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Proc Natl Acad Sci U S A. 2018 Mar 13;115(11):2646-2651. doi: 10.1073/pnas.1715869115. Epub 2018 Feb 27.

Lamellipodium is a myosin-independent mechanosensor.

Author information

1
Department of Physics and Astronomy, University of Rochester, Rochester, NY 14627; poakes@rochester.edu gardel@uchicago.edu.
2
Department of Biology, University of Rochester, Rochester, NY 14627.
3
Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637.
4
James Franck Institute, University of Chicago, Chicago, IL 60637.
5
Department of Physics, University of Chicago, Chicago, IL 60637.
6
Department of Chemistry, University of Chicago, Chicago, IL 60637.
7
Department of Physics and Astronomy, University of Rochester, Rochester, NY 14627.
8
Interdisciplinary Scientist Training Program, University of Chicago, Chicago, IL 60637.
9
Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637; poakes@rochester.edu gardel@uchicago.edu.

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 myosin-II independent 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 experimental 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.

KEYWORDS:

catch-bond; integrin; mechanosensing; myosin-II; nascent adhesion

PMID:
29487208
PMCID:
PMC5856528
DOI:
10.1073/pnas.1715869115
[Indexed for MEDLINE]
Free PMC Article

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