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Science 30 January 1998:
Vol. 279. no. 5351, pp. 707 - 710
DOI: 10.1126/science.279.5351.707
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Reports

Phosphorylation and Activation of p70s6k by PDK1

Nicholas Pullen, * Patrick B. Dennis, * Mirjana Andjelkovic, Almut Dufner, Sara C. Kozma, Brian A. Hemmings, dagger George Thomas dagger

Activation of the protein p70s6k by mitogens leads to increased translation of a family of messenger RNAs that encode essential components of the protein synthetic apparatus. Activation of the kinase requires hierarchical phosphorylation at multiple sites, culminating in the phosphorylation of the threonine in position 229 (Thr229), in the catalytic domain. The homologous site in protein kinase B (PKB), Thr308, has been shown to be phosphorylated by the phosphoinositide-dependent protein kinase PDK1. A regulatory link between p70s6k and PKB was demonstrated, as PDK1 was found to selectively phosphorylate p70s6k at Thr229. More importantly, PDK1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive PDK1 blocked insulin-induced activation of p70s6k.

Friedrich Miescher Institute, Maulbeerstrasse 66, CH-4058, Basel, Switzerland.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed.

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Nuclear translocation of 3'-phosphoinositide-dependent protein kinase 1 (PDK-1): A potential regulatory mechanism for PDK-1 function.
M. A. Lim, C. K. Kikani, M. J. Wick, and L. Q. Dong (2003)
PNAS 100, 14006-14011
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Exposure to Asphalt Fumes Activates Activator Protein-1 through the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway in Mouse Epidermal Cells.
C. Ma, J. Wang, and J. Luo (2003)
J. Biol. Chem. 278, 44265-44272
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Requirement for 3-Phosphoinositide-dependent Kinase-1 (PDK-1) in Insulin-induced Glucose Uptake in Immortalized Brown Adipocytes.
H. Sakaue, A. Nishizawa, W. Ogawa, K. Teshigawara, T. Mori, Y. Takashima, T. Noda, and M. Kasuga (2003)
J. Biol. Chem. 278, 38870-38874
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Transformation of Mammary Epithelial Cells by 3-Phosphoinositide- dependent Protein Kinase-1 Activates {beta}-Catenin and c-Myc, and Down-Regulates Caveolin-1.
Z. Xie, X. Zeng, T. Waldman, and R. I. Glazer (2003)
Cancer Res. 63, 5370-5375
   Abstract »    Full Text »    PDF »
Okadaic-Acid-Induced Inhibition of Protein Phosphatase 2A Produces Activation of Mitogen-Activated Protein Kinases ERK1/2, MEK1/2, and p70 S6, Similar to That in Alzheimer's Disease.
J.-J. Pei, C.-X. Gong, W.-L. An, B. Winblad, R. F. Cowburn, I. Grundke-Iqbal, and K. Iqbal (2003)
Am. J. Pathol. 163, 845-858
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Up-Regulation of Phosphorylated/Activated p70 S6 Kinase and Its Relationship to Neurofibrillary Pathology in Alzheimer's Disease.
W.-L. An, R. F. Cowburn, L. Li, H. Braak, I. Alafuzoff, K. Iqbal, I.-G. Iqbal, B. Winblad, and J.-J. Pei (2003)
Am. J. Pathol. 163, 591-607
   Abstract »    Full Text »    PDF »
Activation of the p70 S6 Kinase and Phosphorylation of the 4E-BP1 Repressor of mRNA Translation by Type I Interferons.
F. Lekmine, S. Uddin, A. Sassano, S. Parmar, S. M. Brachmann, B. Majchrzak, N. Sonenberg, N. Hay, E. N. Fish, and L. C. Platanias (2003)
J. Biol. Chem. 278, 27772-27780
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Mechanism of Ribosomal p70S6 Kinase Activation by Granulocyte Macrophage Colony-stimulating Factor in Neutrophils: COOPERATION OF A MEK-RELATED, THR421/SER424 KINASE AND A RAPAMYCIN-SENSITIVE, mTOR-RELATED THR389 KINASE.
J. A. Lehman, V. Calvo, and J. Gomez-Cambronero (2003)
J. Biol. Chem. 278, 28130-28138
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Phosphoinositide 3-Kinase Activation Regulates Cell Division Time by Coordinated Control of Cell Mass and Cell Cycle Progression Rate.
B. Alvarez, E. Garrido, J. A. Garcia-Sanz, and A. C. Carrera (2003)
J. Biol. Chem. 278, 26466-26473
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Regulation of the Phosphatidylinositol 3-Kinase, Akt/Protein Kinase B, FRAP/Mammalian Target of Rapamycin, and Ribosomal S6 Kinase 1 Signaling Pathways by Thyroid-stimulating Hormone (TSH) and Stimulating type TSH Receptor Antibodies in the Thyroid Gland.
J. M. Suh, J. H. Song, D. W. Kim, H. Kim, H. K. Chung, J. H. Hwang, J. M. Kim, E. S. Hwang, J. Chung, J.-H. Han, et al. (2003)
J. Biol. Chem. 278, 21960-21971
   Abstract »    Full Text »    PDF »
Cytoreductive Effects of Farnesyl Transferase Inhibitors on Multiple Myeloma Tumor Cells.
Y. Shi, J. Gera, J.-h. Hsu, B. Van Ness, and A. Lichtenstein (2003)
Mol. Cancer Ther. 2, 563-572
   Abstract »    Full Text »    PDF »
Mitotic Regulation of Ribosomal S6 Kinase 1 Involves Ser/Thr, Pro Phosphorylation of Consensus and Non-consensus Sites by Cdc2.
O. J. Shah, S. Ghosh, and T. Hunter (2003)
J. Biol. Chem. 278, 16433-16442
   Abstract »    Full Text »    PDF »
Amino acids determining enzyme-substrate specificity in prokaryotic and eukaryotic protein kinases.
L. Li, E. I. Shakhnovich, and L. A. Mirny (2003)
PNAS 100, 4463-4468
   Abstract »    Full Text »    PDF »
Downstream effectors of oncogenic ras in multiple myeloma cells.
L. Hu, Y. Shi, J.-h. Hsu, J. Gera, B. Van Ness, and A. Lichtenstein (2003)
Blood 101, 3126-3135
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Expression of the Serum- and Glucocorticoid-inducible Protein Kinase, Sgk, Is a Cell Survival Response to Multiple Types of Environmental Stress Stimuli in Mammary Epithelial Cells.
M. L. L. Leong, A. C. Maiyar, B. Kim, B. A. O'Keeffe, and G. L. Firestone (2003)
J. Biol. Chem. 278, 5871-5882
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Protein Kinase C Phosphorylates Ribosomal Protein S6 Kinase {beta}II and Regulates Its Subcellular Localization.
T. Valovka, F. Verdier, R. Cramer, A. Zhyvoloup, T. Fenton, H. Rebholz, M.-L. Wang, M. Gzhegotsky, A. Lutsyk, G. Matsuka, et al. (2003)
Mol. Cell. Biol. 23, 852-863
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The Structure and Function of PKN, a Protein Kinase Having a Catalytic Domain Homologous to That of PKC.
H. Mukai (2003)
J. Biochem. 133, 17-27
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Phosphorylation of the Catalytic Subunit of Protein Kinase A. AUTOPHOSPHORYLATION VERSUS PHOSPHORYLATION BY PHOSPHOINOSITIDE-DEPENDENT KINASE-1.
M. J. Moore, J. R. Kanter, K.C. Jones, and S. S. Taylor (2002)
J. Biol. Chem. 277, 47878-47884
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Tuberous sclerosis complex tumor suppressor-mediated S6 kinase inhibition by phosphatidylinositide-3-OH kinase is mTOR independent.
A. Jaeschke, J. Hartkamp, M. Saitoh, W. Roworth, T. Nobukuni, A. Hodges, J. Sampson, G. Thomas, and R. Lamb (2002)
J. Cell Biol. 159, 217-224
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Characterization of Phosphatidylinositol 3-Kinase-dependent Phosphorylation of the Hydrophobic Motif Site Thr389 in p70 S6 Kinase 1.
A. Romanelli, V. C. Dreisbach, and J. Blenis (2002)
J. Biol. Chem. 277, 40281-40289
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Ultraviolet-induced Phosphorylation of p70S6K at Thr389 and Thr421/Ser424 Involves Hydrogen Peroxide and Mammalian Target of Rapamycin but not Akt and Atypical Protein Kinase C.
C. Huang, J. Li, Q. Ke, S. S. Leonard, B.-H. Jiang, X.-S. Zhong, M. Costa, V. Castranova, and X. Shi (2002)
Cancer Res. 62, 5689-5697
   Abstract »    Full Text »    PDF »


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