期刊
FASEB JOURNAL
卷 16, 期 9, 页码 1441-+出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.01-0909fje
关键词
arachidonic acid; leukotriene; p38 MAP kinase
5-Lipoxygenase (5-LO) is the key enzyme in the biosynthesis of proinflammatory leukotrienes. Here, we demonstrate that extracellular signal-regulated kinases (ERKs) can phosphorylate 5-LO in vitro. Efficient phosphorylation required the presence of unsaturated fatty acids and was abolished when Ser-663 was mutated to alanine. In intact HeLa cells stimulated with arachidonic acid (AA), impaired 5-LO product formation was evident in cells expressing the S663A-5-LO mutant compared with cells expressing wild-type 5-LO. For Mono Mac 6 cells, priming with phorbol myristate acetate (PMA) before stimulation with ionophore was required for ERK1/2 activation and efficient 5-LO phosphorylation, in parallel with substantial AA release and 5-LO product formation. Inhibition of PKC by GF109203x or MEK1/2 by U0126 (or PD98059) abolished the 5-LO up-regulation effects of PMA. In contrast, these inhibitors failed to suppress 5-LO product formation induced by stimuli such as AA plus ionophore, which apparently do not involve the ERK1/2 pathway. Based on inhibitor studies, ERKs are also involved in AA-stimulated 5-LO product formation in PMNL, whereas a role for ERKs is not apparent in 5-LO activation induced by ionophore or cell stress. Finally, the data suggest that ERKs and p38 MAPK-regulated MAPKAPKs can act in conjunction to stimulate 5-LO by phosphorylation.
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