Role of actin cytoskeleton and small Rho GTPases in TGFâ signaling

Rapid reorganization of the actin cytoskeleton is one of the earliest cellular responses to many extracellular signals. Transforming Growth Factor-â (TGF-â) regulates cell morphology and growth in a concerted manner via mechanisms that control the actin cytoskeleton. In Swiss3T3 fibroblasts, TGF-â1 induces rapid actin polymerization and formation of stress fibers (1) via a novel non-genomic signaling cascade downstream of the type I receptor (2). This pathway involves rapid RhoA/RhoB and ROCK1 activation, followed by phosphorylation of Limk2, a critical regulator of actin dynamics, and its physiological substrate cofilin. siRNA targeted against Limk2 decreases the endogenous protein levels of Limk2 and blocks the formation of new actin stress fibers. Interestingly, the TGF-â induced RhoA activation and actin reorganization is abolished by the inhibitory Smad7 or by a mutant TGF-â type I receptor (L45 loop) that cannot bind Smad proteins, indicating a possible cross talk between Rho activation and the classical Smad signaling. This hypothesis is supported by adenoviral-mediated expression of Smad2 and Smad3 in Swiss3T3 fibroblasts, which induces long-term potent actin reorganization and Rho activation. Smad3 (and to a lesser extent Smad2) also enhances the expression of á-Smooth Muscle Actin (á-SMA) implying TGF-â mediated fibroblast-myofibroblast differentiation (3). Furthermore, TGF-â increases the steady state mRNA levels and the activity of the promoter of the RhoB but not of the RhoA gene (4). In line with this, in JEG-3 (Smad3-/-) cells, the TGF-â induced transcriptional up-regulation of the RhoB gene and actin polymerization is not observed but it is rescued by adenoviral mediated exogenous expression of Smad3. These data define a novel mechanism of cross talk between the canonical TGF-â/Smad pathway and the Rho GTPases regulating the rapid and long-term actin cytoskeleton reorganization (3,4).

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Speaker: Christos Stournaras
Department of Biochemistry, University of Crete Medical School, 71110 Heraklion, Greece
Time: Monday, 2 February 2009, 13:00