Biochemical characterization of the Eya and PP2A-B55α interaction.

Autor:	Alderman C; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA; Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA; Molecular Biology Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA., Anderson R; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA., Zhang L; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA., Hughes CJ; Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA., Li X; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA., Ebmeier C; Department of Biochemistry, University of Colorado-Boulder, Boulder, Colorado, USA., Wagley ME; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA., Ahn NG; Department of Biochemistry, University of Colorado-Boulder, Boulder, Colorado, USA., Ford HL; Molecular Biology Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA., Zhao R; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA; Molecular Biology Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA. Electronic address: Rui.Zhao@cuanschutz.edu.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2024 Jul; Vol. 300 (7), pp. 107408. Date of Electronic Publication: 2024 May 23.
DOI:	10.1016/j.jbc.2024.107408
Abstrakt:	The eyes absent (Eya) proteins were first identified as co-activators of the six homeobox family of transcription factors and are critical in embryonic development. These proteins are also re-expressed in cancers after development is complete, where they drive tumor progression. We have previously shown that the Eya3 N-terminal domain (NTD) contains Ser/Thr phosphatase activity through an interaction with the protein phosphatase 2A (PP2A)-B55α holoenzyme and that this interaction increases the half-life of Myc through pT58 dephosphorylation. Here, we showed that Eya3 directly interacted with the NTD of Myc, recruiting PP2A-B55α to Myc. We also showed that Eya3 increased the Ser/Thr phosphatase activity of PP2A-B55α but not PP2A-B56α. Furthermore, we demonstrated that the NTD (∼250 amino acids) of Eya3 was completely disordered, and it used a 38-residue segment to interact with B55α. In addition, knockdown and phosphoproteomic analyses demonstrated that Eya3 and B55α affected highly similar phosphosite motifs with a preference for Ser/Thr followed by Pro, consistent with Eya3's apparent Ser/Thr phosphatase activity being mediated through its interaction with PP2A-B55α. Intriguingly, mutating this Pro to other amino acids in a Myc peptide dramatically increased dephosphorylation by PP2A. Not surprisingly, Myc P59A , a naturally occurring mutation hotspot in several cancers, enhanced Eya3-PP2A-B55α-mediated dephosphorylation of pT58 on Myc, leading to increased Myc stability and cell proliferation, underscoring the critical role of this phosphosite in regulating Myc stability. Competing Interests: Conflict of interest The authors declare no conflict of interest with the contents of this article. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu