Mitogen-regulated RSK2-CBP interaction controls their kinase and acetylase activities.
The protein kinase ribosomal S6 kinase 2 (RSK2) has been implicated in phosphorylation of transcription factor CREB and histone H3 in response to mitogenic stimulation by epidermal growth factor. Binding of phospho-CREB to the coactivator CBP allows gene activation through recruitment of the basal transcriptional machinery. Acetylation of H3 by histone acetyltransferase (HAT) activities, such as the one carried by CBP, has been functionally coupled to H3 phosphorylation. While various lines of evidence indicate that coupled histone acetylation and phosphorylation may act in concert to induce chromatin remodeling events facilitating gene activation, little is known about the coupling of the two processes at the signaling level. Here we show that CBP and RSK2 are associated in a complex in quiescent cells and that they dissociate within a few minutes upon mitogenic stimulus. CBP preferentially interacts with unphosphorylated RSK2 in a complex where both RSK2 kinase activity and CBP acetylase activity are inhibited. Dissociation is dependent on phosphorylation of RSK2 on Ser227 and results in stimulation of both kinase and HAT activities. We propose a model in which dynamic formation and dissociation of the CBP-RSK2 complex in response to mitogenic stimulation allow regulated phosphorylation and acetylation of specific substrates, leading to coordinated modulation of gene expression.
Merienne
K
K
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, Université Louis Pasteur, 67404 Illkirch, Strasbourg, France.
Pannetier
S
S
Harel-Bellan
A
A
Sassone-Corsi
P
P
D000115:Acetylesterase / Q000378:metabolism*; D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D050882:CREB-Binding Protein; D004815:Epidermal Growth Factor / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D005982:Glutathione Transferase / Q000378:metabolism; D051548:Histone Acetyltransferases; D006801:Humans; D008934:Mitogens / Q000378:metabolism*; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism*; D010703:Phorbol Esters / Q000494:pharmacology; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism*; D011233:Precipitin Tests; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014466:Ultraviolet Rays
D008934:Mitogens; D009687:Nuclear Proteins; D010703:Phorbol Esters; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; D004815:Epidermal Growth Factor; D000123:Acetyltransferases; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D051548:Histone Acetyltransferases; D005982:Glutathione Transferase; D010770:Phosphotransferases; D019893:Ribosomal Protein S6 Kinases; D000115:Acetylesterase