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Assembly and activation of the Hippo signalome by FAT1 tumor suppressor

Martin D 1 , Degese MS 1 , Vitale-Cross L 1 , Iglesias-Bartolome R 1 , Valera JLC 2 , Wang Z 2 Show all authors , Feng X 2 , Yeerna H 2 , Vadmal V 2 , Moroishi T 3 , Thorne RF 4 , Zaida M 1 , Siegele B 5 , Cheong SC 6 , Molinolo AA 2 , Samuels Y 7 , Tamayo P 2 , Guan KL 2 , Lippman SM 8 , Lyons JG 9 , Gutkind JS 10

Affiliations 

  • 1 Oral and Pharyngeal Cancer Branch, National Institutes of Health, Bethesda, MD 20892, USA
  • 2 University of California San Diego, Moores Cancer Center, La Jolla, CA 92093, USA
  • 3 Department of Pharmacology, University of California, San Diego, CA 92093, USA
  • 4 School of Environmental and Life Sciences, University of Newcastle, and Hunter Cancer Research Alliance, Callaghan, NSW 2308, Australia
  • 5 Department of Pathology School of Medicine, University of Colorado, Colorado, CO 80045, USA
  • 6 Oral Cancer Research Team, Cancer Research, Selangor, Malaysia
  • 7 Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, 76100, Israel
  • 8 University of California San Diego, Moores Cancer Center, La Jolla, CA 92093, USA. [email protected]
  • 9 Dermatology, Bosch Institute, University of Sydney, Camperdown, NSW 2050, Australia
  • 10 Oral and Pharyngeal Cancer Branch, National Institutes of Health, Bethesda, MD 20892, USA. [email protected]
Nat Commun, 2018 07 09;9(1):2372.
PMID: 29985391 DOI: 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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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