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

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... Full description

Journal Title: Nature communications July 9, 2018, Vol.9(1), p.2372
Main Author: Martin, Daniel
Other Authors: Degese, Maria S , Vitale-Cross, Lynn , Iglesias-Bartolome, Ramiro , Valera, Juan Luis Callejas , Wang, Zhiyong , Feng, Xiaodong , Yeerna, Huwate , Vadmal, Vachan , Moroishi, Toshiro , Thorne, Rick F , Zaida, Moraima , Siegele, Bradford , Cheong, Sok C , Molinolo, Alfredo A , Samuels, Yardena , Tamayo, Pablo , Guan, Kun Liang , Lippman, Scott M , Lyons
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 2041-1723 ; DOI: 10.1038/s41467-018-04590-1
Link: http://search.proquest.com/docview/2067139570/?pq-origsite=primo
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title: Assembly and activation of the Hippo signalome by FAT1 tumor suppressor.
format: Article
creator:
  • Martin, Daniel
  • Degese, Maria S
  • Vitale-Cross, Lynn
  • Iglesias-Bartolome, Ramiro
  • Valera, Juan Luis Callejas
  • Wang, Zhiyong
  • Feng, Xiaodong
  • Yeerna, Huwate
  • Vadmal, Vachan
  • Moroishi, Toshiro
  • Thorne, Rick F
  • Zaida, Moraima
  • Siegele, Bradford
  • Cheong, Sok C
  • Molinolo, Alfredo A
  • Samuels, Yardena
  • Tamayo, Pablo
  • Guan, Kun Liang
  • Lippman, Scott M
  • Lyons
subjects:
  • Adaptor Proteins, Signal Transducing–Genetics
  • Cadherins–Metabolism
  • Gene Knockdown Techniques–Physiology
  • Hek293 Cells–Genetics
  • Head and Neck Neoplasms–Metabolism
  • Hepatocyte Growth Factor–Physiology
  • Humans–Genetics
  • Phosphoproteins–Metabolism
  • Protein-Serine-Threonine Kinases–Pathology
  • Proto-Oncogene Proteins–Metabolism
  • Signal Transduction–Genetics
  • Squamous Cell Carcinoma of Head and Neck–Metabolism
  • Squamous Cell Carcinoma of Head and Neck–Physiology
  • Squamous Cell Carcinoma of Head and Neck–Genetics
  • Squamous Cell Carcinoma of Head and Neck–Metabolism
  • Squamous Cell Carcinoma of Head and Neck–Metabolism
  • Squamous Cell Carcinoma of Head and Neck–Genetics
  • Squamous Cell Carcinoma of Head and Neck–Metabolism
  • Squamous Cell Carcinoma of Head and Neck–Pathology
  • Adaptor Proteins, Signal Transducing
ispartof: Nature communications, July 9, 2018, Vol.9(1), p.2372
description: 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. Dysregulation of the Hippo signaling is a frequent event in human malignancies, but the molecular mechanisms remain unclear. Here the authors show that in head and neck squamous carcinoma, FAT1 interacts with the Hippo signaling complex, resulting in the activation of core Hippo kinases and YAP1 inactivation.
language: eng
source:
identifier: E-ISSN: 2041-1723 ; DOI: 10.1038/s41467-018-04590-1
fulltext: fulltext
issn:
  • 20411723
  • 2041-1723
url: Link


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titleAssembly and activation of the Hippo signalome by FAT1 tumor suppressor.
creatorMartin, Daniel ; Degese, Maria S ; Vitale-Cross, Lynn ; Iglesias-Bartolome, Ramiro ; Valera, Juan Luis Callejas ; Wang, Zhiyong ; Feng, Xiaodong ; Yeerna, Huwate ; Vadmal, Vachan ; Moroishi, Toshiro ; Thorne, Rick F ; Zaida, Moraima ; Siegele, Bradford ; Cheong, Sok C ; Molinolo, Alfredo A ; Samuels, Yardena ; Tamayo, Pablo ; Guan, Kun Liang ; Lippman, Scott M ; Lyons
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ispartofNature communications, July 9, 2018, Vol.9(1), p.2372
identifierE-ISSN: 2041-1723 ; DOI: 10.1038/s41467-018-04590-1
subjectAdaptor Proteins, Signal Transducing–Genetics ; Cadherins–Metabolism ; Gene Knockdown Techniques–Physiology ; Hek293 Cells–Genetics ; Head and Neck Neoplasms–Metabolism ; Hepatocyte Growth Factor–Physiology ; Humans–Genetics ; Phosphoproteins–Metabolism ; Protein-Serine-Threonine Kinases–Pathology ; Proto-Oncogene Proteins–Metabolism ; Signal Transduction–Genetics ; Squamous Cell Carcinoma of Head and Neck–Metabolism ; Squamous Cell Carcinoma of Head and Neck–Physiology ; Squamous Cell Carcinoma of Head and Neck–Genetics ; Squamous Cell Carcinoma of Head and Neck–Metabolism ; Squamous Cell Carcinoma of Head and Neck–Metabolism ; Squamous Cell Carcinoma of Head and Neck–Genetics ; Squamous Cell Carcinoma of Head and Neck–Metabolism ; Squamous Cell Carcinoma of Head and Neck–Pathology ; Adaptor Proteins, Signal Transducing
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descriptionDysregulation 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. Dysregulation of the Hippo signaling is a frequent event in human malignancies, but the molecular mechanisms remain unclear. Here the authors show that in head and neck squamous carcinoma, FAT1 interacts with the Hippo signaling complex, resulting in the activation of core Hippo kinases and YAP1 inactivation.
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18Lippman, Scott M
19Lyons, J Guy
20Gutkind, J Silvio
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titleAssembly and activation of the Hippo signalome by FAT1 tumor suppressor.
authorMartin, Daniel ; Degese, Maria S ; Vitale-Cross, Lynn ; Iglesias-Bartolome, Ramiro ; Valera, Juan Luis Callejas ; Wang, Zhiyong ; Feng, Xiaodong ; Yeerna, Huwate ; Vadmal, Vachan ; Moroishi, Toshiro ; Thorne, Rick F ; Zaida, Moraima ; Siegele, Bradford ; Cheong, Sok C ; Molinolo, Alfredo A ; Samuels, Yardena ; Tamayo, Pablo ; Guan, Kun Liang ; Lippman, Scott M ; Lyons
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5Hepatocyte Growth Factor–Physiology
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12Squamous Cell Carcinoma of Head and Neck–Physiology
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15Adaptor Proteins, Signal Transducing
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