ERK1/2 is an endogenous negative regulator of the γsecretase activity
Abstract
As an essential protease in the generation of amyloid beta, gamma-secretase is believed to play an important role in the pathogenesis of Alzheimer's disease. Although a great deal of progress has been made in identifying the components of gamma-secretase complex, the endogenous regulatory mechanism of gamma-secretase is unknown. Here we show that gamma-secretase is endogenously regulated via extracellular signal regulated MAP kinase (ERK) 1/2-dependent mitogen-activated protein kinase (MAPK) pathway. The inhibition of ERK1/2 activity, either by a treatment with a MEK inhibitor or an ERK knockdown transfection, dramatically increased gamma-secretase activity in several different cell types. JNK or p38 kinase inhibitors had little effect, indicating that the effect is specific to ERK1/2-dependent MAPK pathway. Conversely, increased ERK1/2 activity, by adding purified active ERK1/2 or EGF-induced activation of ERK1/2, significantly reduced gamma-secretase activity, demonstrating down-regulation of gamma-secretase activity by ERK1/2. Whereas gamma-secretase expression was not affected by ERK1/2, its activity was enhanced by phosphatase treatment, indicating that ERK1/2 regulates gamma-secretase activity by altering the pattern of phophorylation. Among the components of isolated gamma-secretase complex, only nicastrin was phosphorylated by ERK1/2, and it precipitated with ERK1/2 in a co-immunoprecipitation assay, which suggests binding between ERK1/2 and nicastrin. Our results sho…
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ERK, a mitogen-activated protein kinase (MAPK), has been shown to suppress Aβ production in vitro and in vivo by altering secretase activity.
“ERK, a mitogen-activated protein kinase (MAPK), has been shown to suppress Aβ production in vitro and in vivo by altering secretase activity (24, 25).”
From Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans (2011) · cites this paper as [24]
ERK activation modulates APP processing and Aβ generation.
“ERK activation has been shown to modulate APP processing and Aβ generation (24, 25, 36).”
From Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans (2011) · cites this paper as [24]
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Presenilin-Dependent Receptor Processing Is Required for Axon Guidance
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“About 1.2 3 105 cells were seeded in 12-well tissue culture plates and transfected with 0.5 lg BACE1 promoter constructs using Lipofectamine reagent and Plus reagent (Invitrogen, Carlsbad, CA) (Kim et al., 2005). pRL-TK plasmid (0.1 lg) was cotransfected to normalize transfection efficiencies.”
MethodInfluentialSelf-citationPhosphorylation Signaling in APP Processing in Alzheimer’s Disease
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JNK and ERK1/2 pathways have a dual opposite effect on the expression of BACE1
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“…stabilization and activation, we evaluated the total and activated forms of ERK1/2, JNK1/2, and P38 because they have been also implicated in involving APP processing with increased Aβ deposition (Atkins et al., 1998; Savage et al., 2002; Kim et al., 2006; Cho et al., 2007; Lee et al., 2009).”
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“Further, ERK and JNK regulate the activity and expression of secretase during the process of Aβ production [66,67].”
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“It has been reported that ERK1/2 is an endogenous negative regulator of g-secretase activity, and NSAIDs can inhibit g-secretase activity by inhibiting the Rho-ROCK pathway [6,32,33].”
BackgroundTargeting Notch signaling in pancreatic cancer
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“In addition, ERK1/2 could be a negative regulator of g-secretase activity [20].”
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HIG1, a novel regulator of mitochondrial γ‐secretase, maintains normal mitochondrial function
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“C-Jun N-terminal kinase ( JNK) activates g-secretase [38] whereas ERK1/2 is an endogenous negative regulator of the g-secretase activity [39].”
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“One report shows that ERK1/2 activation down-regulates c-secretase activity (Kim et al. 2006).”
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Rac1 changes the substrate specificity of γ-secretase between amyloid precursor protein and Notch1
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Self-citationPigment Epithelium-Derived Factor Plays a Role in Alzheimer's Disease by Negatively Regulating Aβ42
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“The PS1 expression is controlled by the ERK and JNK pathway [40, 41].”
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“Erk1/2 activation increases the activity of a-secretase (Kojro et al. 2006), which may inhibit the activities of b- and c-secretase (Kim et al. 2006; Tamagno et al. 2009).”
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OCIAD2 activates γ-secretase to enhance amyloid β production by interacting with nicastrin
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Notch signalling influences cell fate decisions and HOX gene induction in axial progenitors
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DUSP6 regulates Notch1 signalling in colorectal cancer
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The Development of an in vivo γ-Secretase Assay using Zebrafish Embryos
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The Dual Role of Kinin/Kinin Receptors System in Alzheimer’s Disease
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“However, ERK1/2 was also reported to be an endogenous negative regulator of AD, because it down-regulates the activity of γ- and β-secretase (Kim et al., 2006; Tamagno et al., 2009).”
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Self-citationBRAF V600E Overrides NOTCH Signaling in Thyroid Cancer
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“It has been previously reported that ERK activation can reduce c -secretase activity by inducing alterations in the phosphorylation of different subunits of the c -secretase complex (37,48).”
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“Multiple studies have shown that MAPK signaling pathways are involved in AD pathology through their regulation of β-secretase (beta-APP-site-cleavage enzyme-1; BACE1) and γ-secretase activities [17,18].”
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“The halflife and activity of NCT are regulated primarily by its phosphorylation by ERK, JNK, and possibly other kinases [33,34].”
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Arsenite suppression of BMP signaling in human keratinocytes
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“Intriguingly, ERK has been shown to be a negative regulator of γ-secretase activity in mouse neuronal cells, probably through phosphorylation of nicastrin, one of the components of the γ-secretase complex (Kim et al., 2006).”
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Amylin and Secretases in the Pathology and Treatment of Alzheimer’s Disease
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γ‐Secretase inhibition promotes fibrotic effects of albumin in proximal tubular epithelial cells
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Regulation of Functional Phenotypes of Cord Blood–Derived Eosinophils by γ-Secretase Inhibitor
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Cross-species genetic screens to identify kinase targets for APP reduction in Alzheimer's disease
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Akt1 phosphorylates Nicastrin to regulate its protein stability and activity
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“Phosphorylation of NCT by Extracellular signalregulated kinase (ERK), c-Jnu N-terminal kinase (JNK), and possibly another kinase regulates the protein stability and activity of NCT (Kim et al. 2006; Kuo et al. 2008).”
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EFFECTS OF COMBLNED EXERCLSE ON ^|^beta;-AMYLOLD AND DHEAs IN ELDERLY WOMEN
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- Authors
- Kim, S., Park, H., Hong, H. S., Baik, E. J., Jung, M. W., & Mook‐Jung, I.
- Affiliations
- Seoul National University (KR)
- Ajou University (KR)
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2005-11-17
- Volume
- 20
- Issue
- 1
- Pages
- 157-159
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W2102565765
- Cited by
- 92
- References
- 85
- Citations by year
- 2024: 2 · 2023: 1 · 2022: 4 · 2021: 2 · 2020: 3 · 2019: 7 · 2018: 3 · 2017: 3 · 2016: 3 · 2015: 3 · 2014: 7 · 2013: 10 · 2012: 5
- FWCI
- 4.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- Ministry of Education, Science and Technology (FPR05C2-010)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- gamma-secretase, ERK1/2, MAPK signaling, nicastrin, protein phosphorylation, amyloid-beta, Alzheimer's disease, MEK inhibitors, protease regulation
- MeSH terms
- Cell Line, Humans, Mutation, Endopeptidases, Phosphorylation, Signal Transduction, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Mitogen-Activated Protein Kinase Kinases, RNA Interference, JNK Mitogen-Activated Protein Kinases, Extracellular Signal-Regulated MAP Kinases, p38 Mitogen-Activated Protein Kinases, Receptors, Notch, Amyloid Precursor Protein Secretases
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