2. Academic Validation
  3. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer

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

  • Nature. 2007 Jul 26;448(7152):439-44. doi: 10.1038/nature05933.
John D Carpten 1,  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,  James E Thomas
Affiliations

Affiliation

  • 1 Division of Integrated Cancer Genomics, Translational Genomics Research Institute, 445 N. Fifth Street, Phoenix, Arizona 85004, USA.
PMID: 17611497 DOI: 10.1038/nature05933
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.

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