Activation of PASK by mTORC1 is required for the onset of the terminal differentiation program
During skeletal muscle regeneration, muscle stem cells (MuSCs) respond to multiple signaling inputs that converge onto mammalian target of rapamycin complex 1 (mTORC1) signaling pathways. mTOR function is essential for establishment of the differentiationcommitted progenitors (early stage of differe...
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| Format: | Article |
| Language: | English |
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Proceedings of the National Academy of Sciences
2020
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| Online Access: | https://hdl.handle.net/1721.1/124691 |
| _version_ | 1811086424121802752 |
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| author | Kang, Seong Anthony Woo Sabatini, David M. |
| author2 | Whitehead Institute for Biomedical Research |
| author_facet | Whitehead Institute for Biomedical Research Kang, Seong Anthony Woo Sabatini, David M. |
| author_sort | Kang, Seong Anthony Woo |
| collection | MIT |
| description | During skeletal muscle regeneration, muscle stem cells (MuSCs) respond to multiple signaling inputs that converge onto mammalian target of rapamycin complex 1 (mTORC1) signaling pathways. mTOR function is essential for establishment of the differentiationcommitted progenitors (early stage of differentiation, marked by the induction of myogenin expression), myotube fusion, and, ultimately, hypertrophy (later stage of differentiation). While a major mTORC1 substrate, p70S6K, is required for myotube fusion and hypertrophy, an mTORC1 effector for the induction of myogenin expression remains unclear. Here, we identified Per-Arnt-Sim domain kinase (PASK) as a downstream phosphorylation target ofmTORC1 in MuSCs during differentiation. We have recently shown that the PASK phosphorylates Wdr5 to stimulate MuSC differentiation by epigenetically activating the myogenin promoter. We show that phosphorylation of PASK by mTORC1 is required for the activation of myogenin transcription, exit from self-renewal, and induction of the myogenesis program. Our studies reveal that mTORC1-PASK signaling is required for the rise of myogenin-positive committed myoblasts (early stage of myogenesis), whereas mTORC1-S6K signaling is required for myoblast fusion (later stage of myogenesis). Thus, our discoveries allow molecular dissection of mTOR functions during different stages of the myogenesis program driven by two different substrates. |
| first_indexed | 2024-09-23T13:25:42Z |
| format | Article |
| id | mit-1721.1/124691 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T13:25:42Z |
| publishDate | 2020 |
| publisher | Proceedings of the National Academy of Sciences |
| record_format | dspace |
| spelling | mit-1721.1/1246912022-10-01T15:13:42Z Activation of PASK by mTORC1 is required for the onset of the terminal differentiation program Kang, Seong Anthony Woo Sabatini, David M. Whitehead Institute for Biomedical Research Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Multidisciplinary During skeletal muscle regeneration, muscle stem cells (MuSCs) respond to multiple signaling inputs that converge onto mammalian target of rapamycin complex 1 (mTORC1) signaling pathways. mTOR function is essential for establishment of the differentiationcommitted progenitors (early stage of differentiation, marked by the induction of myogenin expression), myotube fusion, and, ultimately, hypertrophy (later stage of differentiation). While a major mTORC1 substrate, p70S6K, is required for myotube fusion and hypertrophy, an mTORC1 effector for the induction of myogenin expression remains unclear. Here, we identified Per-Arnt-Sim domain kinase (PASK) as a downstream phosphorylation target ofmTORC1 in MuSCs during differentiation. We have recently shown that the PASK phosphorylates Wdr5 to stimulate MuSC differentiation by epigenetically activating the myogenin promoter. We show that phosphorylation of PASK by mTORC1 is required for the activation of myogenin transcription, exit from self-renewal, and induction of the myogenesis program. Our studies reveal that mTORC1-PASK signaling is required for the rise of myogenin-positive committed myoblasts (early stage of myogenesis), whereas mTORC1-S6K signaling is required for myoblast fusion (later stage of myogenesis). Thus, our discoveries allow molecular dissection of mTOR functions during different stages of the myogenesis program driven by two different substrates. 2020-04-16T14:50:57Z 2020-04-16T14:50:57Z 2019-05-09 2020-01-30T14:29:55Z Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 https://hdl.handle.net/1721.1/124691 Kikani, Chintan K. et al. "Activation of PASK by mTORC1 is required for the onset of the terminal differentiation program." Proceedings of the National Academy of Sciences of the United States of America 116 (2019): 10382-10391 © 2019 The Author(s) en 10.1073/pnas.1804013116 Proceedings of the National Academy of Sciences of the United States of America Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Proceedings of the National Academy of Sciences PNAS |
| spellingShingle | Multidisciplinary Kang, Seong Anthony Woo Sabatini, David M. Activation of PASK by mTORC1 is required for the onset of the terminal differentiation program |
| title | Activation of PASK by mTORC1 is required for the onset of the terminal differentiation program |
| title_full | Activation of PASK by mTORC1 is required for the onset of the terminal differentiation program |
| title_fullStr | Activation of PASK by mTORC1 is required for the onset of the terminal differentiation program |
| title_full_unstemmed | Activation of PASK by mTORC1 is required for the onset of the terminal differentiation program |
| title_short | Activation of PASK by mTORC1 is required for the onset of the terminal differentiation program |
| title_sort | activation of pask by mtorc1 is required for the onset of the terminal differentiation program |
| topic | Multidisciplinary |
| url | https://hdl.handle.net/1721.1/124691 |
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