / Q000502:physiology; D054513:Group IV Phospholipases A2; D007295:Inositol Phosphates / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism*; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011983:Receptors, Purinergic / Q000378:metabolism; D013961:Thyroid Gland / Q000166:cytology
D005819:Genetic Markers; D007295:Inositol Phosphates; D010716:Phosphatidylinositols; D012333:RNA, Messenger; D011983:Receptors, Purinergic; C014575:glycerylphosphoinositol; D048049:Extracellular Signal-Regulated MAP Kinases; D010741:Phospholipases A; D054513:Group IV Phospholipases A2; D054467:Phospholipases A2