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Endothelial FAT1 inhibits angiogenesis by controlling YAP/TAZ protein degradation via E3 ligase MIB2

Author

Listed:
  • Rui Li

    (Max Planck Institute for Heart and Lung Research, Department of Pharmacology)

  • Jingchen Shao

    (Max Planck Institute for Heart and Lung Research, Department of Pharmacology)

  • Young-June Jin

    (Max Planck Institute for Heart and Lung Research, Department of Pharmacology)

  • Haruya Kawase

    (Max Planck Institute for Heart and Lung Research, Department of Pharmacology)

  • Yu Ting Ong

    (Angiogenesis & Metabolism Laboratory)

  • Kerstin Troidl

    (Max Planck Institute for Heart and Lung Research, Department of Pharmacology
    University Hospital Frankfurt and Wolfgang Goethe University Frankfurt)

  • Qi Quan

    (Max Planck Institute for Heart and Lung Research, Department of Pharmacology)

  • Lei Wang

    (Max Planck Institute for Heart and Lung Research, Department of Pharmacology)

  • Remy Bonnavion

    (Max Planck Institute for Heart and Lung Research, Department of Pharmacology)

  • Astrid Wietelmann

    (Small Animal Imaging Service Group)

  • Francoise Helmbacher

    (Aix Marseille Université, CNRS, IBDM UMR 7288, Parc Scientifique de Luminy, Case 907)

  • Michael Potente

    (Angiogenesis & Metabolism Laboratory
    Berlin Institute of Health at Charité—Universitätsmedizin Berlin, and Max Delbrück Center for Molecular Medicine in the Helmholtz Association)

  • Johannes Graumann

    (Max Planck Institute for Heart and Lung Research, Biomolecular Mass Spectrometry Service Group
    Philipps-University Marburg)

  • Nina Wettschureck

    (Max Planck Institute for Heart and Lung Research, Department of Pharmacology
    Goethe University Frankfurt
    Cardiopulmonary Institute
    German Center for Cardiovascular Research, Partner Site Frankfurt)

  • Stefan Offermanns

    (Max Planck Institute for Heart and Lung Research, Department of Pharmacology
    Goethe University Frankfurt
    Cardiopulmonary Institute
    German Center for Cardiovascular Research, Partner Site Frankfurt)

Abstract

Activation of endothelial YAP/TAZ signaling is crucial for physiological and pathological angiogenesis. The mechanisms of endothelial YAP/TAZ regulation are, however, incompletely understood. Here we report that the protocadherin FAT1 acts as a critical upstream regulator of endothelial YAP/TAZ which limits the activity of these transcriptional cofactors during developmental and tumor angiogenesis by promoting their degradation. We show that loss of endothelial FAT1 results in increased endothelial cell proliferation in vitro and in various angiogenesis models in vivo. This effect is due to perturbed YAP/TAZ protein degradation, leading to increased YAP/TAZ protein levels and expression of canonical YAP/TAZ target genes. We identify the E3 ubiquitin ligase Mind Bomb-2 (MIB2) as a FAT1-interacting protein mediating FAT1-induced YAP/TAZ ubiquitination and degradation. Loss of MIB2 expression in endothelial cells in vitro and in vivo recapitulates the effects of FAT1 depletion and causes decreased YAP/TAZ degradation and increased YAP/TAZ signaling. Our data identify a pivotal mechanism of YAP/TAZ regulation involving FAT1 and its associated E3 ligase MIB2, which is essential for YAP/TAZ-dependent angiogenesis.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37671-x
    DOI: 10.1038/s41467-023-37671-x
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