Extensive research over the past decades has identified integrins to be the primary transmembrane receptors that enable cells to respond to external mechanical cues. We reveal here a mechanism whereby syndecan-4 tunes cell mechanics in response to localized tension via a coordinated mechanochemical signalling response that involves activation of two other receptors: epidermal growth factor receptor and β1 integrin. Tension on syndecan-4 induces cell-wide activation of the kindlin-2/β1 integrin/RhoA axis in a PI3K-dependent manner. Furthermore, syndecan-4-mediated tension at the cell–extracellular matrix interface is required for yes-associated protein activation. Extracellular tension on syndecan-4 triggers a conformational change in the cytoplasmic domain, the variable region of which is indispensable for the mechanical adaptation to force, facilitating the assembly of a syndecan-4/α-actinin/F-actin molecular scaffold at the bead adhesion. This mechanotransduction pathway for syndecan-4 should have immediate implications for the broader field of mechanobiology.
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The data that support the findings of this study are available from the corresponding authors upon reasonable request.
The MATLAB code used to track bead displacements in the magnetic tweezers experiments is available from A.E.d.R.H. upon reasonable request. Code used in the MD simulations is available from V.P.H. upon reasonable request.
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This work was supported by the European Research Council (ERC grant no. 282051), the Biotechnology and Biological Sciences Research Council (BBSRC grant no. BB/N018532/1) and the Academy of Finland (grant no. 290506). V.V.M. was supported by an EDUFI (former CIMO) postdoctoral fellowship and Academy of Finland funding for Postdoctoral Researcher (grant no. 323021). We thank M. Morgan (University of Liverpool) for providing MEF cell lines, J. Couchman (University of Copenhagen) for providing syndecan-4 cytoplasmic truncation plasmids (C2 and V domains), J. Qin (Cleveland Clinic) for the kindlin-2-GFP plasmids, C. Wu (University of Pittsburgh) for the kindlin-2 K390A plasmid and F. Di Maggio for help in implementing the initial work with PSCs. We acknowledge CSC–IT Center for Science, Finland for computational resources. We are also grateful to all CMBL members for help and advice throughout this work.
The authors declare no competing interests.
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Chronopoulos, A., Thorpe, S.D., Cortes, E. et al. Syndecan-4 tunes cell mechanics by activating the kindlin-integrin-RhoA pathway. Nat. Mater. 19, 669–678 (2020). https://doi.org/10.1038/s41563-019-0567-1
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