S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Biochemistry & Molecular Biology (생화학교실) Journal Papers (저널논문_생화학교실)
ERK1/2 is an endogenous negative regulator of the gamma-secretase activity
- Kim, Su-Kyoung; Park, Hyun-Jun; Hong, Hyun Seok; Baik, Eun Joo; Jung, Min Whan; Mook-Jung, Inhee
- Issue Date
- FASEB J. 2006 Jan;20(1):157-79. Epub 2005 Nov 17.
- Amyloid Precursor Protein Secretases; Amyloid beta-Protein Precursor/metabolism; Aspartic Endopeptidases; Cell Line; Endopeptidases/*metabolism; Extracellular Signal-Regulated MAP Kinases/antagonists &; inhibitors/genetics/*metabolism; Humans; JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors/metabolism; Mitogen-Activated Protein Kinase Kinases/antagonists &; inhibitors/metabolism; Mutation; Phosphorylation; RNA Interference; Receptors, Notch/metabolism; Signal Transduction; p38 Mitogen-Activated Protein Kinases/metabolism
- 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 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.
- 1530-6860 (Electronic)
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