机械转化
焦点粘着
帕西林
细胞生物学
河马信号通路
刺猬信号通路
生物
信号转导
癌症研究
化学
作者
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 Prinz,Vinay Swaminathan,Chris D. Madsen
标识
DOI:10.1038/s41556-021-00702-0
摘要
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.
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