CCM3 is a gatekeeper in focal adhesions regulating mechanotransduction and YAP/TAZ signalling
© 2021. The Author(s), under exclusive licence to Springer Nature Limited..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:23 |
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| Enthalten in: |
Nature cell biology - 23(2021), 7 vom: 05. Juli, Seite 758-770 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wang, Shan [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 20.09.2021 Date Revised 04.02.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41556-021-00702-0 |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a CCM3 is a gatekeeper in focal adhesions regulating mechanotransduction and YAP/TAZ signalling |
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| 500 | |a Date Revised 04.02.2023 | ||
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| 520 | |a © 2021. The Author(s), under exclusive licence to Springer Nature Limited. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Adaptor Proteins, Signal Transducing |2 NLM | |
| 650 | 7 | |a Apoptosis Regulatory Proteins |2 NLM | |
| 650 | 7 | |a Intracellular Signaling Peptides and Proteins |2 NLM | |
| 650 | 7 | |a Membrane Proteins |2 NLM | |
| 650 | 7 | |a PDCD10 protein, human |2 NLM | |
| 650 | 7 | |a PDCD10 protein, mouse |2 NLM | |
| 650 | 7 | |a PXN protein, human |2 NLM | |
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| 650 | 7 | |a WWTR1 protein, human |2 NLM | |
| 650 | 7 | |a Wwtr1 protein, mouse |2 NLM | |
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| 650 | 7 | |a YAP1 protein, human |2 NLM | |
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