Nerfin-1 represses transcriptional output of Hippo signaling in cell competition
The Hippo tumor suppressor pathway regulates tissue growth in Drosophila by restricting the activity of the transcriptional coactivator Yorkie (Yki), which normally complexes with the TEF/TEAD family DNA-binding transcription factor Scalloped (Sd) to drive the expression of growth-promoting genes. G...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2019-03-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/38843 |
| _version_ | 1818026950402244608 |
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| author | Pengfei Guo Chang-Hyun Lee Huiyan Lei Yonggang Zheng Katiuska Daniela Pulgar Prieto Duojia Pan |
| author_facet | Pengfei Guo Chang-Hyun Lee Huiyan Lei Yonggang Zheng Katiuska Daniela Pulgar Prieto Duojia Pan |
| author_sort | Pengfei Guo |
| collection | DOAJ |
| description | The Hippo tumor suppressor pathway regulates tissue growth in Drosophila by restricting the activity of the transcriptional coactivator Yorkie (Yki), which normally complexes with the TEF/TEAD family DNA-binding transcription factor Scalloped (Sd) to drive the expression of growth-promoting genes. Given its pivotal role as a central hub in mediating the transcriptional output of Hippo signaling, there is great interest in understanding the molecular regulation of the Sd-Yki complex. In this study, we identify Nerfin-1 as a transcriptional repressor that antagonizes the activity of the Sd-Yki complex by binding to the TEA DNA-binding domain of Sd. Consistent with its biochemical function, ectopic expression of Nerfin-1 results in tissue undergrowth in an Sd-dependent manner. Conversely, loss of Nerfin-1 enhances the ability of winner cells to eliminate loser cells in multiple scenarios of cell competition. We further show that INSM1, the mammalian ortholog of Nerfin-1, plays a conserved role in repressing the activity of the TEAD-YAP complex. These findings reveal a novel regulatory mode converging on the transcriptional output of the Hippo pathway that may be exploited for modulating the YAP oncoprotein in cancer and regenerative medicine. |
| first_indexed | 2024-12-10T04:40:09Z |
| format | Article |
| id | doaj.art-d8faeed419ed44e2b08e5add2b1b7224 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T04:40:09Z |
| publishDate | 2019-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-d8faeed419ed44e2b08e5add2b1b72242022-12-22T02:01:55ZengeLife Sciences Publications LtdeLife2050-084X2019-03-01810.7554/eLife.38843Nerfin-1 represses transcriptional output of Hippo signaling in cell competitionPengfei Guo0https://orcid.org/0000-0002-4618-6803Chang-Hyun Lee1Huiyan Lei2Yonggang Zheng3Katiuska Daniela Pulgar Prieto4Duojia Pan5https://orcid.org/0000-0003-2890-4645Department of Physiology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Physiology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Physiology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Physiology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Physiology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Physiology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United StatesThe Hippo tumor suppressor pathway regulates tissue growth in Drosophila by restricting the activity of the transcriptional coactivator Yorkie (Yki), which normally complexes with the TEF/TEAD family DNA-binding transcription factor Scalloped (Sd) to drive the expression of growth-promoting genes. Given its pivotal role as a central hub in mediating the transcriptional output of Hippo signaling, there is great interest in understanding the molecular regulation of the Sd-Yki complex. In this study, we identify Nerfin-1 as a transcriptional repressor that antagonizes the activity of the Sd-Yki complex by binding to the TEA DNA-binding domain of Sd. Consistent with its biochemical function, ectopic expression of Nerfin-1 results in tissue undergrowth in an Sd-dependent manner. Conversely, loss of Nerfin-1 enhances the ability of winner cells to eliminate loser cells in multiple scenarios of cell competition. We further show that INSM1, the mammalian ortholog of Nerfin-1, plays a conserved role in repressing the activity of the TEAD-YAP complex. These findings reveal a novel regulatory mode converging on the transcriptional output of the Hippo pathway that may be exploited for modulating the YAP oncoprotein in cancer and regenerative medicine.https://elifesciences.org/articles/38843Hippo signalingcell competitiontranscription factors |
| spellingShingle | Pengfei Guo Chang-Hyun Lee Huiyan Lei Yonggang Zheng Katiuska Daniela Pulgar Prieto Duojia Pan Nerfin-1 represses transcriptional output of Hippo signaling in cell competition eLife Hippo signaling cell competition transcription factors |
| title | Nerfin-1 represses transcriptional output of Hippo signaling in cell competition |
| title_full | Nerfin-1 represses transcriptional output of Hippo signaling in cell competition |
| title_fullStr | Nerfin-1 represses transcriptional output of Hippo signaling in cell competition |
| title_full_unstemmed | Nerfin-1 represses transcriptional output of Hippo signaling in cell competition |
| title_short | Nerfin-1 represses transcriptional output of Hippo signaling in cell competition |
| title_sort | nerfin 1 represses transcriptional output of hippo signaling in cell competition |
| topic | Hippo signaling cell competition transcription factors |
| url | https://elifesciences.org/articles/38843 |
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