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Collective cell migration requires suppression of actomyosin at cell-cell contacts mediated by DDR1 and the cell polarity regulators Par3 and Par6.

Abstract
Collective cell migration occurs in a range of contexts: cancer cells frequently invade in cohorts while retaining cell-cell junctions. Here we show that collective invasion by cancer cells depends on decreasing actomyosin contractility at sites of cell-cell contact. When actomyosin is not downregulated at cell-cell contacts, migrating cells lose cohesion. We provide a molecular mechanism for this downregulation. Depletion of discoidin domain receptor 1 (DDR1) blocks collective cancer-cell invasion in a range of two-dimensional, three-dimensional and 'organotypic' models. DDR1 coordinates the Par3/Par6 cell-polarity complex through its carboxy terminus, binding PDZ domains in Par3 and Par6. The DDR1-Par3/Par6 complex controls the localization of RhoE to cell-cell contacts, where it antagonizes ROCK-driven actomyosin contractility. Depletion of DDR1, Par3, Par6 or RhoE leads to increased actomyosin contactility at cell-cell contacts, a loss of cell-cell cohesion and defective collective cell invasion.
AuthorsCristina Hidalgo-Carcedo, Steven Hooper, Shahid I Chaudhry, Peter Williamson, Kevin Harrington, Birgit Leitinger, Erik Sahai
JournalNature cell biology (Nat Cell Biol) Vol. 13 Issue 1 Pg. 49-58 (Jan 2011) ISSN: 1476-4679 [Electronic] England
PMID21170030 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Membrane Proteins
  • PARD3 protein, human
  • PARD6A protein, human
  • Green Fluorescent Proteins
  • Actomyosin
  • DDR1 protein, human
  • Receptor Protein-Tyrosine Kinases
  • RND3 protein, human
  • rho GTP-Binding Proteins
Topics
  • Actomyosin (metabolism)
  • Adaptor Proteins, Signal Transducing (genetics, metabolism)
  • Amino Acid Sequence
  • Blotting, Western
  • Cell Adhesion
  • Cell Communication
  • Cell Cycle Proteins (genetics, metabolism)
  • Cell Line
  • Cell Line, Tumor
  • Cell Movement
  • Cell Polarity
  • Green Fluorescent Proteins (genetics, metabolism)
  • Humans
  • Membrane Proteins (genetics, metabolism)
  • Microscopy, Fluorescence
  • Protein Binding
  • RNA Interference
  • Receptor Protein-Tyrosine Kinases (genetics, metabolism)
  • Sequence Homology, Amino Acid
  • Tight Junctions (metabolism)
  • rho GTP-Binding Proteins (genetics, metabolism)

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