Serum- and glucocorticoid-inducible kinase 1 (SGK1) controls notch1 signaling by downregulation of protein stability through Fbw7 ubiquitin ligase

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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37 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)100-112
Number of pages13
JournalJournal of Cell Science
Volume124
Issue number1
DOIs
Publication statusPublished - 2011 Jan 1

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Keywords

  • Dexamethasone
  • Fbw7
  • Notch1-IC
  • Protein degradation
  • SGK1

ASJC Scopus subject areas

  • Cell Biology

Cite this

Mo, J. S., Ann, E. J., Yoon, J. H., Jung, J., Choi, Y. H., Kim, H. Y., Ahn, J. S., Kim, S. M., Kim, M. Y., Hong, J. A., Seo, M. S., Lang, F., Choi, E. J., & Park, H. S. (2011). Serum- and glucocorticoid-inducible kinase 1 (SGK1) controls notch1 signaling by downregulation of protein stability through Fbw7 ubiquitin ligase. Journal of Cell Science, 124(1), 100-112. https://doi.org/10.1242/jcs.073924