Identification of XAF1 as an endogenous AKT inhibitor.

AKT kinase is a key regulator in cell metabolism and survival, and its activation is strictly modulated. Herein, we identify XAF1 (XIAP-associated factor) as a direct interacting protein of AKT1, which strongly binds the N-terminal region of AKT1 to block its K63-linked poly-ubiquitination and subsequent activation. Consistently, Xaf1 knockout causes AKT activation in mouse muscle and fat tissues and reduces body weight gain and insulin resistance induced by high-fat diet. Pathologically, XAF1 expression is low and anti-correlated with the phosphorylated p-T308-AKT signal in prostate cancer samples, and Xaf1 knockout stimulates the p-T308-AKT signal to accelerate spontaneous prostate tumorigenesis in mice with Pten heterozygous loss. And ectopic expression of wild-type XAF1, but not the cancer-derived P277L mutant, inhibits orthotopic tumorigenesis. We further identify Forkhead box O 1 (FOXO1) as a transcriptional regulator of XAF1, thus forming a negative feedback loop between AKT1 and XAF1. These results reveal an important intrinsic regulatory mechanism of AKT signaling. Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

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Min Chen, Kangjunjie Wang, Ying Han, Shukun Yan, Huairui Yuan, Qiuli Liu, Long Li, Ni Li, Hongwen Zhu, Dayun Lu, Kaihua Wang, Fen Liu, Dakui Luo, Yuxue Zhang, Jun Jiang, Dali Li, Lei Zhang, Hongbin Ji, Hu Zhou, Yong Chen, Jun Qin, Daming Gao. Identification of XAF1 as an endogenous AKT inhibitor. Cell reports. 2023 Jul 25;42(7):112690

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PMID: 37384528

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