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

ABSTRACT: 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 hu

SUBMITTER: Parikh C 

PROVIDER: S-EPMC3511101 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature