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

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 Graumann, Nina Wettschureck and Stefan Offermanns ()
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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
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
Johannes Graumann: Max Planck Institute for Heart and Lung Research, Biomolecular Mass Spectrometry Service Group
Nina Wettschureck: Max Planck Institute for Heart and Lung Research, Department of Pharmacology
Stefan Offermanns: Max Planck Institute for Heart and Lung Research, Department of Pharmacology

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37671-x

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