Naturally occurring ether-linked phosphatidylcholine activates phosphatidylinositol 3-kinase and stimulates cell growth.
Phosphatidylcholine (PC) from marine invertebrates is enriched in ether-linked forms. PCs from ray fish, Dasyatis sp., and bivalve, Macoma birmanica, used in the present study, contain 65% and 75% (w/w of total PC) of ether-linked forms, respectively. Ether-linked PCs also occur in mammalian membranes. Agonist-mediated hydrolysis of PC generates second messengers which participate in cellular responses. In this study, we tested whether PCs from marine invertebrates directly affect mammalian cell growth and activity of phosphatidylinositol (Pl-3-kinase). Pl-3-kinase participates in mitogenesis initiated by a variety of growth factors. Pl-3-kinase converts polyphosphoinositides to 3' phosphorylated isomers and these products accumulate in response to mitogenic stimuli. Whether cell membrane lipids regulate Pl-3-kinase activity is not known. The marine animal-derived PCs and dioleoyl DAG (dioleoylglycerol) stimulated growth of murine pre-B lymphocytes, whereas chicken PC (egg lecithin) inhibited growth of these cells. Egg lecithin is also a potent inhibitor of Pl-3-kinase activity in vitro. We studied the effect of PCs and DAG on Pl-3-kinase activity. Unlike egg lecithin, marine animal PCs enhanced Pl-3-kinase activity. We investigated the effect of lipids on Pl-3-kinase substrate utilization. PCs enriched in ether-linked species increased utilization of substrates by Pl-3-kinase. PCs purified from marine organisms also contain a substantially higher percentage of the cis-unsaturated fatty acids, especially of the -omega 3 series (25% and 30% of total fatty acids for Dasyatis sp. and Macoma birmanica, respectively), as compared to vertebrate sources. In spite of differences in fatty acid composition, marine PCs and dioleoyl DAG showed similar effects on cell growth and Pl-3-kinase activity. These findings indicate that ether-linked phospholipids activate Pl-3-kinase and may participate in mitogenic responses.
Misra
S
S
Harvard School of Public Health, Boston, Massachusetts 02115.
Ghosh
A
A
Varticovski
L
L
D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D004075:Diglycerides / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004789:Enzyme Activation; D000431:Ethanol / Q000494:pharmacology; D004987:Ethers / Q000737:chemistry*; D005227:Fatty Acids / Q000032:analysis; D005399:Fishes / Q000033:anatomy & histology / Q000378:metabolism; D007377:Interleukin-3 / Q000494:pharmacology; D008974:Mollusca / Q000033:anatomy & histology / Q000378:metabolism; D010713:Phosphatidylcholines / Q000737:chemistry / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*
D004075:Diglycerides; D004987:Ethers; D005227:Fatty Acids; D007377:Interleukin-3; D010713:Phosphatidylcholines; D000431:Ethanol; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D004121:Dimethyl Sulfoxide