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Discrete roles and bifurcation of PTEN signaling and mTORC1-mediated anabolic metabolism underlie IL-7–driven B lymphopoiesis
Interleukin-7 (IL-7) drives early B lymphopoiesis, but the underlying molecular circuits remain poorly understood, especially how Stat5 (signal transducer and activator of transcription 5)–dependent and Stat5-independent pathways contribute to this process. Combining transcriptome and proteome analy...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5792226/ https://www.ncbi.nlm.nih.gov/pubmed/29399633 http://dx.doi.org/10.1126/sciadv.aar5701 |
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author | Zeng, Hu Yu, Mei Tan, Haiyan Li, Yuxin Su, Wei Shi, Hao Dhungana, Yogesh Guy, Cliff Neale, Geoffrey Cloer, Caryn Peng, Junmin Wang, Demin Chi, Hongbo |
author_facet | Zeng, Hu Yu, Mei Tan, Haiyan Li, Yuxin Su, Wei Shi, Hao Dhungana, Yogesh Guy, Cliff Neale, Geoffrey Cloer, Caryn Peng, Junmin Wang, Demin Chi, Hongbo |
author_sort | Zeng, Hu |
collection | PubMed |
description | Interleukin-7 (IL-7) drives early B lymphopoiesis, but the underlying molecular circuits remain poorly understood, especially how Stat5 (signal transducer and activator of transcription 5)–dependent and Stat5-independent pathways contribute to this process. Combining transcriptome and proteome analyses and mouse genetic models, we show that IL-7 promotes anabolic metabolism and biosynthetic programs in pro-B cells. IL-7–mediated activation of mTORC1 (mechanistic target of rapamycin complex 1) supported cell proliferation and metabolism in a Stat5-independent, Myc-dependent manner but was largely dispensable for cell survival or Rag1 and Rag2 gene expression. mTORC1 was also required for Myc-driven lymphomagenesis. PI3K (phosphatidylinositol 3-kinase) and mTORC1 had discrete effects on Stat5 signaling and independently controlled B cell development. PI3K was actively suppressed by PTEN (phosphatase and tensin homolog) in pro-B cells to ensure proper IL-7R expression, Stat5 activation, heavy chain rearrangement, and cell survival, suggesting the unexpected bifurcation of the classical PI3K-mTOR signaling. Together, our integrative analyses establish IL-7R–mTORC1–Myc and PTEN-mediated PI3K suppression as discrete signaling axes driving B cell development, with differential effects on IL-7R–Stat5 signaling. |
format | Online Article Text |
id | pubmed-5792226 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-57922262018-02-02 Discrete roles and bifurcation of PTEN signaling and mTORC1-mediated anabolic metabolism underlie IL-7–driven B lymphopoiesis Zeng, Hu Yu, Mei Tan, Haiyan Li, Yuxin Su, Wei Shi, Hao Dhungana, Yogesh Guy, Cliff Neale, Geoffrey Cloer, Caryn Peng, Junmin Wang, Demin Chi, Hongbo Sci Adv Research Articles Interleukin-7 (IL-7) drives early B lymphopoiesis, but the underlying molecular circuits remain poorly understood, especially how Stat5 (signal transducer and activator of transcription 5)–dependent and Stat5-independent pathways contribute to this process. Combining transcriptome and proteome analyses and mouse genetic models, we show that IL-7 promotes anabolic metabolism and biosynthetic programs in pro-B cells. IL-7–mediated activation of mTORC1 (mechanistic target of rapamycin complex 1) supported cell proliferation and metabolism in a Stat5-independent, Myc-dependent manner but was largely dispensable for cell survival or Rag1 and Rag2 gene expression. mTORC1 was also required for Myc-driven lymphomagenesis. PI3K (phosphatidylinositol 3-kinase) and mTORC1 had discrete effects on Stat5 signaling and independently controlled B cell development. PI3K was actively suppressed by PTEN (phosphatase and tensin homolog) in pro-B cells to ensure proper IL-7R expression, Stat5 activation, heavy chain rearrangement, and cell survival, suggesting the unexpected bifurcation of the classical PI3K-mTOR signaling. Together, our integrative analyses establish IL-7R–mTORC1–Myc and PTEN-mediated PI3K suppression as discrete signaling axes driving B cell development, with differential effects on IL-7R–Stat5 signaling. American Association for the Advancement of Science 2018-01-31 /pmc/articles/PMC5792226/ /pubmed/29399633 http://dx.doi.org/10.1126/sciadv.aar5701 Text en Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). http://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (http://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
spellingShingle | Research Articles Zeng, Hu Yu, Mei Tan, Haiyan Li, Yuxin Su, Wei Shi, Hao Dhungana, Yogesh Guy, Cliff Neale, Geoffrey Cloer, Caryn Peng, Junmin Wang, Demin Chi, Hongbo Discrete roles and bifurcation of PTEN signaling and mTORC1-mediated anabolic metabolism underlie IL-7–driven B lymphopoiesis |
title | Discrete roles and bifurcation of PTEN signaling and mTORC1-mediated anabolic metabolism underlie IL-7–driven B lymphopoiesis |
title_full | Discrete roles and bifurcation of PTEN signaling and mTORC1-mediated anabolic metabolism underlie IL-7–driven B lymphopoiesis |
title_fullStr | Discrete roles and bifurcation of PTEN signaling and mTORC1-mediated anabolic metabolism underlie IL-7–driven B lymphopoiesis |
title_full_unstemmed | Discrete roles and bifurcation of PTEN signaling and mTORC1-mediated anabolic metabolism underlie IL-7–driven B lymphopoiesis |
title_short | Discrete roles and bifurcation of PTEN signaling and mTORC1-mediated anabolic metabolism underlie IL-7–driven B lymphopoiesis |
title_sort | discrete roles and bifurcation of pten signaling and mtorc1-mediated anabolic metabolism underlie il-7–driven b lymphopoiesis |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5792226/ https://www.ncbi.nlm.nih.gov/pubmed/29399633 http://dx.doi.org/10.1126/sciadv.aar5701 |
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