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| Invited Talk, Saturday, 12:15 – 12:45 |
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| Molecular Mechanotransduction:
how forces trigger cytoskeletal dynamics
Allen Ehrlicher
Harvard University, School of Engineering
and Applied Sciences, Department of Physics, Cambridge, MA 02138, USA |
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| Contact:
| Website |
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Mechanical stresses elicit cellular reactions mediated by chemical signals.
Defective responses to forces underlie human medical disorders, such as
cardiac failure and pulmonary injury. Despite detailed knowledge of the
cytoskeleton’s structure, the specific molecular switches that convert
mechanical stimuli into chemical signals have remained elusive. Here we
identify the actin-binding protein, filamin A (FLNa) as a central mechanotransduction
element of the cytoskeleton by using Fluorescence Loss After photoConversion
(FLAC), a novel high-speed alternative to FRAP. We reconstituted a minimal
system consisting of actin filaments, FLNa and two FLNa-binding partners:
the cytoplasmic tail of ß-integrin, and FilGAP. Integrins form
an essential mechanical linkage between extracellular and intracellular
environments, with ß integrin tails connecting to the actin cytoskeleton
by binding directly to filamin. FilGAP is a FLNa-binding GTPase-activating
protein specific for Rac, which in vivo regulates cell spreading
and bleb formation. We demonstrate that both externally-imposed bulk shear
and myosin II driven forces differentially regulate the binding of integrin
and FilGAP to FLNa. Consistent with structural predictions, strain increases
ß-integrin binding to FLNa, whereas it causes FilGAP to dissociate
from FLNa, providing a direct and specific molecular basis for cellular
mechanotransduction. These results identify the first molecular mechanotransduction
element within the actin cytoskeleton, revealing that mechanical strain
of key proteins regulates the binding of signaling molecules. Moreover,
GAP activity has been shown to switch extravasation from mesenchymal to
amoeboid motility, suggesting that mechanical forces directly impact the
invasiveness of cancer.
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A.J. Ehrlicher, F. Nakamura, J.H. Hartwig,
D.A. Weitz, T.P. Stossel: Mechanical
strain in actin networks regulates FilGAP and integrin binding to filamin
A, Nature, doi:10.1038/nature10430
(2011). |
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