Identification of a mitotic Rac-GEF, Trio, that counteracts MgcRacGAP function during cytokinesis.
Bottom Line: Moreover, Trio depletion specifically rescues the cytokinesis failure induced by MgcRacGAP depletion.Of importance, we demonstrate that this rescue is mediated by the Trio-Rac1 pathway, using GEF-dead mutants of Trio and a specific inhibitor of Rac1 activation by Trio.Overall this work identifies for the first time a GEF controlling Rac1 activation in dividing cells that counteracts MgcRacGAP function in cytokinesis.
Affiliation: Signaling and Cytoskeleton Dynamics Group, University of Montpellier, 34293 Montpellier, France.Show MeSH
Mentions: Rac1 negatively regulates the assembly and constriction of the contractile ring during cytokinesis. This process is regulated by a GAP, MgcRacGAP, which is essential to inhibit Rac1 activation at the cleavage furrow (Canman et al., 2008; Bastos et al., 2012). Collectively our results show that Trio, known mainly for its role in neuronal development, plays an unexpected role in dividing cells, where it controls the activation of the GTPase Rac1 and subsequent F-actin cytoskeleton remodeling. Moreover, Trio depletion or specific inactivation of the Trio-Rac1 pathway rescues the cytokinesis failure induced by MgcRacGAP depletion in HeLa cells. On the basis of these observations, we propose a model in which Trio functions as a GEF of Rac1 during cell division. Trio, which is expressed throughout the cell cycle, activates Rac1 to control F-actin cytoskeleton remodeling at the cell cortex of dividing cells. As previously described, MgcRacGAP is up-regulated in mitosis and targeted to the cleavage furrow to specifically inhibit Rac1 at the cleavage plane during cytokinesis (Hirose et al., 2001; Canman et al., 2008; Seguin et al., 2009; Bastos et al., 2012). MgcRacGAP therefore counteracts the action of Trio by locally and temporally inhibiting Rac1 activation at the division plane, subsequently ensuring accurate cytokinesis (Figure 6).
Affiliation: Signaling and Cytoskeleton Dynamics Group, University of Montpellier, 34293 Montpellier, France.