Abstract

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.

Details

Title
Assembly and activation of the Hippo signalome by FAT1 tumor suppressor
Author
Martin, Daniel 1 ; Degese, Maria S 1 ; Vitale-Cross, Lynn 1 ; Iglesias-Bartolome, Ramiro 2   VIAFID ORCID Logo  ; Callejas Valera, Juan Luis 3 ; Wang, Zhiyong 3 ; Feng, Xiaodong 3 ; Yeerna, Huwate 4 ; Vadmal, Vachan 4 ; Moroishi, Toshiro 5 ; Thorne, Rick F 6 ; Moraima Zaida 1 ; Siegele, Bradford 7 ; Cheong, Sok C 8 ; Molinolo, Alfredo A 4 ; Samuels, Yardena 9 ; Tamayo, Pablo 4   VIAFID ORCID Logo  ; Kun Liang Guan 3   VIAFID ORCID Logo  ; Lippman, Scott M 4 ; J Guy Lyons 10   VIAFID ORCID Logo  ; J Silvio Gutkind 11 

1  Oral and Pharyngeal Cancer Branch, National Institutes of Health, Bethesda, USA 
2  Oral and Pharyngeal Cancer Branch, National Institutes of Health, Bethesda, USA; Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 
3  University of California San Diego, Moores Cancer Center, La Jolla, USA; Department of Pharmacology, University of California, San Diego, USA 
4  University of California San Diego, Moores Cancer Center, La Jolla, USA 
5  Department of Pharmacology, University of California, San Diego, USA 
6  School of Environmental and Life Sciences, University of Newcastle, and Hunter Cancer Research Alliance, Callaghan, Australia 
7  Department of Pathology School of Medicine, University of Colorado, Colorado, USA 
8  Oral Cancer Research Team, Cancer Research, Selangor, Malaysia; Department of Oro-maxillofacial Surgery and Medical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia 
9  Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel 
10  Dermatology, Bosch Institute, University of Sydney, Camperdown, Australia; Cancer Services, Royal Prince Alfred Hospital, Camperdown, Australia; Centenary Institute, Camperdown, Australia 
11  Oral and Pharyngeal Cancer Branch, National Institutes of Health, Bethesda, USA; University of California San Diego, Moores Cancer Center, La Jolla, USA; Department of Pharmacology, University of California, San Diego, USA 
Pages
1-13
Publication year
2018
Publication date
Jul 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-04590-1
ProQuest document ID
2067107427
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.