title: Serum- and glucocorticoid-inducible kinase 1 (SGK1) controls Notch1 signaling by downregulation of protein stability through Fbw7 ubiquitin ligase.
abstract: 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.
authors.affiliation: Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Jung-Soon
authors.initials: JS
authors.lastname: Mo
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Ann
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Yoon
authors.forename: Jane
authors.initials: J
authors.lastname: Jung
authors.forename: Yun-Hee
authors.initials: YH
authors.lastname: Choi
authors.forename: Hwa-Young
authors.initials: HY
authors.lastname: Kim
authors.forename: Ji-Seon
authors.initials: JS
authors.lastname: Ahn
authors.forename: Su-Man
authors.initials: SM
authors.lastname: Kim
authors.forename: Mi-Yeon
authors.initials: MY
authors.lastname: Kim
authors.forename: Ji-Ae
authors.initials: JA
authors.lastname: Hong
authors.forename: Mi-Sun
authors.initials: MS
authors.lastname: Seo
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.forename: Eui-Ju
authors.initials: EJ
authors.lastname: Choi
authors.forename: Hee-Sae
authors.initials: HS
authors.lastname: Park
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005938:Glucocorticoids / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D051881:Receptor, Notch1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; D005938:Glucocorticoids; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D051881:Receptor, Notch1; D044767:Ubiquitin-Protein Ligases; D000099184:Serum-Glucocorticoid Regulated Kinases; C513273:FBXW7 protein, human; C513272:Fbxw7 protein, mouse