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Mol. Cell. Biol., 01 1995, 326-337, Vol 15, No. 1
Copyright © 1995, American Society for Microbiology

Activation of pp70/85 S6 kinases in interleukin-2-responsive lymphoid cells is mediated by phosphatidylinositol 3-kinase and inhibited by cyclic AMP

M Monfar, KP Lemon, TC Grammer, L Cheatham, J Chung, CJ Vlahos and J Blenis
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115.

Activation of phosphatidylinositol 3-kinase (PI3K) and activation of the 70/85-kDa S6 protein kinases (alpha II and alpha I isoforms, referred to collectively as pp70S6k) have been independently linked to the regulation of cell proliferation. We demonstrate that these kinases lie on the same signalling pathway and that PI3K mediates the activation of pp70 by the cytokine interleukin-2 (IL-2). We also show that the activation of pp70S6k can be blocked at different points along the signalling pathway by using specific inhibitors of T-cell proliferation. Inhibition of PI3K activity with structurally unrelated but highly specific PI3K inhibitors (wortmannin or LY294002) results in inhibition of IL-2-dependent but not phorbol ester (conventional protein kinase C [cPKC])-dependent pp70S6k activation. The T-cell immunosuppressant rapamycin potently antagonizes IL-2-(PI3K)- and phorbol ester (cPKC)-mediated activation of pp70S6k. Thus, wortmannin and rapamycin antagonize IL-2-mediated activation of pp70S6k at distinct points along the PI3K-regulated signalling pathway, or rapamycin antagonizes another pathway required for pp70S6k activity. Agents that raise the concentration of intracellular cyclic AMP (cAMP) and activate cAMP-dependent protein kinase (PKA) also inhibit IL-2- dependent activation of pp70S6k. In this case, inhibition appears to occur at least two points in this signalling path. Like rapamycin, PKA appears to act downstream of cPKC-mediated pp70S6k activation, and like wortmannin, PKA antagonizes IL-2-dependent activation of PI3K. The results with rapamycin and wortmannin are of added interest since the yeast and mammalian rapamycin targets resemble PI3K in the catalytic domain.


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  • Scheid, M. P., Duronio, V. (1996). Phosphatidylinositol 3-OH Kinase Activity Is Not Required for Activation of Mitogen-activated Protein Kinase by Cytokines. J. Biol. Chem. 271: 18134-18139 [Abstract] [Full Text]  
  • Crawley, J. B., Williams, L. M., Mander, T., Brennan, F. M., Foxwell, B. M.J. (1996). Interleukin-10 Stimulation of Phosphatidylinositol 3-Kinase and p70 S6 Kinase Is Required for the Proliferative but Not the Antiinflammatory Effects of the Cytokine. J. Biol. Chem. 271: 16357-16362 [Abstract] [Full Text]  
  • Lenormand, P., McMahon, M., Pouyssegur, J. (1996). Oncogenic Raf-1 Activates p70 S6 Kinase via a Mitogen-activated Protein Kinase-independent Pathway. J. Biol. Chem. 271: 15762-15768 [Abstract] [Full Text]  
  • Rankin, S., Hooshmand-Rad, R., Claesson-Welsh, L., Rozengurt, E. (1996). Requirement for Phosphatidylinositol 3`-Kinase Activity in Platelet-derived Growth Factor-stimulated Tyrosine Phosphorylation of p125 Focal Adhesion Kinase and Paxillin. J. Biol. Chem. 271: 7829-7834 [Abstract] [Full Text]  
  • Petritsch, C., Woscholski, Rüd., Edelmann, H. M. L., Ballou, L. M. (1995). Activation of p70 S6 Kinase and erk-encoded Mitogen-activated Protein Kinases Is Resistant to High Cyclic Nucleotide Levels in Swiss 3T3 Fibroblasts. J. Biol. Chem. 270: 26619-26625 [Abstract] [Full Text]  
  • Frost, V., Morley, S. J., Mercep, L., Meyer, T., Fabbro, D., Ferrari, S. (1995). The Phosphodiesterase Inhibitor SQ 20006 Selectively Blocks Mitogen Activation of p70[IMAGE] and Transition to S Phase of the Cell Division Cycle without Affecting the Steady State Phosphorylation of eIF-4E. J. Biol. Chem. 270: 26698-26706 [Abstract] [Full Text]  
  • Han, J.-W., Pearson, R. B., Dennis, P. B., Thomas, G. (1995). Rapamycin, Wortmannin, and the Methylxanthine SQ20006 Inactivate p70[IMAGE] by Inducing Dephosphorylation of the Same Subset of Sites. J. Biol. Chem. 270: 21396-21403 [Abstract] [Full Text]  
  • Wang, J., Auger, K. R., Jarvis, L., Shi, Y., Roberts, T. M. (1995). Direct Association of Grb2 with the p85 Subunit of Phosphatidylinositol 3-Kinase. J. Biol. Chem. 270: 12774-12780 [Abstract] [Full Text]  
  • Kim, S., Jee, K., Kim, D., Koh, H., Chung, J. (2001). Cyclic AMP Inhibits Akt Activity by Blocking the Membrane Localization of PDK1. J. Biol. Chem. 276: 12864-12870 [Abstract] [Full Text]  


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