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A transforming mutation in the pleckstrin homology domain of AKT1 in cancer

Author

Listed:
  • John D. Carpten

    (Translational Genomics Research Institute, 445 N. Fifth Street, Phoenix, Arizona 85004, USA)

  • Andrew L. Faber

    (Cancer Discovery Research,)

  • Candice Horn

    (Cancer Discovery Research,)

  • Gregory P. Donoho

    (Cancer Discovery Research,)

  • Stephen L. Briggs

    (Global Structural Biology,)

  • Christiane M. Robbins

    (Translational Genomics Research Institute, 445 N. Fifth Street, Phoenix, Arizona 85004, USA)

  • Galen Hostetter

    (Translational Genomics Research Institute, 445 N. Fifth Street, Phoenix, Arizona 85004, USA)

  • Sophie Boguslawski

    (Cancer Discovery Research,)

  • Tracy Y. Moses

    (Translational Genomics Research Institute, 445 N. Fifth Street, Phoenix, Arizona 85004, USA)

  • Stephanie Savage

    (Translational Genomics Research Institute, 445 N. Fifth Street, Phoenix, Arizona 85004, USA)

  • Mark Uhlik

    (Cancer Discovery Research,)

  • Aimin Lin

    (Integrative Biology, Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana 46285, USA)

  • Jian Du

    (Cancer Discovery Research,)

  • Yue-Wei Qian

    (Integrative Biology, Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana 46285, USA)

  • Douglas J. Zeckner

    (Cancer Discovery Research,)

  • Greg Tucker-Kellogg

    (Lilly Singapore Centre for Drug Discovery, 1 Science Park Road 04-01, The Capricorn, Singapore Science Park II, 117528 Singapore)

  • Jeffrey Touchman

    (Translational Genomics Research Institute, 445 N. Fifth Street, Phoenix, Arizona 85004, USA)

  • Ketan Patel

    (Lilly Singapore Centre for Drug Discovery, 1 Science Park Road 04-01, The Capricorn, Singapore Science Park II, 117528 Singapore)

  • Spyro Mousses

    (Pharmaceutical Genomics, Translational Genomics Research Institute, TGen Suite 110, 13208 E. Shea Boulevard, Scottsdale, Arizona 85259, USA)

  • Michael Bittner

    (Translational Genomics Research Institute, 445 N. Fifth Street, Phoenix, Arizona 85004, USA)

  • Richard Schevitz

    (Global Structural Biology,)

  • Mei-Huei T. Lai

    (Cancer Discovery Research,)

  • Kerry L. Blanchard

    (Cancer Discovery Research,)

  • James E. Thomas

    (Cancer Discovery Research,)

Abstract

Although AKT1 (v-akt murine thymoma viral oncogene homologue 1) kinase is a central member of possibly the most frequently activated proliferation and survival pathway in cancer, mutation of AKT1 has not been widely reported. Here we report the identification of a somatic mutation in human breast, colorectal and ovarian cancers that results in a glutamic acid to lysine substitution at amino acid 17 (E17K) in the lipid-binding pocket of AKT1. Lys 17 alters the electrostatic interactions of the pocket and forms new hydrogen bonds with a phosphoinositide ligand. This mutation activates AKT1 by means of pathological localization to the plasma membrane, stimulates downstream signalling, transforms cells and induces leukaemia in mice. This mechanism indicates a direct role of AKT1 in human cancer, and adds to the known genetic alterations that promote oncogenesis through the phosphatidylinositol-3-OH kinase/AKT pathway. Furthermore, the E17K substitution decreases the sensitivity to an allosteric kinase inhibitor, so this mutation may have important clinical utility for AKT drug development.

Suggested Citation

  • John D. Carpten & Andrew L. Faber & Candice Horn & Gregory P. Donoho & Stephen L. Briggs & Christiane M. Robbins & Galen Hostetter & Sophie Boguslawski & Tracy Y. Moses & Stephanie Savage & Mark Uhlik, 2007. "A transforming mutation in the pleckstrin homology domain of AKT1 in cancer," Nature, Nature, vol. 448(7152), pages 439-444, July.
    • Handle: RePEc:nat:nature:v:448:y:2007:i:7152:d:10.1038_nature05933
    DOI: 10.1038/nature05933
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    Cited by:

    1. Tripti Shrestha Bhattarai & Tambudzai Shamu & Alexander N. Gorelick & Matthew T. Chang & Debyani Chakravarty & Elena I. Gavrila & Mark T. A. Donoghue & JianJong Gao & Swati Patel & Sizhi Paul Gao & Ma, 2022. "AKT mutant allele-specific activation dictates pharmacologic sensitivities," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Tri Hieu Nim & Le Luo & Jacob K White & Marie-Véronique Clément & Lisa Tucker-Kellogg, 2015. "Non-canonical Activation of Akt in Serum-Stimulated Fibroblasts, Revealed by Comparative Modeling of Pathway Dynamics," PLOS Computational Biology, Public Library of Science, vol. 11(11), pages 1-27, November.
    3. Jennifer B. Shah & Dana Pueschl & Bradley Wubbenhorst & Mengyao Fan & John Pluta & Kurt D’Andrea & Anna P. Hubert & Jake S. Shilan & Wenting Zhou & Adam A. Kraya & Alba Llop Guevara & Catherine Ruan &, 2022. "Analysis of matched primary and recurrent BRCA1/2 mutation-associated tumors identifies recurrence-specific drivers," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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