SIGNALING PATHWAYS INVOLVED IN THE MITOGENIC ACTION OF LYSOPHOSPHATIDYLINOSITOL

Lysophosphatidylinositol has been previously shown to stimulate cell p roliferation in differentiated and in K-ras transformed thyroid cells. Increased levels of lysophosphatidylinositol, but not lysophosphatidy lcholine or lysophosphatidylethanolamine, are present in thyroid as we ll as in other ras-transformed cell lines. We have now investigated th e mechanism of action of this lysolipid by analysing its effects in a differentiated thyroid cell line. Lysophosphatidylinositol did not inc rease the levels of cAMP, the main stimulator of cell proliferation in the thyroid, whereas it stimulated phosphoinositide breakdown, mobili zation of cytosolic Ca2+ and arachidonic acid release, suggesting that it activates both phospholipases C and A(2). None of the effects of l ysophosphatidylinositol were prevented by pretreatment of cells with p ertussis toxin. Instead, the tyrosine kinase inhibitors, tyrphostins A G18 and AG561, completely blocked its mitogenic action. The effects of lysophosphatidylinositol were distinguishable from those of the well known mitogen lysophosphatidic acid, which affected differently the si gnalling pathways analysed and was not mitogenic in ras-transformed ce lls. These results suggest that the mitogenic activity of lysophosphat idylinositol is associated with the activation of phospholipase C and phospholipase A(2) and is relatively specific for ras-transformed cell s.