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

Zhang, Lingdi; Zhou, Hengbo; Li, Xueni; Vartuli, Rebecca L.; Rowse, Michael; Xing, Yongna; Rudra, Pratyaydipta; Ghosh, Debashis; Zhao, Rui; Ford, Heide L.

doi:10.1038/s41467-018-03327-4

Cited by 55 publications

(71 citation statements)

References 56 publications

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“…Extensively studied for its role in eye development (3, 4), the EYES ABSENT (EYA) protein represents a promising target to unravel the molecular mechanisms underlying PPTM. This cotranscription factor with phosphatase activity is highly conserved in the animal kingdom (5) and has been implicated in diverse biological processes such as organ development, innate immunity, DNA damage repair, angiogenesis, and cancer metastasis (6–10). Interestingly, the mammalian ortholog, EYES ABSENT 3 (EYA3) was recently implicated in sheep as a clock-regulated transcription factor in the pituitary gland to promote the transcription of TSHβ , leading to an increase in thyroid-stimulating hormone (TSH) and an induction of summer phenotypes in long photoperiod (11–15).…”

Section: Introductionmentioning

confidence: 99%

EYES ABSENT and TIMELESS integrate photoperiodic and temperature cues to regulate seasonal physiology inDrosophila

Abrieux

Xue

Cai

et al. 2020

Preprint

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Organisms possess photoperiodic timing mechanisms to anticipate variations in day length and temperature as the seasons progress. The nature of the molecular mechanisms interpreting and signaling these environmental changes to elicit downstream neuroendocrine and physiological responses are just starting to emerge. Here, we demonstrate that in Drosophila melanogaster, EYES ABSENT (EYA) acts as a seasonal sensor by interpreting photoperiodic and temperature changes to trigger appropriate physiological responses. We observed that tissue-specific genetic manipulation of eya expression is sufficient to disrupt the ability of flies to sense seasonal cues, thereby altering the extent of female reproductive dormancy. Specifically we observed that EYA proteins, which peak at night in short photoperiod and accumulate at higher levels in the cold, promote reproductive dormancy in female D. melanogaster. Furthermore, we provide evidence indicating that the role of EYA in photoperiodism and temperature sensing is aided by the stabilizing action of the light-sensitive circadian clock protein TIMELESS (TIM). We postulate that increased stability and level of TIM at night under short photoperiod together with the production of cold-induced and light-insensitive TIM isoforms facilitate EYA accumulation in winter conditions. This is supported by our observations that tim null mutants exhibit reduced incidence of reproductive dormancy in simulated winter conditions, while flies overexpressing tim show an increased incidence of reproductive dormancy even in long photoperiod.Significance StatementExtracting information on calendar time from seasonal changes in photoperiod and temperature is critical for organisms to maintain circannual cycles in physiology and behavior. Here we found that in flies, EYES ABSENT (EYA) protein act as a seasonal sensor by adjusting its abundance and circadian phase in response to changes in photoperiod and temperature. We show that the manipulation of EYA levels is sufficient to impair the ability of female Drosophila to regulate seasonal variation in reproductive dormancy. Finally, our results suggest an important role of the circadian clock protein TIMELESS (TIM) in modulating EYA level through its ability to measure night length, linking the circadian clock to seasonal timing.

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Section: Introductionmentioning

confidence: 99%

EYES ABSENT and TIMELESS integrate photoperiodic and temperature cues to regulate seasonal physiology inDrosophila

Abrieux

Xue

Cai

et al. 2020

Preprint

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“…While the less conserved Nterminal domain (NTD) does not contain a sequence motif that shares homology to any other known phosphatase, it has repeatedly been documented that the NTD of Eya members harbors Ser/Thr phosphatase activity (Li et al, 2017;Liu et al, 2012;Okabe et al, 2009;Xu et al, 2014). A recent study suggests that Ser/Thr phosphatase activity reported for Eya3 reflects a close association between the Eya NTD and the PP2A enzyme (Zhang et al, 2018), rather than direct activity of Eya3 itself. Here, we suggest that the CTD of both murine and human Eya1 is essential for full Thr phosphatase activity, as alterations of the D327 residue within the CTD domain reduce Eya1 activity on Thr-containing peptides, albeit to a lesser extent than its activity on Tyr-containing peptides (Li et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…It had been suggested that the Ser/Thr phosphatase activity of Eya3 is not intrinsic but stems from its association with the protein phosphatase 2A (PP2A)-B55α holoenzyme (Zhang et al, 2018). As we hypothesize that phosphorylation state of aPKC depends on Eya1 activity, we asked whether PP2A-B55α is essential for this function.…”

Section: Eya1 Dephosphorylates Atypical Protein Kinase C and Regulatementioning

confidence: 95%

“…However, this view has recently been challenged by a study suggesting that Ser/Thr phosphatase activity of Eya3 might not be intrinsic, but rather arises from association with the PP2A (Zhang et al, 2018). Moreover, since Eya acts as both a cotranscriptional activator and a phosphatase, it is not clear whether the intrinsic phosphatase activity is required for its actions (Ahmed et al, 2012;Li et al, 2003;Wu et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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The Eya1 phosphatase mediates Shh-driven symmetric cell division of cerebellar granule cell precursors

Merk

Zhou

Cohen

et al. 2019

Preprint

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During neural development, stem and precursor cells can divide either symmetrically or asymmetrically. The transition between symmetric and asymmetric cell divisions is a major determinant of precursor cell expansion and neural differentiation, but the underlying mechanisms that regulate this transition are not well understood. Here, we identify the Sonic hedgehog (Shh) pathway as a critical determinant regulating the mode of division of cerebellar granule cell precursors (GCPs). Using partial gain and loss of function mutations within the Shh pathway, we show that pathway activation determines spindle orientation of GCPs, and that mitotic spindle orientation directly correlates with the mode of division. Mechanistically, we show that the phosphatase Eya1 is essential for implementing Shh-dependent GCP spindle orientation. We identify atypical protein kinase C (aPKC) as a direct target of Eya1 activity and show that Eya1 dephosphorylates Threonine (T410) in the activation loop of this polarity complex component. Thus, Eya1 inactivates the cell polarity complex, resulting in reduced phosphorylation of Numb and other components that regulate the mode of division. This Eya1-dependent cascade is critical in linking spindle orientation, cell cycle exit and terminal differentiation.Together these findings demonstrate that a Shh-Eya1 regulatory axis selectively promotes symmetric cell divisions during cerebellar development by coordinating spindle orientation and cell fate determinants.

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“…In addition to its own tyrosine phosphatase activity, EYA has threonine phosphatase activity but only when interacting with the protein phosphatase 2A (PP2A)-B55α holoenzyme. This interaction proved to play a critical role in c-Myc stabilization and late stage metastasis in the breast cancer model [25]. There are four human homologous EYA proteins (EYA 1 to 4), which all contain a highly conserved PTP catalytic domain, termed the Eya Domain (ED) and a variable N-terminal region.…”

Section: Introductionmentioning

confidence: 99%

Analysis of EYA3 Phosphorylation by Src Kinase Identifies Residues Involved in Cell Proliferation

Ionescu

Mentel

Munteanu

et al. 2019

IJMS

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Eyes absent (EYA) are non-thiol-based protein tyrosine phosphatases (PTPs) that also have transcriptional co-activator functions. Their PTP activity is involved in various pathologies. Recently, we demonstrated that Src tyrosine kinase phosphorylates human EYA3 by controlling its subcellular localization. We also found EYA3 s ability to autodephosphorylate, while raising the question if the two opposing processes could be involved in maintaining a physiologically adequate level of phosphorylation. Using native and bottom-up mass spectrometry, we performed detailed mapping and characterization of human EYA3 Src-phosphorylation sites. Thirteen tyrosine residues with different phosphorylation and autodephosphorylation kinetics were detected. Among these, Y77, 96, 237, and 508 displayed an increased resistance to autodephosphorylation. Y77 and Y96 were found to have the highest impact on the overall EYA3 phosphorylation. Using cell cycle analysis, we showed that Y77, Y96, and Y237 are involved in HEK293T proliferation. Mutation of the three tyrosine residues abolished the pro-proliferative effect of EYA3 overexpression. We have also identified a Src-induced phosphorylation pattern of EYA3 in these cells. These findings suggest that EYA3 s tyrosine phosphorylation sites are non-equivalent with their phosphorylation levels being under the control of Src-kinase activity and of EYA3 s autodephosphorylation.

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

Cited by 55 publications

References 56 publications

EYES ABSENT and TIMELESS integrate photoperiodic and temperature cues to regulate seasonal physiology inDrosophila

EYES ABSENT and TIMELESS integrate photoperiodic and temperature cues to regulate seasonal physiology inDrosophila

The Eya1 phosphatase mediates Shh-driven symmetric cell division of cerebellar granule cell precursors

Analysis of EYA3 Phosphorylation by Src Kinase Identifies Residues Involved in Cell Proliferation

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