A dual role model for active Rac1 in cell migration

Abstract

Over time we have come to appreciate that the complex regulation of Rho GTPases involves additional mechanisms beyond the activating role of RhoGEFs, the inactivating function of RhoGAPs and the sequestering activity of RhoGDIs. One class of regulatory mechanisms includes direct modifications of Rho proteins such as isoprenylation, phosphorylation and SUMOylation. Rho GTPases can also regulate each other by means of crosstalk signaling, which is again mostly mediated by GEFs, GAPs and GDIs. More complex mutual regulation ensues when and where two or more Rho proteins activate a common molecular target, i.e., share a common effector. We have recently unraveled a reciprocal mechanism wherein spatiotemporal dynamics of Rac1 activity during migration of Dictyostelium cells is apparently regulated by antagonizing interactions of Rac1-GTP with two distinct effectors. By monitoring specific fluorescent probes, activated Rac1 is simultaneously present at the leading edge, where it participates in Scar/WAVE-mediated actin polymerization, and at the trailing edge, where it induces formation of a DGAP1/cortexillin actin-bundling complex. Strikingly, in addition to their opposed localization, the two populations of activated Rac1 also display opposite kinetics of recruitment to the plasma membrane upon stimulation by chemoattractants. These findings with respect to Rac1 in Dictyostelium suggest a novel principle for regulation of Rho GTPase activity that might also play a role in other cell types and for other Rho family members.

Keywords: :

• Rac1
• DGAP1
• IQGAP
• cortexillin
• SCAR/WAVE
• cell polarization
• actin cytoskeleton
• Rho GTPases
• Dictyostelium

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Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

We thank Dr. Marija-Mary Sopta for critical reading of the manuscript. This work was supported by the Unity through Knowledge Fund grant UKF 1A 10/07 and Ministry of Science, Education and Sport of the Republic of Croatia grant 098-0982913-2858 to I.W., and by grants DAAD-D/07/00065 and DFG FA 330/6-1 to J.F.