Sphingosine-1-Phosphate Formation Activates Phosphatidylinositol-4 Kinase in Basolateral Membranes from Kidney Cells: Crosstalk in Cell Signaling through Sphingolipids and Phospholipids

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Sphingosine-1-phosphate (S1P) and phosphatidylinositol-4 phosphate [PtdIns (4) P] are important second messengers in various cellular processes. Here, we show that S1P and Ptdlns (4) P are formed in purified basolateral membranes (BLM) derived from kidney proximal tubules, indicating the presence of a plasma membrane associated SPK (BLM-SPK) and phosphatidylinositol-4 kinase (PI-4K). We observed that SIP synthesis is linear with time, dependent on protein concentration, and saturable in the presence of increasing concentrations of sphingosine. Different from the observations on cytosolic SPKs, the formation of S1P by BLM-SPK is Mg2+-independent and insensitive to the classical inhibitor of the cytosolic SPKs, DL-threo-dihydrosphingosine. With sphingosine as substrate, the enzyme shows cooperative kinetics (n=3.4) with a K0.5 value of 0.12mM, suggesting that BLM-SPK is different from the previously characterized cytosolic SPK. The formation of Ptdlns (4) P markedly inhibits BLMSPK activity. Conversely, a strong activation of PtdIns (4) P synthesis by the formation of S1P is observed. Taken together, these results indicate that (i) basolateral membranes from kidney cells harbor a SPK activity that potentially regulates renal epithelium function, and (ii) the formation of SIP mediated by SPK enhances PI-4K activity, while Ptdlns (4) P in turn inhibits SPK, suggesting an interplay between these lipid signaling molecules. These findings suggest the possibility of crosstalk between sphingolipids and glycerolipids, which might be involved in the regulation of transepithelial fluxes across the BLM of kidney cells.

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