MNK2 Inhibits eIF4G Activation Through a Pathway Involving Serine-Arginine-Rich Protein Kinase in Skeletal Muscle
MNK2 Inhibits eIF4G Activation Through a Pathway Involving Serine-Arginine-Rich Protein Kinase in Skeletal Muscle
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DOI：
10.1126/scisignal.2002466
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发表时间：
2012-02-14
影响因子：
7.3
通讯作者：
Glass, David J.
中科院分区：
文献类型：
--
作者：
Hu, Shou-Ih;Katz, Mark;Glass, David J.
骨骼肌的质量受活动、新陈代谢和营养的可用性的调节。在肌肉萎缩期间，MNK2表达增加。我们发现，MNK2（丝裂原活化蛋白激酶相互作用激酶2），而不是MNK1，抑制参与促进蛋白质合成的蛋白质，包括真核翻译起始因子4G （eIF4G）和哺乳动物雷帕霉素靶蛋白（mTOR）。eIF4G的丝氨酸1108 （Ser(1108)）磷酸化与增强的蛋白质翻译相关，可被胰岛素样生长因子1促进，并被雷帕霉素或饥饿抑制，这表明该残基的磷酸化受mTOR调控。在培养的肌管中，MNK2的小干扰RNA （siRNA）敲低增加了eIF4G Ser（1108）磷酸化，克服了雷帕霉素对这一磷酸化事件的抑制作用。在缺乏MNK2的小鼠中，腓骨肌eIF4G中Ser（1108）的磷酸化增加，而缺乏MNK1的小鼠则没有，并且在MNK2缺失的动物中，在萎缩条件和饥饿条件下，这种磷酸化的增加保持不变。相反，MNK2的过表达降低了eIF4G Ser（1108）的磷酸化。siRNA筛选显示，富含丝氨酸精氨酸的蛋白激酶将MNK2活性的增加与eIF4G磷酸化的降低联系起来。此外，我们发现MNK2与mTOR相互作用，并通过独立于MNK2激酶活性的机制抑制mTOR靶点核糖体激酶p70S6K （70-kD核糖体蛋白S6激酶）的磷酸化。这些数据表明，MNK2通过其对eIF4G Ser（1108）磷酸化和p70S6K激活的负面影响，在限制蛋白质翻译方面发挥着独特的作用，而其最接近的同类MNK1没有这种作用。
Skeletal muscle mass is regulated by activity, metabolism, and the availability of nutrients. During muscle atrophy, MNK2 expression increases. We found that MNK2 (mitogen-activated protein kinase-interacting kinase 2), but not MNK1, inhibited proteins involved in promoting protein synthesis, including eukaryotic translation initiation factor 4G (eIF4G) and mammalian target of rapamycin (mTOR). Phosphorylation at serine 1108 (Ser(1108)) of eIF4G, which is associated with enhanced protein translation, is promoted by insulin-like growth factor 1 and inhibited by rapamycin or starvation, suggesting that phosphorylation of this residue is regulated by mTOR. In cultured myotubes, small interfering RNA (siRNA) knockdown of MNK2 increased eIF4G Ser(1108) phosphorylation and overcame rapamycin's inhibitory effect on this phosphorylation event. Phosphorylation of Ser(1108) in eIF4G, in gastrocnemius muscle, was increased in mice lacking MNK2, but not those lacking MNK1, and this increased phosphorylation was maintained in MNK2-null animals under atrophy conditions and upon starvation. Conversely, overexpression of MNK2 decreased eIF4G Ser(1108) phosphorylation. An siRNA screen revealed that serine-arginine-rich protein kinases linked increased MNK2 activity to decreased eIF4G phosphorylation. In addition, we found that MNK2 interacted with mTOR and inhibited phosphorylation of the mTOR target, the ribosomal kinase p70S6K (70-kD ribosomal protein S6 kinase), through a mechanism independent of the kinase activity of MNK2. These data indicate that MNK2 plays a unique role, not shared by its closest paralog MNK1, in limiting protein translation through its negative effect on eIF4G Ser(1108) phosphorylation and p70S6K activation.