1. University of North Carolina at Chapel Hill, Department of Pharmacology and Lineberger Cancer Center, Chapel Hill, North Carolina 27599, USA
2. Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
3. †Present addresses: University of California at San Diego, Department of Pathology and Moores Cancer Center, Basic Science Building, Room 1040, 9500 Gilman Drive, MC 0612, La Jolla, California 92093, USA (O.P., R.L.K.); University of North Carolina at Chapel Hill, Department of Pharmacology and Lineberger Cancer Center, Chapel Hill, North Carolina 27599, USA (L.H., K.M.H.)

Correspondence to: Olivier Pertz^1,2,3Klaus M. Hahn^1,2,3 Correspondence and requests for materials should be addressed to K.M.H. (Email: khahn@med.unc.edu) or O.P. (Email: pertz@ucsd.edu).

Rho family GTPases regulate the actin and adhesion dynamics that control cell migration. Current models postulate that Rac promotes membrane protrusion at the leading edge and that RhoA regulates contractility in the cell body^{1, 2}. However, there is evidence that RhoA also regulates membrane protrusion^{3, 4}. Here we use a fluorescent biosensor, based on a novel design preserving reversible membrane interactions, to visualize the spatiotemporal dynamics of RhoA activity during cell migration. In randomly migrating cells, RhoA activity is concentrated in a sharp band directly at the edge of protrusions. It is observed sporadically in retracting tails, and is low in the cell body. RhoA activity is also associated with peripheral ruffles and pinocytic vesicles, but not with dorsal ruffles induced by platelet-derived growth factor (PDGF). In contrast to randomly migrating cells, PDGF-induced membrane protrusions have low RhoA activity, potentially because PDGF strongly activates Rac, which has previously been shown to antagonize RhoA activity^{5, 6}. Our data therefore show that different extracellular cues induce distinct patterns of RhoA signalling during membrane protrusion.

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