内生
蛋白激酶B
鉴定(生物学)
化学
计算生物学
生物
细胞生物学
信号转导
生物化学
生态学
作者
Min Chen,Kangjunjie Wang,Ying Han,Shu-Kun 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
出处
期刊:Cell Reports
[Elsevier]
日期:2023-06-27
卷期号:42 (7): 112690-112690
被引量:4
标识
DOI:10.1016/j.celrep.2023.112690
摘要
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.
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