Activation of the phosphatidylinositol 3-kinase-Akt/protein kinase B signaling pathway in arachidonic acid-stimulated human myeloid and endothelial cells - Involvement of the ErbB receptor family

Although arachidonic acid has been demonstrated to stimulate a wide variety of cellular functions, the responsible mechanisms remain poorly defined. W e now report that arachidonic acid stimulated the activity of class Ia phos phatidylinositol S-kinase (PI3K) in human umbilical vein endothelial cells, HL60 cells, and human neutrophils. Pretreatment of endothelial cells with AG-1478, an inhibitor of the ErbB receptor family, resulted in the suppress ion of PI3K activation by arachidonic acid. The fatty acid enhanced the tyr osine phosphorylation of ErbB4 but not of ErbB2 or ErbB3. The ability of ar achidonic acid to stimulate PI3K activity in neutrophils was suppressed by indomethacin and nordihydroguaiaretic acid, inhibitors of the cyclooxygenas es and lipoxygenases, respectively, but not by 17-octadecynoic acid, an inh ibitor of omega -hydroxylation of arachidonic acid by cytochrome P450 monoo xygenases. Consistent with this, the activity of PI3K in neutrophils was st imulated by 5-hydroxyeicosatetraenoic acid. Arachidonic acid also transient ly stimulated the phosphorylation of Akt on Thr-308 and Ser-473. Although P I3K was not required for the activation of the mitogen-activated protein ki nases, ERK1, ERM2, and p38, in arachidonic acid-stimulated neutrophils, the :fatty acid acted via PI3K to stimulate the respiratory burst. These result s not only define a novel mechanism through which some of the actions of ar achidonic acid are mediated but also demonstrate that, in addition to ErbB1 (epidermal growth factor receptor), ErbB4 can also be transactivated by a non-epidermal growth factor-like ligand.