Epidermal growth factor activates calcium channels by phospholipase A2/5-lipoxygenase-mediated leukotriene C4 production.
Epidermal growth factor (EGF) induces a Ca2+ influx in many cell types, but the underlying mechanisms are so far unresolved. We report that: EGF-induced Ca2+ channel activity is eliminated by lipoxygenase inhibition and is mimicked by artificial induction of lipoxygenase activity; addition of leukotriene C4 can fully mimic EGF in its ability to activate Ca2+ channels; and EGF induces a rapid accumulation of intracellular leukotriene C4. In addition, we show that EGF-induced, Ca(2+)-dependent membrane hyperpolarization and junB proto-oncogene expression are dependent on lipoxygenase activity, whereas EGF-induced cytoplasmic alkalinization is not. We conclude that PLA2/5-lipoxygenase-mediated leukotriene C4 production constitutes a novel and specific signal transduction pathway in growth factor action.
Peppelenbosch
M P
MP
Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Utrecht.
Tertoolen
L G
LG
den Hertog
J
J
de Laat
S W
SW
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000201:enzymology; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054467:Phospholipases A2; D000090063:Proto-Oncogene Mas; D013189:SRS-A / Q000096:biosynthesis; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D000098:Acetophenones; D015220:Calcium Channels; D016859:Lipoxygenase Inhibitors; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D013189:SRS-A; D004815:Epidermal Growth Factor; D001094:Arachidonate 5-Lipoxygenase; D010741:Phospholipases A; D054467:Phospholipases A2; C006821:4-bromophenacyl bromide