PR55α-containing protein phosphatase 2A complexes promote cancer cell migration and invasion through regulation of AP-1 transcriptional activity

• DOI: 10.1038/onc.2014.26
• Publication Date: 2014-03-17T12:01:48Z
• Authors: O Gilan; J Diesch; M Amalia; K Jastrzebski; A C Chueh; N M Verrills; R B Pearson; J M Mariadason; E Tulchinsky; R D Hannan; A S Dhillon
• Keywords: Cancer Research; 570; Proto-Oncogene Proteins c-jun; tumour cells; Proto-Oncogene Mas; 03 medical and health sciences; 1311 Genetics; Cell Movement; Cell Line, Tumor; Neoplasms; Genetics; 1312 Molecular Biology; Humans; 1306 Cancer Research; Protein Phosphatase 2; Phosphorylation; PR55α; Molecular Biology; 0303 health sciences; protein phosphatase 2A; Gene Expression Regulation, Neoplastic; Transcription Factor AP-1; cancer cells; Proto-Oncogene Proteins c-fos; Protein Binding

The proto-oncogene c-Jun is a component of activator protein-1 (AP-1) transcription factor complexes that regulates processes essential for embryonic development, tissue homeostasis and malignant transformation. Induction of gene expression by c-Jun involves stimulation of its transactivation ability and upregulation of DNA binding capacity. While it is well established that the former requires JNK-mediated phosphorylation of S63/S73, the mechanism(s) through which binding of c-Jun to its endogenous target genes is regulated remains poorly characterized. Here we show that interaction of c-Jun with chromatin is positively regulated by protein phosphatase 2A (PP2A) complexes targeted to c-Jun by the PR55α regulatory subunit. PR55α-PP2A specifically dephosphorylates T239 of c-Jun, promoting its binding to genes regulating tumour cell migration and invasion. PR55α-PP2A also enhanced transcription of these genes, without affecting phosphorylation of c-Jun on S63. These findings suggest a critical role for interplay between JNK and PP2A pathways determining the functional activity of c-Jun/AP-1 in tumour cells.