Phosphoproteomic mapping reveals distinct signaling actions and activation of muscle protein synthesis by Isthmin-1

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 intrac...

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Published in:	eLife Vol. 11
Main Authors:	Zhao, Meng, Banhos Danneskiold-Samsøe, Niels, Ulicna, Livia, Nguyen, Quennie, Voilquin, Laetitia, Lee, David E, White, James P, Jiang, Zewen, Cuthbert, Nickeisha, Paramasivam, Shrika, Bielczyk-Maczynska, Ewa, Van Rechem, Capucine, Svensson, Katrin J
Format:	Journal Article
Language:	English
Published:	England eLife Sciences Publications Ltd 28-09-2022 eLife Sciences Publications, Ltd
Subjects:	1-Phosphatidylinositol 3-kinase AKT protein Amino acids Amino Acids - metabolism Animals Antidiabetics Cell Biology Diabetes Diabetes mellitus Genes Glucose Glucose - metabolism Hypoglycemic Agents - metabolism Insulin Insulin - metabolism Insulin resistance Intercellular Signaling Peptides and Proteins - metabolism Intracellular signalling Kinases Ligands Mechanistic Target of Rapamycin Complex 1 - metabolism Metabolic disorders Metabolism Mice muscle Muscle function Muscle Proteins - metabolism Muscle, Skeletal - metabolism Musculoskeletal system Ontology Peptide mapping Peptides Phosphatidylinositol 3-Kinases - metabolism Phosphorylation Principal components analysis Protein Biosynthesis Protein synthesis Proteins proteomics Proto-Oncogene Proteins c-akt - metabolism Signal transduction signaling Skeletal muscle TOR protein TOR Serine-Threonine Kinases - metabolism mouse cell biology signaling proteomics muscle
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Summary:	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, 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2050-084X 2050-084X
DOI:	10.7554/eLife.80014