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

MPG-Autoren
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Li,  Rui
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons248843

Shao,  Jingchen
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons239385

Jin,  Y. J.
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons290564

Haruya,  Kawase
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons239433

Ong,  Yu Ting
Angiogenesis & Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224203

Troidl,  Kerstin
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons228678

Wang,  Lei
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons239389

Bonnavion,  Remy
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224397

Wietelmann,  Astrid
Small Animal Magnetic Resonance Imaging, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224364

Potente,  Michael
Angiogenesis & Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons228784

Graumann,  Johannes
Biomolecular Mass Spectrometry, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224211

Wettschureck,  Nina
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224185

Offermanns,  Stefan
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Zitation

Li, R., Shao, J., Jin, Y. J., Haruya, K., Ong, Y. T., Troidl, K., et al. (2023). Endothelial FAT1 inhibits angiogenesis by controlling YAP/TAZ protein degradation via E3 ligase MIB2. NATURE COMMUNICATIONS, 14(1): 1980. doi:10.1038/s41467-023-37671-x.


Zitierlink: https://hdl.handle.net/21.11116/0000-000D-54C3-8
Zusammenfassung
The authors report that endothelial protocadherin FAT1 inhibits endothelial proliferation and angiogenesis by promoting degradation of the transcriptional cofactors YAP and TAZ by direct interaction with the E3 ubiquitin ligase Mind Bomb-2 (MIB2).
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.