Signaling and Regulation Pten Regulates Aurora-A and Cooperates with Fbxw7 in Modulating Radiation-Induced Tumor Development

The Aurora-A kinase gene is frequently amplified and/or overexpressed in a variety of human cancers, leading to major efforts to develop therapeutic agents targeting this pathway. Here, we show that Aurora-A is targeted for ubiquitination and subsequent degradation by the F-box protein FBXW7 in a process that is regulated by GSK3b. Using a series of truncated Aurora-A proteins and site-directed mutagenesis, we identified distinct FBXW7 and GSK3b-binding sites in Aurora-A. Mutation of critical residues in either site substantially disrupts degradation of Aurora-A. Furthermore, we show that loss of Pten results in the stabilization of Aurora-A by attenuating FBXW7dependent degradation of Aurora-A through the AKT/GSK3b pathway. Moreover, radiation-induced tumor latency is significantly shortened in Fbxw7þ/ Ptenþ/ mice as compared with either Fbxw7þ/ or Ptenþ/ mice, indicating that Fbxw7 and Pten appear to cooperate in suppressing tumorigenesis. Our results establish a novel posttranslational regulatory network inwhich the Pten and Fbxw7pathways appear to converge on the regulation of Aurora-A level. Mol Cancer Res; 1–11. 2012 AACR.