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.
Highlights
The Eya proteins were initially discovered as factors required for normal eye development in Drosophila[1] and as essential co-activators of the Six family of homeoproteins[2,3,4]
We further demonstrate that Eya[3] regulates the stability of c-Myc not via an intrinsic Thr phosphatase activity, but rather by controlling the dephosphorylation of c-Myc at pT58 through phosphatase 2A (PP2A), suggesting that Eya[3] may change the function of PP2A from tumor suppressive to tumor promotional
In line with a tumor promotional role of the Eya3–PP2A complex, we demonstrate in mouse models of breast cancer metastasis that Eya[3] that is unable to interact with B55α has reduced metastasis, and that knockdown (KD) of the B55α subunit inhibits metastasis
Summary
The Eya proteins were initially discovered as factors required for normal eye development in Drosophila[1] and as essential co-activators of the Six family of homeoproteins[2,3,4]. The Thr phosphatase activity of Eya has been implicated in innate immunity[18,20], and more recently in the dephosphorylation and stabilization of c-Myc during development[21,22], but its role in tumor initiation and/or progression has not been explored. We further demonstrate that Eya[3] regulates the stability of c-Myc not via an intrinsic Thr phosphatase activity, but rather by controlling the dephosphorylation of c-Myc at pT58 through PP2A, suggesting that Eya[3] may change the function of PP2A from tumor suppressive to tumor promotional. In line with a tumor promotional role of the Eya3–PP2A complex, we demonstrate in mouse models of breast cancer metastasis that Eya[3] that is unable to interact with B55α has reduced metastasis, and that knockdown (KD) of the B55α subunit inhibits metastasis. Our results reveal a previously unrecognized function of Eya in regulating PP2A activity, which in turn influences c-Myc stability, as well as tumor progression
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