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Identification of the first Rho–GEF inhibitor, TRIPα, which targets the RhoA‐specific GEF domain of Trio
Author(s) -
Schmidt Susanne,
Diriong Sylvie,
Méry Jean,
Fabbrizio Eric,
Debant Anne
Publication year - 2002
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(02)02928-9
Subject(s) - rhoa , guanine nucleotide exchange factor , microbiology and biotechnology , aptamer , gtpase , cytoskeleton , actin , actin cytoskeleton , chemistry , biology , biochemistry , cell , signal transduction
The Rho–guanine nucleotide exchange factors (Rho–GEFs) remodel the actin cytoskeleton via their Rho–GTPase targets and affect numerous physiological processes such as transformation and cell motility. They are therefore attractive targets to design specific inhibitors that may have therapeutic applications. Trio contains two Rho–GEF domains, GEFD1 and GEFD2, which activate the Rac and RhoA pathways, respectively. Here we have used a genetic screen in yeast to select in vivo peptides coupled to thioredoxin, called aptamers, that could inhibit GEFD2 activity. One aptamer, TRIAPα (TRio Inhibitory APtamer), specifically blocks GEFD2‐exchange activity on RhoA in vitro. The corresponding peptide sequence, TRIPα, inhibits TrioGEFD2‐mediated activation of RhoA in intact cells and specifically reverts the neurite retraction phenotype induced by TrioGEFD2 in PC12 cells. Thus TRIPα is the first Rho–GEF inhibitor isolated so far, and represents an important step in the design of inhibitors for the expanding family of Rho–GEFs.