Integrin Mechano-chemical Signaling Generates Plasma Membrane Nanodomains that Promote Cell Spreading

Cell. 2019 Jun 13;177(7):1738-1756.e23. doi: 10.1016/j.cell.2019.04.037. Epub 2019 May 16.

Abstract

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • CHO Cells
  • Cricetulus
  • Focal Adhesion Protein-Tyrosine Kinases / genetics
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism
  • Humans
  • Integrin beta1 / genetics
  • Integrin beta1 / metabolism*
  • Mechanotransduction, Cellular*
  • Membrane Microdomains / genetics
  • Membrane Microdomains / metabolism*
  • Vinculin / genetics
  • Vinculin / metabolism
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism
  • src-Family Kinases / genetics
  • src-Family Kinases / metabolism

Substances

  • Integrin beta1
  • VCL protein, human
  • RHOA protein, human
  • Vinculin
  • Focal Adhesion Protein-Tyrosine Kinases
  • src-Family Kinases
  • rhoA GTP-Binding Protein