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

Lingdi Zhang, Hengbo Zhou, Xueni Li, Rebecca L Vartuli, Michael Rowse, Yongna Xing, Pratyaydipta Rudra, Debashis Ghosh, Rui Zhao () and Heide L Ford ()
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Lingdi Zhang: University of Colorado Denver Anschutz Medical Campus
Hengbo Zhou: University of Colorado Anschutz Medical Campus
Xueni Li: University of Colorado Denver Anschutz Medical Campus
Rebecca L Vartuli: University of Colorado Anschutz Medical Campus
Michael Rowse: University of Wisconsin-Madison
Yongna Xing: University of Wisconsin-Madison
Pratyaydipta Rudra: University of Colorado Anschutz Medical Campus
Debashis Ghosh: University of Colorado Anschutz Medical Campus
Rui Zhao: University of Colorado Denver Anschutz Medical Campus
Heide L Ford: University of Colorado Denver Anschutz Medical Campus

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-03327-4

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