The Role Of Force Sensing In The Interplay Between Cell Adhesion And The Actin Cytoskeleton

Prof. Alexander D. Bershadsky
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel.

Tuesday 1 September, Location: MRC-LMCB, Time: 16:30

Transmembrane adhesion receptors of the integrin family, and associated cytoplasmic plaque proteins, function as mechanosensory units, responding to forces generated by the actomyosin cytoskeletal network. Such responses provide feedback signals that affect the organization and function of the cytoskeleton. Here, we address several novel aspects of this feedback signaling between the cytoskeleton and adhesion. As a cell spreads over or migrates along a rigid planar substrate, the actin network within the cell’s lamellar protrusions organizes itself into two domains: the lamellipodium (a narrow peripheral zone characterized by a dense, branched actin network) and the lamellum (an inner zone whose actin network is sparser, and contains distinct radial or circumferential actin bundles). We found that nascent cell-matrix adhesions appear underneath the lamellipodium, and rapidly induce formation of a distinct boundary between it and the lamellum. We propose a physical mechanism by means of which the lamellipodium-lamellum boundary is generated, acquires shape, and changes as the cell moves forward. This mechanism provides a clue to the adhesion-dependent organization of the entire actin cytoskeleton, including the system of circumferential and radial actin bundles (stress fibers).  Maturation and further growth of the nascent adhesions depend, in turn, on the myosin-II-driven forces generated by the stress fibers. Cell spreading on rigid substrates eventually leads to polarization of both cell shape and the actin cytoskeleton via a process involving the growth of some adhesions, and the disappearance of others. On the “soft” (5 kPa) substrate, the ability of cells to polarize was significantly suppressed. In our search for genes regulating the rigidity-dependent cell polarization, cells were transfected with a library of siRNAs that suppressed the expression of 85 protein tyrosine kinases (PTKs)]. Our screening method enabled us to identify a group of PTKs involved in the control of cell polarization by extracellular matrix rigidity.

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Bershadsky, A., Kozlov, M. & Geiger, B. Adhesion-mediated mechanosensitivity: a time to experiment, and a time to theorize. Curr Opin Cell Biol 18, 472-81 (2006).
Geiger, B., Spatz, J.P. & Bershadsky, A.D. Environmental sensing through focal adhesions. Nat Rev Mol Cell Biol 10, 21-33 (2009).

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