YAP Fuels Cerebral Cavernous Malformations by Regulating KLF4 Transcriptional Activity and Protein Stability.
7 affiliations
- 1Life Sciences Institute Zhejiang University Hangzhou Zhejiang China.
- 2Department of Cardiovascular Surgery the First Affiliated Hospital School of Medicine Zhejiang University Hangzhou Zhejiang China.
- 3Department of Pathology The First Affiliated Hospital School of Medicine Zhejiang University Hangzhou Zhejiang China.
- 4Department of Respiratory and Critical Care Medicine Center For Oncology Medicine the Fourth Affiliated Hospital of School of Medicine and International School of Medicine International Institutes of Medicine Zhejiang University Yiwu Zhejiang China.
- 5Zhejiang Key Laboratory of Precision Diagnosis and Treatment for Lung Cancer Yiwu Zhejiang China.
- 6The MOE Key Laboratory of Biosystems Homeostasis & Protection Zhejiang University Hangzhou Zhejiang China.
- 7State Key Laboratory of Transvascular Implantation Devices Hangzhou China.
Abstract
Cerebral cavernous malformations (CCMs), which frequently predispose patients to strokes or seizures, primarily arise from endothelial specific loss-of-function mutations in the CCM genes, and occasionally accompanied by gain-of-function mutations in PIK3CA and MAP3K3. While the Hippo pathway is a well-established regulator of tissue homeostasis, its emerging relevance in vascular pathology particularly its precise role in CCM pathogenesis remains poorly understood. In this study, we demonstrate that CCM gene deficiency suppresses endothelial Hippo signaling, as evidenced by diminished LATS activity, alongside concomitant elevation of YAP expression and nuclear translocation in both human and mouse CCM lesions. Notably, endothelial-specific deletion of Yap mitigates CCM lesion formation, reinforces endothelial junctions, enhances inflammatory resistance, and decreases KLF4 protein levels in a CCM mouse model. Conversely, intracranial Adeno-associated virus (AAV)-mediated inhibition of LATS or activation of YAP promoted CCMs formation under Ccm2 deficiency. Mechanistically, under the dual coordination of negative regulation by LATS and positive regulation by MAP3K3, YAP orchestrates KLF4 transcriptional activity and protein stability. This is achieved through a direct interaction with KLF4 that shields it from β-TrCP-mediated proteasomal degradation, thereby driving CCM progression. Collectively, our findings unveil a novel dimension to Hippo pathway regulation and underscore YAP as a pivotal driver of CCM pathogenesis.
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BibTeX
@article{ye2026fuels,
title = {{YAP Fuels Cerebral Cavernous Malformations by Regulating KLF4 Transcriptional Activity and Protein Stability.}},
author = {Tingting Ye and Qi Zheng and Zonghao Hu and Haonan Fan and Zhongxing Sun and Xiya Li and Haomin Mo and Chengdong Chang and Yanhua Xu and Kai Wang and Dong Fang and Hai Song},
journal = {MedComm},
year = {2026},
month = oct,
doi = {10.1002/mco2.71086},
url = {https://europepmc.org/article/MED/42921278},
note = {CC BY},
}
RIS
TY - JOUR
TI - YAP Fuels Cerebral Cavernous Malformations by Regulating KLF4 Transcriptional Activity and Protein Stability.
AU - Tingting Ye
AU - Qi Zheng
AU - Zonghao Hu
AU - Haonan Fan
AU - Zhongxing Sun
AU - Xiya Li
AU - Haomin Mo
AU - Chengdong Chang
AU - Yanhua Xu
AU - Kai Wang
AU - Dong Fang
AU - Hai Song
PY - 2026
DA - 2026/10/23
JO - MedComm
DO - 10.1002/mco2.71086
UR - https://europepmc.org/article/MED/42921278
AB - Cerebral cavernous malformations (CCMs), which frequently predispose patients to strokes or seizures, primarily arise from endothelial specific loss-of-function mutations in the CCM genes, and occasionally accompanied by gain-of-function mutations in PIK3CA and MAP3K3. While the Hippo pathway is a well-established regulator of tissue homeostasis, its emerging relevance in vascular pathology particularly its precise role in CCM pathogenesis remains poorly understood. In this study, we demonstrate that CCM gene deficiency suppresses endothelial Hippo signaling, as evidenced by diminished LATS activity, alongside concomitant elevation of YAP expression and nuclear translocation in both human and mouse CCM lesions. Notably, endothelial-specific deletion of Yap mitigates CCM lesion formation, reinforces endothelial junctions, enhances inflammatory resistance, and decreases KLF4 protein levels in a CCM mouse model. Conversely, intracranial Adeno-associated virus (AAV)-mediated inhibition of LATS or activation of YAP promoted CCMs formation under Ccm2 deficiency. Mechanistically, under the dual coordination of negative regulation by LATS and positive regulation by MAP3K3, YAP orchestrates KLF4 transcriptional activity and protein stability. This is achieved through a direct interaction with KLF4 that shields it from β-TrCP-mediated proteasomal degradation, thereby driving CCM progression. Collectively, our findings unveil a novel dimension to Hippo pathway regulation and underscore YAP as a pivotal driver of CCM pathogenesis.
SN - 2688-2663
ER -