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首页> 外文期刊>Molecular cell >RIG-I Modulates Src-Mediated AKT Activation to Restrain Leukemic Stemness
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RIG-I Modulates Src-Mediated AKT Activation to Restrain Leukemic Stemness

机译：RIG-I调节Src介导的AKT激活以抑制白血病。

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摘要

Retinoic acid (RA)-inducible gene I (RIG-I) is highly upregulated and functionally implicated in the RA-induced maturation of acute myeloid leukemia (AML) blasts. However, the underlying mechanism and the biological relevance of RIG-I expression to the maintenance of leukemogenic potential are poorly understood. Here, we show that RIG-I, without priming by foreign RNA, inhibits the Src-facilitated activation of AKT-mTOR in AML cells. Moreover, in a group of primary human AML blasts, RIG-I reduction renders the Src family kinases hyperactive in promoting AKT activation. Mechanistically, a PxxP motif in RIG-I, upon the N-terminal CARDs' association with the Src SH1 domain, competes with the AKT PxxP motif for recognizing the Src SH3 domain. In accordance, mutating PxxP motif prevents Rig-I from inhibiting AKT activation, cytokine-stimulated myeloid progenitor proliferation, and invivo repopulating capacity of leukemia cells. Collectively, our data suggest an antileukemia activity of RIG-I via competitively inhibiting Src/AKT association.
机译：维甲酸（RA）诱导基因I（RIG-I）在RA诱导的急性髓细胞白血病（AML）胚成熟中高度上调，并且在功能上有牵连。然而，人们对RIG-I表达与维持白血病发生潜能的潜在机制和生物学相关性了解甚少。在这里，我们显示RIG-I无需外源RNA引发即可抑制AML细胞中Src促进的AKT-mTOR激活。此外，在一组主要的人类AML原始细胞中，RIG-I的还原使Src家族激酶在促进AKT激活中活性较高。从机理上讲，RIG-I中的PxxP基序在N末端CARD与Src SH1域结合后，与AKT PxxP基序竞争以识别Src SH3域。相应地，突变PxxP基序防止Rig-1抑制AKT活化，细胞因子刺激的髓样祖细胞增殖以及白血病细胞的体内繁殖能力。总的来说，我们的数据表明RIG-1的抗白血病活性是通过竞争性抑制Src / AKT缔合。

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