Activation of Akt1 by human 5-hydroxytryptamine (serotonin)(1B) receptors is sensitive to inhibitors of MEK

Akt1/protein kinase B and the mitogen-activated protein (MAP) kinases extra cellular signal-regulated kinase 1 (ERK1) and ERK2 have been shown to promo te cell survival in a cell-specific manner. Since many receptors activate b oth pathways, inhibitors are commonly used to study the relative role of ea ch pathway. In the present study, we examined the effects of PD098059 and U 0126, two structurally dissimilar inhibitors of MAP kinase kinase (MEK1/2), on the activation of ERK and Akt stimulated by human 5-hydroxytryptamine(1 B) (serotonin) (5HT(1B)) receptors. Surprisingly, pathways for activation o f both ERK and Akt were found to be sensitive to the two MEK inhibitors at concentrations commonly used to selectively inhibit the activation of ERK. Both compounds caused complete inhibition of phosphorylation of ERK and a m aximal 60% inhibition of 5-HT1B receptor-mediated phosphorylation of Akt. I nhibition of Akt activation required almost complete inhibition of ERK. Tra nsfection with cDNA for activated forms of MEK1/2 caused increased phosphor ylation of ERK but not of Akt, demonstrating that independent activation of MEK/ERK was insufficient for activation of Akt. Therefore, it is not clear whether inhibition of activation of Akt resulted from selective inhibition of MEK or from additional actions on other unidentified common pathways. N evertheless, our findings that PD098059 and U0126 inhibit activation of Akt at commonly used concentrations demonstrate that in at least some systems, these compounds inhibit activation of both ERK and Akt, and cannot be used to discern the relative roles of each pathway in mediating cellular respon ses.