2. Academic Validation
  3. FAK, vinculin, and talin control mechanosensitive YAP nuclear localization

FAK, vinculin, and talin control mechanosensitive YAP nuclear localization

  • Biomaterials. 2024 Jul:308:122542. doi: 10.1016/j.biomaterials.2024.122542.
Elijah N Holland 1,  Marc A Fernández-Yagüe 2,  Dennis W Zhou 3,  Eric B O'Neill 4,  Ayanna U Woodfolk 5,  Ana Mora-Boza 4,  Jianping Fu 6,  David D Schlaepfer 7,  Andrés J García 8
Affiliations

Affiliations

  • 1 Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA; School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
  • 2 Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA; Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA; Department of Chemistry, Queen Mary University of London, London, UK.
  • 3 Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA; Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
  • 4 Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA; Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
  • 5 Mathematics Department, Spelman College, Atlanta, GA, USA; Bioengineering Department, North Carolina A&T State University, Greensboro, NC, USA.
  • 6 Department of Mechanical Engineering, Department of Biomedical Engineering, Department of Cell & Developmental Biology, University of Michigan, Ann Arbor, MI, USA.
  • 7 Moores Cancer Center, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Diego, La Jolla, CA, USA.
  • 8 Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA; Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA. Electronic address: [email protected].
PMID: 38547833 DOI: 10.1016/j.biomaterials.2024.122542
Abstract

Focal adhesions (FAs) are nanoscale complexes containing clustered Integrin receptors and intracellular structural and signaling proteins that function as principal sites of mechanotransduction in part via promoting the nuclear translocation and activation of the transcriptional coactivator yes-associated protein (YAP). Knockdown of FA proteins such as focal adhesion kinase (FAK), talin, and vinculin can prevent YAP nuclear localization. However, the mechanism(s) of action remain poorly understood. Herein, we investigated the role of different functional domains in vinculin, talin, and FAK in regulating YAP nuclear localization. Using genetic or pharmacological inhibition of fibroblasts and human mesenchymal stem cells (hMSCs) adhering to deformable substrates, we find that disruption of vinculin-talin binding versus talin-FAK binding reduces YAP nuclear localization and transcriptional activity via different mechanisms. Disruption of vinculin-talin binding or knockdown of talin-1 reduces nuclear size, traction forces, and YAP nuclear localization. In contrast, disruption of the talin binding site on FAK or elimination of FAK catalytic activity did not alter nuclear size yet still prevented YAP nuclear localization and activity. These data support both nuclear tension-dependent and independent models for matrix stiffness-regulated YAP nuclear localization. Our results highlight the importance of vinculin-talin-FAK interactions at FAs of adherent cells, controlling YAP nuclear localization and activity.

Keywords

Focal adhesion; Mechanotransduction; Micropillar array; Rigidity sensing.

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