PHOSPHATIDATE PHOSPHOHYDROLASE AND SIGNAL-TRANSDUCTION

A Mg2+-independent and N-ethylmaleimide-insensitive phosphatidate phos phohydrolase (PAP-2) has been identified in the plasma membrane of cel ls and it has been purified. The enzyme is a multi-functional phosphoh ydrolase that can dephosphorylate phosphatidate, lysophosphatidate, sp hingosine l-phosphate and ceramide l-phosphate and these substrates ar e competitive inhibitors of the reaction. The action of PAP-2 could te rminate signalling by these bioactive lipids and at the same time gene rates compounds such as diacylglycerol, sphingosine and ceramide which are also potent signalling molecules. In relation to phosphatidate me tabolism, sphingosine (or sphingosine l-phosphate) stimulates phosphol ipase D and thus the formation of phosphatidate. At the same time sphi ngosine inhibits PAP-2 activity thus further increasing phosphatidate concentrations. By contrast, ceramides inhibit the activation of phosp holipase D by a wide variety of agonists and increase the dephosphoryl ation of phosphatidate, lysophosphatidate, sphingosine l-phosphate and ceramide l-phosphate. These actions demonstrate 'cross-talk' between the glycerolipid and sphingolipid signalling pathways and the involvem ent of PAP-2 in modifying the balance of the bioactive lipids generate d by these pathways during cell activation.