Phosphatidylcholine breakdown and signal transduction

PC hydrolysis by PLA2, PLC or PLD is a widespread response elicited by most growth factors, cytokines, neurotransmitters, hormones and other extracellular signals. The mechanisms can involve G-proteins, PKC, Ca2+ and tyrosine kinase activities. Although an agonist-responsive cytosolic PLA2 has been purified, cloned and sequenced, the agonist-responsive form(s) of PC-PLC has not been identified and no form of PC-PLD has been purified or cloned. Regulation of PLA2 by Ca2+ and MAPK is well established and involves membrane translocation and phosphorylation, respectively. PKC regulation of the enzyme in intact cells is probably mediated by MAPK. The question of G-protein control of PLA2 remains controversial since the nature of the G-protein is unknown and it is not established that its interaction with the enzyme is direct or not. Growth factor regulation of PLA2 involves tyrosine kinase activity, but not necessarily PKC. It may be mediated by MAPK. The physiological significance of PLA2 activation is undoubtedly related to the release of AA for eicosanoid production, but the LPC formed may have actions also. There is much evidence that PKC regulates PC-PLC and PC-PLD and this is probably a major mechanism by which agonists that promote PI hydrolysis secondarily activate PC hydrolysis. Since no agonist-responsive forms of either phospholipase have been isolated, it is not clear that PKC exerts its effects directly on the enzymes. Although it is assumed that a phosphorylation mechanism is involved, this may not be the case, and regulation may be by protein-protein interactions. G-protein control of PC-PLD is well-established, although, again, it has not been demonstrated that this is direct, and the nature of the G-protein(s) involved is unknown. In some cell types, there is evidence of the participation of a soluble protein, which may be a low Mr GTP-binding protein. What role this plays in the activation of PC-PLD is obscure. Agonist activation of PC hydrolysis in cells is usually Ca(2+)-dependent, but the step at which Ca2+ is involved is unclear, since PC-PLD and PC-PLC per se are not influenced by physiological concentrations of the ion. Most growth factors promote PC hydrolysis and this is mainly due to activation of PKC as a result of PI breakdown. However, in some cases, PC breakdown occurs in the absence of PI hydrolysis, implying another mechanism that does not involve PI-derived DAG.(ABSTRACT TRUNCATED AT 400 WORDS)