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Modulation of the Protein Kinase Activity of mTOR

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TOR

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 279))

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Abstract

mTOR is a founding member of a family of protein kinases having catalytic domains homologous to those in phosphatidylinositol 3-OH kinase. mTOR participates in the control by insulin of the phosphorylation of lipin, which is required for adipocyte differentiation, and the two translational regulators, p70S6K and PHAS-I. The phosphorylation of mTOR, itself, is stimulated by insulin in Ser2448, a site that is also phosphorylated by protein kinase B (PKB) in vitro and in response to activation of PKB activity in vivo. Ser2448 is located in a short stretch of amino acids not found in the two TOR proteins in yeast. A mutant mTOR lacking this stretch exhibited increased activity, and binding of the antibody, mTAb-1, to this region markedly increased mTOR activity. In contrast, rapamycin-FKBP12 inhibited mTOR activity towards both PHAS-I and p70S6K, although this complex inhibited the phosphorylation of some sites more than that of others. Mutating Ser2035 to Ile in the FKBP12-rapamycin binding domain rendered mTOR resistant to inhibition by rapamycin. Unexpectedly, this mutation markedly decreased the ability of mTOR to phosphorylate certain sites in both PHAS-I and p70S6K. The results support the hypotheses that rapamycin disrupts substrate recognition instead of directly inhibiting phosphotransferase activity and that mTOR activity in cells is controlled by the phosphorylation of an inhibitory regulatory domain containing the mTAb-1 epitope.

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Abbreviations

cAMP:

Adenosine 3′,5′ cyclic phosphate

eIF:

Eukaryotic initiation factor

4E-BP1:

eIF4E-binding protein 1

FKBP-12:

FK506 binding protein of M r = 12,O0O

GST:

Glutathione S transferase

HEK:

Human embryonic kidney

PHAS:

Phosphorylated heat- and acid-stable eIF4E-binding protein

mTAb:

mTOR antibody

mTOR:

Mammalian target of rapamycin

PI 3-kinase:

Phosphatidylinositol 3-OH kinase

PKB:

Protein kinase B

p70S6K :

M r = 70,OOO ribosomal protein S6 kinase

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Author information

Authors and Affiliations

  1. Department of Pharmacology, University of Virginia School of Medicine, 1300 Jefferson Park Avenue, Charlottesville, VA, 22908-0735, USA

    J. C. Lawrence, L. P. McMahon & K. M. Choi

  2. Bristol-Myers Squibb Pharmaceutical Research Institute, Rt. 206 and Province Line Road, Princeton, NJ, 08543-4000, USA

    T.-A. Lin

Authors
  1. J. C. Lawrence
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  2. T.-A. Lin
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  3. L. P. McMahon
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  4. K. M. Choi
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Editor information

Editors and Affiliations

  1. Friedrich-Miescher-Institute, Maulbeerstrasse 66, 4058, Basel, Switzerland

    George Thomas

  2. Whitehead Institute, 9 Cambridge Center, Cambridge, MA, 02142, USA

    David M. Sabatini MD, PhD

  3. Biozentrum, University of Basel, Klingelbergstrasse 70, 4056, Basel, Switzerland

    Michael N. Hall

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© 2004 Springer-Verlag Berlin Heidelberg

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Lawrence, J.C., Lin, TA., McMahon, L.P., Choi, K.M. (2004). Modulation of the Protein Kinase Activity of mTOR. In: Thomas, G., Sabatini, D.M., Hall, M.N. (eds) TOR. Current Topics in Microbiology and Immunology, vol 279. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-18930-2_12

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  • DOI: https://doi.org/10.1007/978-3-642-18930-2_12

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-62360-8

  • Online ISBN: 978-3-642-18930-2

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