Epidermal loss of Gα(q) confers a migratory and differentiation defect in keratinocytes

G-protein coupled receptors (GPCRs), which activate heterotrimeric G proteins, are an essential class of transmembrane receptors that are responsible for a myriad of signaling events in normal and pathologic conditions. Two members of the G protein family, Gα(q) and Gα(11), activate one of the main GPCR pathways and function as oncogenes by integrating mitogen-stimulated signaling cascades that are active under malignant conditions. Recently, it has been shown that targeted deletion of Gα(11) and Gα(q) from endothelial cells impairs the Rho-mediated formation of focal adherens junctions, suggesting that Gα(11/q) signaling may also play a significant role in cytoskeletal-mediated cellular responses in epithelial cells. Indeed, combined deletion of Gα(11) and Gα(q) confers a significant migratory defect in keratinocytes that delays cutaneous wound healing in an in vivo setting. This delay can be attributed to a defect during the reepithelialization phase due to significantly attenuated migratory capacity of Gα(q)-null keratinocytes under combined Gα(11) deficiency. In fact, cells lacking Gα(11/q) demonstrate a severely reduced ability to respond to mitogenic and migratory signals in the microenvironment, leading to inappropriate and premature terminal differentiation. These results suggest that Gα(11/q) signaling pathways may be critical for integrating mitogenic signals and cytoskeletal function to achieve normal physiological responses. Emergence of a malignant phenotype may therefore arise from both under- and overexpression of Gα(11/q) signaling, implicating its upstream regulation as a potential therapeutic target in a host of pathologic conditions.