Role of STRAP in regulating GSK3β function and Notch3 stabilization
Open Access
- 15 May 2011
- journal article
- Published by Taylor & Francis Ltd in Cell Cycle
- Vol. 10 (10), 1639-1654
- https://doi.org/10.4161/cc.10.10.15630
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 show for the first time 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 co-upregulated 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.Keywords
This publication has 61 references indexed in Scilit:
- PR55α, a Regulatory Subunit of PP2A, Specifically Regulates PP2A-mediated β-Catenin DephosphorylationJournal of Biological Chemistry, 2009
- Activation Domain-dependent Monoubiquitylation of Gal4 Protein Is Essential for Promoter Binding in VivoPublished by Elsevier BV ,2008
- Conditional Switches for Extracellular Matrix Patterning inDrosophila melanogasterGenetics, 2008
- The Wnt Pool of Glycogen Synthase Kinase 3β Is Critical for Trophic-Deprivation-Induced Neuronal DeathMolecular and Cellular Biology, 2008
- Axin and GSK3-β control Smad3 protein stability and modulate TGF-β signalingGenes & Development, 2008
- GSK-3 inhibitors induce chromosome instabilityBMC Cell Biology, 2007
- Large‐scale mapping of human protein–protein interactions by mass spectrometryMolecular Systems Biology, 2007
- Ubiquitin-binding domainsBiochemical Journal, 2006
- Activating Mutations of NOTCH1 in Human T Cell Acute Lymphoblastic LeukemiaScience, 2004
- Modulation of Notch Signaling During SomitogenesisAnnual Review of Cell and Developmental Biology, 2003