Role of Lipins in Regulating Phospholipase D Signalling
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Abstract
A potential therapeutic target in cancer is phospholipase D (PLD), which converts phosphatidylcholine into phosphatidic acid, a lipid second messenger in cell signalling. The lipid phosphate phosphatases are considered to convert PLD-generated phosphatidic acid to diacylglycerol. However, the lipid phosphate phosphatases are integral membrane proteins with catalytic sites on the extracellular or lumenal sides of membranes whereas phosphatidic acid accumulates on the cytosolic leaflet of membranes. The other enzymes that dephosphorylate phosphatidic acid, the lipins, are cytosolic proteins that translocate to membranes. This project investigated whether lipin-1 and lipin-2 regulate PLD signalling. The results show that phosphatidic acid accumulation in breast cancer cells resulted from PLD1 and PLD2 activation and activity of calcium-dependent diacylglycerol kinases. Depletion of lipin-1 did not affect PLD-dependent phosphatidic acid accumulation in fibroblasts. This work provides the first evidence that increased phosphatidic acid phosphatase activity of lipins is associated with membranes in response to PLD stimulation.