ERK1/2 is an endogenous negative regulator of the gamma-secretase activity

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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.-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 show that ERK1/ 2 is an endogenous regulator of gamma-secretase, which raises the possibility that ERK1/2 down-regulates gamma-secretase activity by directly phosphorylating nicastrin.
Publisher
FEDERATION AMER SOC EXP BIOL
Issue Date
2005-11
Language
English
Article Type
Article
Keywords

AMYLOID PRECURSOR PROTEIN; ALZHEIMERS-DISEASE; SIGNAL-TRANSDUCTION; BETA-SECRETASE; MAP KINASE; HUMAN BRAIN; IN-VIVO; INTRAMEMBRANE PROTEOLYSIS; GLYCOSYLATED NICASTRIN; INTRACELLULAR DOMAIN

Citation

FASEB JOURNAL, v.19, pp.157 - +

ISSN
0892-6638
DOI
10.1096/fj.05-4055fje
URI
http://hdl.handle.net/10203/93180
Appears in Collection
BS-Journal Papers(저널논문)
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