Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 16, Issue 1, Pages 84-96Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E04-04-0277
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Funding
- NCI NIH HHS [CA076537, R01 CA076537, T32 CA075924, R29 CA076537, CA75924] Funding Source: Medline
- NIGMS NIH HHS [GM068487, R01 GM068487] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [T32CA075924, R29CA076537, R01CA076537] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM068487] Funding Source: NIH RePORTER
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Although it is known that the spatial coordination of Rac and Rho activity is essential for cell migration, the molecular mechanisms regulating these GTPases during migration are unknown. We found that the expression of constitutively activated R-Ras (38V) blocked membrane protrusion and random migration. In contrast, expression of dominant negative R-Ras (41A) enhanced migrational persistence and membrane protrusion. Endogenous R-Ras is necessary for cell migration, as cells that were transfected with siRNA for R-Ras did not migrate. Expression of R-Ras (38V) decreased Rac activity and increased Rho activity around the entire cell periphery, whereas expression of dominant negative R-Ras (41A) showed the converse, suggesting that R-Ras can spatially activate Rho and inactivate Rac. Consistent with this role, endogenous R-Ras localized and was preferentially activated at the leading edge of migratory cells in response to adhesion. The effects of R-Ras on cell migration are mediated by PI3-Kinase, as an effector mutant that uncouples PI3-Kinase binding from R-Ras (38V) rescued migration. From these data, we hypothesize that R-Ras plays a key role in cell migration by locally regulating the switch from Rac to Rho activity after membrane protrusion and adhesion.
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