Journal Article

Disruption of PH–kinase domain interactions leads to oncogenic activation of AKT in human cancers

Brandhuber, Barbara J, Seshagiri, Somasekar, Sagolla, Meredith, Stawiski, Eric, Lorenzo, Maria N, Wu, Wen-I, Lin, Jie, Yuan, Wenlin, Foo, Catherine K, Skelton, Nicholas J, Jackson, Marlena, Rondon, Jesus, Lin, Kui, Chaudhuri, Subhra, Stern, Howard M, Wu, Jiansheng, Guillory, Joseph, Franke, Yvonne, Stinson, Jeremy, Lee, Brian, Wu, Thomas D, Li, Hong, Bowman, Krista K, Kljavin, Noelyn M, Parikh, Chaitali, Janakiraman, Vasantharajan, Stokoe, David

2012

Overview

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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: 3T3 cells / Allosteric regulation / Allosteric Regulation - drug effects / Allosteric Regulation - genetics / Animals / Biological Sciences / Cancer / Cell growth / Cell Line, Tumor / Cell Membrane - drug effects / Cell Membrane - enzymology / Cell membranes / Cell Transformation, Neoplastic - drug effects / Cell Transformation, Neoplastic - genetics / Cell Transformation, Neoplastic - pathology / cell viability / Cells / Datasets / Enzyme Activation - drug effects / Humans / Inhibitory concentration 50 / Kinases / Mice / Models, Molecular / Mutant Proteins - metabolism / mutants / Mutation / Mutation - genetics / Neoplasms - enzymology / Neoplasms - genetics / NIH 3T3 Cells / Oncogenes / Oncogenes - genetics / patients / pleckstrin / Protein Binding - drug effects / Protein Binding - genetics / Protein Kinase Inhibitors - pharmacology / Protein Transport - drug effects / Proto-Oncogene Proteins c-akt - chemistry / Proto-Oncogene Proteins c-akt - genetics / Proto-Oncogene Proteins c-akt - metabolism / Signal Transduction - drug effects / Signal Transduction - genetics / Somatic mutation / thymoma