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J. Biol. Chem., Vol. 278, Issue 7, 5388-5398, February 14, 2003

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Synergy of Epidermal Growth Factor and 12(S)-Hydroxyeicosatetraenoate on Protein Kinase C Activation in Lens Epithelial Cells^*

Jianzheng Zhou, Robert N. Fariss^§, and Peggy S. Zelenka^¶

From the  Laboratory of Molecular and Developmental Biology and the ^§ Laboratory of Mechanisms of Ocular Diseases, NEI, National Institutes of Health, Bethesda, Maryland 20892

12(S)-Hydroxyeicosatetraenoic acid (12(S)HETE) is a bioactive metabolite of arachidonic acid synthesized by 12-lipoxygenase. The 12-lipoxygenase blocker, baicalein, prevents epidermal growth factor (EGF)-induced activation of protein kinase C (PKC)  and  in lens epithelial cells, whereas supplementation with 12(S)HETE reverses this effect, suggesting that EGF and 12(S)HETE may work together to activate PKC. This study investigates the mechanism of PKC activation by EGF and 12(S)HETE. 12(S)HETE alone directed translocation of PKC through the C1 rather than the C2 domain, without activating phosphoinositide 3-kinase (PI3K) or MAPK signaling or increasing intracellular calcium concentration. In the presence of baicalein, EGF triggered an asymmetric phosphorylation of the EGF receptor initiating signaling through PI3K and MAPK, but not PLC. Together, 12(S)HETE and EGF synergistically increased phosphorylation of PKC in the activation loop and C terminus as well as PKC-specific activity. PI3K inhibitors blocked phosphorylation, but MEK1 inhibitors did not. Microvesicles containing phosphatidylinositol 3,4,5-trisphosphate mimicked the action of EGF on PKC activity in the presence of 12(S)HETE. Kinase-inactive PKC mutations in either activation loop or C terminus were effectively translocated by 12(S)HETE, as was PKC in the presence of chelerythrine or Gö-6983. These findings indicate that unphosphorylated PKC is translocated to the membrane by 12(S)HETE and phosphorylated by EGF-dependent PI3K signaling, to generate catalytically competent PKC.

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