Role of STRAP in regulating GSK3β function and Notch3 stabilization
| Autor: | Wan-guang Zhang, Nilesh D. Kashikar, Pierre P. Massion, Pran K. Datta, Adriana Gonzalez |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Scaffold protein
Ankyrins Molecular Sequence Data Plasma protein binding Biology Glycogen Synthase Kinase 3 Axin Protein GSK-3 Report Cell Line Tumor Ankyrin Humans Amino Acid Sequence Phosphorylation RNA Small Interfering Molecular Biology GSK3B Receptor Notch3 Adaptor Proteins Signal Transducing chemistry.chemical_classification Glycogen Synthase Kinase 3 beta Receptors Notch Ubiquitination Signal transducing adaptor protein RNA-Binding Proteins Cell Biology Cell biology Neoplasm Proteins Protein Structure Tertiary Repressor Proteins Biochemistry chemistry Ankyrin repeat RNA Interference Lithium Chloride Sequence Alignment Developmental Biology Protein Binding |
| Zdroj: | Cell cycle (Georgetown, Tex.). 10(10) |
| ISSN: | 1551-4005 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|