生物
PI3K/AKT/mTOR通路
磷酸化
mTORC1型
蛋白质稳态
细胞生物学
信号转导
骨骼肌
蛋白激酶B
原癌基因蛋白质c-akt
蛋白质磷酸化
胰岛素受体
胰岛素
蛋白激酶A
胰岛素抵抗
内分泌学
作者
Meng Zhao,Niels Banhos Dannieskiold-Samsøe,Lívia Uličná,Quennie Nguyen,Laëtitia Voilquin,David E. Lee,James P. White,Zewen Jiang,Nickeisha Cuthbert,Shrika Paramasivam,Ewa Bielczyk-Maczyńska,Capucine Van Rechem,Katrin J. Svensson
出处
期刊:eLife
[eLife Sciences Publications, Ltd.]
日期:2022-09-28
卷期号:11
被引量:3
摘要
The secreted protein isthmin-1 (Ism1) mitigates diabetes by increasing adipocyte and skeletal muscle glucose uptake by activating the PI3K-Akt pathway. However, while both Ism1 and insulin converge on these common targets, Ism1 has distinct cellular actions suggesting divergence in downstream intracellular signaling pathways. To understand the biological complexity of Ism1 signaling, we performed phosphoproteomic analysis after acute exposure, revealing overlapping and distinct pathways of Ism1 and insulin. We identify a 53% overlap between Ism1 and insulin signaling and Ism1-mediated phosphoproteome-wide alterations in ~450 proteins that are not shared with insulin. Interestingly, we find several unknown phosphorylation sites on proteins related to protein translation, mTOR pathway, and, unexpectedly, muscle function in the Ism1 signaling network. Physiologically, Ism1 ablation in mice results in altered proteostasis, including lower muscle protein levels under fed and fasted conditions, reduced amino acid incorporation into proteins, and reduced phosphorylation of the key protein synthesis effectors Akt and downstream mTORC1 targets. As metabolic disorders such as diabetes are associated with accelerated loss of skeletal muscle protein content, these studies define a non-canonical mechanism by which this antidiabetic circulating protein controls muscle biology.
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