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Cell Aggregation Assays to Evaluate the Binding of the Drosophila Notch with Trans-Ligands and its Inhibition by Cis-Ligands
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Cell Aggregation Assays to Evaluate the Binding of the Drosophila Notch with Trans-Ligands and its Inhibition by Cis-Ligands

Published on: January 2, 2018

Role of STRAP in regulating GSK3β function and Notch3 stabilization

Nilesh D Kashikar1, Wanguang Zhang, Pierre P Massion

  • 1Vanderbilt University School of Medicine, Nashville, TN USA.

Cell Cycle (Georgetown, Tex.)
|April 20, 2011
PubMed

Insights

The scaffold protein STRAP binds Glycogen synthase kinase 3β (GSK3β) and stabilizes Notch3, a protein implicated in non-small cell lung cancer. STRAP

Area of Science:

  • Cellular signaling pathways
  • Protein-protein interactions
  • Cancer biology

Background:

  • Glycogen synthase kinase 3β (GSK3β) regulates cellular processes by phosphorylating substrates.
  • The recruitment mechanisms for many GSK3β substrates remain unclear.
  • Notch signaling is implicated in various cancers, including non-small cell lung cancer (NSCLC).

Purpose of the Study:

  • To elucidate the interaction between GSK3β and its novel scaffold protein, STRAP.
  • To investigate the role of STRAP in the regulation of Notch3 stability and function.
  • To explore the potential oncogenic role of STRAP in non-small cell lung cancer.

Main Methods:

  • Co-immunoprecipitation assays to establish protein binding.
  • Use of small-molecule inhibitors to probe protein interactions.
  • In vivo ubiquitination assays to assess protein stability.
  • Immunohistochemical staining of tissue microarrays for co-localization studies.

Main Results:

  • STRAP binds to GSK3β via its WD40 domains, forming a ternary complex with GSK3β and Axin.
  • STRAP binds to the intracellular fragment of Notch3 (ICN3) through its ankyrin repeat region.
  • STRAP reduces ICN3 ubiquitination, leading to ICN3 stabilization.
  • STRAP and Notch3 are co-upregulated and co-localized in a significant proportion of NSCLC tissues.

Conclusions:

  • STRAP acts as a scaffold protein that modulates GSK3β activity towards Notch3.
  • STRAP stabilizes ICN3, potentially contributing to its oncogenic functions in NSCLC.
  • The findings reveal a novel regulatory mechanism for Notch3 and highlight STRAP as a potential therapeutic target in NSCLC.

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