Cited by 92Alzheimer's disease research and treatmentsProtein Kinase Regulation and GTPase SignalingDementia and Cognitive Impairment Research

ERK1/2 is an endogenous negative regulator of the γsecretase activity

Kim, Su‐Kyoung, Park, Hyun‐Jung, Hong, Hyun Seok, Baik, Eun Joo, Jung, Min Whan, Mook‐Jung, Inhee·2006·The FASEB Journal

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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Crossref · 10.1096/fj.05-4055fje

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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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