ABSTRACT
Here we set out to describe a working model for S6 kinase (S6K) activation by insulin, the upstream signaling components which control this response, and the downstream effects of kinase activation on cell growth and insulin production. At the level of primary structure, the kinase is found to contain at least nine phosphorylation sites that mediate kinase activation by altering the interactions of distinct intramolecular domains in a hierarchical fashion. This model of kinase activation has been a powerful tool in identifying the proximal receptor components that control the activation process, although S6K kinases which control a number of functionally essential phosphorylation sites have yet to be identified. In addition to hormones and growth factors, it is clear that S6K is activated independently by essential amino acids, which, together with insulin, play an important role in maintaining normal cellular homeostasis. At the translational level, through the phosphorylation of the 40S ribosomal protein S6, S6K is involved in controlling the expression of a family of mRNAs which encode for proteins of the protein synthetic apparatus. Finally, recent studies strongly support a model whereby S6K is also an integral downstream signaling component in the transcriptional regulation of insulin in pancreatic β cells.
