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The lamellipodium is a myosin independent mechanosensor

View ORCID ProfilePatrick W. Oakes, Tamara C. Bidone, Yvonne Beckham, Austin V. Skeeters, Guillermina R. Ramirez-San Juan, Stephen P. Winter, Gregory A. Voth, Margaret L. Gardel
doi: https://doi.org/10.1101/186437
Patrick W. Oakes
aInstitute for Biophysical Dynamics, University of Chicago, and Chicago, IL 60637
bJames Franck Institute, University of Chicago, and Chicago, IL 60637
cDepartment of Physics, University of Chicago, and Chicago, IL 60637
eDepartment of Physics & Astronomy, University of Rochester, and Rochester, NY 14627
fDepartment of Biology, University of Rochester, Rochester, NY 14627
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  • ORCID record for Patrick W. Oakes
Tamara C. Bidone
aInstitute for Biophysical Dynamics, University of Chicago, and Chicago, IL 60637
bJames Franck Institute, University of Chicago, and Chicago, IL 60637
dDepartment of Chemistry, University of Chicago, Chicago, IL 60637
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Yvonne Beckham
aInstitute for Biophysical Dynamics, University of Chicago, and Chicago, IL 60637
bJames Franck Institute, University of Chicago, and Chicago, IL 60637
cDepartment of Physics, University of Chicago, and Chicago, IL 60637
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Austin V. Skeeters
eDepartment of Physics & Astronomy, University of Rochester, and Rochester, NY 14627
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Guillermina R. Ramirez-San Juan
aInstitute for Biophysical Dynamics, University of Chicago, and Chicago, IL 60637
bJames Franck Institute, University of Chicago, and Chicago, IL 60637
cDepartment of Physics, University of Chicago, and Chicago, IL 60637
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Stephen P. Winter
gInterdisciplinary Scientist Training Program, University of Chicago, Chicago, IL 60637
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Gregory A. Voth
aInstitute for Biophysical Dynamics, University of Chicago, and Chicago, IL 60637
bJames Franck Institute, University of Chicago, and Chicago, IL 60637
dDepartment of Chemistry, University of Chicago, Chicago, IL 60637
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Margaret L. Gardel
aInstitute for Biophysical Dynamics, University of Chicago, and Chicago, IL 60637
bJames Franck Institute, University of Chicago, and Chicago, IL 60637
cDepartment of Physics, University of Chicago, and Chicago, IL 60637
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Abstract

The ability of adherent cells to sense changes in the mechanical properties of their extracellular environments is critical to numerous aspects of their physiology. It has been well documented that cell attachment and spreading are sensitive to substrate stiffness. Here we demonstrate that this behavior is actually biphasic, with a transition that occurs around a Young’s modulus of ∼7 kPa. Furthermore, we demonstrate that, contrary to established assumptions, this property is independent of myosin II activity. Rather, we find that cell spreading on soft substrates is inhibited due to reduced nascent adhesion formation within the lamellipodium. Cells on soft substrates display normal leading edge protrusion activity, but these protrusions are not stabilized due to impaired adhesion assembly. Enhancing integrin-ECM affinity through addition of Mn2+ recovers nascent adhesion assembly and cell spreading on soft substrates. Using a computational model to simulate nascent adhesion assembly, we find that biophysical properties of the integrin-ECM bond are optimized to stabilize interactions above a threshold matrix stiffness that is consistent with the experimentally observations. Together these results suggest that myosin II-independent forces in the lamellipodium are responsible for mechanosensation by regulating new adhesion assembly, which in turn, directly controls cell spreading. This myosin II-independent mechanism of substrate stiffness sensing could potentially regulate a number of other stiffness sensitive processes.

Significance Statement Cell physiology can be regulated by the mechanics of the extracellular environment. Here, we demonstrate that cell spreading is a mechanosensitive process regulated by weak forces generated at the cell periphery and independent of motor activity. We show that stiffness sensing depends on the kinetics of the initial adhesion bonds that are subjected to forces driven by protein polymerization. This work demonstrates how the binding kinetics of adhesion molecules are sensitively tuned to a range of forces that enable mechanosensation.

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Posted September 08, 2017.
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The lamellipodium is a myosin independent mechanosensor
Patrick W. Oakes, Tamara C. Bidone, Yvonne Beckham, Austin V. Skeeters, Guillermina R. Ramirez-San Juan, Stephen P. Winter, Gregory A. Voth, Margaret L. Gardel
bioRxiv 186437; doi: https://doi.org/10.1101/186437
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The lamellipodium is a myosin independent mechanosensor
Patrick W. Oakes, Tamara C. Bidone, Yvonne Beckham, Austin V. Skeeters, Guillermina R. Ramirez-San Juan, Stephen P. Winter, Gregory A. Voth, Margaret L. Gardel
bioRxiv 186437; doi: https://doi.org/10.1101/186437

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