Regulation of Ribosomal S6 Kinase 2 by Effectors of the Phosphoinositide 3-Kinase Pathway

• Published in: The Journal of biological chemistry Vol. 276; no. 11; pp. 7884 - 7891
• Main Authors: Martin, Kathleen A., Schalm, Stefanie S., Richardson, Celeste, Romanelli, Angela, Keon, Kristen L., Blenis, John
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.03.2001; American Society for Biochemistry and Molecular Biology
• Subjects: cdc42 GTP-Binding Protein - physiology; cdc42 protein; Cells, Cultured; Humans; Isoenzymes - metabolism; Phosphatidylinositol 3-Kinases - physiology; Phosphoinositide 3-kinase; phosphoinositide-dependent kinase 1; Protein Kinase C - physiology; rac protein; Ribosomal Protein S6 Kinases - metabolism; Ribosomal S6 kinase 2
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M006969200

Ribosomal S6 kinase (S6K1), through phosphorylation of the 40 S ribosomal protein 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 vitroand is regulated by the phosphatidylinositide 3-kinase (PI3-K) and mammalian target of rapamycin pathways in vivo. Here, we characterize S6K2 regulation by PI3-K signaling intermediates and compare its regulation to that of S6K1. We report that S6K2 is activated similarly to S6K1 by the PI3-K effectors phosphoinositide-dependent kinase 1, Cdc42, Rac, and protein kinase Cζ but that S6K2 is more sensitive to basal activation by myristoylated protein kinase Cζ 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 activation 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 effectors but that sequences unique to S6K2 contribute to stronger inhibition of its kinase activity. Understanding the regulation of the two S6K homologs may provide insight into the physiological roles of these kinases.