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ERK1/2 is an endogenous negative regulator of the gamma-secretase activity
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- Authors
- Issue Date
- 2005-10-19
- Citation
- FASEB J. 2006 Jan;20(1):157-79. Epub 2005 Nov 17.
- Keywords
- 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
- 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 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.
- ISSN
- 1530-6860 (Electronic)
- Language
- English
- URI
- http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16293708
https://hdl.handle.net/10371/29731
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