Positive Role of IQGAP1, an Effector of Rac1, in Actin-Meshwork Formation at Sites of Cell-Cell Contact

Abstract

The small guanosine triphosphatase Rac1 is activated by E-cadherin-mediated cell-cell adhesion and is required for the accumulation of actin filaments, E-cadherin, and ␤-catenin at sites of cell-cell contact. However, the modes of activation and action of Rac1 remain to be clarified. We here found that suppression of IQGAP1, an actin-binding protein and an effector of Rac1, by small interfering RNA apparently reduced the accumulation of actin filaments, E-cadherin, and ␤-catenin at sites of cell-cell contact in Madin-Darby canine kidney II epithelial cells under the conditions in which knockdown of Rac1 reduced them. Knockdown of Rac1 did not affect the localization of these junctional components in cells expressing a constitutively active IQGAP1 mutant defective in Rac1/Cdc42 binding. Knockdown of either Rac1 or IQGAP1 accelerated the 12-O-tetradecanoylphorbol-13-acetate-induced cell-cell dissociation. The basal Rac1 activity, which was maintained by E-cadherin-mediated cell-cell adhesion, was inhibited in the IQGAP1-knocked down cells, whereas the Rac1 activity was increased in the cells overexpressing IQGAP1. Together, these results indicate that Rac1 enhances the accumulation of actin filaments, E-cadherin, and ␤-catenin by acting on IQGAP1 and suggest that there exists a positive feedback loop comprised of "E-cadherin-mediated cell-cell adhesion3 Rac1 activation3actin-meshwork formation by IQGAP13increasing E-cadherin-mediated cell-cell adhesion."

Adenomatous polyposis coli plays a key role, in vivo, in coordinating assembly of the neuronal nicotinic postsynaptic complex

“…Accumulating evidence suggests that APC, EB1, MACF and IQGAP1 are evolutionarily conserved proteins that function in targeting proteins to and stabilizing cadherin/β-catenin-rich intercellular junctions in skin, wings and muscle of Drosophila and mammals. (Strumpf and Volk, 1998;Karakesisoglou et al, 2000;Gundersen, 2002;Briggs and Sacks, 2003;Subramanian et al, 2003;Noritake et al, 2004;Shaw et al, 2007). The present study suggests a novel neural role for these proteins as key organizers of the nicotinic receptor postsynaptic complex.…”

“…Thus, IQGAP1 further links APC and EB1-tagged microtubules to the submembranous F-actin network. Perturbing the function of APC, EB1, MACF or IQGAP1 (by heterozygous mutation, RNAi knockdown or function-blocking antibodies) reduces the accumulation of microtubules and F-actin at intercellular contact sites (Mogensen et al, 2002;Kodama et al, 2003;Noritake et al, 2004;Reilein and Nelson, 2005;Shaw et al, 2007) . Similarly, the interactions of APC, EB1 and shot/kakapo (Drosophila ortholog of MACF) are essential for organizing and maintaining a unique microtubule-rich and F-actin-rich domain at the Drosophila muscle-tendon junction, and for restricting the localization of specific components to this site (Prokop et al, 1998;Strumpf and Volk, 1998;Subramanian et al, 2003).…”

“…Our model is further based on studies in non-neuronal cells that show IQGAP1 and macrophin (MACF, microtubule-actin cross-linking factor) interact with APC and EB1 Slep et al, 2005). These proteins bind to and regulate the dynamics of EB1-tagged microtubules and submembranous F-actin at specialized intercellular junctions (Barth et al, 2002;Jefferson et al, 2004;Noritake et al, 2004). However, little is known about the function of these proteins at neuronal synapses.…”

Rac1 Signaling Stimulates N-cadherin Expression, Mesenchymal Condensation, and Chondrogenesis

“…There is strong evidence that Rac1/Cdc42 and RhoA signaling have antagonizing roles in later stages of chondrocyte differentiation (39), as well as in other cell types (40,41), but the roles of Rac1 and Cdc42 in the differentiation of mesenchymal precursor cells to early chondrocytes have not been described. Furthermore, it has been determined in other cell types that Rac1 and Cdc42 regulation of cortical actin is essential in the stabilization of cadherin dependent cellular junctions (34,(42)(43)(44). Because the formation these junctions is essential for the commitment of cells to the chondrogenic lineage (6, 7), we hypothesized that Rac1/Cdc42 signaling promotes chondrogenesis, in part through modulation of cell-cell interactions.…”

“…Rac1 and Cdc42 have been shown to regulate cortical actin organization (34,35) and to be involved in the formation of lamellipodia and filopodia, respectively (36). In contrast, RhoA acting through Rho-kinase (ROCK) promotes the formation of stress fibers and spindle-shaped cells (32,37).…”