Regulation of ribosomal S6 kinase 2 by effectors of the phosphoinositide 3-kinase pathway

Ribosomal S6 kinase (S6K1), through phosphorylation of the 40 S ribosomal p rotein S6 and regulation of 5'-terminal oligopyrimidine tract mRNAs, is an important regulator of cellular translational capacity. S6K1 has also been implicated in regulation of cell size. We have recently identified S6K2, a homolog of S6K1, which phosphorylates S6 in vitro and is regulated by the p hosphatidylinositide 3-kinase (PI3-K) and mammalian target of rapamycin pat hways in vivo. Here, we characterize S6K2 regulation by PI3-K signaling int ermediates and compare its regulation to that of S6K1, We report that S6K2 is activated similarly to S6K1 by the PI3-K effecters phosphoinositide-depe ndent kinase 1, Cdc42, Rac, and protein kinase C zeta but that S6K2 is more sensitive to basal activation by myristoylated protein kinase C zeta than is S6K1. The C-terminal sequence of S6K2 is divergent from that of S6K1, We find that the S6K2 C terminus plays a greater role in S6K2 regulation than does the S6K1 C terminus by functioning as a potent inhibitor of activatio n by various agonists, Removal of the S6K2 C terminus results in an enzyme that is hypersensitive to agonist-dependent activation. These data suggest that S6K1 and S6K2 are similarly activated by PI3-K effecters but that sequ ences unique to S6K2 contribute to stronger inhibition of its kinase activi ty. Understanding the regulation of the two S6K homologs may provide insigh t into the physiological roles of these kinases.