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Edited by Janis K. Burkhardt, Children’s Hospital of Philadelphia, Ardmore, PA, and accepted by Editorial Board Member Yale E. Goldman November 2, 2020 (received for review May 22, 2020)
Significance
The current paradigm for force transmission between cells and the extracellular matrix is the focal adhesion clutch, in which highly dynamic bonds involving the cytoskeletal linker proteins talin and vinculin transmit tension between moving actin filaments and immobile integrins. We found, however, that while dynamic bonds dominate at cell edges where actin flow is rapid, force transfer in adhesions further from the edge that may be linked to actin bundles is transmitted mainly through more stable interactions. Vinculin contributes to stable and not dynamic bonds as previously thought. We identify the protein interactions that mediate these mechanisms and demonstrate modulation by matrix stiffness. These data therefore substantially revise our view of force transmission in cell-matrix adhesions.
Abstract
Integrin-dependent adhesions mediate reciprocal exchange of force and information between the cell and the extracellular matrix. These effects are attributed to the “focal adhesion clutch,” in which moving actin filaments transmit force to integrins via dynamic protein interactions. To elucidate these processes, we measured force on talin together with actin flow speed. While force on talin in small lamellipodial adhesions correlated with actin flow, talin tension in large adhesions further from the cell edge was mainly flow-independent. Stiff substrates shifted force transfer toward the flow-independent mechanism. Flow-dependent force transfer required talin’s C-terminal actin binding site, ABS3, but not vinculin. Flow-independent force transfer initially required vinculin and at later times the central actin binding site, ABS2. Force transfer through integrins thus occurs not through a continuous clutch but through a series of discrete states mediated by distinct protein interactions, with their ratio modulated by substrate stiffness.
Footnotes
- ↵1To whom correspondence may be addressed. Email: martin.schwartz{at}yale.edu.
Author contributions: T.P.D. and M.A.S. designed research; T.P.D., S.J.A., B.H., and A.K. performed research; T.P.D., B.H., and A.K. contributed new reagents/analytic tools; T.P.D. analyzed data; and T.P.D. and M.A.S. wrote the paper.
The authors declare no competing interest.
This article is a PNAS Direct Submission. J.K.B. is a guest editor invited by the Editorial Board.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2010292117/-/DCSupplemental.
Data Availability.
Quantitative fluorescence speckle microscopy (QFSM) software (34) and TFM software (37) are open source and available on GitHub (https://github.com/DanuserLab). MATLAB code and code used to prepare movie database files (for QFSM), analyze FRET, and correlate FRET with actin flow are available at https://github.com/TristanDriscoll/FRET-Speckle (39).
Published under the PNAS license.
References
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Actin flow-dependent and -independent force transmission through integrins
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