| Serum- and glucocorticoid-inducible kinase 1 (SGK1) controls Notch1 signaling by downregulation of protein stability through Fbw7 ubiquitin ligase. | |
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MedLine Citation:
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PMID: 21147854 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Notch is a transmembrane protein that acts as a transcriptional factor in the Notch signaling pathway for cell survival, cell death and cell differentiation. Notch1 and Fbw7 mutations both lead the activation of the Notch1 pathway and are found in the majority of patients with the leukemia T-ALL. However, little is known about the mechanisms and regulators that are responsible for attenuating the Notch signaling pathway through Fbw7. Here, we report that the serum- and glucocorticoid-inducible protein kinase SGK1 remarkably reduced the protein stability of the active form of Notch1 through Fbw7. The protein level and transcriptional activity of the Notch1 intracellular domain (Notch1-IC) were higher in SGK1-deficient cells than in SGK1 wild-type cells. Notch1-IC was able to form a trimeric complex with Fbw7 and SGK1, thereby SGK1 enhanced the protein degradation of Notch1-IC via a Fbw7-dependent proteasomal pathway. Furthermore, activated SGK1 phosphorylated Fbw7 at serine 227, an effect inducing Notch1-IC protein degradation and ubiquitylation. Moreover, accumulated dexamethasone-induced SGK1 facilitated the degradation of Notch1-IC through phosphorylation of Fbw7. Together our results suggest that SGK1 inhibits the Notch1 signaling pathway via phosphorylation of Fbw7. |
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Authors:
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Jung-Soon Mo; Eun-Jung Ann; Ji-Hye Yoon; Jane Jung; Yun-Hee Choi; Hwa-Young Kim; Ji-Seon Ahn; Su-Man Kim; Mi-Yeon Kim; Ji-Ae Hong; Mi-Sun Seo; Florian Lang; Eui-Ju Choi; Hee-Sae Park |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-12-08 |
Journal Detail:
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Title: Journal of cell science Volume: 124 ISSN: 1477-9137 ISO Abbreviation: J. Cell. Sci. Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2010-12-21 Completed Date: 2011-05-23 Revised Date: 2011-11-02 |
Medline Journal Info:
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Nlm Unique ID: 0052457 Medline TA: J Cell Sci Country: England |
Other Details:
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Languages: eng Pagination: 100-12 Citation Subset: IM |
Affiliation:
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Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Cycle Proteins / genetics, metabolism* Cell Line Down-Regulation* F-Box Proteins / genetics, metabolism* Glucocorticoids / metabolism Humans Immediate-Early Proteins / genetics, metabolism* Mice Mice, Knockout Phosphorylation Protein Stability Protein-Serine-Threonine Kinases / genetics, metabolism* Receptor, Notch1 / chemistry*, genetics, metabolism* Signal Transduction* Ubiquitin-Protein Ligases / genetics, metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Cell Cycle Proteins; 0/F-Box Proteins; 0/Fbxw7 protein, mouse; 0/Glucocorticoids; 0/Immediate-Early Proteins; 0/Receptor, Notch1; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/serum-glucocorticoid regulated kinase; EC 6.3.2.19/FBXW7 protein, human; EC 6.3.2.19/Ubiquitin-Protein Ligases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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