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ERK1/2 is an endogenous negative regulator of the gamma-secretase activity
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Kim, Su-Kyoung | - |
dc.contributor.author | Park, Hyun-Jun | - |
dc.contributor.author | Hong, Hyun Seok | - |
dc.contributor.author | Baik, Eun Joo | - |
dc.contributor.author | Jung, Min Whan | - |
dc.contributor.author | Mook-Jung, Inhee | - |
dc.date.accessioned | 2010-01-12T06:37:47Z | - |
dc.date.available | 2010-01-12T06:37:47Z | - |
dc.date.issued | 2005-10-19 | - |
dc.identifier.citation | FASEB J. 2006 Jan;20(1):157-79. Epub 2005 Nov 17. | en |
dc.identifier.issn | 1530-6860 (Electronic) | - |
dc.identifier.uri | http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16293708 | - |
dc.identifier.uri | https://hdl.handle.net/10371/29731 | - |
dc.description.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. | en |
dc.language.iso | en | en |
dc.publisher | Federation of American Society of Experimental Biology (FASEB) | en |
dc.subject | Amyloid Precursor Protein Secretases | en |
dc.subject | Amyloid beta-Protein Precursor/metabolism | en |
dc.subject | Aspartic Endopeptidases | en |
dc.subject | Cell Line | en |
dc.subject | Endopeptidases/*metabolism | en |
dc.subject | Extracellular Signal-Regulated MAP Kinases/antagonists & | en |
dc.subject | inhibitors/genetics/*metabolism | en |
dc.subject | Humans | en |
dc.subject | JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors/metabolism | en |
dc.subject | Mitogen-Activated Protein Kinase Kinases/antagonists & | en |
dc.subject | inhibitors/metabolism | en |
dc.subject | Mutation | en |
dc.subject | Phosphorylation | en |
dc.subject | RNA Interference | en |
dc.subject | Receptors, Notch/metabolism | en |
dc.subject | Signal Transduction | en |
dc.subject | p38 Mitogen-Activated Protein Kinases/metabolism | en |
dc.title | ERK1/2 is an endogenous negative regulator of the gamma-secretase activity | en |
dc.type | Article | en |
dc.contributor.AlternativeAuthor | 김수경 | - |
dc.contributor.AlternativeAuthor | 박현정 | - |
dc.contributor.AlternativeAuthor | 홍현석 | - |
dc.contributor.AlternativeAuthor | 백은주 | - |
dc.contributor.AlternativeAuthor | 정민환 | - |
dc.contributor.AlternativeAuthor | 묵인희 | - |
dc.identifier.doi | 10.1096/fj.05-4055fje | - |
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