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Published online December 26, 2006
doi:10.1083/jcb.200605135
The Journal of Cell Biology, Vol. 176, No. 1, 35-42
The Rockefeller University Press, 0021-9525 $30.00
© 2006 Sahai et al.
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Report

 Smurf1 regulates tumor cell plasticity and motility through degradation of RhoA leading to localized inhibition of contractility

Erik Sahai2, Raquel Garcia-Medina1, Jacques Pouysségur1, and Emmanuel Vial1

1 Centre National de la Recherche Scientifique, UMR 6543, Centre Antoine Lacassagne, Nice 06189, France
2 Tumour Cell Biology Laboratory, Cancer Research UK London Research Institute, London WC2A 3PX, England, UK

Correspondence to E. Vial: evial{at}unice.fr

Rho GTPases participate in various cellular processes, including normal and tumor cell migration. It has been reported that RhoA is targeted for degradation at the leading edge of migrating cells by the E3 ubiquitin ligase Smurf1, and that this is required for the formation of protrusions. We report that Smurf1-dependent RhoA degradation in tumor cells results in the down-regulation of Rho kinase (ROCK) activity and myosin light chain 2 (MLC2) phosphorylation at the cell periphery. The localized inhibition of contractile forces is necessary for the formation of lamellipodia and for tumor cell motility in 2D tissue culture assays. In 3D invasion assays, and in in vivo tumor cell migration, the inhibition of Smurf1 induces a mesenchymal–amoeboid–like transition that is associated with a more invasive phenotype. Our results suggest that Smurf1 is a pivotal regulator of tumor cell movement through its regulation of RhoA signaling.

Abbreviations used in this paper: MLC, myosin light chain; ROCK, Rho kinase; shRNA, short hairpin RNA.


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