Journal
MOLECULAR NEUROBIOLOGY
Volume 58, Issue 5, Pages 2204-2214Publisher
SPRINGER
DOI: 10.1007/s12035-020-02254-0
Keywords
Dual-specificity phosphatases; Notch; Presenilin-1; ERK1/2; Neuronal differentiation
Categories
Funding
- Ministry of Science and Technology, Taiwan [MOST 107-2320-B-001-019, MOST 107-0210-01-19-01, MOST 108-3114-Y-001-002, MOST 108-2320-B-001-009, MOST 109-2320-B-001-016]
- Academia Sinica [AS-SUMMIT-108]
- Program for Translational Innovation of Biopharmaceutical Development - Technology Supporting Platform Axis [AS-KPQ-106-TSPA]
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Research showed that DUSP15 can affect Notch processing by regulating ERK1/2 activity to influence Notch protein levels, revealing a novel signaling axis.
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, Notch Delta E) protein and its cleaved product, Notch intracellular domain (NICD). The overall ratio of Notch Delta E to NICD was unchanged by overexpression of DUSP15, suggesting that the effect is independent of gamma-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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