Assembly and activation of the Hippo signalome by FAT1 tumor suppressor

Assembly and activation of the Hippo signalome by FAT1 tumor suppressor.

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1038/s41467-018-04590-1
Journal or Publication Title: Nature Communications
Volume: 9
Number: 1
Date: 2018
Divisions: Immune Imaging
Depositing User: General Admin
Identification Number: 10.1038/s41467-018-04590-1
ISSN: 2041-1723
Date Deposited: 03 Jan 2021 22:48
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.

Creators:
Creators
Email
Martin, Daniel
UNSPECIFIED
Degese, Maria S.
UNSPECIFIED
Vitale-Cross, Lynn
UNSPECIFIED
Iglesias-Bartolome, Ramiro
UNSPECIFIED
Valera, Juan Luis Callejas
UNSPECIFIED
Wang, Zhiyong
UNSPECIFIED
Feng, Xiaodong
UNSPECIFIED
Yeerna, Huwate
UNSPECIFIED
Vadmal, Vachan
UNSPECIFIED
Moroishi, Toshiro
UNSPECIFIED
Thorne, Rick F.
UNSPECIFIED
Zaida, Moraima
UNSPECIFIED
Siegele, Bradford
UNSPECIFIED
Cheong, Sok C.
UNSPECIFIED
Molinolo, Alfredo A.
UNSPECIFIED
Samuels, Yardena
UNSPECIFIED
Tamayo, Pablo
UNSPECIFIED
Guan, Kun Liang
UNSPECIFIED
Lippman, Scott M.
UNSPECIFIED
Lyons, J. Guy
UNSPECIFIED
Gutkind, J. Silvio
UNSPECIFIED
Last Modified: 03 Jan 2021 22:48
URI: https://eprints.centenary.org.au/id/eprint/522

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