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.
Authors	Cristina Hidalgo-Carcedo, Steven Hooper, Shahid I Chaudhry, Peter Williamson, Kevin Harrington, Birgit Leitinger, Erik Sahai
Journal	Nature cell biology (Nat Cell Biol) Vol. 13 Issue 1 Pg. 49-58 (Jan 2011) ISSN: 1476-4679 [Electronic] England
PMID	21170030 (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 Discoidin Domain Receptor 1 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 Discoidin Domain Receptor 1 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)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!