CCM3 is a gatekeeper in focal adhesions regulating mechanotransduction and YAP/TAZ signalling

Shan Wang, Emelie Englund, Pontus Kjellman, Zhen Li, Johannes Kumra Ahnlide, Carmen Rodriguez-Cupello, Mattia Saggioro, Ryu Kanzaki, Kristian Pietras, David Lindgren, Håkan Axelson, Christelle N. Prinz, Vinay Swaminathan, Chris D. Madsen

Research output: Contribution to journalArticlepeer-review


The YAP/TAZ transcriptional programme is not only a well-established driver of cancer progression and metastasis but also an important stimulator of tissue regeneration. Here we identified Cerebral cavernous malformations 3 (CCM3) as a regulator of mechanical cue-driven YAP/TAZ signalling, controlling both tumour progression and stem cell differentiation. We demonstrate that CCM3 localizes to focal adhesion sites in cancer-associated fibroblasts, where it regulates mechanotransduction and YAP/TAZ activation. Mechanistically, CCM3 and focal adhesion kinase (FAK) mutually compete for binding to paxillin to fine-tune FAK/Src/paxillin-driven mechanotransduction and YAP/TAZ activation. In mouse models of breast cancer, specific loss of CCM3 in cancer-associated fibroblasts leads to exacerbated tissue remodelling and force transmission to the matrix, resulting in reciprocal YAP/TAZ activation in the neighbouring tumour cells and dissemination of metastasis to distant organs. Similarly, CCM3 regulates the differentiation of mesenchymal stromal/stem cells. In conclusion, CCM3 is a gatekeeper in focal adhesions that controls mechanotransduction and YAP/TAZ signalling.

Original languageEnglish
Pages (from-to)758-770
Number of pages13
JournalNature Cell Biology
Issue number7
Publication statusPublished - 2021

Subject classification (UKÄ)

  • Cell and Molecular Biology


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