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

Noopur Bhore; Bo Jeng Wang; Po Fan Wu; Yen Lurk Lee; Yun Wen Chen; Wen Ming Hsu; Hsinyu Lee; Yi Shuian Huang; Ding I. Yang; Yung Feng Liao

doi:10.1007/s12035-020-02254-0

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

Noopur Bhore, Bo Jeng Wang, Po Fan Wu, Yen Lurk Lee, Yun Wen Chen, Wen Ming Hsu, Hsinyu Lee, Yi Shuian Huang, Ding I. Yang, Yung Feng Liao^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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.

Original language	English
Pages (from-to)	2204-2214
Number of pages	11
Journal	Molecular Neurobiology
Volume	58
Issue number	5
DOIs	https://doi.org/10.1007/s12035-020-02254-0
State	Published - May 2021

Keywords

Dual-specificity phosphatases
ERK1/2
Neuronal differentiation
Notch
Presenilin-1

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

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{\textquoteright}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.",

keywords = "Dual-specificity phosphatases, ERK1/2, Neuronal differentiation, Notch, Presenilin-1",

author = "Noopur Bhore and Wang, {Bo Jeng} and Wu, {Po Fan} and Lee, {Yen Lurk} and Chen, {Yun Wen} and Hsu, {Wen Ming} and Hsinyu Lee and Huang, {Yi Shuian} and Yang, {Ding I.} and Liao, {Yung Feng}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.",

year = "2021",

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doi = "10.1007/s12035-020-02254-0",

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T1 - Dual-Specificity Phosphatase 15 (DUSP15) Modulates Notch Signaling by Enhancing the Stability of Notch Protein

AU - Bhore, Noopur

AU - Wang, Bo Jeng

AU - Wu, Po Fan

AU - Lee, Yen Lurk

AU - Chen, Yun Wen

AU - Hsu, Wen Ming

AU - Lee, Hsinyu

AU - Huang, Yi Shuian

AU - Yang, Ding I.

AU - Liao, Yung Feng

PY - 2021/5

Y1 - 2021/5

N2 - 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.

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

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