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

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, Aimin Lin, Jian Du, Yue-Wei Qian, Douglas J. Zeckner, Greg Tucker-Kellogg, Jeffrey Touchman, Ketan Patel, Spyro Mousses, Michael Bittner, Richard Schevitz, Mei-Huei T. Lai, Kerry L. Blanchard () and James E. Thomas ()
Additional contact information
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,

Nature, 2007, vol. 448, issue 7152, 439-444

Abstract: 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.

Date: 2007
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DOI: 10.1038/nature05933

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