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

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

Author information

1
National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bellary Road, Bangalore, India.
2
National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bellary Road, Bangalore, India; St. Johns Research Institute, Bangalore, India.
3
Mechanobiology Institute, National University of Singapore, Singapore, Singapore.
4
National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bellary Road, Bangalore, India; Institute for Stem Cell Biology and Regenerative Medicine, Bellary Road, Bangalore, India. Electronic address: mayor@ncbs.res.in.

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

PMID:
31104842
DOI:
10.1016/j.cell.2019.04.037
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