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. Author manuscript; available in PMC: 2014 Feb 8.
Published in final edited form as: Oncogene. 2012 Sep 10;32(32):3765–3781. doi: 10.1038/onc.2012.388

Figure 12.

Figure 12

Repression of Nrf2 by β-TrCP occurs in both a GSK-3-dependent and a GSK-3-independent manner

Nrf2 is subject to dual regulation by Keap1 and β-TrCP. The cartoon shows that Nrf2 is repressed by Keap1 though DLG and ETGE motifs in its Neh2 domain, both of which are required for ubiquitylation of the CNC-bZIP protein by Cul3-Rbx1. By contrast, Nrf2 is repressed by β-TrCP though DSGIS and DSAPGS motifs in its Neh6 domain, each of which is sufficient for ubiquitylation of the CNC-bZIP protein by Cul1-Rbx1. Phosphorylation of the DSGIS motif increases its degron activity, and this is positively regulated by GSK-3. The GSK-3 inhibitor CT99021 decreases the degron activity of the DSGIS destruction motif whereas PI3K and PKB/Akt inhibitors increase the degron activity of the DSGIS motif. By contrast, the DSAPGS destruction motif is not influenced by GSK-3 activity.