Extracellular signal-regulated kinases phosphorylate 5-lipoxygenase and stimulate 5-lipoxygenase product formation in leukocytes

SPECIFIC AIMS>5-Lipoxygenase (LO) is the key enzyme in the biosynthesis of the proinflammatory leukotrienes (LTs). The aim of this study was to determine whether extracellular signal-regulated kinases (ERKs) are able to phosphorylate 5-LO and if ERK-mediated phosphorylation could stimulate cellular 5-LO product synthesis.PRINCIPAL FINDINGS1. 5-LO is phosphorylated by ERK2, which is promoted by unsaturated fatty acidsPurified 5-LO was dose-dependently phosphorylated by active ERK2 in vitro (Fig. 1⤻ A). Compared with the excellent ERK substrate myelin basic protein (MBP), 5-LO was ∼20- to 30-fold less efficiently phosphorylated by ERK2. However, AA or the unsaturated fatty acids (UFAs) oleic acid and linoleic acid (10–50 μM) increased 5-LO phosphorylation by ERK2 in a dose-dependent fashion up to 25-fold (Fig. 1B⤻ ), whereas the saturated fatty acids arachidic acid and palmitic acid failed to enhance 5-LO phosphorylation rates (Fig. 1C⤻ ). Opposite effects of AA were observed when MBP was used as substrate....