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).
Cuadrado, A, Chowdhry, S, Rojo, AI, Rada, P, Hayes, JD, McMahon, M
Motohashi, H, Yamamoto, M, Kensler, TW
Rada, P, Garcia-Mayoral, MF, Cotte, A, Innamorato, NG, Van Leuven, F, Cuadrado, A, Devijver, H, Rojo, AI, Evrard-Todeschi, N, Hayes, JD, Tobón-Velasco, JC, Jaworski, T, Bertho, G
Yamamoto, M, Baird, L
de Sagarra, RM, Velasco, D, Cuadrado, A, Salazar, M, Rojo, AI
McMahon, M, Cuadrado, A, Zhang, Y, Hayes, JD, Chowdhry, S, Sutherland, C
Cuadrado, A, Medina-Campos, ON, Pedraza-Chaverri, J, Rojo, AI, Rada, P, Zúñiga-Toalá, A, Espada, S, López-Gazcón, A
protein serine/threonine kinase activity of GSK3B [nucleoplasm]
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