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Title: Force loading explains spatial sensing of ligands by cells
Author: Oria, Roger
Wiegand, Tina
Escribano, Jorge
Elosegui Artola, Alberto
Uriarte, Juan José
Moreno Pulido, Cristian
Platzman, Ilia
Delcanale, Pietro
Albertazzi, Lorenzo
Navajas Navarro, Daniel
Trepat Guixer, Xavier
Garcia Aznar, Jose Manuel
Cavalcanti Adam, Elisabetta Ada
Roca-Cusachs Soulere, Pere
Keywords: Matriu extracel·lular
Extracellular matrix
Issue Date: 14-Dec-2017
Publisher: Nature Publishing Group
Abstract: Cells can sense the density and distribution of extracellular matrix (ECM) molecules by means of individual integrin proteins and larger, integrin-containing adhesion complexes within the cell membrane. This spatial sensing drives cellular activity in a variety of normal and pathological contexts(1,2). Previous studies of cells on rigid glass surfaces have shown that spatial sensing of ECM ligands takes place at the nanometre scale, with integrin clustering and subsequent formation of focal adhesions impaired when single integrin-ligand bonds are separated by more than a few tens of nanometres(3-6). It has thus been suggested that a crosslinking 'adaptor' protein of this size might connect integrins to the actin cytoskeleton, acting as a molecular ruler that senses ligand spacing directly(3,7-9). Here, we develop gels whose rigidity and nanometrescale distribution of ECM ligands can be controlled and altered. We find that increasing the spacing between ligands promotes the growth of focal adhesions on low-rigidity substrates, but leads to adhesion collapse on more-rigid substrates. Furthermore, disordering the ligand distribution drastically increases adhesion growth, but reduces the rigidity threshold for adhesion collapse. The growth and collapse of focal adhesions are mirrored by, respectively, the nuclear or cytosolic localization of the transcriptional regulator protein YAP. We explain these findings not through direct sensing of ligand spacing, but by using an expanded computational molecular-clutch model(10,11), in which individual integrin-ECM bonds-the molecular clutches-respond to force loading by recruiting extra integrins, up to a maximum value. This generates more clutches, redistributing the overall force among them, and reducing the force loading per clutch. At high rigidity and high ligand spacing, maximum recruitment is reached, preventing further force redistribution and leading to adhesion collapse. Measurements of cellular traction forces and actin flow speeds support our model. Our results provide a general framework for how cells sense spatial and physical information at the nanoscale, precisely tuning the range of conditions at which they form adhesions and activate transcriptional regulation.
Note: Versió postprint del document publicat a:
It is part of: Nature, 2017, vol. 552, num. 7684, p. 219-224
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ISSN: 0028-0836
Appears in Collections:Articles publicats en revistes (Institut de Bioenginyeria de Catalunya (IBEC))
Articles publicats en revistes (Biomedicina)

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