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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-09-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/80014 |
| _version_ | 1797990813148381184 |
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| author | Meng Zhao Niels Banhos Danneskiold-Samsøe Livia Ulicna Quennie Nguyen Laetitia Voilquin David E Lee James P White Zewen Jiang Nickeisha Cuthbert Shrika Paramasivam Ewa Bielczyk-Maczynska Capucine Van Rechem Katrin J Svensson |
| author_facet | Meng Zhao Niels Banhos Danneskiold-Samsøe Livia Ulicna Quennie Nguyen Laetitia Voilquin David E Lee James P White Zewen Jiang Nickeisha Cuthbert Shrika Paramasivam Ewa Bielczyk-Maczynska Capucine Van Rechem Katrin J Svensson |
| author_sort | Meng Zhao |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T08:42:14Z |
| format | Article |
| id | doaj.art-a676e29254204708a042c755a7058675 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T08:42:14Z |
| publishDate | 2022-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-a676e29254204708a042c755a70586752022-12-22T04:34:09ZengeLife Sciences Publications LtdeLife2050-084X2022-09-011110.7554/eLife.80014Phosphoproteomic mapping reveals distinct signaling actions and activation of muscle protein synthesis by Isthmin-1Meng Zhao0https://orcid.org/0000-0002-5415-8335Niels Banhos Danneskiold-Samsøe1Livia Ulicna2Quennie Nguyen3Laetitia Voilquin4https://orcid.org/0000-0003-2138-4819David E Lee5James P White6Zewen Jiang7https://orcid.org/0000-0002-3852-8666Nickeisha Cuthbert8Shrika Paramasivam9Ewa Bielczyk-Maczynska10https://orcid.org/0000-0002-0558-1188Capucine Van Rechem11https://orcid.org/0000-0002-5408-6124Katrin J Svensson12https://orcid.org/0000-0001-5376-5128Department of Pathology, Stanford University School of Medicine, Stanford, United States; Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, United States; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, United StatesDepartment of Pathology, Stanford University School of Medicine, Stanford, United StatesDepartment of Pathology, Stanford University School of Medicine, Stanford, United StatesDepartment of Pathology, Stanford University School of Medicine, Stanford, United StatesDepartment of Pathology, Stanford University School of Medicine, Stanford, United States; Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, United States; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, United StatesDuke Molecular Physiology Institute, Duke University School of Medicine, Durham, United States; Department of Medicine, Duke University School of Medicine, Durham, United StatesDuke Molecular Physiology Institute, Duke University School of Medicine, Durham, United States; Department of Medicine, Duke University School of Medicine, Durham, United States; Duke Center for the Study of Aging and Human Development, Duke University School of Medicine, Durham, United StatesDepartment of Pathology, Stanford University School of Medicine, Stanford, United States; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, United States; Diabetes Center, University of California, San Francisco, San Francisco, United StatesDepartment of Pathology, Stanford University School of Medicine, Stanford, United StatesDepartment of Pathology, Stanford University School of Medicine, Stanford, United StatesStanford Diabetes Research Center, Stanford University School of Medicine, Stanford, United States; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, United States; Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, United StatesDepartment of Pathology, Stanford University School of Medicine, Stanford, United StatesDepartment of Pathology, Stanford University School of Medicine, Stanford, United States; Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, United States; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, United StatesThe 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.https://elifesciences.org/articles/80014proteomicssignalingmuscle |
| spellingShingle | Meng Zhao Niels Banhos Danneskiold-Samsøe Livia Ulicna Quennie Nguyen Laetitia Voilquin David E Lee James P White Zewen Jiang Nickeisha Cuthbert Shrika Paramasivam Ewa Bielczyk-Maczynska Capucine Van Rechem Katrin J Svensson Phosphoproteomic mapping reveals distinct signaling actions and activation of muscle protein synthesis by Isthmin-1 eLife proteomics signaling muscle |
| title | Phosphoproteomic mapping reveals distinct signaling actions and activation of muscle protein synthesis by Isthmin-1 |
| title_full | Phosphoproteomic mapping reveals distinct signaling actions and activation of muscle protein synthesis by Isthmin-1 |
| title_fullStr | Phosphoproteomic mapping reveals distinct signaling actions and activation of muscle protein synthesis by Isthmin-1 |
| title_full_unstemmed | Phosphoproteomic mapping reveals distinct signaling actions and activation of muscle protein synthesis by Isthmin-1 |
| title_short | Phosphoproteomic mapping reveals distinct signaling actions and activation of muscle protein synthesis by Isthmin-1 |
| title_sort | phosphoproteomic mapping reveals distinct signaling actions and activation of muscle protein synthesis by isthmin 1 |
| topic | proteomics signaling muscle |
| url | https://elifesciences.org/articles/80014 |
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