Although group IVA cytosolic phospholipase A(2) (cPLA(2)alpha) has been reported to be phosphorylated at multiple Ser residues, the mechanisms by which phosphorylation at different sites regulates cPLA(2)alpha activities are not fully understood. To explore the possibility that phosphorylation of Ser(727) modulates cellular protein-protein interactions, we measured the effect of Ser(727) mutations on the interaction of cPLA(2)alpha with a reported cPLA(2)alpha-binding protein, p11. In vitro activity assays and membrane binding measurements by surface plasmon resonance analysis showed that a heterotetramer (A2t) of p11 and annexin A2, but not p11 or annexin A2 alone, directly binds cPLA(2)alpha via Ser(727), which keeps the enzyme from binding the membrane and catalyzing the phospholipid hydrolysis. Phosphorylation of Ser(727) disrupts this inhibitory cPLA(2)alpha-A2t interaction, thereby activating cPLA(2)alpha. Subcellular translocation and activity measurements in HEK293 cells cotransfected with cPLA(2)alpha and p11 also showed that p11, in the form of A2t, inhibits cPLA(2)alpha by the same mechanism and that phosphorylation of Ser(727) activates cPLA(2)alpha by interfering with the inhibitory cPLA(2)alpha-A2t interaction. Collectively, these studies provide new insight into the regulatory mechanism of cPLA(2)alpha through Ser(727) phosphorylation.
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