Meta-Biol

• Pathways

GSK3B promotes the nuclear, KEAP1-independent degradation of NFE2L2 by the BTRC:CUL1 E3 ligase (reviewed in Baird and Yamamoto, 2020; Yamamoto et al, 2018). In contrast to the KEAP1:CUL3 degradation, which makes use of an NFE2L2 degron in Neh2, the nuclear GSK3B-CUL1 degron of NFE2L2 is located in Neh6. This domain contains a DSGIS motif at residues 334-338 that is phosphorylated in vitro and in vivo by GSK3B to promote NFE2L2 ubiquitination and subsequent degradation (Salazar et al, 2006; Rada et al, 2011; Rada et al, 2012; Rojo et al, 2012; Chowdhry et al, 2013). Inhibitory phosphorylation of GSK3B by active PI3K/AKT signaling abrogates this nuclear degradation of NFE2L2 (Salazar et al, 2006; Rada et al, 2011; Chowdhry et al, 2013; Rojo et al, 2012; reviewed in Baird and Yamamoto, 2020; Yamamoto et al, 2018).