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 GSK3β. Using a series of truncated Aurora-A proteins and site-directed mutagenesis, we identified distinct FBXW7 and GSK3β-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 FBXW7-dependent degradation of Aurora-A through the AKT/GSK3β pathway. Moreover, radiation-induced tumor latency is significantly shortened in Fbxw7(+/-)Pten(+/-) mice as compared with either Fbxw7(+/-) or Pten(+/-) mice, indicating that Fbxw7 and Pten appear to cooperate in suppressing tumorigenesis. Our results establish a novel posttranslational regulatory network in which the Pten and Fbxw7 pathways appear to converge on the regulation of Aurora-A level.
Pubmed ID: 22513362 RIS Download
Animals | Aurora Kinase A | Aurora Kinases | Binding Sites | Blotting, Western | Cell Line | F-Box Proteins | Female | Gamma Rays | Glycogen Synthase Kinase 3 | Glycogen Synthase Kinase 3 beta | HCT116 Cells | HEK293 Cells | Humans | Male | Mice | Mice, Inbred C57BL | Mice, Knockout | Mutation | NIH 3T3 Cells | Neoplasms, Radiation-Induced | PTEN Phosphohydrolase | Protein Binding | Protein-Serine-Threonine Kinases | Time Factors | Ubiquitin | Ubiquitin-Protein Ligases