Disruption of PH-kinase domain interactions leads to oncogenic activation of AKT in human cancers
| Autor: | Thomas D. Wu, Maria N. Lorenzo, Nicholas J. Skelton, Yvonne Franke, Chaitali Parikh, Wenlin Yuan, Marlena Jackson, Vasantharajan Janakiraman, Meredith Sagolla, Kui Lin, Barbara J. Brandhuber, Jeremy Stinson, Catherine K. Foo, Eric Stawiski, Hong Li, Wen-I Wu, Joseph Guillory, Somasekar Seshagiri, Jiansheng Wu, David Stokoe, Howard M. Stern, Noelyn M. Kljavin, Subhra Chaudhuri, Jesus Rondon, Brian Lee, Jie Lin, Krista K. Bowman |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Allosteric regulation AKT1 Biology medicine.disease_cause Mice Allosteric Regulation Cell Line Tumor Neoplasms medicine Animals Humans Protein kinase A Protein kinase B Protein Kinase Inhibitors Mutation Multidisciplinary Cell Membrane Oncogenes Biological Sciences Pleckstrin homology domain Enzyme Activation Protein Transport Cell Transformation Neoplastic Protein kinase domain Cancer research NIH 3T3 Cells Mutant Proteins Signal transduction Proto-Oncogene Proteins c-akt Protein Binding Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 109(47) |
| ISSN: | 1091-6490 |
| Popis: | The protein kinase v-akt murine thymoma viral oncogene homolog (AKT), a key regulator of cell survival and proliferation, is frequently hyperactivated in human cancers. Intramolecular pleckstrin homology (PH) domain–kinase domain (KD) interactions are important in maintaining AKT in an inactive state. AKT activation proceeds after a conformational change that dislodges the PH from the KD. To understand these autoinhibitory interactions, we generated mutations at the PH–KD interface and found that most of them lead to constitutive activation of AKT. Such mutations are likely another mechanism by which activation may occur in human cancers and other diseases. In support of this likelihood, we found somatic mutations in AKT1 at the PH–KD interface that have not been previously described in human cancers. Furthermore, we show that the AKT1 somatic mutants are constitutively active, leading to oncogenic signaling. Additionally, our studies show that the AKT1 mutants are not effectively inhibited by allosteric AKT inhibitors, consistent with the requirement for an intact PH–KD interface for allosteric inhibition. These results have important implications for therapeutic intervention in patients with AKT mutations at the PH–KD interface. |
| Databáze: | OpenAIRE |
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