IQGAP1 and calmodulin modulate E-cadherin function

Ca2+-dependent cell-cell adhesion is mediated by the cadherin family of tra nsmembrane proteins. Adhesion is achieved by hemophilic interaction of the extracellular domains of cadherins on adjacent cells, with the cytoplasmic regions serving to couple the complex to the cytoskeleton. IQGAP1, a novel RasGAP-related protein that interacts with the cytoskeleton, binds to actin , members of the Rho family, and E-cadherin, Calmodulin binds to IQGAP1 and regulates its association with Cdc42 and actin. Here we demonstrate compet ition between calmodulin and E-cadherin for binding to IQGAP1 both in vitro and in a normal cellular milieu. Immunocytochemical analysis in MCF-7 (E-c adherin positive) and MDA-MB-231 (E-cadherin negative) epithelial cells rev ealed that E-cadherin is required for accumulation of IQGAP1 at cell-cell j unctions. The cell-permeable calmodulin antagonist CGS9343B significantly i ncreased IQGAP1 at areas of MCF-7 cell-cell contact, with a concomitant dec rease in the amount of E-cadherin at cell-cell junctions. Analysis of E-cad herin function revealed that CGS9343B significantly decreased homophilic E- cadherin adhesion, On the basis of these data, we propose that disruption o f the binding of calmodulin to IQGAP1 enhances the association of IQGAP1 wi th components of the cadherin-catenin complex at cell-cell junctions, resul ting in impaired E-cadherin function.