Regulation of Protein Kinase C by Sphingosine/Lysosphingolipids
Protein kinase C was discovered in rat brain cytosol as a cyclic nucleotide-independent protein kinase (Inoue et al., 1977: Takai et al., 1977a,b). The proenzyme form, protein kinase C, could be activated by proteolysis or by a membrane factor in the presence of Ca2+ (Takai et al., 1979a,b). The membrane factor was initially identified as phospholipid, with phosphatidylserine (PS) being most effective (Takai et al., 1979a,b). At this point, protein kinase C was referred to as the phospholipid- and Ca2+-dependent protein kinase. Crude lipid extracts from brain proved to be more effective than PS and Ca2+ in activating the enzyme; this led to the discovery of a neutral lipid, sn-1,2-diacylglycerol (DAG), which increased the enzyme’s affinity for both PS and Ca2+ (Kishimoto et al., 1980). DAG could activate protein kinase C at resting levels of Ca2+. DAGs were thus discovered to be “second messengers,” since DAG production in response to extracellular agents, including hormones, neurotransmitters, and growth factors, had long been known to occur from an accelerated metabolism of the phosphatidylinositols (PIs) (Kishimoto et al., 1980; Berridge and Irvine, 1984; Nishizuka, 1984a,b; 1986 Bell, 1986).
KeywordsProtein Kinase HL60 Cell Phorbol Ester Mixed Micelle Crude Lipid Extract
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