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

Authors
Kim, SK; Park, HJ; Hong, HS; Baik, EJ; Jung, MW; Mook-Jung, I
Citation
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 20(1):157-159, 2006
Journal Title
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN
0892-66381530-6860
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.
MeSH terms
Amyloid Precursor Protein SecretasesAmyloid beta-Protein Precursor/metabolismAspartic Acid EndopeptidasesCell LineEndopeptidases/metabolism*Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitorsExtracellular Signal-Regulated MAP Kinases/geneticsExtracellular Signal-Regulated MAP Kinases/metabolism*HumansJNK Mitogen-Activated Protein Kinases/antagonists & inhibitorsJNK Mitogen-Activated Protein Kinases/metabolismMitogen-Activated Protein Kinase Kinases/antagonists & inhibitorsMitogen-Activated Protein Kinase Kinases/metabolismMutationPhosphorylationRNA InterferenceReceptors, Notch/metabolismSignal Transductionp38 Mitogen-Activated Protein Kinases/metabolism
DOI
10.1096/fj.05-4055fje
PMID
16293708
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Physiology
Journal Papers > Research Organization > Institute for Medical Sciences
AJOU Authors
백, 은주정, 민환
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