Assembly and activation of the Hippo signalome by FAT1 tumor suppressor

Daniel Martin, Maria S. Degese, Lynn Vitale-Cross, Ramiro Iglesias-Bartolome, Juan Luis Callejas Valera, Zhiyong Wang, Xiaodong Feng, Huwate Yeerna, Vachan Vadmal, Toshiro Moroishi, Rick F. Thorne, Moraima Zaida, Bradford Siegele, Sok C. Cheong, Alfredo A. Molinolo, Yardena Samuels, Pablo Tamayo, Kun Liang Guan, Scott M. Lippman (), J. Guy Lyons and J. Silvio Gutkind ()
Additional contact information
Daniel Martin: National Institutes of Health
Maria S. Degese: National Institutes of Health
Lynn Vitale-Cross: National Institutes of Health
Ramiro Iglesias-Bartolome: National Institutes of Health
Juan Luis Callejas Valera: Moores Cancer Center
Zhiyong Wang: Moores Cancer Center
Xiaodong Feng: Moores Cancer Center
Huwate Yeerna: Moores Cancer Center
Vachan Vadmal: Moores Cancer Center
Toshiro Moroishi: University of California
Rick F. Thorne: and Hunter Cancer Research Alliance
Moraima Zaida: National Institutes of Health
Bradford Siegele: University of Colorado
Sok C. Cheong: Cancer Research
Alfredo A. Molinolo: Moores Cancer Center
Yardena Samuels: The Weizmann Institute of Science
Pablo Tamayo: Moores Cancer Center
Kun Liang Guan: Moores Cancer Center
Scott M. Lippman: Moores Cancer Center
J. Guy Lyons: University of Sydney
J. Silvio Gutkind: National Institutes of Health

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04590-1

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