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.
Pursiheimo
Juha-Pekka
JP
Turku Centre for Biotechnology, University of Turku, and Abo Akademi University, Tykistökatu 6B, BioCity, 20520 Turku, Finland. juha-pekka.pursiheimo@juvantia.com
Kieksi
Anni
A
Jalkanen
Markku
M
Salmivirta
Markku
M
D016475:3T3 Cells; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054638:Dual Specificity Phosphatase 1; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D017874:Immediate-Early Proteins / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D013449:Sulfonamides; D015854:Up-Regulation; D018631:ras Proteins / Q000378:metabolism*
D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D007546:Isoquinolines; D013449:Sulfonamides; D016222:Fibroblast Growth Factor 2; D015124:8-Bromo Cyclic Adenosine Monophosphate; D004815:Epidermal Growth Factor; D019908:Proto-Oncogene Proteins c-raf; D017868:Cyclic AMP-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D017027:Protein Tyrosine Phosphatases; D018631:ras Proteins; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide