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Integrin Mechano-chemical Signaling Generates Plasma Membrane Nanodomains that Promote Cell Spreading
- Kalappurakkal, Joseph Mathew, Anilkumar, Anupama Ambika, Patra, Chandrima, van Zanten, Thomas S., Sheetz, Michael P., Mayor, Satyajit
- Cell 2019 v.177 no.7 pp. 1738-1756.e23
- CD29 antigen, ligands, lipids, mutants, myosin, nanoparticles, non-specific protein-tyrosine kinase, plasma membrane, signal transduction
- 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.