REDD2 is enriched in skeletal muscle and inhibits mTOR signaling in response to leucine and stretch
REDD2 is enriched in skeletal muscle and inhibits mTOR signaling in response to leucine and stretch
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DOI：
10.1152/ajpcell.00464.2008
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发表时间：
2009-03-01
影响因子：
5.5
通讯作者：
Esser, Karyn A.
中科院分区：
文献类型：
--
作者：
Miyazaki, Mitsunori;Esser, Karyn A.
宫崎骏M，Esser Ka.REDD2在骨骼肌中丰富，并抑制亮氨酸和拉伸反应中的mTOR信号。Am J Physiol Cell Physiol 296：C583-C592,2009。首次发表于2009年1月7日；doi：10.1152/ajpcell.00464.2008。-雷帕霉素的蛋白激酶哺乳动物靶标(MTOR)被公认为骨骼肌大小的关键调节因子。在这项研究中，我们确定了应激反应基因REDD2(在发育和DNA损伤反应2中调节)是mTOR信号的负调节因子，主要在骨骼肌中表达。在肌细胞中过表达REDD2显著抑制基础mTOR信号，并减弱mTOR对亮氨酸添加或机械拉伸的反应。REDD2对mTOR信号的抑制作用可能是在Akt信号的下游或非Akt信号的下游和Rheb(脑内富含RAS同系物)的上游介导的。使用小干扰(Si)RNA敲除结节性硬化症复合体2(TSC2)可以有效地激活mTOR信号，并足以挽救REDD2对mTOR活性的抑制，提示REDD2通过调节TSC2功能发挥作用。免疫沉淀分析表明，REDD2不直接与TSC1或TSC2相互作用。然而，我们发现REDD2与14-3-3蛋白形成一个复合体，REDD2表达的增加竞争性地将TSC2从14-3-3中分离出来，并抑制mTOR信号转导。这些发现表明，REDD2是骨骼肌特异性的mTOR信号抑制调节剂，TSC2和14-3-3是REDD2和mTOR功能之间的关键分子联系。
Miyazaki M, Esser KA. REDD2 is enriched in skeletal muscle and inhibits mTOR signaling in response to leucine and stretch. Am J Physiol Cell Physiol 296: C583-C592, 2009. First published January 7, 2009; doi:10.1152/ajpcell.00464.2008.-The protein kinase mammalian target of rapamycin (mTOR) is well established as a key regulator of skeletal muscle size. In this study, we determined that the stress responsive gene REDD2 (regulated in development and DNA damage responses 2) is a negative regulator of mTOR signaling and is expressed predominantly in skeletal muscle. Overexpression of REDD2 in muscle cells significantly inhibited basal mTOR signaling and diminished the response of mTOR to leucine addition or mechanical stretch. The inhibitory function of REDD2 on mTOR signaling seems to be mediated downstream or independent of Akt signaling and upstream of Rheb (Ras homolog enriched in brain). Knock down of tuberous sclerosis complex 2 (TSC2) using small interfering (si) RNA potently activated mTOR signaling and was sufficient to rescue REDD2 inhibition of mTOR activity, suggesting that REDD2 functions by modulating TSC2 function. Immunoprecipitation assays demonstrated that REDD2 does not directly interact with either TSC1 or TSC2. However, we found that REDD2 forms a complex with 14-3-3 protein and that increasing expression of REDD2 acts to competitively dissociate TSC2 from 14-3-3 and inhibits mTOR signaling. These findings demonstrate that REDD2 is a skeletal muscle specific inhibitory modulator of mTOR signaling and identify TSC2 and 14-3-3 as key molecular links between REDD2 and mTOR function.