Lysophosphatidate-induced cell proliferation: identification and dissection of signaling pathways mediated by G proteins.
Lysophosphatidate (LPA), the simplest natural phospholipid, is highly mitogenic for quiescent fibroblasts. LPA-induced cell proliferation is not dependent on other mitogens and is blocked by pertussis toxin. LPA initiates at least three separate signaling cascades: activation of a pertussis toxin-insensitive G protein mediating phosphoinositide hydrolysis with subsequent Ca2+ mobilization and stimulation of protein kinase C; release of arachidonic acid in a GTP-dependent manner, but independent of prior phosphoinositide hydrolysis; and activation of a pertussis toxin-sensitive Gi protein mediating inhibition of adenylate cyclase. The peptide bradykinin mimics LPA in inducing the first two responses but fails to activate Gi and to stimulate DNA synthesis. Our data suggest that the mitogenic action of LPA occurs through Gi or a related pertussis toxin substrate and that the phosphoinositide hydrolysis-protein kinase C pathway is neither required nor sufficient, by itself, for mitogenesis. The results further suggest that LPA or LPA-like phospholipids may have a novel role in G protein-mediated signal transduction.
van Corven
E J
EJ
Division of Cellular Biochemistry, The Netherlands Cancer Institute, Amsterdam.
Groenink
A
A
Jalink
K
K
Eichholtz
T
T
Moolenaar
W H
WH
D037361:Adenylate Cyclase Toxin; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D001920:Bradykinin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002455:Cell Division; D002460:Cell Line; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000502:physiology*; D006131:Growth Inhibitors / Q000494:pharmacology; D006133:Growth Substances / Q000502:physiology*; D006801:Humans; D006868:Hydrolysis; D008246:Lysophospholipids / Q000502:physiology*; D037342:Pertussis Toxin; D010716:Phosphatidylinositols / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D010738:Type C Phospholipases / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D001095:Arachidonic Acids; D006131:Growth Inhibitors; D006133:Growth Substances; D008246:Lysophospholipids; D010716:Phosphatidylinositols; D010566:Virulence Factors, Bordetella; D016718:Arachidonic Acid; D004247:DNA; D000242:Cyclic AMP; D037342:Pertussis Toxin; D011493:Protein Kinase C; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; D001920:Bradykinin; D002118:Calcium