![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 16, Issue 1, 84-96, January 2005
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
* Department of Pharmacology, University of Wisconsin, Madison, WI 53706;
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037
Submitted April 1, 2004;
Accepted October 21, 2004
Monitoring Editor: Mark Ginsberg
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.
Abbreviations used: ECM, extracellular matrix; PI3-Kinase, phosphatidylinositol 3'-Kinase; ROCK, Rho Kinase.
The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).
Corresponding author. E-mail address: pjkeely{at}facstaff.wisc.edu.
This article has been cited by other articles:
|
|
 |
|
  B. J. McHugh, R. Buttery, Y. Lad, S. Banks, C. Haslett, and T. Sethi Integrin activation by Fam38A uses a novel mechanism of R-Ras targeting to the endoplasmic reticulum J. Cell Sci., January 1, 2010; 123(1): 51 - 61. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Issa, T. X. Le, A. N. Shoushtari, J. D. Shields, and M. A. Swartz Vascular Endothelial Growth Factor-C and C-C Chemokine Receptor 7 in Tumor Cell-Lymphatic Cross-talk Promote Invasive Phenotype Cancer Res., January 1, 2009; 69(1): 349 - 357. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. C. Stuart, Z. Jia, A. Messenberg, B. Joshi, T. M. Underhill, H. Moukhles, and I. R. Nabi Localized Rho GTPase Activation Regulates RNA Dynamics and Compartmentalization in Tumor Cell Protrusions J. Biol. Chem., December 12, 2008; 283(50): 34785 - 34795. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Leve, W. de Souza, and J. A. Morgado-Diaz A Cross-Link between Protein Kinase A and Rho-Family GTPases Signaling Mediates Cell-Cell Adhesion and Actin Cytoskeleton Organization in Epithelial Cancer Cells J. Pharmacol. Exp. Ther., December 1, 2008; 327(3): 777 - 788. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ito, Y. Shimada, T. Kan, S. David, Y. Cheng, Y. Mori, R. Agarwal, B. Paun, Z. Jin, A. Olaru, et al. Pituitary Tumor-Transforming 1 Increases Cell Motility and Promotes Lymph Node Metastasis in Esophageal Squamous Cell Carcinoma Cancer Res., May 1, 2008; 68(9): 3214 - 3224. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Lehto, M. I. Mayranpaa, T. Pellinen, P. Ihalmo, S. Lehtonen, P. T. Kovanen, P.-H. Groop, J. Ivaska, and V. M. Olkkonen The R-Ras interaction partner ORP3 regulates cell adhesion J. Cell Sci., March 1, 2008; 121(5): 695 - 705. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Takaya, T. Kamio, M. Masuda, N. Mochizuki, H. Sawa, M. Sato, K. Nagashima, A. Mizutani, A. Matsuno, E. Kiyokawa, et al. R-Ras Regulates Exocytosis by Rgl2/Rlf-mediated Activation of RalA on Endosomes Mol. Biol. Cell, May 1, 2007; 18(5): 1850 - 1860. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Oinuma, H. Katoh, and M. Negishi R-Ras Controls Axon Specification Upstream of Glycogen Synthase Kinase-3beta through Integrin-linked Kinase J. Biol. Chem., January 5, 2007; 282(1): 303 - 318. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. E. Goldfinger, C. Ptak, E. D. Jeffery, J. Shabanowitz, D. F. Hunt, and M. H. Ginsberg RLIP76 (RalBP1) is an R-Ras effector that mediates adhesion-dependent Rac activation and cell migration J. Cell Biol., September 11, 2006; 174(6): 877 - 888. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. De Jesus, M. B. Stope, P. A. O. Weernink, Y. Mahlke, C. Borgermann, V. N. Ananaba, C. Rimmbach, D. Rosskopf, M. C. Michel, K. H. Jakobs, et al. Cyclic AMP-dependent and Epac-mediated Activation of R-Ras by G Protein-coupled Receptors Leads to Phospholipase D Stimulation J. Biol. Chem., August 4, 2006; 281(31): 21837 - 21847. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Eisen, S. Walid, D. R. Ratcliffe, and G. K. Ojakian Regulation of epithelial tubule formation by Rho family GTPases Am J Physiol Cell Physiol, May 1, 2006; 290(5): C1297 - C1309. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Dail, M. Richter, P. Godement, and E. B. Pasquale Eph receptors inactivate R-Ras through different mechanisms to achieve cell repulsion J. Cell Sci., April 1, 2006; 119(7): 1244 - 1254. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Ada-Nguema, H. Xenias, M. P. Sheetz, and P. J. Keely The small GTPase R-Ras regulates organization of actin and drives membrane protrusions through the activity of PLC{epsilon} J. Cell Sci., April 1, 2006; 119(7): 1307 - 1319. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Liu, D. C. Radisky, C. M. Nelson, H. Zhang, J. E. Fata, R. A. Roth, and M. J. Bissell Mechanism of Akt1 inhibition of breast cancer cell invasion reveals a protumorigenic role for TSC2. PNAS, March 14, 2006; 103(11): 4134 - 4139. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Vallim, C. B. Nichols, L. Fernandes, K. L. Cramer, and J. A. Alspaugh A Rac Homolog Functions Downstream of Ras1 To Control Hyphal Differentiation and High-Temperature Growth in the Pathogenic Fungus Cryptococcus neoformans Eukaryot. Cell, June 1, 2005; 4(6): 1066 - 1078. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Holly, M. K. Larson, and L. V. Parise The Unique N-Terminus of R-Ras Is Required for Rac Activation and Precise Regulation of Cell Migration Mol. Biol. Cell, May 1, 2005; 16(5): 2458 - 2469. [Abstract] [Full Text] [PDF]
|
|
