Assembly and activation of the Hippo signalome by FAT1 tumor suppressor

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

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Official URL: https://doi.org/10.1038/s41467-018-04590-1

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.

Item Type: Article
Uncontrolled Keywords: Adaptor Proteins, Signal Transducing; Cadherins; Gene Knockdown Techniques; Head and Neck Neoplasms; HEK293 Cells; Hepatocyte Growth Factor; Humans; Phosphoproteins; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins; Signal Transduction; Squamous Cell Carcinoma of Head and Neck
Subjects: R Medicine
R Medicine > RK Dentistry
Divisions: Faculty of Dentistry
Depositing User: Ms. Juhaida Abd Rahim
Date Deposited: 27 May 2019 07:04
Last Modified: 27 May 2019 07:04
URI: http://eprints.um.edu.my/id/eprint/21330

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