Published online 21 February 2006. doi:10.1083/jcb.1725iti2
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 172, Number 5, 639-639
Who Pix up Rac1?
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ß-Pix (green) brings Rac1 (red) to ruffles and focal adhesions.
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Members of the large family of Rho GTPases are master regulators of the cytoskeletal changes necessary for cell adhesion, migration, and division. On page 759, ten Klooster et al. show how the activity of a Rho GTPase is spatially restricted by its COOH-terminal domain. The findings suggest that this highly variable region might provide the zip code for many different Rho members.
The COOH-terminal domain is known for its lipid-anchoring ability. But since membranes abound in the cell, that ability did not explain the specific localization of different GTPases. A COOH-terminal peptide of Rac1 had been shown to disrupt normal Rac1 activity, so the authors used this domain to pull down interacting proteins. The screen picked up Rac1's own activator, an exchange factor called ß-Pix.
ß-Pix was found in focal adhesions at the leading edge of migrating cells, where Rac1 activity is known to drive polarized actin polymerization. ß-Pix was also necessary for Rac1-mediated membrane ruffling.
The Rac1 binding site on ß-Pix can also be occupied by an effector kinase called Pak1. The authors show that Pak1 binding to ß-Pix normally prevents Rac1 activation. But Pak1 phosphorylation (as occurs upon integrin ligation) releases it from ß-Pix, thus freeing ß-Pix to recruit and activate Rac1.
The targeting mechanisms of most other Rho GTPase have not been determined. Given their highly divergent sequences, the COOH-terminal domains probably mediate interactions with a variety of adaptors that might control the localization of individual Rho GTPase members.
Nicole LeBrasseur
lebrasn{at}rockefeller.edu
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Targeting and activation of Rac1 are mediated by the exchange factor ß-Pix
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