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

Nat Cell Biol. 2021 Jul;23(7):758-770. doi: 10.1038/s41556-021-00702-0. Epub 2021 Jul 5.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cancer-Associated Fibroblasts / metabolism*
  • Cancer-Associated Fibroblasts / pathology
  • Cell Communication
  • Cell Differentiation
  • Cell Line, Tumor
  • Female
  • Focal Adhesion Kinase 1 / metabolism
  • Focal Adhesions / genetics
  • Focal Adhesions / metabolism*
  • Focal Adhesions / pathology
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mechanotransduction, Cellular*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mesenchymal Stem Cells / metabolism
  • Mesenchymal Stem Cells / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Metastasis
  • Paxillin / metabolism
  • Phosphorylation
  • Protein Binding
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Stress, Mechanical
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • YAP-Signaling Proteins
  • src-Family Kinases / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • PDCD10 protein, human
  • PDCD10 protein, mouse
  • PXN protein, human
  • Paxillin
  • Proto-Oncogene Proteins
  • Pxn protein, mouse
  • Transcription Factors
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • WWTR1 protein, human
  • Wwtr1 protein, mouse
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • Yap1 protein, mouse
  • Focal Adhesion Kinase 1
  • PTK2 protein, human
  • Ptk2 protein, mouse
  • src-Family Kinases