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Assembly and activation of the Hippo signalome by FAT1 tumor suppressor

Author

Listed:
  • Daniel Martin

    (National Institutes of Health)

  • Maria S. Degese

    (National Institutes of Health)

  • Lynn Vitale-Cross

    (National Institutes of Health)

  • Ramiro Iglesias-Bartolome

    (National Institutes of Health
    National Institutes of Health)

  • Juan Luis Callejas Valera

    (Moores Cancer Center
    University of California)

  • Zhiyong Wang

    (Moores Cancer Center
    University of California)

  • Xiaodong Feng

    (Moores Cancer Center
    University of California)

  • Huwate Yeerna

    (Moores Cancer Center)

  • Vachan Vadmal

    (Moores Cancer Center)

  • Toshiro Moroishi

    (University of California)

  • Rick F. Thorne

    (and Hunter Cancer Research Alliance)

  • Moraima Zaida

    (National Institutes of Health)

  • Bradford Siegele

    (University of Colorado)

  • Sok C. Cheong

    (Cancer Research
    University of Malaya)

  • Alfredo A. Molinolo

    (Moores Cancer Center)

  • Yardena Samuels

    (The Weizmann Institute of Science)

  • Pablo Tamayo

    (Moores Cancer Center)

  • Kun Liang Guan

    (Moores Cancer Center
    University of California)

  • Scott M. Lippman

    (Moores Cancer Center)

  • J. Guy Lyons

    (University of Sydney
    Royal Prince Alfred Hospital
    Centenary Institute)

  • J. Silvio Gutkind

    (National Institutes of Health
    Moores Cancer Center
    University of California)

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.

Suggested Citation

  • 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. , 2018. "Assembly and activation of the Hippo signalome by FAT1 tumor suppressor," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04590-1
    DOI: 10.1038/s41467-018-04590-1
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    Cited by:

    1. Ankur Chakravarthy & Ian Reddin & Stephen Henderson & Cindy Dong & Nerissa Kirkwood & Maxmilan Jeyakumar & Daniela Rothschild Rodriguez & Natalia Gonzalez Martinez & Jacqueline McDermott & Xiaoping Su, 2022. "Integrated analysis of cervical squamous cell carcinoma cohorts from three continents reveals conserved subtypes of prognostic significance," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Rui Li & Jingchen Shao & Young-June Jin & Haruya Kawase & Yu Ting Ong & Kerstin Troidl & Qi Quan & Lei Wang & Remy Bonnavion & Astrid Wietelmann & Francoise Helmbacher & Michael Potente & Johannes Gra, 2023. "Endothelial FAT1 inhibits angiogenesis by controlling YAP/TAZ protein degradation via E3 ligase MIB2," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Cheng-Hai Zhang & Yao Gao & Han-Hwa Hung & Zhu Zhuo & Alan J. Grodzinsky & Andrew B. Lassar, 2022. "Creb5 coordinates synovial joint formation with the genesis of articular cartilage," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    4. Atanu Paul & Stefano Annunziato & Bo Lu & Tianliang Sun & Olivera Evrova & Lara Planas-Paz & Vanessa Orsini & Luigi M. Terracciano & Olga Charlat & Zinger Yang Loureiro & Lei Ji & Raffaella Zamponi & , 2022. "Cell adhesion molecule KIRREL1 is a feedback regulator of Hippo signaling recruiting SAV1 to cell-cell contact sites," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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