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Dual-Specificity Phosphatase 15 (DUSP15) Modulates Notch Signaling by Enhancing the Stability of Notch Protein

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Abstract

Dual-specificity phosphatases (DUSPs) comprise a unique group of enzymes that dephosphorylate signaling proteins at both phospho-serine/threonine and phospho-tyrosine residues. Since Notch signaling is an essential pathway for neuronal cell fate determination and development that is also upregulated in Alzheimer’s disease tissues, we sought to explore whether and how DUSPs may impact Notch processing. Our results show that overexpression of DUSP15 concomitantly and dose-dependently increased the steady-state levels of recombinant Notch (extracellular domain-truncated Notch, NotchΔE) protein and its cleaved product, Notch intracellular domain (NICD). The overall ratio of NotchΔE to NICD was unchanged by overexpression of DUSP15, suggesting that the effect is independent of γ-secretase. Interestingly, overexpression of DUSP15 also dose-dependently increased phosphorylated ERK1/2. Phosphorylated ERK1/2 is known to be positively correlated with Notch protein level, and we found that DUSP15-mediated regulation of Notch was dependent on ERK1/2 activity. Together, our findings reveal the existence of a previously unidentified DUSP15-ERK1/2-Notch signaling axis, which could potentially play a role in neuronal differentiation and neurological disease.

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Abbreviations

AD:

Alzheimer’s disease

APP:

Amyloid precursor protein

Aβ:

Amyloid-β

BCA:

Bicinchoninic acid assay

C99:

γ-Secretase-derived 99-amino acid C-terminal fragment of APP

CFP:

Cyan fluorescent protein

CSL:

CBF-1/RBPJ-κ, Suppressor of Hairless, Lag-1 protein

DUSP:

Dual-specificity phosphatase

EGFP:

Enhanced green fluorescent protein

EYFP:

Enhanced yellow fluorescent protein

ECL:

Enhanced chemiluminescence

EGFR:

Epidermal growth factor receptor

ERK:

Extracellular signal-regulated kinase

FBS:

Fetal bovine serum

FGF:

Fibroblast growth factor

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

HEK293:

Human embryonic kidney 293 cells

MAML:

Mastermind-like protein

MAPK/SAPK:

Mitogen-activated or stress-activated protein kinase

NotchΔE-GV:

NotchΔE-Gal4-VP16 stable cell line

NICD:

Notch intracellular domain

NotchΔE:

Extracellular domain-truncated Notch protein

PBS:

Phosphate-buffered saline

PDGFRB:

Platelet-derived growth factor receptor β

PP:

Protein phosphatase

PS1:

Presenilin 1

PTP:

Protein tyrosine phosphatase

PVDF:

Polyvinylidene difluoride

RIPA:

Radioimmunoprecipitation assay buffer

RNAi:

Ribonucleic acid interference

SNX:

Sorting nexin

STEP:

Striatal-enriched protein tyrosine phosphatase

TBST:

Tris-buffered saline, 0.1% Tween 20

TGF-β:

Transforming growth factor-β

Wnt:

Wingless-related integration site protein

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Acknowledgments

We thank Dr. Chi-Hon Lee for generous support and the Core Facility of the Institute of Cellular and Organismic Biology, Academia Sinica, for technical support. The authors also thank the National RNAi Core Facility at Academia Sinica in Taiwan for providing shRNA reagents and related services. We thank Dr. Marcus Calkins for critical reading of the manuscript.

Funding

This study was supported by Ministry of Science and Technology, Taiwan Grants MOST 107-2320-B-001-019, MOST 107-0210-01-19-01, MOST 108-3114-Y-001-002, MOST 108-2320-B-001-009, and MOST 109-2320-B-001-016 (to Y.-F.L.); the Academia Sinica AS-SUMMIT-108 (Y.-F.L.); the Program for Translational Innovation of Biopharmaceutical Development – Technology Supporting Platform Axis [Grant No. AS-KPQ-106-TSPA, to Y.-F.L. (NP7)].

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Authors and Affiliations

  1. Laboratory of Molecular Neurobiology, Institute of Cellular and Organismic Biology, Academia Sinica, ICOB 238, 128 Sec. 2 Academia Rd, Taipei, 11529, Taiwan

    Noopur Bhore, Bo-Jeng Wang, Po-Fan Wu, Yun-Wen Chen & Yung-Feng Liao

  2. Taiwan International Graduate Program in Interdisciplinary Neuroscience, National Yang-Ming University, Academia Sinica, Taipei, Taiwan

    Noopur Bhore, Yi-Shuian Huang, Ding-I Yang & Yung-Feng Liao

  3. Taiwan International Graduate Program in Interdisciplinary Neuroscience, National Cheng Kung University, Academia Sinica, Taipei, Taiwan

    Po-Fan Wu, Yi-Shuian Huang & Yung-Feng Liao

  4. TIGP in Molecular Medicine, National Yang-Ming University, Academia Sinica, Taipei, Taiwan

    Yen-Lurk Lee & Yi-Shuian Huang

  5. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

    Yen-Lurk Lee & Yi-Shuian Huang

  6. Department of Surgery, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan

    Wen-Ming Hsu

  7. Department of Life Science, National Taiwan University, Taipei, Taiwan

    Hsinyu Lee

  8. Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan

    Ding-I Yang

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  1. Noopur Bhore
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Contributions

N.B. and Y.-F.L conceived the study. N.B. and Y.-F.L. designed the experiments. N.B. and B.-J.W. performed the research experiments. P.-F.W., Y.-L.L., and Y.-W.C. assisted in experimental techniques. W.-M.H., H.L., Y.-S.H., and D.-I.Y. contributed new reagents/analytic tools. N.B. and Y.-F.L. analyzed and interpreted data. N.B. and Y.-F.L. wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yung-Feng Liao.

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Bhore, N., Wang, BJ., Wu, PF. et al. Dual-Specificity Phosphatase 15 (DUSP15) Modulates Notch Signaling by Enhancing the Stability of Notch Protein. Mol Neurobiol 58, 2204–2214 (2021). https://doi.org/10.1007/s12035-020-02254-0

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