Crosstalk between Aurora-A and GSK3β/β-catenin pathways induces c-Myc and cyclin D1

5507 Aurora-A is a centrosome serine/threonine kinase which is frequently altered in human malignancy and its overexpression induces malignant phenotype in different cell types. However, the molecular mechanism by which Aurora-A contributes to oncogenic transformation is still largely unknown even though it plays a key role in mitosis. Here we demonstrate that Aurora-A upregulates c-Myc and cyclin D1 through regulation of glycogen synthase kinase (GSK)-3β/β-catenin pathway. Knockdown Aurora-A by RNAi considerably reduces expression of c-Myc and cyclin D1 whereas ecopic expression of Aurora-A significantly increases expression of c-Myc and cyclin D1 at both RNA and protein levels as well as their promoter activity. Mutation of TCF binding sites abrogates Aurora-A-induced promoter activities. Further, we observed Aurora-A phosphorylation of GSK3β in vitro and in vivo , which resulted in the accumulation of β-catenin in the nucleus. Phosphorylation peptide mapping and immunoblotting analysis with anti-phospho-GSK3β-S9 antibody revealed that serine-9 of GSK3β, a site targeted by Akt and Wnt pathways, is phosphorylated by Aurora-A. Expression of nonphosphorylatable GSK3β-S9A considerably decreases c-Myc and cyclin D1 levels induced by Aurora-A. Thus, our findings provide the first evidence that Aurora-A crosstalks with GSK3β/β-catenin pathway to upregulate c-Myc and cyclin D1 which may mediate Aurora-A oncogenic signaling.