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; J Silvio Gutkind

doi:10.1038/s41467-018-04590-1

Assembly and activation of the Hippo signalome by FAT1 tumor suppressor

Nat Commun. 2018 Jul 9;9(1):2372. doi: 10.1038/s41467-018-04590-1.

Authors

Daniel Martin¹, Maria S Degese¹, Lynn Vitale-Cross¹, Ramiro Iglesias-Bartolome^{1

2}, Juan Luis Callejas Valera^{3

4}, Zhiyong Wang^{3

4}, Xiaodong Feng^{3

4}, Huwate Yeerna³, Vachan Vadmal³, Toshiro Moroishi⁴, Rick F Thorne⁵, Moraima Zaida¹, Bradford Siegele⁶, Sok C Cheong^{7

8}, Alfredo A Molinolo³, Yardena Samuels⁹, Pablo Tamayo³, Kun Liang Guan^{3

4}, Scott M Lippman¹⁰, J Guy Lyons^{11

12

13}, J Silvio Gutkind^{14

15

16}

Affiliations

¹ Oral and Pharyngeal Cancer Branch, National Institutes of Health, Bethesda, MD 20892, USA.
² Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, MD, USA.
³ University of California San Diego, Moores Cancer Center, La Jolla, CA 92093, USA.
⁴ Department of Pharmacology, University of California, San Diego, CA 92093, USA.
⁵ School of Environmental and Life Sciences, University of Newcastle, and Hunter Cancer Research Alliance, Callaghan, NSW 2308, Australia.
⁶ Department of Pathology School of Medicine, University of Colorado, Colorado, CO 80045, USA.
⁷ Oral Cancer Research Team, Cancer Research, Selangor, Malaysia.
⁸ 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, 76100, Israel.
¹⁰ University of California San Diego, Moores Cancer Center, La Jolla, CA 92093, USA. [email protected].
¹¹ Dermatology, Bosch Institute, University of Sydney, Camperdown, NSW 2050, Australia.
¹² Cancer Services, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia.
¹³ Centenary Institute, Camperdown, NSW 2050, Australia.
¹⁴ Oral and Pharyngeal Cancer Branch, National Institutes of Health, Bethesda, MD 20892, USA. [email protected].
¹⁵ University of California San Diego, Moores Cancer Center, La Jolla, CA 92093, USA. [email protected].
¹⁶ Department of Pharmacology, University of California, San Diego, CA 92093, USA. [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism
Adaptor Proteins, Signal Transducing / physiology*
Cadherins / genetics
Cadherins / metabolism
Cadherins / physiology*
Gene Knockdown Techniques
HEK293 Cells
Head and Neck Neoplasms / genetics*
Head and Neck Neoplasms / metabolism
Head and Neck Neoplasms / pathology
Hepatocyte Growth Factor / metabolism
Hippo Signaling Pathway
Humans
Phosphoproteins / genetics
Phosphoproteins / metabolism
Phosphoproteins / physiology*
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
Proto-Oncogene Proteins / metabolism
Signal Transduction
Squamous Cell Carcinoma of Head and Neck / genetics*
Squamous Cell Carcinoma of Head and Neck / metabolism
Squamous Cell Carcinoma of Head and Neck / pathology
Transcription Factors
YAP-Signaling Proteins

Substances

Adaptor Proteins, Signal Transducing
Cadherins
FAT1 protein, human
Phosphoproteins
Proto-Oncogene Proteins
Transcription Factors
YAP-Signaling Proteins
YAP1 protein, human
macrophage stimulating protein
Hepatocyte Growth Factor
Protein Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding