Role of STRAP in regulating GSK3β function and Notch3 stabilization

Nilesh D. Kashikar, Wanguang Zhang, Pierre P. Massion, Adriana L. Gonzalez, Pran K. Datta

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Glycogen synthase kinase 3β (GSK3β) can regulate a broad range of cellular processes in a variety of cell types and tissues through its ability to phosphorylate its substrates in a cell- and time-specific manner. Although it is known that Axin and presenilin help to recruit β-catenin/Smad3 and tau protein to GSK3β, respectively, it is not clear how many of the other GSK3β substrates are recruited to it. Here, we have established the binding of GSK3β with a novel scaffold protein, STRAP through its WD40 domains. In a new finding, we have observed that STRAP, GSK3β and Axin form a ternary complex together. We, for the first time, show that intracellular fragment of Notch3 (ICN3) binds with GSK3β through the ankyrin repeat domain. this binding between STRAP and GSK3β is reduced by small molecule inhibitors of GSK3β. Further studies revealed that STRAP also binds ICN3 through the ankyrin repeat region and this binding is enhanced in a proteasomal inhibition-dependent manner. In vivo ubiquitination studies indicate that STRAP reduces ubiquitination of ICN3, suggesting a role of STRAP in stabilizing ICN3. This is supported by the fact that STRAP and Notch3 are coup-regulated and co-localized in 59% of non small-cell lung cancers as observed in an immunohistochemical staining of tissue microarrays. These results provide a potential mechanism by which STRAP regulates GSK3β function and Notch3 stabilization, and further support the oncogenic functions of STRAP.

Original languageEnglish (US)
Pages (from-to)1639-1654
Number of pages16
JournalCell Cycle
Volume10
Issue number10
DOIs
StatePublished - May 15 2011

Keywords

  • Axin
  • GSK3β
  • Lung cancer
  • Notch3
  • STRAP
  • Ubiquitination

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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  • Cite this

    Kashikar, N. D., Zhang, W., Massion, P. P., Gonzalez, A. L., & Datta, P. K. (2011). Role of STRAP in regulating GSK3β function and Notch3 stabilization. Cell Cycle, 10(10), 1639-1654. https://doi.org/10.4161/cc.10.10.15630