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Finding the weakest link – exploring integrin-mediated mechanical molecular pathways
Pere Roca-Cusachs, Thomas Iskratsch, Michael P. Sheetz


From the extracellular matrix to the cytoskeleton, a network of molecular links connects cells to their environment. Molecules in this network transmit and detect mechanical forces, which subsequently determine cell behavior and fate. Here, we reconstruct the mechanical pathway followed by these forces. From matrix proteins to actin through integrins and adaptor proteins, we review how forces affect the lifetime of bonds and stretch or alter the conformation of proteins, and how these mechanical changes are converted into biochemical signals in mechanotransduction events. We evaluate which of the proteins in the network can participate in mechanotransduction and which are simply responsible for transmitting forces in a dynamic network. Besides their individual properties, we also analyze how the mechanical responses of a protein are determined by their serial connections from the matrix to actin, their parallel connections in integrin clusters and by the rate at which force is applied to them. All these define mechanical molecular pathways in cells, which are emerging as key regulators of cell function alongside better studied biochemical pathways.


  • Funding

    The work of our laboratory was supported in part by a grant by the Spanish Ministry of Economy and Competitiveness [grant number BFU2011-23111].

  • This article is part of a Minifocus on Mechanotransduction. For further reading, please see related articles: ‘Deconstructing the third dimension – how 3D culture microenvironments alter cellular cues’ by Brendon M. Baker and Christopher S. Chen (J. Cell Sci. 125, 3015-3024). ‘Signalling through mechanical inputs – a coordinated process’ by Huimin Zhang and Michel Labouesse (J. Cell Sci. 125, 3039-3049). ‘United we stand – integrating the actin cytoskeleton and cell–matrix adhesions in cellular mechanotransduction’ by Ulrich S. Schwarz and Margaret L. Gardel (J. Cell Sci. 125, 3051-3060). ‘Mechanosensitive mechanisms in transcriptional regulation’ by Akiko Mammoto et al. (J. Cell Sci. 125, 3061-3073). ‘Molecular force transduction by ion channels – diversity and unifying principles’ by Sergei Sukharev and Frederick Sachs (J. Cell Sci. 125, 3075-3083).

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