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Controlling Small Guanine-Nucleotide-Exchange Factor Function through Cytoplasmic RNA Intramers
Günter Mayer, Michael Blind, Wolfgang Nagel, Thomas Böhm, Thomas Knorr, Catherine L. Jackson, Waldemar Kolanus and Michael Famulok
Proceedings of the National Academy of Sciences of the United States of America
Vol. 98, No. 9 (Apr. 24, 2001), pp. 4961-4965
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/3055547
Page Count: 5
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ADP-ribosylation factor (ARF) GTPases and their regulatory proteins have been implicated in the control of diverse biological functions. Two main classes of positive regulatory elements for ARF have been discovered so far: the large Sec7/Gea and the small cytohesin/ARNO families, respectively. These proteins harbor guanine-nucleotide-exchange factor (GEF) activity exerted by the common Sec7 domain. The availability of a specific inhibitor, the fungal metabolite brefeldin A, has enabled documentation of the involvement of the large GEFs in vesicle transport. However, because of the lack of such tools, the biological roles of the small GEFs have remained controversial. Here, we have selected a series of RNA aptamers that specifically recognize the Sec7 domain of cytohesin 1. Some aptamers inhibit guanine-nucleotide exchange on ARF1, thereby preventing ARF activation in vitro. Among them, aptamer M69 exhibited unexpected specificity for the small GEFs, because it does not interact with or inhibit the GEF activity of the related Gea2-Sec7 domain, a member of the class of large GEFs. The inhibitory effect demonstrated in vitro clearly is observed as well in vivo, based on the finding that M69 produces similar results as a dominant-negative, GEF-deficient mutant of cytohesin 1: when expressed in the cytoplasm of T-cells, M69 reduces stimulated adhesion to intercellular adhesion molecule-1 and results in a dramatic reorganization of F-actin distribution. These highly specific cellular effects suggest that the ARF-GEF activity of cytohesin 1 plays an important role in cytoskeletal remodeling events of lymphoid cells.
Proceedings of the National Academy of Sciences of the United States of America © 2001 National Academy of Sciences