Role of S6 phosphorylation and S6 kinase in cell growth

This article reviews our current knowledge of the role of ribosomal protein S6 phosphorylation and the S6 kinase (S6K) signaling pathway in the regulation of cell growth and proliferation. Although 40S ribosomal protein S6 phosphorylation was first described 25 years ago, it only recently has been implicated in the translational up-regulation of mRNAs coding for the components of protein synthetic apparatus. These mRNAs contain an oligopyrimidine tract at their 5' transcriptional start site, termed a 5'TOP, which has been shown to be essential for their regulation at the translational level. In parallel, a great deal of information has accumulated concerning the identification of the signaling pathway and the regulatory phosphorylation sites involved in controlling S6K activation. Despite this knowledge we are only beginning to identify the direct upstream elements involved in growth factor-induced kinase activation. Use of the immunosupressant rapamycin, a bacterial macrolide, in conjunction with dominant interfering and activated forms of S6K1 has helped to establish the role of this signaling cascade in the regulation of growth and proliferation. In addition, current studies employing the mouse as well as Drosophila melanogaster have provided new insights into physiological function of S6K in the animal. Deletion of the S6K1 gene in mouse cells led to an animal of reduced size and the identification of the S6K1 homolog, S6K2, whereas loss of dS6K function in Drosophila demonstrated its paramount importance in development and growth control.