Cell
Volume 177, Issue 7, 13 June 2019, Pages 1738-1756.e23
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Article
Integrin Mechano-chemical Signaling Generates Plasma Membrane Nanodomains that Promote Cell Spreading

https://doi.org/10.1016/j.cell.2019.04.037Get rights and content
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Highlights

  • Integrin signaling triggers RhoA-Formin to drive acto-myosin based nanoclustering

  • Force-mediated vinculin activation promotes GPI-anchored protein nanoclustering

  • GPI-anchored protein nanoclusters regulate Fibronectin-mediated integrin function

  • Integrins represent an active element of the actin-membrane composite model

Summary

Glycosylphosphatidylinositol-anchored proteins (GPI-APs) are a major class of lipid-anchored plasma membrane proteins. GPI-APs form nanoclusters generated by cortical acto-myosin activity. While our understanding of the physical principles governing this process is emerging, the molecular machinery and functional relevance of GPI-AP nanoclustering are unknown. Here, we first show that a membrane receptor signaling pathway directs nanocluster formation. Arg-Gly-Asp motif-containing ligands bound to the β1-integrin receptor activate src and focal adhesion kinases, resulting in RhoA signaling. This cascade triggers actin-nucleation via specific formins, which, along with myosin activity, drive the nanoclustering of membrane proteins with actin-binding domains. Concurrently, talin-mediated activation of the mechano-transducer vinculin is required for the coupling of the acto-myosin machinery to inner-leaflet lipids, thereby generating GPI-AP nanoclusters. Second, we show that these nanoclusters are functional; disruption of their formation either in GPI-anchor remodeling mutants or in vinculin mutants impairs cell spreading and migration, hallmarks of integrin function.

Keywords

integrin
mechanotransduction
cell spreading
membrane domains
nanoclusters
GPI-anchored proteins
vinculin
active actin-membrane composite
cell signaling
active rafts

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