Polarized Distribution Of IQGAP Proteins In Gastric Parietal Cells And Their Roles In Regulated Epithelial Cell Secretion

Actin cytoskeleton plays an important role in the establishment and maintenance of epithelial cell polarity. Cdc42, a member of Rho GTPase family, modulates actin dynamics via its regulators, such as IQGAP proteins. Gastric parietal cells are polarized epithelial cells in which regulated acid secretion occurs in the apical membrane upon stimulation. Previous studies show shown that actin isoforms are polarized to different membrane domains and that the integrity of the actin cytoskeleton is essential for acid secretion. To dissert the molecular mechanisms underlying polarized actin cytoskeleton network between apical and basolateral membranes, I have carried out antibody screen to identify actin cytoskeletal regulators that are polarized to apical membrane of the gastric parietal cells. My study had revealed that Cdc42 is preferentially distributed to the apical membrane of gastric parietal cells. In addition, two Cdc42 regulators, IQGAP1 and IQGAP2, are present in gastric parietal cells. Interestingly, IQGAP2 is polarized to the apical membrane of the parietal cells while IQGAP1 is mainly distributed to the basolateral membrane. An IQGAP peptide that competes with full-length IQGAP proteins for Cdc42-binding in vitro also inhibits acid secretion in SLO-permeabilized gastric glands. Furthermore, this peptide disrupts the association of IQGAP and Cdc42 with the apical actin cytoskeleton and prevents the apical membrane remodeling upon stimulation. We propose...