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

Joseph Mathew Kalappurakkal, Anupama Ambika Anilkumar, Chandrima Patra, Thomas S. van Zanten, Michael Sheetz, Satyajit Mayor

Research output: Contribution to journalArticle

11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1738-1756.e23
JournalCell
Volume177
Issue number7
DOIs
StatePublished - Jun 13 2019
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Kalappurakkal, J. M., Anilkumar, A. A., Patra, C., van Zanten, T. S., Sheetz, M., & Mayor, S. (2019). Integrin Mechano-chemical Signaling Generates Plasma Membrane Nanodomains that Promote Cell Spreading. Cell, 177(7), 1738-1756.e23. https://doi.org/10.1016/j.cell.2019.04.037