Smurf1 regulates tumor cell plasticity and motility through degradation of RhoA leading to localized inhibition of contractility.
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.
Sahai
Erik
E
Centre National de la Recherche Scientifique, UMR 6543, Centre Antoine Lacassagne, Nice 06189, France.
Garcia-Medina
Raquel
R
Pouysségur
Jacques
J
Vial
Emmanuel
E
D000818:Animals; D024722:Cardiac Myosins / Q000378:metabolism; D002465:Cell Movement; D004789:Enzyme Activation; D020868:Gene Silencing; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D018994:Myosin Light Chains / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology*; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011554:Pseudopodia; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; D018994:Myosin Light Chains; C107184:myosin light chain 2; C498342:SMURF1 protein, human; D044767:Ubiquitin-Protein Ligases; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D024722:Cardiac Myosins; D020742:rhoA GTP-Binding Protein