Protein kinase A balances the growth factor-induced Ras/ERK signaling.

Protein kinase A (PKA) has been proposed to regulate the signal transduction through the Ras/extracellular-regulated kinase (ERK) pathway. Here we demonstrate that when the PKA activity was inhibited prior to growth factor stimulus the signal flow through the Ras/ERK pathway was significantly increased. Furthermore, the data indicated that this PKA-mediated regulation was simultaneously targeted to the upstream kinase Raf-1 and to the ERK-specific phosphatase mitogen-activated protein kinase phosphatase-1 (MKP-1). Moreover, our data suggested that the level of PKA activity determined the transcription rate of mkp-1 gene, whereas the Ras/ERK signal was required to protect the MKP-1 protein against degradation. These results point to a tight regulatory relationship between PKA and the growth factor signaling, and further suggest an important role for basal PKA activity in such regulation. We propose that PKA adjusts the activity of the Ras/ERK pathway and maintains it within a physiologically appropriate level.