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

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.

• Authors: 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, James E Thomas
• Journal: Nature (Nature) Vol. 448 Issue 7152 Pg. 439-44 (Jul 26 2007) ISSN: 1476-4687 [Electronic] England
• PMID: 17611497 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Proteins
• Phosphoproteins
• platelet protein P47
• AKT1 protein, human
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Blood Proteins (chemistry)
• Breast Neoplasms (genetics)
• Cell Transformation, Neoplastic (genetics)
• Colorectal Neoplasms (genetics)
• DNA Mutational Analysis
• Enzyme Activation (genetics)
• Female
• Humans
• Leukemia (genetics)
• Mice
• Models, Molecular
• Mutation (genetics)
• Neoplasms (genetics, pathology)
• Ovarian Neoplasms (genetics)
• Phosphoproteins (chemistry)
• Protein Structure, Tertiary (genetics)
• Protein Transport
• Proto-Oncogene Proteins c-akt (chemistry, genetics, metabolism)
• Sequence Homology, Amino Acid