In addition to KEAP1:CUL3-mediated degradation in the cytosol, NFE2L2 appears to also be subject to degradation by a BTRC:CUL1 E3 ligase (reviewed in Cuadrado, 2015; Baird and Yamamoto, 2020; Yamamoto et al, 2018). Degradation by the BTRC:CUL1 pathway is mediated by interaction with the NFE2L2 Neh6 domain, and is stimulated by GSK3B-mediated phosphorylation of the Neh6 DSGIS motif. GSK3B-dependent Neh6 phosphorylation is primed by the phosphorylation of a cluster of adjacent serines by unknown kinase(s) (Salazar et al, 2006; Rada et al, 2011; Rada et L, 2012; Rojo et al, 2012; Chen et al, 2017; reviewed in Baird and Yamamoto, 2020). Inhibitory phosphorylation of GSK3B by activated PI3K/AKT signaling relieves BTRC:CUL1-mediated NFE2L2 degradation and provides a biochemical link between activated PI3K signaling and increased NFE2L2 pathway activity (reviewed in Cuadrado, 2015; Baird and Yamamoto, 2020; Yamamoto et al, 2018).
Motohashi, H, Yamamoto, M, Kensler, TW
Cuadrado, A, Chowdhry, S, Rojo, AI, Rada, P, Hayes, JD, McMahon, M
Yamamoto, M, Baird, L
Wang, P, Liao, Y, Liu, K, Wang, H, Gao, Y, Chen, Y, Yao, J, Zhang, J, Liu, Q, Wang, XJ, Tang, X, Wong, CCL, Hai, Y
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
de Sagarra, RM, Velasco, D, Cuadrado, A, Salazar, M, Rojo, AI
Cuadrado, A
Cuadrado, A, Medina-Campos, ON, Pedraza-Chaverri, J, Rojo, AI, Rada, P, Zúñiga-Toalá, A, Espada, S, López-Gazcón, A
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