Regulatory mechanism and physiological role of cytosolic phospholipase A2.
Cytosolic phospholipase A2alpha (cPLA2alpha) preferentially hydrolyzes phospholipids containing arachidonic acid and plays a key role in the biosynthesis of eicosanoids. This review discusses the essential features of cPLA2alpha regulation and addresses new insights into the functional properties of this enzyme. Full activation of the enzyme requires Ca2+ binding to an N-terminal C2 domain and phosphorylation on serine residues. Ca2+ binding induces translocation of cPLA2alpha from the cytosol to the perinuclear membranes. Serine phosphorylation is mediated by mitogen-activated protein kinases (MAPKs), Ca2+/calmodulin-dependent protein kinase II, and MAPK-interacting kinase Mnk1. Interaction with proteins and lipids, which include vimentin, annexins, NADPH oxidase, phosphatidylcholine, phosphatidylinositol 4,5-bisphosphate (PIP2), and ceramide-1-phosphate, can also modulate the activity of cPLA2alpha. Recent evidence has established the physiological and pathological roles of cPLA2alpha using cPLA2alpha knockout mice. This enzyme has been implicated in fertility, striated muscle growth, renal concentration, postischemic brain injury, arthritis, inflammatory bone resorption, intestinal polyposis, pulmonary fibrosis, acute respiratory distress syndrome, and autoimmune encephalomyelitis. Now novel three paralogs, cPLA2beta, cPLA2gamma, and cPLA2delta, have been identified in humans. cPLA2gamma is distinct from others in that it is farnesylated and lacks the C2 domain. Biological roles for these new enzymes have not yet been defined.
Hirabayashi
Tetsuya
T
Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan. thirabayashi-tky@umin.ac.jp
Murayama
Toshihiko
T
Shimizu
Takao
T
D003600:Cytosol / Q000201:enzymology*; D008958:Models, Molecular; D010741:Phospholipases A / Q000737:chemistry / Q000378:metabolism*; D054467:Phospholipases A2; D010766:Phosphorylation; D011487:Protein Conformation
D010741:Phospholipases A; D054467:Phospholipases A2