FAK, vinculin, and talin control mechanosensitive YAP nuclear localization

Area of Science:

• Cell Biology
• Mechanobiology
• Molecular Signaling

Background:

• Focal adhesions (FAs) are critical for mechanotransduction, linking the extracellular matrix to the cytoskeleton.
• FAs regulate the nuclear translocation and activation of the transcriptional coactivator yes-associated protein (YAP).
• The precise mechanisms by which FA proteins control YAP localization remain unclear.

Purpose of the Study:

• To investigate the roles of specific functional domains within vinculin, talin, and focal adhesion kinase (FAK) in regulating YAP nuclear localization.
• To differentiate between nuclear tension-dependent and independent pathways controlling YAP localization in response to matrix stiffness.

Main Methods:

• Utilized genetic and pharmacological inhibition in fibroblasts and human mesenchymal stem cells (hMSCs).
• Studied cells adhering to deformable substrates to mimic varying matrix stiffness.
• Assessed the impact of disrupting vinculin-talin and talin-FAK interactions on YAP localization, nuclear size, and cellular traction forces.

Main Results:

• Disrupting vinculin-talin binding or reducing talin-1 levels decreased nuclear size, traction forces, and YAP nuclear localization.
• In contrast, disrupting talin binding to FAK or inhibiting FAK's catalytic activity prevented YAP nuclear localization and activity without altering nuclear size.
• These findings suggest distinct mechanisms for matrix stiffness-regulated YAP nuclear localization.

Conclusions:

• Vinculin-talin-FAK interactions within focal adhesions are crucial for controlling YAP nuclear localization and transcriptional activity.
• Data support models involving both nuclear tension-dependent and independent pathways in matrix stiffness-mediated YAP regulation.
• Highlights the complex interplay of FA components in mechanotransduction pathways governing YAP activity.