Assembly and activation of the Hippo signalome by FAT1 tumor suppressor
Dysregulation of the Hippo signaling pathway and the consequent YAP1 activation is a frequent event in human malignancies, yet the underlying molecular mechanisms are still poorly understood. A pancancer analysis of core Hippo kinases and their candidate regulating molecules revealed few alterations...
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Nature Research
2018
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| author | Martin, Daniel Degese, Maria S. Vitale-Cross, Lynn Iglesias-Bartolome, Ramiro Valera, Juan Luis Callejas Wang, Zhiyong Feng, Xiaodong Yeerna, Huwate Vadmal, Vachan Moroishi, Toshiro Thorne, Rick F. Zaida, Moraima Siegele, Bradford Cheong, Sok Ching Molinolo, Alfredo A. Samuels, Yardena Tamayo, Pablo Guan, Kun Liang Lippman, Scott M. Lyons, J. Guy Gutkind, J. Silvio |
| author_facet | Martin, Daniel Degese, Maria S. Vitale-Cross, Lynn Iglesias-Bartolome, Ramiro Valera, Juan Luis Callejas Wang, Zhiyong Feng, Xiaodong Yeerna, Huwate Vadmal, Vachan Moroishi, Toshiro Thorne, Rick F. Zaida, Moraima Siegele, Bradford Cheong, Sok Ching Molinolo, Alfredo A. Samuels, Yardena Tamayo, Pablo Guan, Kun Liang Lippman, Scott M. Lyons, J. Guy Gutkind, J. Silvio |
| author_sort | Martin, Daniel |
| collection | UM |
| description | Dysregulation of the Hippo signaling pathway and the consequent YAP1 activation is a frequent event in human malignancies, yet the underlying molecular mechanisms are still poorly understood. A pancancer analysis of core Hippo kinases and their candidate regulating molecules revealed few alterations in the canonical Hippo pathway, but very frequent genetic alterations in the FAT family of atypical cadherins. By focusing on head and neck squamous cell carcinoma (HNSCC), which displays frequent FAT1 alterations (29.8%), we provide evidence that FAT1 functional loss results in YAP1 activation. Mechanistically, we found that FAT1 assembles a multimeric Hippo signaling complex (signalome), resulting in activation of core Hippo kinases by TAOKs and consequent YAP1 inactivation. We also show that unrestrained YAP1 acts as an oncogenic driver in HNSCC, and that targeting YAP1 may represent an attractive precision therapeutic option for cancers harboring genomic alterations in the FAT1 tumor suppressor genes. |
| first_indexed | 2024-03-06T05:53:51Z |
| format | Article |
| id | um.eprints-21330 |
| institution | Universiti Malaya |
| last_indexed | 2024-03-06T05:53:51Z |
| publishDate | 2018 |
| publisher | Nature Research |
| record_format | dspace |
| spelling | um.eprints-213302019-05-27T07:04:24Z http://eprints.um.edu.my/21330/ Assembly and activation of the Hippo signalome by FAT1 tumor suppressor Martin, Daniel Degese, Maria S. Vitale-Cross, Lynn Iglesias-Bartolome, Ramiro Valera, Juan Luis Callejas Wang, Zhiyong Feng, Xiaodong Yeerna, Huwate Vadmal, Vachan Moroishi, Toshiro Thorne, Rick F. Zaida, Moraima Siegele, Bradford Cheong, Sok Ching Molinolo, Alfredo A. Samuels, Yardena Tamayo, Pablo Guan, Kun Liang Lippman, Scott M. Lyons, J. Guy Gutkind, J. Silvio R Medicine RK Dentistry Dysregulation of the Hippo signaling pathway and the consequent YAP1 activation is a frequent event in human malignancies, yet the underlying molecular mechanisms are still poorly understood. A pancancer analysis of core Hippo kinases and their candidate regulating molecules revealed few alterations in the canonical Hippo pathway, but very frequent genetic alterations in the FAT family of atypical cadherins. By focusing on head and neck squamous cell carcinoma (HNSCC), which displays frequent FAT1 alterations (29.8%), we provide evidence that FAT1 functional loss results in YAP1 activation. Mechanistically, we found that FAT1 assembles a multimeric Hippo signaling complex (signalome), resulting in activation of core Hippo kinases by TAOKs and consequent YAP1 inactivation. We also show that unrestrained YAP1 acts as an oncogenic driver in HNSCC, and that targeting YAP1 may represent an attractive precision therapeutic option for cancers harboring genomic alterations in the FAT1 tumor suppressor genes. Nature Research 2018 Article PeerReviewed Martin, Daniel and Degese, Maria S. and Vitale-Cross, Lynn and Iglesias-Bartolome, Ramiro and Valera, Juan Luis Callejas and Wang, Zhiyong and Feng, Xiaodong and Yeerna, Huwate and Vadmal, Vachan and Moroishi, Toshiro and Thorne, Rick F. and Zaida, Moraima and Siegele, Bradford and Cheong, Sok Ching and Molinolo, Alfredo A. and Samuels, Yardena and Tamayo, Pablo and Guan, Kun Liang and Lippman, Scott M. and Lyons, J. Guy and Gutkind, J. Silvio (2018) Assembly and activation of the Hippo signalome by FAT1 tumor suppressor. Nature Communications, 9 (1). p. 2372. ISSN 2041-1723, DOI https://doi.org/10.1038/s41467-018-04590-1 <https://doi.org/10.1038/s41467-018-04590-1>. https://doi.org/10.1038/s41467-018-04590-1 doi:10.1038/s41467-018-04590-1 |
| spellingShingle | R Medicine RK Dentistry Martin, Daniel Degese, Maria S. Vitale-Cross, Lynn Iglesias-Bartolome, Ramiro Valera, Juan Luis Callejas Wang, Zhiyong Feng, Xiaodong Yeerna, Huwate Vadmal, Vachan Moroishi, Toshiro Thorne, Rick F. Zaida, Moraima Siegele, Bradford Cheong, Sok Ching Molinolo, Alfredo A. Samuels, Yardena Tamayo, Pablo Guan, Kun Liang Lippman, Scott M. Lyons, J. Guy Gutkind, J. Silvio Assembly and activation of the Hippo signalome by FAT1 tumor suppressor |
| title | Assembly and activation of the Hippo signalome by FAT1 tumor suppressor |
| title_full | Assembly and activation of the Hippo signalome by FAT1 tumor suppressor |
| title_fullStr | Assembly and activation of the Hippo signalome by FAT1 tumor suppressor |
| title_full_unstemmed | Assembly and activation of the Hippo signalome by FAT1 tumor suppressor |
| title_short | Assembly and activation of the Hippo signalome by FAT1 tumor suppressor |
| title_sort | assembly and activation of the hippo signalome by fat1 tumor suppressor |
| topic | R Medicine RK Dentistry |
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