A transforming mutation in the pleckstrin homology domain of AKT1 in cancer
| Autor: | Christiane M. Robbins, Mark Uhlik, Jeffrey W. Touchman, Andrew L. Faber, Mei-Huei T. Lai, Stephanie Savage, Aimin Lin, Galen Hostetter, Jian Du, Yue-Wei Qian, Gregory P. Donoho, Tracy Moses, Michael L. Bittner, Kerry L. Blanchard, Spyro Mousses, Stephen L. Briggs, Douglas J. Zeckner, Sophie Boguslawski, Candice Horn, Greg Tucker-Kellogg, Ketan J. Patel, James E. Thomas, Richard W. Schevitz, John D. Carpten |
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| Rok vydání: | 2007 |
| Předmět: |
Models
Molecular medicine.medical_specialty DNA Mutational Analysis AKT1 Breast Neoplasms Biology medicine.disease_cause Mice Germline mutation Protein structure Mutant protein Internal medicine Neoplasms medicine Animals Humans Ovarian Neoplasms Mutation Multidisciplinary Leukemia Oncogene Sequence Homology Amino Acid Blood Proteins Phosphoproteins Molecular biology humanities Transport protein Protein Structure Tertiary Pleckstrin homology domain Enzyme Activation Protein Transport Endocrinology Cell Transformation Neoplastic Female Colorectal Neoplasms Proto-Oncogene Proteins c-akt |
| Zdroj: | Nature. 448(7152) |
| ISSN: | 1476-4687 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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