Eya3 partners with PP2A to induce c-Myc stabilization and tumor progression

• Published in: Nature communications Vol. 9; no. 1; pp. 1047 - 14
• Main Authors: Zhang, Lingdi, Zhou, Hengbo, Li, Xueni, Vartuli, Rebecca L, Rowse, Michael, Xing, Yongna, Rudra, Pratyaydipta, Ghosh, Debashis, Zhao, Rui, Ford, Heide L
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.03.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 38; 59; 631/67/1347; 64; 692/4028/67/1347; Animals; Breast cancer; c-Myc protein; Cell Line, Tumor; Control stability; Dephosphorylation; Destabilization; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; HEK293 Cells; Humanities and Social Sciences; Humans; Immunohistochemistry; Mass Spectrometry; Metastases; Mice; multidisciplinary; Myc protein; Phosphatase; Phosphoprotein phosphatase; Phosphorylation; Protein Binding; Protein phosphatase; Protein Phosphatase 2 - genetics; Protein Phosphatase 2 - metabolism; Protein Stability; Protein Tyrosine Phosphatases - genetics; Protein Tyrosine Phosphatases - metabolism; Proteins; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Science; Science (multidisciplinary); Transcription factors; Xenografts; Xenotransplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-03327-4

Eya genes encode a unique family of multifunctional proteins that serve as transcriptional co-activators and as haloacid dehalogenase-family Tyr phosphatases. Intriguingly, the N-terminal domain of Eyas, which does not share sequence similarity to any known phosphatases, contains a separable Ser/Thr phosphatase activity. Here, we demonstrate that the Ser/Thr phosphatase activity of Eya is not intrinsic, but arises from its direct interaction with the protein phosphatase 2A (PP2A)-B55α holoenzyme. Importantly, Eya3 alters the regulation of c-Myc by PP2A, increasing c-Myc stability by enabling PP2A-B55α to dephosphorylate pT58, in direct contrast to the previously described PP2A-B56α-mediated dephosphorylation of pS62 and c-Myc destabilization. Furthermore, Eya3 and PP2A-B55α promote metastasis in a xenograft model of breast cancer, opposing the canonical tumor suppressive function of PP2A-B56α. Our study identifies Eya3 as a regulator of PP2A, a major cellular Ser/Thr phosphatase, and uncovers a mechanism of controlling the stability of a critical oncogene, c-Myc. Eya proteins are characterised by phosphatase activity associated with both the evolutionary conserved region and the less conserved N-terminal domain (NTD). Here the authors show that NTD mediates the interaction with PP2A and regulates c-Myc phosphorylation and stability, potentially switching PP2A from a tumour suppressor to an oncogene.